melphalan and Melanoma

Patients with liver metastasis from uveal melanoma have a poor prognosis. Efficacy and safety of hepatic transarterial chemoembolization (TACE) using melphalan and microspheres was evaluated.. Monocentric retrospective study of all consecutive patients treated by TACE using melphalan and 250μm calibrated microspheres between 2004 and 2016. Radiological response was assessed according to RECIST 1.1, modified (m)-RECIST and EASL on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). The primary endpoint was overall survival (OS). Liver metastasis response, hepatic, extrahepatic and global progression free survival (PFS) complications were evaluated with the common terminology criteria for adverse events version 4.0 (CTCAE 4.0) and survival factors were secondary endpoints.. Thirty-four patients underwent 138 TACE (4; 4.1 sessions; range 1-9). Median OS was 16.5 months (mean 21.6 months). Liver metastasis response combining partial and complete response was 42.4%, 97%, 97% with RECIST 1.1, mRECIST, EASL, respectively. There were 58 severe (CTCAE≥3) but manageable complications in 28 patients, except for 1 toxic death.. For patients with liver metastases from uveal melanoma ineligible for local treatments, TACE using melphalan may be performed as first line therapy in metastatic miliary disease from uveal melanomas with careful supportive care.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Antineoplastic Agents, Alkylating; Chemoembolization, Therapeutic; Female; Humans; Liver Neoplasms; Male; Melanoma; Melphalan; Microspheres; Middle Aged; Prognosis; Progression-Free Survival; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Treatment Outcome; Uveal Neoplasms

The Hepatic CHEMOSAT. Delcath Systems Inc., New York, NY, USA.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Female; Humans; Liver Neoplasms; Male; Melanoma; Melanoma, Cutaneous Malignant; Melphalan; Middle Aged; Skin Neoplasms

Regional chemotherapy involves the targeted delivery of high dose chemotherapy to an affected area. In the limbs, the two main methods employed are isolated limb perfusion (ILP) and isolated limb infusion (ILI), with advantages and disadvantages to each technique. The aim of this review was to clarify the roles of each technique in the management of locally advanced soft tissue malignancies of the extremities.. Relevant articles were identified from a comprehensive literature search using the PubMed database. Keywords included isolated limb perfusion, isolated limb infusion, in-transit melanoma and sarcoma. No restrictions on publication date were used.. Regional chemotherapy may be used to secure local control in a range of soft tissue malignancies not amenable to standard excision and is increasingly used as an induction treatment in soft tissue sarcoma. Though both ILI and ILP are well established in the management of in-transit melanoma, ILP should be preferentially used in soft tissue sarcoma.. Regional chemotherapy is an effective treatment for locally advanced extremity malignancies and the technique used should be tailored to patient and tumour factors.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Neoplasm Recurrence, Local; Risk Assessment; Role; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Survival Rate; Treatment Outcome

The management of melanoma in-transit metastases (IT-mets) is challenging. For many years, the absence of effective systemic therapy has prompted physicians to focus on regional therapies for melanoma confined to the limb. The introduction of isolated limb perfusion (ILP) and isolated limb infusion (ILI) has enabled effective delivery of cytotoxic drugs in an isolated circuit, so as to overcome systemic toxicity and maximize local response. Both techniques have evolved over years and both tumor necrosis factor (TNF)-alpha-based ILP and ILI have distinct indications. The development of new systemic treatment options for patients with melanoma in the past decade has shed a new light on melanoma therapy. The present manuscript focuses on the modern role of ILI and ILP in the treatment of patients with melanoma with in-transit metastases in the era of effective systemic therapy. The response and control rates of ILI/ILP are still superior to rates achieved with systemic agents. The extent of disease in patients with stage III disease, however, warrants effective systemic treatment to prolong survival. There is great potential in combining rapid response therapy such as ILI/ILP with systemic agents for sustainable response. Trial results are eagerly awaited.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Humans; Infusions, Intravenous; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms; Survival Analysis; Treatment Outcome

Indications for treatment of melanoma in-transit metastases (ITMs) confined to the limb with isolated limb perfusion (ILP) are not well defined. This study reports the Groningen regional therapeutic perfusion experience with melphalan (M-ILP) and TNF-melphalan (TM-ILP) for ITMs, and reviews of the melanoma TNF-melphalan ILP literature. Between 1991 and 2012, 60 patients were treated with ILP. Patients with "small" ITMs received M-ILP (10-13 mg melphalan/L limb volume) and patients with "bulky" disease TM-ILP (1-4 mg TNF); 19 M-ILPs and 41 TM-ILPs were performed, 26 Stage IIIB, 31 Stage IIIB and 1 stage IV disease. Overall response after 57 ILPs was 90%; CR 27 (45%), PR 27 (45%), no response 3 (5%); after 9 M-ILPs CR 6 (32%) and 41 TM-ILPs CR 21 (51%, P = 0.124). For younger patients (<65 years) CR was 69% and for elderly patients 29% (P = 0.003). For low volume disease (<5 ITMs) CR was 75% and for high volume disease (≥5 ITMs) 41% (P = 0.038). After median follow-up of 15 months (range, 1-144) there was local recurrence or disease progression in 36 patients (60%). Positive lymph node status was associated with local progression, absence of CR and Stage IIIC disease; these were independent prognostic factors for progression to systemic disease. M-ILP is an effective regional treatment for melanoma ITMs, whereas for bulky disease TM-ILP should be the first choice. In-field progression-free survival after ILP is determined by the biological behavior of the ITMs and the patient's immune system.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Humans; Melanoma; Melphalan; Neoplasm Metastasis; Tumor Necrosis Factor-alpha

Isolated limb perfusion with melphalan is a well-established and effective treatment for inoperable melanoma metastases of the extremities, with an overall response rate of 80% and a complete response rate of 54%. The surgical technique is complex and serious morbidity can occur, but with attention to detail major side effects can be kept to a minimum. This article reviews the technique, results and other aspects of this sophisticated form of treatment.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Humans; Melanoma; Melphalan; Randomized Controlled Trials as Topic

Isolated limb infusion (ILI) was developed as a simplified and minimally invasive alternative to isolated limb perfusion (ILP) to treat unresectable limb melanoma. A number of centers around the world have reported their results using this procedure. In this study a systematic review of reported ILI experiences was undertaken. A literature search was conducted according to the guidelines for systematic reviews in order to select eligible papers reporting limb toxicity and response rates following ILI using melphalan and actinomycin D to treat limb melanoma. A total of 576 patients from seven publications were included. Regional toxicity following ILI was low: no visible effect of the treatment or slight erythema or edema was observed in 79% of the patients, while considerable erythema and/or edema with blistering was experienced by 19%. In 2% there was a threatened or actual compartment syndrome. No procedure-related amputation was reported. Complete response occurred in 33% of the patients and partial response in 40%, an overall response rate of 73%. Stable disease and progressive disease were achieved in 14% and 13% of the patients, respectively. This first systematic review of ILI procedures using melphalan and actinomycin D indicates that regional toxicity was generally low, with satisfactory response rates. When comparing ILI and ILP, it must be borne in mind that ILI is often performed in significantly older patients and in patients with higher stages of disease, which decreases the likelihood of a favorable response.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Humans; Melanoma; Melphalan; Neoplasm Metastasis

In-transit metastases occur in approximately 3% of melanoma patients, can be very symptomatic and survival in this group may be prolonged. Regional chemotherapy with melphalan delivered by isolated limb perfusion (ILP) or isolated limb infusion (ILI) are effective treatment options which are generally well tolerated. ILI is a less invasive and simpler alternative to ILP. ILI is tolerated better than ILP, though is probably less effective. Complete response rates are 45- 69% for ILP and 23-44% for ILI. The limb is often warmed to lower temperatures in ILI compared to ILP and the limb becomes progressively more hypoxic and acidotic during ILI, each of these parameters potentially having an effect on outcome. ILP & ILI are used primarily as palliative options when excision of in-transit metastases is unfeasible but can be used as an adjunctive procedure to surgery, for other tumour types such as merkel cell carcinoma, and can be repeated if indicated. For ILI correction of melphalan dose for ideal body weight has been shown to substantially decrease the rates of severe local toxicity while maintaining complete response rates, but overall response rate is reduced. Combination treatment with tumour necrosis factor α has been used with variable outcomes and new combinations with buthionine sulfoximine and ADH-1 are being investigated.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Humans; Melanoma; Melphalan; Neoplasm Recurrence, Local; Skin Neoplasms

For in-transit melanoma confined to the extremities, regional chemotherapy in the form of hyperthermic isolated limb perfusion and isolated limb infusion are effective treatment modalities carrying superior response rates to current standard systemic therapy. Despite high response rates, most patients will eventually recur, supporting the role for novel research aimed at improving durable responses and minimizing toxicity. Although the standard cytotoxic agent for regional chemotherapy is melphalan, alternative agents such as temozolomide are currently being tested, with promising preliminary results. Current strategies for improving chemosensitivity to regional chemotherapy are aimed at overcoming classic resistance mechanisms such as drug metabolism and DNA repair, increasing drug delivery, inhibiting tumor-specific angiogenesis, and decreasing the apoptotic threshold of melanoma cells. Concurrent with development and testing of these agents, genomic profiling and biomolecular analysis of acquired tumor tissue may define patterns of tumor resistance and sensitivity from which personalized treatment may be tailored to optimize efficacy. In this article rational strategies for treatment of in-transit melanoma are outlined, with special emphasis on current translational and clinical research efforts.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Bevacizumab; Disease Progression; Humans; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasm Staging; Skin Neoplasms; Treatment Outcome

The treatment of in-transit metastasis of melanoma remains challenging and is essentially dictated by the biological behavior of melanoma. When lesions are large or numerous, isolated limb perfusion (ILP) is an attractive treatment modality. In this review an overview of literature on treatment options of melanoma in-transit metastases will be discussed.. Most recent studies report on tumor necrosis factor (TNF) and melphalan based ILP (TM-ILP) series or mixed series of TM-ILP and melphalan only based ILP (M-ILP). After TM-ILP complete response rates of 70% (range 44-90%) have been reported, while for M-ILP this is lower with complete response rates of 54% (range 40-76%). The only randomized trial comparing TM-ILP and M-ILP revealed no clear benefit of TNF at 3 months, but improved outcome at 6 months and in patients with bulky disease. Reports on isolated limb infusion (ILI) with melphalan and actinimycin D indicate lower response rates, but similar local control rates as M-ILP at lower cost.. ILP is an attractive treatment option in melanoma patients with multiple in-transit metastases. In our opinion TM-ILP is superior to M-ILP as it achieves higher response rates, especially in patients with bulky disease. When lesions are small and in the distal two-thirds of the leg only, ILI is a valuable alternative.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Humans; Melanoma; Melphalan; Skin Neoplasms; Tumor Necrosis Factor-alpha

In-transit melanoma metastases are often confined to a limb. In this circumstance, treatment by isolated limb perfusion or isolated limb infusion can be a remarkably effective regional treatment option.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Skin Neoplasms; Tumor Necrosis Factor-alpha

Isolated limb perfusion (ILP) involves the administration of chemotherapy drugs directly into a limb involved by locoregional metastases. Unresectable locally advanced melanoma of the limbs represents one of the clinical settings in which ILP has demonstrated benefits.. A systematic review of the literature on ILP for patients with unresectable locally advanced melanoma of the limbs was conducted. MEDLINE, EMBASE, and Cochrane database searches were conducted to identify studies fulfilling the following inclusion criteria: hyper- or normothermic ILP with melphalan with or without tumor necrosis factor (TNF) or other drugs providing valid data on clinical response, survival, or toxicity. To allocate levels of evidence and grades of recommendation the Scottish Intercollegiate Guidelines Network system was used.. Twenty-two studies including 2,018 ILPs were selected with a clear predominance of observational studies (90.90%) against experimental studies (9.10%). The median complete response rate to ILP was of 58.20%, with a median overall response rate of 90.35%. ILP with melphalan yielded a median complete response rate of 46.50%, against a 68.90% median complete response rate for melphalan plus TNF ILP. The median 5-year overall-survival rate was 36.50%, with a median overall survival interval of 36.70 months. The Wieberdink IV and V regional toxicity rates were 2.00% and 0.65%, respectively.. ILP is effective in achieving clinical responses in patients with unresectable locally advanced melanoma of the limbs. The disease-free and overall survival rates provided by ILP are acceptable. ILP is safe, with a low incidence of severe regional and systemic toxicity.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Extremities; Humans; Melanoma; Melphalan; Spain; Treatment Outcome

Isolated limb infusion (ILI) is a simple, minimally invasive technique of delivering high concentrations of cytotoxic drugs to a diseased limb for achieving disease control in that limb. Recent studies have suggested that mild hyperthermic (38 degrees C) ILI might be the best initial treatment for extensively recurrent limb melanoma given its simplicity, low morbidity and a complete response rate of 30 - 40%.. Since 1994 when ILI was first described by Thompson et al., the procedure has been adopted by several centres around the world; research and improvements in the technique have resulted in reduction in limb toxicity without reducing its clinical efficacy. The pharmacokinetics of melphalan and the clinical efficacy and adverse effects of ILI from various centres are summarised. Minor but possibly important differences in the ILI techniques used in different institutions may be important in improving its efficacy and reducing the toxic effects.. An understanding of the efficacy and toxicity associated with ILI with cytotoxic drugs in melanoma patients and of methods to optimise regional therapy for malignant disease in a limb.. ILI with mild hyperthermia (38 degrees C) is well tolerated with tumour remission rates in melanoma patients similar to those achieved by isolated limb perfusion. Mild (grade I - II) and moderate/severe (grade > or = III) limb toxicities occur in 58 - 68% and 32 - 41% of patients, respectively, but long-term morbidity is rare. A high peak and high final melphalan concentration in the infusate, the AUC of melphalan concentration in the infusate and an increased postoperative serum creatine phosphokinase concentration are factors predictive of acute regional toxicity. Drug dose adjusted for ideal body weight and gender may reduce acute toxicity following ILI. It has been suggested that the use of papaverine prior to the infusion of melphalan might increase its efficacy, but it may also increase toxicity. Large prospective studies are needed to more accurately define the perioperative factors that influence acute regional toxicity after ILI and to establish strategies to optimise clinical outcome.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Hyperthermia, Induced; Infusions, Intra-Arterial; Male; Melanoma; Melphalan; Risk Factors; Skin Neoplasms; Treatment Outcome

Isolated limb perfusion is the preferred treatment option for locally advanced melanoma and sarcoma confined to a limb. This treatment results in high response rates with a satisfying duration of response in both tumours. A drawback of isolated limb perfusion, however, is the invasive and complex character of the procedure.Isolated limb infusion has been designed as a minimally invasive alternative to isolated limb perfusion. Treatment results of this simple technique, reported by various centres worldwide, show comparable response rates for melanoma and sarcoma. Therefore isolated limb infusion may replace isolated limb perfusion in the future as the preferred treatment option for these locally advanced limb tumours.

Topics: Animals; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melanoma; Melphalan; Prognosis; Sarcoma; Vascular Diseases

In-transit disease is a unique form of regional lymphatic spread of melanoma that is considered an infrequent event although certain high-risk subgroups have been identified with higher incidence rates. Although this disease entity is associated with a high risk for distant relapse, regionally focused treatment of disease is important due to the high morbidity associated with in-transit disease. Isolated limb perfusion has been a utilized method of regional treatment since the 1950's. The technical aspects, indications, historical results, and toxicity of limb perfusion are reviewed. Finally, perfusion based treatment of in-transit melanoma is an excellent model for studying novel agents and regimens in both the pre-clinical and patient care setting.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Hyperthermia, Induced; Lymphatic Metastasis; Melanoma; Melphalan; Randomized Controlled Trials as Topic; Tumor Necrosis Factor-alpha

Two forms of regional chemotherapy for the treatment of advanced melanoma or sarcoma of the extremity are isolated limb perfusion (ILP) and the more recently described isolated limb infusion (ILI). Melphalan is the most commonly employed agent in both ILP and ILI, although it is often used in conjunction with other cytotoxic and/or biologic therapies. While ILP and ILI are far more effective for the treatment of extremity disease than is systemic therapy, there is still significant room for improvement in outcomes, from the standpoint of both response rate and toxicity. An understanding of the pharmacokinetics of regional chemotherapy would allow for the prediction of tumor response and toxicity and therefore patient outcomes. In addition, elucidating the mechanisms of drug resistance would lead to opportunities to develop effective chemo-modulators that enhance the effectiveness of ILP and ILI. This paper reviews progress in these two key areas of active investigation.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Drug Resistance, Neoplasm; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Sarcoma

The biological behavior of melanoma is unpredictable. Three to five per cent of melanoma patients will develop in-transit lesions and the median time to recurrence ranges between 13-16 months. At the time of recurrence the risk of occult nodal metastasis, with clinically negative regional lymph nodes, is as high as 50%. The risk of in-transit lesions depends on the tumor biology and not on the surgical approach to the regional lymph nodes. The high incidence of in-transit lesions at the lower limb may be caused by the gravity and delayed lymphatic drainage. The treatment of limited disease is local excision, laser ablation, cryosurgery, while multiple in-transit lesions or bulky disease located in a limb can be successfully treated with regional chemotherapy, a therapeutic isolated limb perfusion or infusion with melphalan or a combination of melphalan and tumor necrosis factor (TNF) alpha. If local regional treatment or systemic dacarbazine based systemic treatment fails, novel systemic treatment strategies with vaccines, antibodies and gene therapy are currently investigated.

Topics: Antineoplastic Agents; Combined Modality Therapy; Europe; Humans; Hyperthermia, Induced; Lymph Nodes; Lymphatic Metastasis; Melanoma; Melphalan; Neoplasm Recurrence, Local; Skin Neoplasms; Tumor Necrosis Factor-alpha

Hyperthermic isolated limb perfusion (HILP) with melphalan and more recently isolated limb infusion (ILI) with melphalan +/- dactinomycin are common treatment modalities for both in-transit melanoma of the extremity and advanced extremity sarcoma. In order to further optimize treatment, future research should focus on selection of appropriate patients, verification of a technique that produces consistent results while maintaining acceptable toxicity, and development of novel strategies and agents. Development of these novel agents and strategies has potential to not only improve the efficacy of regional chemotherapy but may also help guide future strategies for systemic treatment.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials, Phase I as Topic; Humans; Lymphatic Metastasis; Melanoma; Melphalan; Sarcoma

Recombinant human tumour necrosis factor (TNF) has a selective effect on angiogenic vessels in tumours. Given that it induces vasoplegia, its clinical use has been limited to administration through isolated limb perfusion (ILP) for regionally advanced melanomas and soft tissue sarcomas of the limbs. When combined with the alkylating agent melphalan, a single ILP produces a very high objective response rate. In melanoma, the complete response (CR) rate is around 80% and the overall objective response rate greater than 90%. In soft tissue sarcomas that are inextirpable, ILP is a neoadjuvant treatment resulting in limb salvage in 80% of the cases. The CR rate averages 20% and the objective response rate is around 80%. The mode of action of TNF-based ILP involves two distinct and successive effects on the tumour-associated vasculature: first, an increase in endothelium permeability leading to improved chemotherapy penetration within the tumour tissue, and second, a selective killing of angiogenic endothelial cells resulting in tumour vessel destruction. The mechanism whereby these events occur involves rapid (of the order of minutes) perturbation of cell-cell adhesive junctions and inhibition of alphavbeta3 integrin signalling in tumour-associated vessels, followed by massive death of endothelial cells and tumour vascular collapse 24 hours later. New, promising approaches for the systemic use of TNF in cancer therapy include TNF targeting by means of single chain antibodies or endothelial cell ligands, or combined administration with drugs perturbing integrin-dependent signalling and sensitizing angiogenic endothelial cells to TNF-induced death.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Cell Adhesion; Cell Division; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Female; Humans; Inflammation; Integrin alphaVbeta3; Liver Neoplasms; Male; Melanoma; Melphalan; Mice; Mice, Nude; Models, Molecular; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Osteosarcoma; Protein Conformation; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Recombinant Proteins; Remission Induction; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor Decoy Receptors; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

Recombinant human TNF (rhTNF) has a selective effect on endothelial cells in tumour angiogenic vessels. Its clinical use has been limited because of its property to induce vascular collapsus. TNF administration through isolated limb perfusion (ILP) for regionally advanced melanomas and soft tissue sarcomas of the limbs was shown to be safe and efficient. When combined to the alkylating agent melphalan, a single ILP produces a very high objective response rate. ILP with TNF and melphalan provided the proof of concept that a vasculotoxic strategy combined to chemotherapy may produce a strong anti-tumour effect. The registered indication of TNF-based ILP is a regional therapy for regionally spread tumours. In soft tissue sarcomas, it is a limb sparing neoadjuvant treatment and, in melanoma in-transit metastases, a curative treatment. Despite its demonstrated regional efficiency TNF-based ILP is unlikely to have any impact on survival. High TNF dosages induce endothelial cells apoptosis, leading to vascular destruction. However, lower TNF dosage produces a very strong effect that is to increase the drug penetration into the tumour, presumably by decreasing the intratumoural hypertension resulting in better tumour uptake. TNF-ILP allowed the identification of the role of alphaVbeta3 integrin deactivation as an important mechanism of antiangiogenesis. Several recent studies have shown that TNF targeting is possible, paving the way to a new opportunity to administer TNF systemically for improving cancer drug penetration. TNF was the first agent registered for the treatment of cancer that improves drug penetration in tumours and selectively destroys angiogenic vessels.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Vessels; Chemotherapy, Cancer, Regional Perfusion; Humans; Interferon-gamma; Melanoma; Melphalan; Neoplasms; Pilot Projects; Recombinant Proteins; Sarcoma; Tumor Necrosis Factor-alpha

Malignant melanoma represents a particular challenge for dermatologists and oncologists because of its high and increasing incidence and the poor prognosis of patients with thick primary tumors (T3, T4). In advanced stages of melanoma, cutaneous and subcutaneous metastases have a special significance, as they markedly affect the patient and may lead to a limitation in quality of life. While topical therapy is possible, there are only limited clinical studies. The location, number, size and distribution of skin metastases, involvement of internal organs, age and general condition should be considered in assessing therapeutic options. Especially with solitary, easily accessible metastases, surgical excision represents the therapy of choice. Ablation using CO(2) laser is an alternative. With extensive metastases in just one extremity, isolated limb perfusion (ILP) with melphalan is an option, while multiple, smaller metastases can be irradiated. Further, several chemotherapeutic agents and immune modulators can be used topically, peri- and intralesionally.

Topics: Antineoplastic Agents, Alkylating; Humans; Laser Therapy; Melanoma; Melphalan; Practice Guidelines as Topic; Practice Patterns, Physicians'; Radiotherapy; Skin Neoplasms

Topics: Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Doxorubicin; Extremities; Humans; Melanoma; Melphalan; Middle Aged; Patient Selection; Salvage Therapy; Sarcoma; Skin Neoplasms; Tumor Necrosis Factor-alpha

Metastatic or primary unresectable cancers confined to the liver are the sole or life-limiting component of disease for many patients with colorectal cancer, ocular melanoma, neuroendocrine tumors, or primary colangio- or hepatocellular carcinomas. Regional treatment strategies including infusional chemotherapy and local ablative therapy are under investigation, but have limitations with respect to the clinical conditions under which they can be employed. Isolated hepatic perfusion (IHP) was first clinically applied over 40 years ago, but because of its technical complexity, the attendant potential morbidity, and the lack of documented efficacy, it has not enjoyed consistent or widespread evaluation. In light of the antitumor activity with isolated limb perfusion with tumor necrosis factor (TNF) and melphalan in patients with unresectable extremity sarcoma or in transit melanoma, this regimen has been administered via IHP at several centers worldwide for patients with unresectable liver cancers. IHP with TNF and melphalan can result in significant regression of advanced refractory cancers from multiple histologies confined to the liver. Patient selection is important to ensure good results with minimal morbidity and mortality. Work to define the appropriate clinical groups is ongoing at many clinical centers.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Eye Neoplasms; Humans; Hyperthermia, Induced; Liver Neoplasms; Melanoma; Melphalan; Tumor Necrosis Factor-alpha

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Extremities; Humans; Limb Salvage; Melanoma; Melphalan; Multicenter Studies as Topic; Neovascularization, Pathologic; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

Isolated limb perfusion is a surgical procedure for delivering a high dose of chemotherapeutic or immunochemotherapeutic agent to a localised area, thus avoiding the severity of side-effects caused by systemic administration. This technique is generally used for treatment of patients with tumours of the limbs and extremities. We have done a systematic review of randomised controlled trials assessing the effectiveness of this treatment in patients with melanoma of the extremities. Four trials of 1038 patients met our inclusion criteria and were analysed. Although our analysis confirmed the reported increase in survival in two of the trials, neither had sufficient power to detect significant benefit for perfusion. Results from the trials showed that prophylactic perfusion has an equivocal effect on survival in patients with limb melanoma. Therefore, current evidence suggests that prophylactic isolated limb perfusion cannot be recommended as a routine adjunct to standard surgery in patients with high-risk primary limb melanoma, but only as a treatment for local disease control if other forms of locoregional therapy are not available.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melanoma; Melphalan; Randomized Controlled Trials as Topic; Survival Analysis

Isolated limb perfusion with melphalan is the treatment of choice for multiple (small) melanoma-in-transit metastases. The use of tumour necrosis factor alpha (TNFalpha) in isolated limb perfusion is successful for treatment of locally advanced limb soft-tissue sarcomas and other large tumours; this approach can avoid the need for amputation. TNFalpha was approved in Europe after a multicentre trial in patients with locally advanced soft-tissue sarcomas, deemed unresectable by an independent review committee; the response rate to isolated limb perfusion with TNFalpha plus melphalan was 76% and the limb was saved in 71% of patients. Moreover, the trial showed the efficacy of isolated limb perfusion of TNFalpha and melphalan against various other limb-threatening tumours such as skin cancers and drug-resistant bony sarcomas. Laboratory models of isolated limb perfusion have helped to elucidate mechanisms of action and to develop new treatment modalities. They have identified TNFalpha-mediated vasculotoxic effects on the tumour vasculature and have shown that addition of TNFalpha to the perfusate results in an increase of three to six times in uptake of melphalan or doxorubicin by tumours. New vasoactive drugs and new mechanisms of action are being discovered. Moreover, isolated limb perfusion is an effective modality for gene therapy mediated by an adenoviral vector. Various clinical phase I-II studies can be expected in the next few years.

Topics: Aged; Aged, 80 and over; Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Melanoma; Melphalan; Rats; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

On the basis of personal experience and a review of the literature, the authors have evaluated the results obtained with hyperthermic antiblastic perfusion (HAP) for the treatment of stage II, III and IIIAB limb melanoma. The evaluation showed that today HAP may be considered a safe and effective treatment, with a major complication rate ranging between 1% and 4%. In terms of tumor response, locoregional control and survival, this treatment has provided better results than other regional chemotherapeutic modalities and undoubtedly better results than those obtained with conventional, even radical, surgery. The multivariate analysis showed that, of the treatment-related prognostic factors, the minimum tumor temperature influenced the percentage of complete response (CR) to the greatest extent (P<0.03), with a positive trend also with regard to the dosage of the antiblastic drug employed (P<0.08). In turn, the complete response rate was a determinant as far as locoregional control (50%; P<0.0009) and disease-free (51.4%; P=0.0009) and overall survival (63%; P<0.009) rates were concerned. Of the tumor-related prognostic factors, the number of lesions (P<0.0014), sex (P<0.04), and the number of disease recurrences (P<0.01) appear to influence overall survival.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Combined Modality Therapy; Disease-Free Survival; Extremities; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Survival Analysis

Isolated limb perfusion (ILP) is a well-established locoregional procedure to deliver high doses of cytostatics to an extremity with multiple in-transit lesions from cutaneous melanoma, with minimal systemic and mild local toxicity. This approach is quite sophisticated and requires accurate monitoring of systemic leakage and of the temperature of the affected limb in order to avoid major systemic and local side effects. Mephalan (L-PAM) is considered the reference drug, although complete responses are reported in only about 50% of patients. Since the early 1990s, tumor necrosis factor-alpha (TNF-alpha) was administered with melphalan in ILP aiming to improve the therapeutic index of this procedure. However, despite the impressive results reported, its role still remains controversial, seemingly confined to large tumor bulk. Fotemustine ILP was proposed as a less toxic alternative to L-PAM, after the results of a pilot experience claiming similar response rates with less local toxicity. A formal phase 1-2 study is now underway to confirm these findings. More straightforward procedures, such as isolated limb infusion, are appealing, as they seem capable of achieving good response rates, are easily repeatable, and are less costly. Larger series are required to validate such results. As potential agents to be delivered through ILP, new vasoactive drugs and agents with new mechanisms of action that interplay with chemotherapy, as well as virus-mediated gene therapy, are being developed.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Genetic Therapy; Humans; Melanoma; Melphalan; Neoplasm Staging; Nitrosourea Compounds; Organophosphorus Compounds; Pilot Projects; Remission Induction; Reproducibility of Results; Skin Neoplasms; Tumor Necrosis Factor-alpha

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Humans; Leg; Melanoma; Melphalan; Neoplasm Recurrence, Local; Skin Neoplasms

Progressive growth of unresectable metastatic or primary malignancies confined to the liver is a significant clinical problem. Approximately 25% of patients with colorectal cancer will develop metastatic disease exclusively or largely confined to liver, the vast majority of which are not amenable to surgical resection. Despite aggressive systemic or regional chemotherapy, survival is only 12 to 18 months. More than 80% of patients with ocular melanoma develop liver metastases as the first site of recurrent disease, and death from hepatic disease progression typically occurs 2 to 7 months after diagnosis. In addition, the liver is also the preferred site of metastatic disease for gastrointestinal or pancreatic neuroendocrine tumors. A number of physiological and anatomic features of the liver make it an ideal organ for regionally directed therapy to allow dose intensification to the cancer-burdened area while reducing or eliminating unnecessary systemic toxicity. To that end, complete vascular isolation and perfusion of the liver using a recirculating extracorporeal circuit, also called isolated hepatic perfusion (IHP), has been under clinical evaluation at our institution and others. In this article, we review the current results with IHP and its potential utility in the treatment of patients with unresectable hepatic malignancies.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Colorectal Neoplasms; Combined Modality Therapy; Humans; Hyperthermia, Induced; Liver Neoplasms; Melanoma; Melphalan; Tumor Necrosis Factor-alpha

Isolated limb perfusion is used to treat unresectable sarcoma, melanoma, and other select tumors. It is performed in the OR and requires collaboration by surgeons, perioperative nurses, anesthesia care providers, pharmacists, perfusion technologists, and nuclear medicine personnel. The procedure involves complete isolation of the vascular supply to a limb before an infusion of high dose chemotherapeutic medications.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Perioperative Nursing; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

Topics: Amputation, Surgical; Antineoplastic Agents, Alkylating; Arm; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Humans; Hyperthermia, Induced; Leg; Melanoma; Melphalan; Sarcoma; Skin Neoplasms; Tumor Necrosis Factor-alpha

The mainstay of treatment of cutaneous melanoma is surgical excision. Excision of the primary disease, lymph node metastases, and in some instances, distant metastases is the only therapeutic strategy that leads to long-term disease-free survival with rare exceptions. Surgical treatment of melanoma can be divided into therapy of the primary lesion, treatment of the lymph nodes, treatment of distant metastases, and treatment of in-transit disease by regional administration of intravascular chemotherapeutics. The current recommendations for each of these four areas is discussed in this review.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Humans; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms

To examine the frequency and duration of complete remission for locally recurrent and metastatic limb melanoma after isolated limb perfusion (ILP) with cytotoxic agents.. A case series of 114 consecutive therapeutic ILPs performed between April 1984 and April 1994 and a review of previously published studies.. A tertiary referral center for melanoma treatment, located at a university teaching hospital.. Of 111 assessable ILPs, 81 (73%) resulted in complete limb tumor remission and 14 (13%) resulted in partial remission (defined as a reduction in size of tumor deposits by > 50%). Complete remission was maintained in 37 (46%) of the 81 cases without any further treatment (median follow-up, 33 months; range, 8-112 months). Of the other 44 cases, disease subsequently recurred in the perfused limb (median time to recurrence, 9.5 months; range, 2-65 months). In 19 of these cases, however, the limb was again disease free at last follow-up after local surgery (12 cases) or a repeat ILP (7 cases). Overall, complete locoregional control was achieved after 50% of assessable ILPs, and a long-term disease-free state in the limb was achieved, with or without further treatment, in 56 (69%) of the 81 cases in which an initial complete remission occurred. For 743 therapeutic ILPs undertaken in 12 series previously reported in the literature, an initial complete remission was reported in 50% of these cases and partial remission in 32%.. Therapeutic ILP is an effective form of treatment for patients with recurrent and metastatic limb melanoma, achieving short- and long-term results that are superior to those achievable by any other form of treatment currently used.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Dactinomycin; Female; Follow-Up Studies; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Remission Induction; Time Factors; Treatment Outcome

The addition of hyperthermia (HT) to regional isolated perfusion (RIP) with Melphalan theoretically has two advantages. Firstly, heat can selectively kill cells in poorly vascularised areas that are usually not reached by the drug. Secondly, in vitro data have revealed that the effect of Melphalan is enhanced at temperatures 39-45 degrees C. However, for the simultaneous application of Melphalan and HT, as it is given in most institutes, both normal and tumour tissues within the volume are treated with both modalities. It is unclear whether--for the same heat dose--the cytotoxicity of Melphalan is enhanced more in tumour tissue than in normal tissues. As the applied dose of Melphalan in RIP is selected on maximum acceptable toxicity, any enhancement of toxicity is undesired. Indeed, Melphalan application at temperatures > 41 degrees C has resulted in unacceptable toxicity. In most institutes, the hyperthermia dose is reduced in comparison to application as a single-modality treatment, to allow simultaneous combination without unacceptable toxicity. In this review, the rationale for two different approaches is summarised which may make it possible to improve the benefit from the theoretical advantage of the use of HT in RIP. It is meant to stimulate discussion as a possible first step in the design of new treatment protocols.

Topics: Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Humans; Hyperthermia, Induced; Melanoma; Melphalan

Topics: Arm; Chemotherapy, Cancer, Regional Perfusion; Drug Therapy, Combination; Humans; Interferon-gamma; Leg; Melanoma; Melphalan; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

Topics: Animals; Antineoplastic Agents; Cricetinae; Liver Neoplasms; Melanoma; Melphalan; Perfusion; Tumor Necrosis Factor-alpha

Recombinant tumor necrosis factor-alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side-effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the efficient dose in animals. Isolation perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-transit metastases (stage IIIA or AB) we obtained a 91% complete response, compared with 52% after ILP with melphalan alone. Release of nanograms levels of TNF alpha in the systemic circulation was evident but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man.

Topics: Animals; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Drug Administration Schedule; Drug Synergism; Hemodynamics; Humans; Interferon-gamma; Melanoma; Melphalan; Neoplasm Metastasis; Pilot Projects; Recombinant Proteins; Transplantation, Heterologous; Tumor Necrosis Factor-alpha

The Surgery Branch of the National Cancer Institute has initiated several clinical trials involving the use of high-dose TNF in isolated limb perfusions. A phase III trial compares the three drug combination of TNF, interferon-gamma (IFN-gamma) and melphalan with a standard melphalan-alone perfusion in a prospective randomized trial. Another protocol escalates the dose of TNF in the perfusate to define the maximally tolerated dose that can be administered in this regional manner. A third protocol adds systemic high-dose interleukin-2 postoperatively to a TNF, IFN, and melphalan limb perfusion for patients with stage IV melanoma with the bulk of the disease in the extremity. This brief review highlights the rationale and study design of these TNF limb perfusion protocols.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Dose-Response Relationship, Drug; Extremities; Humans; Interferon-gamma; Interleukin-2; Melanoma; Melphalan; Prospective Studies; Randomized Controlled Trials as Topic; Tumor Necrosis Factor-alpha

Isolated limb perfusion (ILP) with melphalan is an effective treatment for recurrent melanoma, but complete remission is achieved only in about 40% of patients. Regional toxicity is common, causing short-term disability and occasional longterm incapacity. Methods to maximize the efficacy and minimize the toxicity were investigated in 210 ILPs undertaken at the Sydney Melanoma Unit. Toxicity was found to be related to peak melphalan concentration, as well as to the area under the curve and maximum temperature. A dye dilution technique has been developed to measure perfusion circuit volume, so that a drug dose can be given to achieve an appropriate concentration. ILP with cisplatin was less effective and produced greater toxicity than ILP with melphalan; other drugs and drug combinations warrant investigation. Prophylactic ondansetron successfully controlled post-operative nausea and vomiting in most patients. Daily measurement of serum creatine phosphokinase (CPK) allowed early recognition of impending severe toxicity, with the greatest risk if CPK exceeded 1000 IU/l after the first post-perfusion day. Isolated limb 'infusion' (ILI) with melphalan, using percutaneously inserted catheters, is a much simpler procedure than ILP and has been found to be effective and easily repeated. The morbidity of ILP and ILI may be minimized by excluding the foot or hand with a rubber bandage.

Topics: Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Humans; Hyperthermia, Induced; Melanoma; Melphalan

Topics: Animals; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Drug Screening Assays, Antitumor; Extremities; Humans; Immunologic Factors; Interferon-gamma; Melanoma; Melphalan; Mice; Mice, Inbred BALB C; Neoplasms; Sarcoma; Sarcoma, Experimental; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

Little progress has been made in the systemic treatment of melanoma, that is for disseminated stage IV disease. However, the tumour resistance to therapy, especially chemotherapy can be overcome in melanoma by high doses of anticancer agents administered regionally. The purpose of this paper is to illustrate this concept by two modes of regional treatment namely: (1) isolation perfusion of the limbs with high doses of cytokines and chemotherapy under hyperthermia and (2) local treatment of metastatic melanoma. The third part will be devoted to the role of another regional treatment, radiotherapy, where the association with hyperthermy also looks promising.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Feasibility Studies; Female; Humans; Interferon-gamma; Male; Melanoma; Melphalan; Middle Aged; Recombinant Proteins; Tumor Necrosis Factor-alpha

Topics: Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Temperature

Hyperthermic antiblastic isolated perfusion is a method largely used for the treatment of locally advanced limb melanoma. The method requires vascular isolation and hyperthermic perfusion of the limb using an extracorporeal circuit and administering the melphalan as antiblastic drug. Twenty-six patients with primary or recurrent melanoma of the limbs have undergone this treatment at our Institute. There were no cases of operative mortality and systemic toxicity was negligible. The local complications were transitory and no patient showed symptoms of nervous toxicity or permanent functional damage. Two cases of deep thrombophlebitis and two of lymphocele were documented a few months after treatment. Four clinically complete responses, 3 partial and 2 cases of stable disease were observed in the 9 patients treated with unexcised lesions. Our data like the totality of the present experience points to the safety of this method in the therapy of locally advanced limb melanoma. Nevertheless further controlled studies are required to define its role in order to improve survival.

Topics: Adult; Aged; Anesthesia, General; Arm; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Humans; Hyperthermia, Induced; Leg; Melanoma; Melphalan; Middle Aged; Monitoring, Intraoperative; Posture

Thermochemotherapy through regional CEC has been applied to malignant melanomas of the limbs for a long time as it was described by Creech and Krementz more than twenty years ago. Strangely enough, its application has remained confidential in France. In order to assess this method, we have been applying it to 128 consecutive patients from January 1, 1982 to January 1, 1990. After the exclusion of 9 patients (7 technical failures, 1 wrong diagnosis, 1 improper inclusion), the remaining series is of 119 patients for 125 infusions. The average distance in time is 3.4 years. The series includes 31 men and 88 women with an average age of 51.2 + 14.2 years (23-75) with malignant melanoma of the upper limb (25 cases) or lower limb (94 cases). The histological type of the tumor was nodular in 47 cases (39.5%), SSM in 40 cases (33.6%), acrolentiginous in 26 cases (22%) and undetermined in 6 cases (5%). All lesions were high-risk malignant melanomas for which Clark's index was higher than III and Breslow's index higher than 1.5 mm in 103 cases (16 cases in which Breslow's index ranged from 1 to 1.5 mm were included at the beginning of the series). Chemotherapy utilized Mephalan with a dose of 0.8 to 1.5 mg/kg of body weight, delivered through monomelic CEC and under hyperthermia at 41 degrees C during 45 to 50 minutes, via a cannulation of the axillary artery and vein in the upper limb and of the common femoral artery and vein in the lower limb.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Actuarial Analysis; Adult; Aged; Arm; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Skin Neoplasms

Subungual melanoma is rare and represents only 1% to 3% of all diagnosed melanomas in Western countries. The tumor is frequently mistaken for a benign lesion and the delay in diagnosis and final treatment may be responsible for the high local recurrence rate and the low disease-free survival rate. From 1965 to 1982 the combined-modality therapy of amputation and adjuvant isolated regional perfusion with melphalan with or without dactinomycin was used in the treatment of 22 patients with subungual melanoma. Disease was staged according to the M. D. Anderson classification, as follows: stage I (primary melanoma), 11 patients; stage IIIA (in-transit metastases and/or satellitosis), three patients; stage IIIB (regional lymph nodes), seven patients; and stage IIIAB (in-transit metastases and/or satellitosis and regional lymph nodes), one patient. There were no cardiovascular complications and no treatment mortality. During a follow-up of at least 4.5 years, 12 patients (55%) developed distant metastases, including four patients with stage I disease (36%) and eight patients with stage III disease (73%). There were no locoregional recurrences. The median survival was three years (range, 0.5 to 12.5 years) and the overall five-year survival was 40%, with 56% of patients having stage I disease and 27% having stage III disease. The prognosis of subungual melanoma is determined by the stage of the disease. Isolated regional perfusion may prolong disease-free survival in patients with subungual melanoma compared with previously published data.

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dactinomycin; Female; Humans; Lymph Node Excision; Male; Melanoma; Melphalan; Middle Aged; Nail Diseases; Prognosis

Topics: Chemotherapy, Cancer, Regional Perfusion; Humans; Melanoma; Melphalan; Radiotherapy Dosage

Topics: Chemotherapy, Cancer, Regional Perfusion; Humans; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Melphalan; Prognosis

The available evidence suggests that if benefit is to be obtained from high dose chemotherapy regimens, it will be in patients whose tumours are either untreated or still responding to conventional therapy. In each of the diseases discussed in this chapter the optimum timing of the treatment regimen has still to be determined. Effective regimens have been found but it is probable that further improvements can be made. In small cell lung cancer initial high dose therapy followed by non-cross-resistant regimens may prove effective. In glioma studies with high dose therapy before irradiation are awaited and may offer the best means of exploiting this approach to treatment. In breast cancer some impressive responses have occurred but the category of patient likely to benefit has not yet been defined. In melanoma high dose treatment is likely to benefit only those patients with probable minimal disease after surgery.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Breast Neoplasms; Carcinoma, Small Cell; Carmustine; Cell Separation; Cisplatin; Colonic Neoplasms; Cyclophosphamide; Etoposide; Glioma; Humans; Lung Neoplasms; Male; Melanoma; Melphalan; Neoplasms; Testicular Neoplasms; Whole-Body Irradiation

The role of perfusion, normothermic and hyperthermic, in the curative treatment of melanoma remains controversial. Survival appears to be somewhat improved over that of surgery alone in all stages, especially with hyperthermic perfusion, but all comparisons have been retrospective and uncontrolled. In addition to the usual problems with historical controls, melanoma presents its own special problems because of its unpredictable natural history in any given individual and the multiplicity of factors known to affect prognosis. It is unfortunate that hundreds of patients have been treated in uncontrolled studies. Randomized trials continue to be necessary to define this role and even then careful attention will have to be paid to the distribution of known prognostic factors in each group to insure a comparable cohort of patients. The response of melanoma to perfusion is clearly significant, however, and the response rate seems to be improved with hyperthermic perfusion. Hyperthermic perfusion appears to be a useful palliative treatment for locally advanced melanoma of the extremity, especially for which the alternative surgical therapy would be amputation.

Topics: Arm; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dactinomycin; Humans; Hyperthermia, Induced; Leg; Lymphatic Metastasis; Melanoma; Melphalan; Neoplasm Recurrence, Local; Neoplasm Staging

Thirty-nine patients with clinical Stage I malignant melanoma of the extremities were treated with hyperthermic perfusion chemotherapy using melphalan followed by excision or wide re-excision of the area and regional lymph node dissection. Four patients with positive lymph nodes, on histologic examination, were considered pathologic Stage II. Seventy-two patients with clinical Stage I extremity melanomas, who were treated by conventional surgical methods, served as concurrent controls, and were comparable in the distribution of their various pretreatment characteristics. The actuarial survivals for clinical Stage I perfusion patients calculated by the life-table method at 5, 10, and 15 years were 91%, 86%, and 77%, respectively, and disease-free survivals were 85%, 80%, and 80%, respectively. These figures were significantly better than controls. A Breslow depth of invasion of greater than 1.5 mm showed a significant difference in both clinical and pathologic Stage I disease as compared with the controls. Similarly, perfused patients aged less than or equal to 50 years survived significantly better than controls in both clinical and pathologic Stage I disease. The literature has been reviewed.

Topics: Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Hot Temperature; Humans; Lymph Node Excision; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Prognosis

Topics: Adolescent; Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Child; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Radiotherapy, High-Energy; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms

Topics: Adult; Aged; Biopsy; Carmustine; Cyclophosphamide; Dactinomycin; Female; Humans; Hydroxyurea; Male; Melanoma; Melphalan; Microscopy, Electron; Middle Aged; Prognosis; Skin Neoplasms; Sunlight; Wounds and Injuries

Topics: Adenocarcinoma; Alkylating Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Carmustine; Cyclohexanes; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Hodgkin Disease; Humans; Hydroxyurea; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphoma; Melanoma; Melphalan; Multiple Myeloma; Nitrosourea Compounds; Prednisone; Vincristine

Topics: Alkylating Agents; Amides; Animals; Antigen-Antibody Reactions; Antimetabolites; Antineoplastic Agents; Carmustine; Humans; Imidazoles; Immunity, Cellular; Immunotherapy; Ketosteroids; Lymphocyte Transfusion; Melanoma; Melphalan; Mice; Nitrosourea Compounds; Perfusion; Pregnenes; Procarbazine; Prognosis; Sex Factors; Skin Neoplasms; Triazenes; Vaccination; Vinca Alkaloids; Vincristine

Topics: Abdominal Neoplasms; Alkylating Agents; Animals; Antimetabolites; Antineoplastic Agents; Carcinoma, Basal Cell; Choriocarcinoma; Cyclophosphamide; Dactinomycin; Dysgerminoma; Female; Fluorouracil; Head; Head and Neck Neoplasms; Hodgkin Disease; Humans; Injections, Intra-Arterial; Leg; Melanoma; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Nitrogen Mustard Compounds; Pregnancy; Sarcoma; Sarcoma, Ewing; Skin Neoplasms; Vinblastine; Wilms Tumor

Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver.. Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.. Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively.. M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Liver; Liver Neoplasms; Male; Melanoma; Melphalan; Perfusion; Prospective Studies

To investigate the safety and toxicity of percutaneous hepatic perfusion with melphalan (M-PHP) with the Delcath Systems' second-generation (GEN 2) filter and compare the outcomes with historical data from studies using the first-generation filter.. A prospective, single-arm, single-center phase II study was carried out including 35 patients with unresectable, histologically confirmed liver metastases from ocular melanoma between February 2014 and June 2017. Main exclusion criteria were extrahepatic disease and age > 75 years. M-PHP was performed with melphalan 3 mg/kg (maximum dose 220 mg). Safety and toxicity were assessed according to the Common Terminology Criteria for Adverse Events version 4.03.. A total of 67 M-PHPs were performed in 35 patients (median 2 procedures). Although hematologic grade 3/4 events were seen in the majority of patients (thrombocytopenia 54.5%, leukopenia 75.6%, neutropenia 66.7%, anemia (only grade 3) 18.1%), these were all well manageable or self-limiting. Of the non-hematologic grade 3 events (n = 14), febrile neutropenia (n = 3), pulmonary emboli (n = 2) and post-procedural hemorrhage (n = 2) were most common. A case of sepsis with bacterial pharyngitis was the only non-hematologic grade 4 event. Prior therapy for liver metastases was found to be a predictor of late grade 3/4 neutropenia with an odds ratio of 5.5 (95% CI 1.4-21.7).. M-PHP using the GEN 2 filter has an acceptable safety and toxicity profile, and seems to reduce hematologic toxicity when compared to M-PHP with a first-generation filter. Prior therapy of liver metastases is a possible predictive factor in developing grade 3/4 hematologic toxicity.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Eye Neoplasms; Female; Hemofiltration; Humans; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Prospective Studies

Percutaneous hepatic perfusion (PHP) with melphalan is an effective treatment for patients with hepatic metastases, but associated with high rates of bone marrow depression. To reduce systemic toxicity, improvements have been made to the filtration system. In pre-clinical studies, the Delcath System's GEN2 filter was superior to the first-generation filters. In this clinical study, we analysed the pharmacokinetics and toxicity of PHP using the new GEN2 filter.. Starting February 2014, two prospective phase II studies were initiated in patients with hepatic metastases from ocular melanoma or colorectal cancer. In 10 PHP procedures performed in the first 7 enrolled patients, blood samples were obtained to determine filter efficiency and systemic drug exposure. PHP was performed with melphalan 3 mg/kg with a maximum of 220 mg. Complications were assessed according to CTCAE v4.03. Response was assessed according to RECIST 1.1.. Pharmacokinetic analysis of blood samples showed an overall filter efficiency of 86% (range 71.1-95.5%). The mean filter efficiency decreased from 95.4% 10 min after the start of melphalan infusion to 77.5% at the end of the procedure (p = 0.051). Bone marrow depression was seen after up to 80.0% of 10 procedures, but was self-limiting and mostly asymptomatic. No hypotension-related complications or procedure-related mortality occurred.. The GEN2 filter has a higher melphalan filter efficiency compared to the first-generation filters and a more consistent performance. PHP with the GEN2 filter appears to have an acceptable safety profile, but this needs further validation in larger studies.

Topics: Adult; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Eye Neoplasms; Female; Hemofiltration; Humans; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Prospective Studies; Treatment Outcome

Isolated limb perfusion (ILP) is a treatment option for patients with in-transit metastases of malignant melanoma in the extremities, as well as locally advanced sarcoma. ILP allows for a delivery of high-dose chemotherapy to an isolated extremity with minimal systemic toxicity. However, local toxicity like oedema, blistering, nerve damage and compartment syndrome can occur. Myoglobin measurements have been used as a screening method to predict the most severe cases of local toxicity. The aim was to investigate if myoglobin is a predictive factor for local toxicity after ILP in patients with melanoma in-transit metastases.. One hundred and ninety-three patients were treated for the first time with ILP for in-transit metastases between 2001 and 2015. Myoglobin was measured once the first hours after the perfusion (POD0), and for the first five post-operative days (POD1-5). Local toxicity was graded according to Wieberdink, and grouped in mild (I and II), moderate (III), and severe (IV and V). Wieberdink-groups were compared with myoglobin measurements, and myoglobin measurements were compared between gender, perfusion time, perfusion temperature and cannulated vessels.. There is no statistically significant difference in myoglobin serum levels during the first five days post perfusion between patients suffering from mild, moderate or severe local toxicity. There is no difference between toxicity groups when it comes to distribution of sex, tumour size, or tumour numbers.. Levels of myoglobin do not predict local toxicity for patients with melanoma in-transit metastases treated with ILP when measured during the first five post-operative days.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Myoglobin; Skin Neoplasms; Young Adult

Hyperthermic isolated limb perfusion (HILP) represents an alternative to amputation for patients with either in-transit melanoma or unresectable soft tissue sarcoma, entailing delivery of high-dose chemotherapy after isolation of the extremity, under hyperthermic conditions. Stabilization of the Esmarch elastic bandage is so far performed with the use of Steinmann pins. In this study, we presented our experience with HILP and demonstrated an alternative technique for limb isolation using an Omni-tract retractor instead of the traditional Steinmann pin, while comparing the two methods.. Forty patients, 28 with recurrent in-transit melanoma and 12 with locally advanced/recurrent sarcoma of the limbs, underwent HILP in a single institution and were included in the study. The Steinmann pin was applied in the first 23 cases, whereas the Omni-tract retractor was applied in the latter 17 patients.. The median follow-up for the whole study group was 17.5 mo, whereas the overall response rate was 92.9% for melanoma and 75% for sarcoma patients. Both overall survival and local progression-free survival differed significantly between patients with complete response and those with partial response, stable disease or progressive disease. The use of the Omni-tract retractor was advantageous in every examined field, with the overall complication rate, duration of analgesic administration, and total opioid and paracetamol dose, being significantly less in the Omni-tract patient group.. Although this study was not a randomized trial, we consider that the noninvasive application of the Omni-tract retractor will gain significant acceptance, by contributing to the reduction of HILP complications.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Prospective Studies; Sarcoma; Soft Tissue Neoplasms; Survival Analysis; Tourniquets; Treatment Outcome; Tumor Necrosis Factor-alpha

For patients with melanoma metastases in the pelvic and groin regions, the median survival time (MST) was 8 mo with old treatments, whereas today is approximately 20 mo with new target therapy and novel immunotherapy. Unfortunately, approximately 30% of patients are nonresponsive to these new drugs.. Thirty-six patients, previously progressing after standard treatments, collectively received 146 melphalan (30 mg/m. The median follow-up time was 15 mo. Among 36 patients, three patients were alive without evidence of disease after 62, 95, and 118 mo, respectively. Thirty-three patients died of melanoma. The overall MST was 15 mo. The 5-y survival rate was 8%. The MST was 37 mo for stage IIIB; 19 mo for stage IIIC; and 6 mo for stage IV. The MST was 11 mo for patients with ≥1 mitosis per mm. Pelvic/inguinal perfusion is a safe and feasible treatment for patients with advanced melanoma. Further studies are necessary to establish if it may play a role in patients who fail current systemic therapies.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Follow-Up Studies; Hemofiltration; Humans; Hypoxia; Male; Melanoma; Melphalan; Middle Aged; Pelvic Neoplasms; Prospective Studies; Skin Neoplasms; Survival Analysis; Treatment Outcome

Isolated pelvic perfusion (IPP) can be used to treat unresectable melanoma metastases of the pelvis. IPP can be performed either by surgical or percutaneous approaches, using different balloon catheters. The aim of this study was to examine whether the surgical and percutaneous approaches were comparable with respect to tumor drug exposure in the pelvis.. A pharmacokinetic study was performed in 5 melanoma patients treated with surgical IPP and five with percutaneous IPP. Both groups received melphalan at the dose of 30 mg/m. Tumor exposure to drug using these two methods did not statistically differ and both methods, therefore, can be adopted interchangeably, utilizing a perfusion blood flow rate of approximately 120 ml/min. The small sample size is a limitation of this study but our preliminary results can be used to calculate the effect size of a larger trial. Trial Registration Clinical Trials.gov Identifier NCT01920516; date of trial registration: August 6, 2013.

Topics: Aged; Antineoplastic Agents, Alkylating; Area Under Curve; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Pelvic Neoplasms; Pelvis; Pilot Projects; Statistics, Nonparametric; Surgical Procedures, Operative

In-transit metastases of melanoma occur in 5-8% of all melanoma patients. In case of extensive locoregional disease, Tumor necrosis factor-α and melphalan-based isolated limb perfusion (TM-ILP) had proven to yield excellent local control. Here, we report on repeat TM-ILP for locoregional recurrence after isolated limb perfusion. Between 1991 and 2013, 37 consecutive repeat TM-ILPs were analyzed in 32 different patients. Three patients underwent a third TM-ILP. During a median follow-up of 20 months after repeat TM-ILP, the overall response rate was 86%. Complete response (CR) was recorded after 24 TM-ILPs (65%). CR after first TM-ILP was a strong predictor for successful repeat TM-ILP in terms of clinical response and local recurrence. Local toxicity was mild (70% Wieberdink I-II). The local recurrence rate was 59%. Five-year overall survival was 35%. Repeat TM-ILP is a safe treatment modality in melanoma patients with recurrent in-transit metastases of melanoma. Those with a CR after first TM-ILP benefit the most from repeat TM-ILP.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Drug Administration Schedule; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Skin Neoplasms; Tumor Necrosis Factor-alpha

Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 35% of the patients, with the liver being the most common site for metastases. These metastases are generally refractory to systemic chemotherapy, and the median survival for patients with liver metastases is about 6 months. This phase II trial reports the experience of isolated hepatic perfusion (IHP) as a treatment option.. A total of 34 patients with isolated liver metastasis from ocular melanoma underwent IHP. An overall survival comparison was made using data retrieved from the National Patient Register managed by the Swedish National Board of Health and Welfare.. An overall radiological response was seen in 68% of the patients, with 12% having a complete response. Time to local progression was 7 months; 68% of the patients developed extrahepatic metastases after a median of 13 months, and the median overall survival was 24 months. There was a significant survival advantage of 14 months (p = 0.029) when comparing these patients with a control group consisting of the longest surviving patients in Sweden with uveal melanoma liver metastases not treated with IHP.. IHP is a treatment option with a high response rate and a potential survival benefit of more than 1 year. IHP should be considered an option in the treatment of uveal melanoma metastases. A randomized trial comparing IHP and best alternative care will start during 2013 (the SCANDIUM trial, ClinicalTrials.gov identifier NCT01785316).

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Disease Progression; Eye Neoplasms; Female; Follow-Up Studies; Humans; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Perfusion; Postoperative Complications; Prognosis; Registries; Survival Rate; Sweden; Young Adult

Diffuse isolated liver metastases are the dominant mode of tumor progression in a number of cancers and present a major treatment challenge for oncologists. An experimental treatment, percutaneous hepatic perfusion (PHP), utilizes partial venovenous cardiopulmonary bypass to allow administration of high-dose chemotherapy directly and solely to the liver with filtration of chemotherapeutic agents from the blood prior to its return to the systemic circulation, thereby minimizing toxic systemic effects. The following case series describes the management of 5 patients with metastatic melanoma undergoing serial PHPs.. A single-center experience from a national multi-center random-assignment trial comparing PHP to best alternative care (BAC) in patients with diffuse melanoma liver metastases.. A tertiary care hospital.. Five patients with metastatic melanoma to the liver.. Five patients underwent a total of fifteen PHPs using a venovenous bypass circuit with hemofiltration, receiving hepatic intra-arterial melphalan, 3 mg/kg of ideal body weight, for 30 minutes with a total of 60 minutes of hemofiltration.. Five patients tolerated the procedure well with transient hemodynamic and metabolic changes.. In patients with diffuse isolated liver metastases, PHP is a safe and well-tolerated procedure that can be performed more than once and is associated with marked anti-tumor activity in some patients.

Topics: Antineoplastic Agents, Alkylating; Body Temperature; Cardiopulmonary Bypass; Catheterization; Female; Hemofiltration; Humans; Liver Circulation; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Perfusion

Isolated limb infusion (ILI) is a percutaneous method of delivering regional chemotherapy to patients with recurrent tumors of the extremity. This study determines predictors of response, survival, and limb salvage.. Single institution data from a prospective clinical trial and subsequent ILI experience were reviewed. Limb tumor burden was assessed in melanoma patients with "high" (≥10 lesions or one lesion >3 cm) or "low" burden (<10 lesions and no lesion >3 cm). Response was assessed at 3 months from ILI.. Between 1999 and 2011, 62 patients underwent ILI (58 melanoma, 2 Merkel cell carcinoma (MCC), 2 soft tissue sarcoma (STS)). Low tumor burden patients had more complete responses (CR) (11/23, 48%) than high tumor burden (3/32, 9%, P < 0.001); they had higher 5-year survival (69% vs. 29%, P = .007). Five-year survival rates based on response: 91% CR, 53% partial response (PR), 25% less than PR (P = 0.042, CR vs. PR). 7 patients (11%) underwent amputation due to disease progression; 3 had prior CR or PR.. Low tumor burden is a significant predictor of response in melanoma patients. Response to ILI is a significant predictor of survival. Progression of limb disease requiring amputation is not associated with any factors.

Topics: Adult; Aged; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Disease Progression; Drug Administration Schedule; Extremities; Female; Humans; Kaplan-Meier Estimate; Limb Salvage; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Prospective Studies; Retrospective Studies; Sarcoma; Skin Neoplasms; Treatment Outcome; Tumor Burden

The aim was to describe tumour response, complications, recurrence and survival after hyperthermic isolated limb perfusion (ILP) with melphalan or melphalan in combination with tumour necrosis factor-alpha in patients with melanoma metastases confined to an extremity.. A total of 84 perfusions were performed (53 women, 31 men, median age 63 years) from 1993 to 2010. 95% of the perfusions were administered to the lower limbs and 5% to the upper limbs. The inclusion criteria were recurrent and/or clinically apparent cutaneous/subcutaneous extremity in-transit melanoma metastases.. The response rate after ILP was 85%; 42% had complete response (CR), 43% partial response (PR), 12% no change (NC) and 3% progression. Two- and five-year survival rates were 57% and 31%, respectively, and they were higher for patients with than without lymph node metastases. Time from ILP to recurrence was a median of seven months (range 1-37 months) for patients with CR or PR. Survival was longer for patients with CR or PR than for patients showing NC or progression. Several patients had mild or moderate local toxicity reactions, two patients developed severe local toxicity.. ILP induces tumour regression in the vast majority of patients. One patient, i.e. 1% of the group, died from surgical complications. Otherwise, ILP treatment had an acceptable morbidity in this group of very sick patients. We are convinced that the treatment should be offered to improve local disease control in patients with multiple and/or recurrent melanoma confined to an extremity if surgical excision is not possible.. not relevant.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Disease Progression; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Prospective Studies; Skin Neoplasms; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha

Following regional chemotherapy (RC) for melanoma, approximately 75 % of patients will progress. The role of immunotherapy after RC has not been well established.. A prospective, single-institution database of 243 patients with in-transit melanoma (1995-2013) was queried for patients who had progression of disease after RC with melphalan and subsequently received systemic immunotherapy. Fifteen patients received IL-2 only, 12 received ipilimumab only, and 6 received IL-2 followed by ipilimumab. Fisher's exact test was used to determine if there was a difference in number of complete responders after immunotherapy.. With IL-2 alone, all patients progressed. After ipilimumab alone, three patients had a complete response and nine had progressive disease. Six additional patients received IL-2 first then ipilimumab. All six progressed on IL-2 but three went on to have a complete response to ipilimumab while three progressed. The use of ipilimumab at any time in patients who progressed after RC was associated with higher rate of complete response compared to use of IL-2 alone (33 vs. 0 %; p = 0.021).. Patients with progression after regional therapy for melanoma may benefit from immunologic therapy. In this group of patients, immune checkpoint blockade with ipilimumab has a higher complete response rate than T cell stimulation with IL-2, with no complete responders in the IL-2 only group. Furthermore, the complete response rate for ipilimumab in our cohort is higher than reported response rates in the literature for ipilimumab alone, suggesting that the effects of immunotherapy may be bolstered by previous regional treatment.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Disease Progression; Extremities; Female; Follow-Up Studies; Humans; Immunotherapy; Interleukin-2; Ipilimumab; Male; Melanoma; Melphalan; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Prognosis; Prospective Studies; Survival Rate

To improve isolated hepatic perfusion (IHP), we performed a phase I dose-escalation study to determine the optimal oxaliplatin dose in combination with a fixed melphalan dose.. Between June 2007 and July 2008, 11 patients, comprising of 8 colorectal cancer and 3 uveal melanoma patients and all with isolated liver metastases, were treated with a one hour IHP with escalating doses of oxaliplatin combined with 100 mg melphalan. Samples of blood and perfusate were taken during IHP treatment for pharmacokinetic analysis of both drugs and patients were monitored for toxicity, response and survival.. Dose limiting sinusoidal obstruction syndrome (SOS) occurred at 150 mg oxaliplatin. The areas under the concentration-time curves (AUC) of oxaliplatin at the maximal tolerated dose (MTD) of 100 mg oxaliplatin ranged from 11.9 mg/L h to 16.5 mg/L h. All 4 patients treated at the MTD showed progressive disease 3 months after IHP.. In view of similar and even higher doses of oxaliplatin applied in both systemic treatment and hepatic artery infusion (HAI), applying this dose in IHP is not expected to improve treatment results in patients with isolated hepatic metastases.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Cohort Studies; Colorectal Neoplasms; Female; Humans; Liver Neoplasms; Male; Maximum Tolerated Dose; Melanoma; Melphalan; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Treatment Outcome; Uveal Neoplasms

Isolated limb perfusion (ILP) is a treatment option most commonly used in the treatment of melanoma in-transit metastases of the extremities. The principle idea is to surgically isolate a region of the body and then deliver a high concentration of a chemotherapeutic agent together with hyperthermia. There have been three randomised trials exploring whether adjuvant ILP to patients with recurrent or high-risk primary melanomas increases survival; one of these trials has now been updated with a 25-year follow-up.. The original study randomised 69 patients (between 1981 and 1989) with their first satellite or in-transit recurrence to either wide excision (WE group, n = 36 patients) or to WE and adjuvant ILP (WE + ILP group, n = 33 patients). Follow-up data 25 years later concerning survival and cause of death was retrieved from the Swedish National Cause of Death Register.. In the WE + ILP group there were 20 deaths (61%) due to melanoma compared with 26 deaths (72%) in the WE group (p = 0.31). Median melanoma-specific survival was 95 months for WE + ILP compared to 38 months for the WE group, an almost 5 year benefit without statistical significance (p = 0.24).. There is no evidence that adjuvant ILP prolongs survival in patients with high-risk or recurrent melanoma; however, the existing randomised trials are largely underpowered to detect such a difference. New studies are exploring systemic immunological effects of ILP, and a combination of regional therapy and immunotherapy may serve as a rationale for new trials using ILP in the future.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Skin Neoplasms

The isolated limb infusion (ILI) technique is a simpler and less invasive alternative to isolated limb perfusion, which allows regional administration of high-dose chemotherapy to patients with advanced melanoma and other malignancies restricted to a limb.. Patients from two institutions, treated by ILI between 1998 and 2009 for extensive disease restricted to a limb, were included. The cohort included 31 patients with melanoma who presented with in-transit metastases or an extensive primary lesion, one patient with squamous cell carcinoma and another with epithelioid sarcoma not suitable for local surgical treatment.. A complete response was achieved in 26.3% of patients and a partial response in 52.6%. Toxicity was assessed according to the Wieberdink limb toxicity scale. Grade II toxicity was noted in 39.5% of patients, grade III in 50% and grade IV in 10.5%. Toxicity was correlated with the results of a number of clinical and laboratory tests. The toxicity of melphalan and actinomycin D was dose-dependent. For melphalan, the relationship between toxicity and mean dose was as follows: grade II--34.7 mg; grades III and IV--47.5 mg (P = 0.012). The relationship between toxicity and maximum serum creatine phosphokinase (CPK) was as follows: grade II--431.5 U/L; grades III and IV--3228 U/L (P = 0.010).. Toxicity after ILI is dose-dependent and serum CPK correlates with toxicity.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dactinomycin; Dose-Response Relationship, Drug; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Treatment Outcome

L19-TNF is a tumor-targeting immunocytokine composed of the human L19 antibody binding to extra domain B (ED-B) of fibronectin of newly formed blood vessels, and of human TNF. This exploratory trial evaluates safety and clinical activity of L19-TNF plus melphalan-containing isolated limb perfusion (ILP) in extremity melanoma patients.. Seven and 10 patients received 325 µg and 650 µg of L19-TNF, respectively, during the ILP. Patients were studied for safety, tolerability, and clinical activity of this experimental L19-TNF ILP procedure.. Non-hematologic toxicity of L19-TNF ILP was very low, but severe myelosuppression was seen in four patients. Although L19-TNF was administered at a TNF-equivalent dose of only 3.13 and 6.25% of the approved TNF (Beromun®) dose of 4 mg, L19-TNF ILP induced objective responses in 86 and 89% of patients, respectively, including a complete response (CR) in 5/10 patients treated with L19-TNF ILP at 650 µg that was durable at 12 months in four patients. No CR was seen at 325 µg of L19-TNF.. ILP with L19-TNF had a favorable safety and a promising activity profile at a dose of 650 µg of L19-TNF, supporting the exploration of higher L19-TNF doses and a Phase II trial comparing L19-TNF ILP with standard melphalan-containing ILP.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Recombinant Fusion Proteins; Skin Neoplasms; Treatment Outcome

To assess the efficacy of isolated pelvic perfusion (IPP) with tumor necrosis factor (TNF)-α and melphalan in patients with locally advanced cancers in the pelvic and groin area requiring mutilating surgery.. A total of 27 patients were enrolled (carcinoma, n = 17; sarcoma/melanoma, n = 4; and endocrine tumor, n = 6). They were candidates for exarticulation (n = 3) or exenteration (n = 11) or were judged unresectable (n = 13). In installing IPP, tourniquets were positioned around both thighs, and an inflated pressure suit was placed at a subthoracic position. Tumor necrosis factor-α (300 μg) was injected in the perfusate, followed 5 minutes later by melphalan at 1.5 mg/kg. After 30 minutes, the remaining drugs were washed out. Leakage was assessed with technetium Tc 99m radiolabeled human serum albumin, and a pharmacokinetic study was performed. Efficacy was based on the complete response rate observed on magnetic resonance imaging.. Pelvic/systemic ratios of melphalan/TNF/technetium Tc 99m were 14.2/7/3.6. Responses on magnetic resonance imaging were as follows: 30% complete, 30% partial, 19% no change, and 15% progression. Two patients were not evaluable because they did not receive the treatment. Pre-IPP/post-IPP median percentage of necrosis on magnetic resonance imaging was 10%/70%. Median follow-up was 43 months. Median overall survival was 17 months. Twelve-month survival rate, disease-free survival, and local and metastatic recurrence rates were 67%, 30%, 57%, and 26%, respectively.. Isolated pelvic perfusion with TNF-α compares favorably with historical data, as it was observed in limb perfusion and could provide a chance to translate its successful combination with chemotherapy into treatment of locally advanced pelvic cancers.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Endocrine Gland Neoplasms; Female; Humans; Hyperthermia, Induced; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Melanoma; Melphalan; Middle Aged; Pelvic Neoplasms; Recurrence; Sarcoma; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha

Isolated limb infusion with melphalan (ILI-M) corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximate 29 % complete response (CR) rate. Sorafenib, a multi-kinase inhibitor, has been shown to augment tumor response to chemotherapy in preclinical studies.. A multi-institutional, dose-escalation, phase I study was performed to evaluate the safety and antitumor activity of sorafenib in combination with ILI-M. Patients with AJCC stage IIIB/IIIC/IV melanoma were treated with sorafenib starting at 400 mg daily for 7 days before and 7 days after ILI-M corrected for IBW. Toxicity, drug pharmacokinetics, and tumor protein expression changes were measured and correlated with clinical response at 3 months.. A total of 20 patients were enrolled at two institutions. The maximum tolerated dose (MTD) of sorafenib in combination with ILI-M was 400 mg. Four dose-limiting toxicities occurred, including soft tissue ulcerations and compartment syndrome. There were three CRs (15 %) and four partial responses (20 %). Of patients with the Braf mutation, 83 % (n = 6) progressed compared with only 33 % without (n = 12). Short-term sorafenib treatment did alter protein expression as measured with reverse phase protein array (RPPA) analysis, but did not inhibit protein expression in the MAP kinase pathway. Sorafenib did not alter melphalan pharmacokinetics.. This trial defined the MTD of systemically administered sorafenib in combination with ILI-M. Although some responses were seen, the addition of sorafenib to ILI-M did not appear to augment the effects of melphalan but did increase regional toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Extremities; Female; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Melanoma; Melphalan; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Prognosis; Protein Array Analysis; Skin Neoplasms; Sorafenib; Tissue Distribution

Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity.. Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.. In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one).. To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Cadherins; Chemotherapy, Cancer, Regional Perfusion; Drug Therapy, Combination; Extremities; Female; Gene Expression Profiling; Humans; Immunoenzyme Techniques; Male; Melanoma; Melphalan; Middle Aged; Oligonucleotide Array Sequence Analysis; Oligopeptides; Peptides, Cyclic; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Skin Neoplasms; Survival Rate; Treatment Outcome

Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) are used to manage advanced extremity melanoma, but no consensus exists as to which treatment is preferable and how to monitor patients post-treatment.. Using a prospectively maintained database, we reviewed our experience with melphalan-based HILP (which included 62 first-time and 10 second-time) and ILI (which included 126 first-time and 18 second-time) procedures performed in 188 patients. PET/CT was obtained 3 months postregional treatment for 1 year and then every 6 months thereafter.. Overall response rate (complete response [CR] + partial response) of HILP was 81% (80% CI, 73-87%), and overall response rate from ILI was 43% (80% CI, 37-49%) for first-time procedures only. HILP had a CR rate of 55% with a median duration of 32 months, and ILI had a CR rate of 30% with median duration of 24 months. Patients who experienced a regional recurrence after initial regional treatment were more likely to achieve a CR after repeat HILP (50%, n = 10) compared with repeat ILI (28%, n = 18). Although the spectrum of toxicity was similar for ILI and HILP, the likelihood of rare catastrophic complication of limb loss was greater with HILP (2 of 62) than ILI (0 of 122). PET/CT was effective for surveillance after regional therapy to identify regional nodal and pulmonary disease that was not clinically evident, but often amenable to surgical resection (25 of 49; 51% of cases). In contrast, PET/CT was not effective at predicting complete response to treatment with an accuracy of only 50%.. In the largest single-institution regional therapy series reported to date, we found that although ILI is effective and well-tolerated, HILP is a more definitive way to control advanced disease.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Hyperthermia, Induced; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Positron-Emission Tomography; Skin Neoplasms; Survival Rate; Tomography, X-Ray Computed

Isolated limb infusion (ILI) with cytotoxic drugs has been used since 1992 to treat advanced melanoma confined to a limb. Over this time the technique has undergone progressive modification. In this study we evaluated our experience with ILI by analyzing outcome and toxicity from an "early" and a "late" treatment period.. We compared the results from our institution for 94 patients treated by ILI in the early period (1992-1999) with the results for 91 patients treated in the late period (2000-2007). All patients had advanced limb melanoma and received a combination of melphalan and actinomycin D.. The patient characteristics of the early and late groups were similar, but there was greater tumor load in the late group, who had a significantly greater number of lesions (median 4 vs. 5; p = 0.02) and deeper tumor infiltration (p = 0.03). Drug circulation times were longer in the late group: 22 vs. 31 min (p < 0.0001). In the late group, higher initial and final limb temperatures were achieved. Overall response rates were 85% in both groups. The late treatment group showed a trend towards less toxicity (p = 0.06).. Response rates and survival following ILI for advanced melanoma in our late treatment period were similar to those of our early treatment period, despite the significantly greater tumor load of the patients treated in the late period. This could be attributed to increased experience and protocol modifications, which allowed longer drug exposure times and higher limb temperatures to be achieved without increased toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Survival Rate; Time Factors; Treatment Outcome

Isolated limb infusion (ILI) is a minimally invasive technique of delivering regional chemotherapy in patients with advanced melanoma or soft-tissue sarcoma of the limb. We report the final results of the first clinical trial of ILI in North America (NCT00004250). Eligible patients had recurrent melanoma or unresectable soft-tissue sarcoma of the limb. Angiographic catheters were positioned just above the knee or elbow of the extremity. General anesthesia was performed, a proximal tourniquet inflated, and a normothermic, low flow, hypoxic infusion of melphalan and dactinomycin circulated through the involved limb for 20 min. Tumor response and morbidity were assessed using standard criteria. Thirty-seven patients were accrued to the trial and 44 ILIs were performed (eight patients had two ILIs); one patient was not treated. Of the 32 evaluable patients, 17 (53%) had a significant response at 3 months: 25% of patients had a complete response and 28% of patients had a partial response. The median duration of complete response was 1 year (5-32 months). Morbidity was acceptable, with peak erythema, edema, and pain experienced at 2 weeks and considered 'moderate' in most patients. No patients developed compartment syndrome or required amputation because of ILI. ILI is well tolerated. More than half of the treated patients experienced a complete or partial response.

Topics: Adult; Aged; Aged, 80 and over; Anesthesia, General; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brachial Artery; Catheterization, Peripheral; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Infusions, Intra-Arterial; Male; Melanoma; Melphalan; Middle Aged; Popliteal Artery; Radiography, Interventional; Remission Induction; Sarcoma

Isolated limb infusion with melphalan is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximately 30% complete response (CR) rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes and when given systemically in a preclinical model of regional melphalan therapy demonstrated synergistic antitumor activity. A phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with in-transit extremity melanoma was performed.. Dose escalation cohorts of 3 patients each received 1000, 2000, and 4000 mg (10 patients) of ADH-1 administered intravenously on Days 1 and 8 with standard dose melphalan via isolated limb infusion on Day 1. N-cadherin immunohistochemistry staining and quantitative polymerase chain reaction analysis were performed on pretreatment tumor. Response was defined at 3 months using modified Response Evaluation Criteria in Solid Tumors.. Sixteen patients have been treated with no observed dose-limiting toxicities. Common treatment-related grade 1 or 2 toxicities included skin/dermatologic (n=14) and pain (n=12). Grade 3 toxicities included shortness of breath (n=1), hypertension (n=1), serologic toxicities (n=4), and 1 grade 4 creatine phosphokinase elevation. In-field responses included 8 CRs, 2 partial responses, 1 stable disease, and 5 progressive diseases. Pharmacokinetic analysis demonstrated increasing ADH-1 concentrations at each dose and minimal variability in melphalan drug levels.. Systemic ADH-1 at a dose of 4000 mg on Days 1 and 8 in combination with melphalan via isolated limb infusion is a well-tolerated, novel targeted therapy approach to regionally advanced melanoma. The number of CRs exceeded expectations, suggesting that targeting N-cadherin may be a new strategy for overcoming melanoma chemoresistance.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Drug Administration Schedule; Extremities; Female; Humans; Male; Melanoma; Melphalan; Oligopeptides; Peptides, Cyclic; Skin Neoplasms; Survival Analysis

Isolated limb infusion (ILI) is a recently described minimally invasive technique developed in Australia for delivering regional chemotherapy. This study examined the efficacy and toxicity of ILI, compared to hyperthermic isolated limb perfusion (HILP), in treating extremity in-transit melanoma.. Variables from a prospective single institution database of 120 regionally treated melanoma patients (1995-2007) were compared using chi-square analysis. This included 61 consecutive ILI treatments in 58 patients and 59 HILP treatments in 54 patients. Response was defined at 3 months using the response evaluation criteria in solid tumors (RECIST). ILI was performed using melphalan (LPAM) and dactinomycin for 30 min after limb temperature reached 37 degrees C. HILP was performed using LPAM for 60 min after limb temperature reached 38.5 degrees C.. For ILI (n = 61), the complete response (CR) rate was 30%, the partial response (PR) rate was 14%, and there was no response (NR) in 56% of patients. The median duration of CR was 12 months and 18% of patients experienced (grade >or=3) toxicity. HILP (n = 59) was associated with a better (P < 0.001) response rate (CR 57%, PR 31%, and NR 12%) however, more patients (32%) experienced grade >or=3 toxicity (P = 0.037). The dose of LPAM was corrected for ideal body weight (IBW) in 40 out of 61 ILI procedures, and 13 of 59 HILP procedures. This dosing modification was associated with decreased toxicity (P = 0.024) without diminishing response.. ILI was found to be a well-tolerated alternative to HILP. While ILI does not appear to be as effective as HILP, it does seem to be associated with less morbidity.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Prospective Studies; Reproducibility of Results; Skin Neoplasms; Treatment Outcome

Isolated limb infusion (ILI) is a minimally invasive technique of delivering regional chemotherapy in patients with advanced melanoma or soft tissue sarcoma of the limb. Reports from Australia of efficacy similar to that of isolated limb perfusion prompted us to conduct a phase II trial to evaluate the efficacy and safety of ILI.. Eligible patients had American Joint Committee on Cancer stage IIIB or IIIC melanoma or unresectable soft tissue sarcoma of the limb. Angiographic catheters were positioned just above the knee or elbow of the extremity. General anesthesia was performed, a proximal tourniquet was inflated, and a normothermic, low-flow, hypoxic infusion of melphalan and dactinomycin was circulated through the involved limb for 20 minutes. The tumor response was assessed by using standard criteria at 3 months. Morbidity was determined in the hospital and at 2, 6, and 12 weeks.. Twenty-five patients were accrued to the trial, and 32 ILIs were performed (8 patients had 2 ILIs); 1 patient was not treated. Of the 22 assessable patients, 11 (50%) had a significant response at 3 months: 23% of patients had a complete response, and 27% of patients had a partial response. The median duration of complete response was 1 year (range, 6-32 months). Morbidity was acceptable. Peak morbidity occurred at 2 weeks and was considered moderate in most patients. Limb edema and erythema were common. No patient developed compartment syndrome or required amputation.. ILI is well tolerated. Half of the patients experienced a complete or partial response.

Topics: Adult; Aged; Aged, 80 and over; Angiography; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Sarcoma; Skin Neoplasms; Treatment Outcome

To determine in a randomized prospective multi-institutional trial whether the addition of tumor necrosis factor alpha (TNF-alpha) to a melphalan-based hyperthermic isolated limb perfusion (HILP) treatment would improve the complete response rate for locally advanced extremity melanoma.. Patients with locally advanced extremity melanoma were randomly assigned to receive melphalan or melphalan plus TNF-alpha during standard HILP. Patient randomization was stratified according to disease/treatment status and regional nodal disease status.. The intervention was completed in 124 patients of the 133 enrolled. Grade 4 adverse events were observed in 14 (12%) of 129 patients, with three (4%) of 64 in the melphalan-alone arm and 11 (16%) of 65 in the melphalan-plus-TNF-alpha arm (P = .0436). There were two toxicity-related lower extremity amputations in the melphalan-plus-TNF-alpha arm, and one disease progression-related upper extremity amputation in the melphalan-alone arm. There was no treatment-related mortality in either arm of the study. One hundred sixteen patients were assessable at 3 months postoperatively. Sixty-four percent of patients (36 of 58) in the melphalan-alone arm and 69% of patients (40 of 58) in the melphalan-plus-TNF-alpha arm showed a response to treatment at 3 months, with a complete response rate of 25% (14 of 58 patients) in the melphalan-alone arm and 26% (15 of 58 patients) in the melphalan-plus-TNF-alpha arm (P = .435 and P = .890, respectively).. In locally advanced extremity melanoma treated with HILP, the addition of TNF-alpha to melphalan did not demonstrate a significant enhancement of short-term response rates over melphalan alone by the 3-month follow-up, and TNF-alpha plus melphalan was associated with a higher complication rate.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Patient Selection; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha; United States

Melphalan (L-PAM) hyperthermic isolated limb perfusion (HILP) is currently considered the standard treatment for patients with in-transit metastases from cutaneous melanoma. We here report on the results of L-PAM and low-dose tumor necrosis factor (TNF)alpha HILP in patients with bulky disease.. Twenty patients underwent TNFalpha (1 mg) and L-PAM (10 mg/L) HILP. Perfusion was performed for 90 minutes, and systemic leakage was strictly monitored. Locoregional toxicity was evaluated according to Wieberdink's criteria, whereas tumor response was evaluated with physical examination and ultrasound scan with or without fine-needle aspiration of any suspected recurrence.. In all cases, systemic leakage was <5%. No postoperative deaths occurred, and locoregional toxicity was mild (grade 1 or 2) in 95% of patients. A complete tumor response was obtained in 14 patients (70%), and partial responses were obtained in 5 patients (25%). After a median follow-up of 18 months, six patients are alive and disease free, seven are alive with local or distant recurrence or both, and seven have died of disease.. Low-dose TNFalpha HILP can achieve tumor responses comparable with those reported with higher doses of cytokine. Moreover, this drug regimen is associated with acceptable local toxicity, carries a smaller risk of systemic toxicity, and incurs lower costs.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Female; Humans; Hyperthermia, Induced; Italy; Leg; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Survival Rate; Tumor Necrosis Factor-alpha

Uveal melanoma is the most common primary intraocular tumour in adults. After treatment of the primary tumour, up to 50% of patients will ultimately develop metastases. Treatment options for metastases are limited. When uveal melanoma metastases are confined to the liver, isolated hepatic perfusion (IHP) could be a treatment option. Herein, we report the results of a small group of patients with uveal melanoma metastases of the liver treated with IHP. Eight patients with uveal melanoma metastases confined to the liver underwent IHP with high-dose melphalan (200 mg) for 1 h. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria and tumour response was assessed according to World Health Organization criteria. The tumour response rate (complete or partial remission) was 50%. The median time to progression was 6.7 months (range, 1.7-16.9 months). The overall median survival was 9.9 months (range, 4.7-34.6 months), with a 1 year survival of 50% and a 2 year survival of 37.5%. Three patients experienced grade 3-4 hepatotoxicity which was transient within 3 months. Although only a small group of patients has been treated and evaluated so far, IHP is a treatment option for uveal melanoma metastases confined to the liver which can result in tumour responses and may lead to survival benefits in a selective group of patients.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Choroid Neoplasms; Disease Progression; Female; Humans; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Survival Rate; Time Factors; Treatment Outcome; Uveal Neoplasms

Hypoxic pelvic and limb perfusion by means of a balloon occlusion technique was evaluated in patients with recurrent melanoma of the lower limbs who were non-responders to isolated hyperthermic limb perfusion or who were not eligible for this procedure. A pilot study was performed in 17 patients, who underwent hypoxic pelvic and limb perfusion with 50 mg/m(2) of melphalan or 50 mg/m(2) of melphalan and 25 mg/m(2) of mitomycin C. Each procedure was followed by haemofiltration. A leakage monitoring study was performed in five of the 17 patients. The response rate and time to disease progression were the primary endpoints, with overall survival as the secondary endpoint. During the procedures there were no technical, haemodynamic or vascular complications, and no deaths occurred during surgery or in the postoperative period. Significant leakage (median 40%) was measured in the five patients studied. No severe systemic or regional toxicity was observed. After one course of treatment, the objective response rate was 47% (95% confidence interval 22.5-71.5%), the median time to disease progression was 10 months (range 2-40 months), and the 3 year overall survival was 20%. Hypoxic pelvic and limb perfusion seems to be a safe and effective treatment for patients with unresectable recurrent limb melanoma who are not eligible for isolated hyperthermic limb perfusion. Due to the non-homogeneity of the study, with some patients receiving a combination of melphalan and mitomycin C and others receiving only melphalan, it is not possible to make definite conclusions with regard to efficacy. Further studies are necessary to establish whether the response rates can be improved by using different drug regimens.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Extremities; Female; Humans; Hypoxia; Male; Maximum Tolerated Dose; Melanoma; Melphalan; Middle Aged; Mitomycin; Neoplasm Recurrence, Local; Pilot Projects; Skin Neoplasms; Survival Rate; Time Factors

Isolated limb perfusion (ILP) with recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and melphalan harbors the risk of septic shock-like syndrome. Pentoxifyllin (PTX) produced a beneficial effect on cytokine response and survival in animal experiments of septic shock, and we were interested to explore its effect during TNF-ILP in humans.. Eighteen consecutive patients underwent TNF-ILP and received PTX (30 mg/kg/day), whereas another 13 consecutive patients did not. PTX was given systemically after the limb extracorporeal circulation was started. Cardiac index, systemic vascular resistance (SVR), and pulmonary vascular resistance were recorded via a Swan-Ganz catheter. Blood levels of TNF-alpha, interleukin-6, procalcitonin, and lipopolysaccharide-binding protein were determined before, during, and after ILP.. After reperfusion, systemic levels of TNF-alpha were significantly less increased in the PTX group (peak, 2.8 vs. 1.3 ng/mL; P <.05), as were interleukin-6 values (peak, 68 vs. 22 pg/mL; P <.02) and lipopolysaccharide-binding protein plasma levels (peak, 215 vs. 105 micro g/mL; P <.03). Differences in cardiac index, SVR, and mean arterial blood pressure were not significantly different. Norepinephrine or dobutamine to maintain SVR was less required in the PTX group.. PTX attenuates systemic cytokine production and influences components of the systemic inflammatory response after TNF-ILP. PTX may play a beneficial role in the management of septic shock-like syndrome, particularly in patients with leakage from the ILP circuit.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Enzyme Inhibitors; Extremities; Female; Humans; Inflammation; Male; Melanoma; Melphalan; Middle Aged; Pentoxifylline; Sarcoma; Shock, Septic; Skin Neoplasms; Soft Tissue Neoplasms; Syndrome; Tumor Necrosis Factor-alpha

The aim of this study was to assess the results of an isolated limb perfusion (ILP) schedule with high dose hyperthermia (42-43 degrees C) and melphalan, applied sequentially in patients with advanced melanoma of the limbs. Seventeen patients with extensive recurrent or bulky melanoma of a limb were treated with hyperthermic femoral ILP (42-43 degrees C) without drugs followed by normothermic (37-38 degrees C) ILP with melphalan. Eleven patients (65%) had a complete response. Three patients (27%) had limb recurrences after 5, 6 and 18 months, respectively. The 5 year limb recurrence-free interval for patients with a complete response was 63%. Limb toxicity was mild; pressure-related blistering and transient sensory disturbances occurred after the hyperthermic ILP, and 88% of the patients had a grade II reaction (mild erythema and oedema) after the second ILP. This sequential ILP schedule resulted in a high complete response rate and a low limb-recurrence rate in patients with extensive, recurrent melanoma of the limbs at the cost of only mild toxicity. This regimen could be an alternative to ILP with tumour necrosis factor-alpha and melphalan.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Disease-Free Survival; Feasibility Studies; Female; Humans; Hyperthermia, Induced; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Treatment Outcome

Liver metastases are the sole or life-limiting component of disease in the majority of patients with ocular melanoma who recur. Because median survival after diagnosis of liver metastases is short and no satisfactory treatment options exist, we have conducted clinical trials evaluating isolated hepatic perfusion (IHP) for patients afflicted with this condition.. Twenty-nine patients (male: 14, female: 15; mean age, 49 years) with unresectable liver metastases from ocular melanoma were treated with a 60-min hyperthermic IHP using 1.5 mg/kg of melphalan (mean total dose 105 mg). Via laparotomy, perfusion inflow was established with a cannula in the gastroduodenal artery and outflow via a cannula positioned in an isolated segment of the retrohepatic inferior vena cava. Portal and infra-renal inferior vena cava blood flow was shunted externally to the axillary vein using a veno-veno bypass circuit. Patients were assessed for toxicity, radiographic response, and survival.. There was no treatment related mortality and transient grade 3/4 hepatic toxicity was observed in 19 patients (65%). Mean length of operation and hospital stay was 8.3 h and 10 days, respectively. There were 3 (10%) complete responses (duration: 12, 14+, 15 months) and 15 partial responses (52%; mean duration: 10 months). The initial site of disease progression included liver in 17 of 25 patients (68%) who recurred. At a median follow-up of 30.7 months the median actuarial progression-free and overall survivals were 8 and 12.1 months, respectively.. IHP with melphalan alone results in significant regression of established liver metastases for patients with ocular melanoma. However, after IHP, disease progression is most commonly observed in the liver, and survival after disease progression is short. On the basis of a pattern of tumor progression predominantly in liver, continued clinical evaluation of hepatic directed therapy in this patient population is justified.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Disease Progression; Disease-Free Survival; Eye Neoplasms; Female; Humans; Hyperthermia, Induced; Liver; Liver Neoplasms; Magnetic Resonance Imaging; Male; Melanoma; Melphalan; Middle Aged; Perfusion; Time Factors; Treatment Outcome

Hyperthermic antiblastic perfusion (HAP) has been proven to be an effective treatment of loco-regional spreading limb melanoma. The mean complete response (CR) rate obtained is 54%, with an objective responses (OR) rate ranging between 70% and 100%. Recently, Tumor Necrosis Factor (TNFalpha) has been employed at high dosages (3-4 mg) in association to Melphalan and hyperthermia. This trimodality combination increased the percentage of CR (70%-90%), but systemic toxicity was also reported due to high TNF doses. A phase I - II study was undertaken in order to assess the MTD of TNFalpha in association to true hyperthermia (41.5 degrees C) and Melphalan. Twenty patients affected with stages IIIA (9 patients), IIIAB (10 patients), and IV (1 patient) were enrolled in this study. The trimodality treatment did not increase the local and systemic toxicity. CR was observed in 70% of the patients, PR in 20% with on OR rate of 90%. These figures are overlapping those obtained with high TNF dosages. No correlation was observed between tumor responses and TNF doses. Taking into account that 70% of our patients have been treated with TNF dosages between 0.5 mg on 1.6 mg, we conclude that 1 mg is the best dosage to be applied during HAP. Patients with bulky tumor are the best candidate to TNF perfusion, because no differences have been observed in terms of CR in patients with low tumor burden treated with TNF-Melphalan-hyperthermia or Melphalan-hyperthermia.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dose-Response Relationship, Drug; Extremities; Female; Humans; Hyperthermia, Induced; Male; Maximum Tolerated Dose; Melanoma; Melphalan; Middle Aged; Survival Analysis; Tumor Necrosis Factor-alpha

Isolated limb perfusion (ILP) is currently considered the standard treatment for melanoma patients with extensive in-transit disease, and L-PAM, combined or not with TNF, represents the most active drug. We here report on our clinical experience with TNF-based limb perfusion. Thirty-seven stage III patients underwent TNF-based limb perfusion, 22 with bulky disease, 15 with recurrences after perfusion with L-PAM. Ten patients were enrolled in a phase I-II study and treated with escalating doses of TNF (0.5-3 mg). The impact of disease burden, temperature, perfusion duration was assessed on tumor response. No postoperative death was observed. No significant systemic toxicity was recorded. Locoregional toxicity was G5 in one patient, G3 in 2, G2 in 9 and G1 in 25. Twenty-four (66%) patients had complete response, 11 (31%) partial and 1 (3%) no change. After a median follow-up of 20 months 14 (38%) patients are NED, 10 (27%) are AWD and 13 (35%) DOD. No significant statistical difference for tumor response were seen for disease burden, ILP temperatures and duration. Our results showed that it is possible to modify the perfusion schedule, without compromising the response rate but with lower cost and toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Skin Neoplasms; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

The treatment of patients with advanced or recurrent pelvic melanoma, which are often associated with lesions in the lower limbs, is still unsatisfactory and controversial. A simplified hypoxic pelvic and limb perfusion has been recently recommended to provide therapeutic options for palliation and possibly cure.. A nonrandomized and noncontrolled phase II experimental study was performed in 11 patients with symptomatic unresectable recurrent melanoma of the pelvis and limb. Patients were submitted to hypoxic pelvic and limb perfusion with 25 mg/m(2) of melphalan, 50 mg/m(2) of cisplatin, 300 mg/m(2) of dacarbazine, and 75 mg/m(2) of epirubicin by means of a simplified balloon occlusion technique. Response rate and time to disease progression were the primary endpoints; overall survival was the secondary endpoint.. During the procedures there were no technical, hemodynamic, or vascular complications, and no deaths occurred during surgery or in the postoperative period. Response rate was 82% (95% confidence interval, 58% to 100%). Median time to disease progression was 12 months (range 9 to 30 months). Three-year overall survival was 34%.. Hypoxic pelvic and limb perfusion is a safe and good palliative treatment for patients with unresectable recurrent melanoma. Further studies are necessary to to confirm these data and to establish if refinements can be made with acceptable toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Dacarbazine; Disease Progression; Disease-Free Survival; Epirubicin; Female; Hemodynamics; Humans; Hypoxia; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Palliative Care; Pelvis; Skin Neoplasms; Treatment Outcome

This study sought to use a microdialysis technique to relate clinical and biochemical responses to the time course of melphalan concentrations in the subcutaneous interstitial space and in tumour tissue (melanoma, malignant fibrous histiocytoma, Merkel cell tumour and osteosarcoma) in patients undergoing regional chemotherapy by Isolated Limb Infusion (ILI). 19 patients undergoing ILI for treatment of various limb malignancies were monitored for intra-operative melphalan concentrations in plasma and, using microdialysis, in subcutaneous and tumour tissues. Peak and mean concentrations of melphalan were significantly higher in plasma than in subcutaneous or tumour microdialysate. There was no significant difference between drug peak and mean concentrations in interstitial and tumour tissue, indicating that there was no preferential uptake of melphalan into the tumours. The time course of melphalan in the microdialysate could be described by a pharmacokinetic model which assumed melphalan distributed from the plasma into the interstitial space. The model also accounted for the vascular dispersion of melphalan in the limb. Tumour response in the whole group to treatment was partial response: 53.8% (n = 7); complete response: 33.3% (n = 5); no response: 6.7% (n = 1). There was a significant association between tumour response and melphalan concentrations measured over time in subcutaneous microdialysate (P< 0.01). No significant relationship existed between the severity of toxic reactions in the limb or peak plasma creatine phosphokinase levels and peak melphalan microdialysate or plasma concentrations. It is concluded that microdialysis is a technique well suited for measuring concentrations of cytotoxic drug during ILI. The possibility of predicting actual concentrations of cytotoxic drug in the limb during ILI using our model opens an opportunity for improved drug dose calculation. The combination of predicting tissue concentrations and monitoring in microdialysate of subcutaneous tissue could help optimise ILI with regard to post-operative limb morbidity and tumour response.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Extremities; Histiocytoma, Benign Fibrous; Humans; Melanoma; Melphalan; Microdialysis; Middle Aged; Neoplasms; Osteosarcoma; Treatment Outcome

There are no satisfactory treatment options for patients with ocular melanoma metastatic to liver, and after liver metastases are identified, median survival is only between 2 and 7 months. Because liver metastases are the sole or life-limiting component of disease in the vast majority of patients who recur, we reasoned that complete vascular isolation and perfusion of the liver might result in clinically meaningful regression of disease. Between September 1994 and July 1999, 22 patients (13 women and 9 men; mean age, 49 years) with ocular melanoma metastatic to liver were treated with a 60-min hyperthermic isolated hepatic perfusion (IHP) using melphalan alone (1.5-2.5 mg/kg, n = 11) or with tumor necrosis factor (TNF, 1.0 mg, n = 11). Via a laparotomy, IHP inflow was via the hepatic artery alone (n = 17) or hepatic artery and portal vein (n = 5) and outflow from an isolated segment of inferior vena cava. Most patients had advanced tumor burden with a mean percentage of hepatic replacement of 25% (range, 10-75%) and a median number of metastatic nodules of 25 (range, 5 to >50). Complete vascular isolation was confirmed in all patients using a continuous intraoperative leak monitoring technique with 131I radiolabeled albumin. There was one treatment mortality (5%). The overall response rate in 21 patients was 62% including 2 radiographic complete responses (9.5%) and 11 partial responses (52%). The overall median duration of response was 9 months (range, 5-50) and was significantly longer in those treated with TNF than without (14 versus 6 months, respectively; P = 0.04). Overall median survival in 22 patients was 11 months. These data indicate that a single 60-min IHP can result in significant regression of advanced hepatic metastases from ocular melanoma. TNF appears to significantly prolong the duration of response.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Eye Neoplasms; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Portal Vein; Tumor Necrosis Factor-alpha

Cytokines have been implicated in the pathogenesis of the euthyroid sick syndrome. Isolated limb perfusion (ILP) with recombinant human tumor necrosis factor alpha (rTNF) and melphalan in patients with melanoma or sarcoma is accompanied by high systemic TNF levels. We examined the prolonged effects (7 days) of ILP on thyroid hormone metabolism with respect to induction and recovery of the euthyroid sick syndrome in six cancer patients. After ILP, when the limb is reconnected to the systemic circulation, leakage of residual rTNF resulted in systemic peak levels at 10 minutes postperfusion followed by a parallel increase in plasma interleukin-6 (IL-6) and cortisol, with maximum levels at 4 hours (P < .05). A rapid decrease was observed at 5 minutes for plasma triiodothyronine (T3), reverse T3 (rT3), thyroxine (T4), and thyroxine-binding globulin (TBG) (P < .05), whereas free T4 (FT4) and T3-uptake showed a sharp increase, with peak levels at 5 minutes (P < .05). T3, T4, and TBG levels remained low until 24 hours after ILP In contrast, rT3 increased above pretreatment values to maximum levels at 24 hours (P < .05). Plasma thyrotropin (TSH) showed an initial decrease at 4 hours postperfusion (P < .05) but exceeded pretreatment values from day 1 to day 7 (by +94%+/-43% to +155%+/-66%, P < .05), preceding the recovery of T4 and T3 levels. T3 and rT3 returned to initial values at day 4. T4 and TBG levels recovered at day 2. T4 exceeded basal values at days 5 to 7 (P < .05). It is concluded that ILP with rTNF induces a euthyroid sick syndrome either directly or indirectly through other mediators such as IL-6 or cortisol. The recovery from this euthyroid sick syndrome is, at least in part, TSH-dependent, since the prolonged elevation of TSH values preceded and persisted during the normalization of T3 and the elevation of T4 levels. This biphasic pattern of induction of and recovery from the euthyroid sick syndrome may be a general feature of nonthyroidal disease. The euthyroid sick syndrome should be interpreted not only in relation to the presence of nonthyroidal diseases but also in relation to the recovery from these diseases.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Cytokines; Euthyroid Sick Syndromes; Female; Humans; Hydrocortisone; Male; Melanoma; Melphalan; Middle Aged; Perfusion; Recombinant Proteins; Sarcoma; Soft Tissue Neoplasms; Thyroid Hormones; Thyrotropin; Thyroxine-Binding Proteins; Time Factors; Tumor Necrosis Factor-alpha

Despite reports that i.v. melphalan is active in the settings of conditioning regimens utilizing high-dose chemotherapy for autologous bone marrow transplantation and in isolated limb perfusion for the treatment of malignant melanoma, its activity at conventional doses has never been defined in this disease. We conducted a phase II study of conventional-dose i.v. melphalan (30 mg/m2) in 17 patients with metastatic melanoma. All patients were previously untreated with chemotherapy with performance status 0, 1 or 2. Forty-seven cycles were given with a median of two cycles. One patient was not evaluable due to early death. There were no responses in the 16 patients, resulting in a 0% response rate (95% confidence interval = 0-17%). We conclude that conventional-dose melphalan by i.v. administration has no appreciable activity in patients with metastatic malignant melanoma.

Topics: Adrenal Gland Neoplasms; Adult; Aged; Antineoplastic Agents, Alkylating; Brain Neoplasms; Dose-Response Relationship, Drug; Female; Gastrointestinal Neoplasms; Hematologic Diseases; Humans; Liver Neoplasms; Lung Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Soft Tissue Neoplasms; Treatment Outcome

To determine the toxicity and efficacy of isolated hepatic perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan (Alkeran) under mild hyperthermic conditions.. A phase I trial was performed. Eleven patients with unresectable metastatic malignancies in the liver were pre-treated with 3 x 10(6) U leukocyte IFN daily 2 days before the perfusion. The liver was isolated and inflow catheters inserted in the hepatic artery and the portal vein. The hepatic veins were drained via a catheter in the retrohepatic caval vein. The venous blood flow from the lower extremities and the splanchnic circulation was bypassed to the axillar vein. The liver circuit was perfused with oxygenated blood and 30-200 microg TNF-alpha was added. At 39 degrees C in the liver circuit 0.5 mg/kg melphalan was added and the perfusion was continued for 1 h.. Six patients underwent re-operation due to post-operative bleeding. Two patients died of coagulopathy or multiple organ failure within the first post-operative month. Three of six patients with liver metastases from malignant melanoma or leiomyosarcoma showed a partial response while no patients with liver metastases from colorectal cancer showed any response. The mean survival time was 20 months, which is within the same range as seen in previous isolated hepatic perfusion (IHP) studies.. IHP with this drug regimen is a method with a considerable toxicity, though it is hard to distinguish between toxicity from TNF-alpha and that from the perfusion procedure itself. The method was not effective in patients with colorectal liver metastasis, but the results in melanoma and leiomyosarcoma patients warrant further studies.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Extracorporeal Membrane Oxygenation; Female; Hepatic Artery; Humans; Hyperthermia, Induced; Leiomyosarcoma; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Radiography; Tumor Necrosis Factor-alpha

Severe systemic toxicity and hemodynamic changes after isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF-alpha) and melphalan, with or without interferon-gamma, have been reported in several series. We studied whether these side effects could be precluded by preventing leakage from the isolated circuit into the systemic circulation.. Clinical and pharmacokinetic data for 20 consecutive patients with recurrent melanoma of the limbs who were treated by ILP with TNF-alpha (3-4 mg) and melphalan, with or without interferon-gamma, were studied. Leakage rates and TNF-alpha levels were determined during and after ILP and were correlated with systemic toxicity and hemodynamic changes.. Only two patients experienced leaks (2% and 13%) during ILP. For 18 patients without leakage, the mean peak systemic TNF-alpha level was 2.8 ng/ml at 10 minutes after ILP. After leakage, the peak systemic TNF-alpha levels were 31.9 and 88.3 ng/ml at 5 minutes. Toxicity was mild and consisted mainly of fever (n = 17) and nausea/vomiting (n = 19) during the first day after ILP. Some patients developed tachycardia (n = 6), hypotension (n = 3; responding immediately to fluid challenge), a decrease in the WBC count (n = 3; grade I) or thrombocyte count (n = 11; grade I/II, no hemorrhage or therapeutic intervention), or hepatotoxicity [cytolysis (n = 15; 14 grade I/II and 1 grade IV) or hyperbilirubinemia (n = 7; grade I/II, all resolving spontaneously)]. Patients with tachycardia or hepatotoxicity exhibited significantly higher TNF-alpha levels after ILP, compared with other patients.. Systemic toxicity after ILP with TNF-alpha is minimal and does not differ from that after ILP with melphalan alone when leakage is adequately controlled.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hypotension; Interferon-gamma; Leukopenia; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Tachycardia; Thrombocytopenia; Tumor Necrosis Factor-alpha

This open, multicentre, randomized phase II trial was conducted to determine the effect of isolated limb perfusion (ILP) with tumour necrosis factor-alpha (TNFalpha) in combination with melphalan with or without interferon-gamma (IFNgamma) in patients with in-transit metastases of melanoma of the limbs (MD Anderson stage IIIA or IIIAB, AJCC stage III). The 64 patients included were randomized to receive either a two- drug regimen consisting of TNFalpha and melphalan (TM-ILP) or a three-drug regimen consisting of TNFalpha, melphalan and INFgamma (TIM-ILP). Patients randomized to receive IFNgamma were pretreated for 2 days before the ILP with once daily 0.2 mg IFNgamma subcutaneously and also received the same amount of IFNgamma during ILP. A total of 47 complete responses (73%) were reported, 22 (69%) of which occurred in the TM-ILP group and 25 (78%) in the TIM-ILP group; the difference was not significant. The 14 partial responses (22%) were split evenly between the treatment groups. In the TM-ILP group, two cases of stable disease and one case of progressive disease were reported. The overall response rate (complete plus partial responses) was 100% in the TIM-ILP group and 91% in the TM-ILP group, yielding an overall response of 95% for this study. In the historical control data, where 103 patients had received melphalan alone (M-ILP), there were 54 records of complete responses (52%) and 80 of complete or partial responses (78%). The median survival time estimated by the Kaplan-Meier method was 819 days for the TM-ILP group, > 705 days for the TIM-ILP group and 873 days for the combined study population; estimates for time to local progression or recurrence were 327 days, in excess of 498 days and 405 days, respectively. The corresponding figure for the historical controls was 338 days. These data suggest that TNFalpha associated with melphalan may be superior to melphalan alone for ILP.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Extremities; Female; Humans; Interferon-gamma; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Recurrence; Skin Neoplasms; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha

To test the hypothesis that 41.8 degrees C x 60 min whole body hyperthermia (WBH) induces increased serum levels of soluble necrosis factor receptors (sTNF-R).. We tested the serum of cancer patients for changes in sTNF-RI and RII levels, as a function of time, pre and post: (1) WBH alone, (2) WBH and chemotherapy, i.e., melphalan (L-PAM), and (3) L-PAM alone.. For sTNF-RI there was a marked increase (over pre-treatment values, i.e., 86%) in serum levels after WBH alone (n = 3), which peaked 2.5 h post-WBH; L-PAM (iv) only resulted in a dip in sTNF-RI seen 40 min postadministration; the combination (WBH + L-PAM), resulted in both the dip at 40 min and the increase at 2.5 h post-treatment. For sTNF-RII both WBH alone (n = 3) and WBH + L-PAM (n = 2), there was an increase in receptor serum levels of 25% and 30%, respectively, which peaked 5.5 h post-treatment, and remained elevated at 24 h. L-PAM alone resulted in a dip in levels only at 40 min post-treatment. sTNF-RI and RII levels returned to baseline values within 7 days post-treatment.. 41.8 degrees C WBH results in transient increases in TNF-RI and RII. These results may have therapeutic implications for the application of WBH to TNF mediated disease processes.

Topics: Adult; Antineoplastic Agents, Alkylating; Body Temperature; Cohort Studies; Female; Humans; Hyperthermia, Induced; Interleukin-10; Male; Melanoma; Melphalan; Middle Aged; Pancreatic Neoplasms; Receptors, Tumor Necrosis Factor; Rheumatic Diseases; Skin Neoplasms; Solubility; Tumor Necrosis Factor-alpha

The systemic side effects of isolated limb perfusion (ILP) with rhTNF alpha and melphalan are characterised by the induction of a systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), a serum marker of bacterial sepsis, was investigated with respect to its role in SIRS after TNF-ILP. Serum-PCT was analysed in 24 patients (12 male, 12 female), who treated by ILP for regionally metastasized melanoma (n = 8) or locally advanced soft tissue sarcoma (n = 16). Serum samples were analysed pre- and intraoperatively, and at defined intervals after reperfusion of the limb. In addition to PCT, serum IL-6 and IL-8 were analysed in 11 patients. PCT was significantly elevated over baseline after ILP with a maximum between 8 and 36 hours (p < 0.001). Even 96 hours after reperfusion, PCT was still significantly elevated as compared to baseline levels (p = 0.005). There was no correlation to the systemic leakage rate during the perfusion. IL-6 and IL-8 were also significantly increased after ILP (p = 0.001), but the maximum peaks of both cytokines were reached much earlier than for PCT (IL-8 max. at 1 hour and IL-6 max. at 4 hours after reperfusion). Serum procalcitonin is induced as part of the specific SIRS after ILP with rhTNF alpha and melphalan. It may be induced directly by rhTNF alpha or by different cytokines, as serum peaks of IL-6 and IL-8 are reached well before the peak of PCT. Determination of PCT prior to and after ILP with TNF might be useful to assess patients at risk of developing hyperdynamic shock.

Topics: Antineoplastic Combined Chemotherapy Protocols; Calcitonin; Calcitonin Gene-Related Peptide; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Interleukin-6; Interleukin-8; Male; Melanoma; Melphalan; Predictive Value of Tests; Protein Precursors; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

The acute-phase response and anaemia of chronic disease are characterized by hypoferraemia associated with an increased ferritin synthesis, which might be mediated by the activated cytokine cascade.. We examined the prolonged effects of isolated limb perfusion (ILP) with recombinant human tumour necrosis factor alpha (rTNF), recombinant human interferon gamma (rIFN-gamma) and melphalan on interleukin (IL) 6 and acute-phase protein levels, iron status and serum transferrin receptor (sTfR) levels in 12 patients with melanoma or sarcoma. Patients were treated with ILP during 90 min after pretreatment with rIFN-gamma during 2 days.. After ILP, leakage of TNF resulted in systemic peak levels at 3 min followed by an increase in IL-6 with maximum levels at 4h. C-reactive protein (CRP) rose at 4 h to peak levels at day 2, whereas alpha 1-antitrypsin and alpha 1-acid glycoprotein increased to maximum levels at day 3. Albumin and transferrin levels decreased after ILP and recovered after day 2. Serum iron and sTfR levels decreased during pretreatment and after ILP to minimum levels at 8 h and day 1 respectively. This was associated with an increase in serum ferritin levels, which paralleled CRP values.. Our data point to a central role for the cytokine network in the modulation of iron metabolism in the acute-phase response and anaemia of chronic disease. TNF, possibly via induction of IL-6, and IFN-gamma induce hypoferraemia, which may in part result from a decrease in tissue iron release based on a primary stimulation of ferritin synthesis. The fall in sTfR levels may reflect an impaired erythroid growth and/or TfR expression mediated by TNF and IFN-gamma.

Topics: Acute-Phase Proteins; Adult; Aged; alpha 1-Antitrypsin; Anemia; C-Reactive Protein; Chemotherapy, Cancer, Regional Perfusion; Female; Ferritins; Humans; Interferon-gamma; Interleukin-6; Iron; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Orosomucoid; Receptors, Transferrin; Recombinant Proteins; Sarcoma; Serum Albumin; Time Factors; Transferrin; Tumor Necrosis Factor-alpha

Patients with primary cutaneous melanoma > or = 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival.. A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia. Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness > or = 3 mm.. Median follow-up duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND). The impact of ILP was clearly on the occurrence-as first site of progression - of in-transit metastases (ITM), which were reduced from 6.6% to 3.3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%. There was no benefit from ILP in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP.. Prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Disease Progression; Extremities; Female; Humans; Hypothermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Risk Factors; Skin Neoplasms

A randomized controlled trial of prophylactic isolated hyperthermic limb perfusion (IHLP) using melphalan at 2 mg/kg body weight has been performed on a total of 30 patients with primary melanoma of the lower limb > or = 1.7 mm thick. Excision (control, n = 14) was compared to excision plus IHLP (n = 16). The two groups were well matched for sex, tumour thickness and duration of follow-up (control group median: 63 months (range: 16-108), perfusion group median: 80 months (range: 37-113)). Recurrent disease developed in nine of the control group, seven of whom have died. In the perfusion group only two patients have developed recurrent disease, both of whom have died (recurrence: P < 0.004, mortality: P < 0.03, using Fishers' exact probability test). Inguino-femoral nodal recurrence occurred in five of nine control patients, but in only one patient in the perfusion group. These data support the use of adjuvant IHLP in the management of poor-prognosis primary melanoma of the lower limb.

Topics: Actuarial Analysis; Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Adjuvant; Disease Progression; Disease-Free Survival; Female; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Perfusion; Prognosis; Prospective Studies; Treatment Outcome

Following isolated limb perfusion (ILP) with TNF alpha and melphalan the damage to muscle tissue and its systemic consequences in terms of myoglobinemia and myoglobinuria as well as the activation of the cytokine cascade were investigated. We measured the compartmental pressure of the limb during and after perfusion and determined the serum changes of myoglobin, creatine kinase (CK), interleukin (IL)-6, IL-1, s-IL-2-receptor, TNF-receptor, and ICAM-1 levels. The compartmental pressure rose significantly during ILP and decreased after reperfusion. Following its course, the decision whether to perform a fasciotomy or not can be more reliably made. Serum myoglobin levels exceeded 200 times normal values and the increase occurred significantly earlier than that of CK, thus enabling judgement of the risk of renal failure (crush kidney syndrome). The elevation of serum IL-1 and IL-6 values correlated with the frequency of cardiopulmonary problems (hyperdynamic shock) and facilitated counter-maneuvers. Our data, although obtained from ILP with TNF alpha, could be used to monitor toxicity also when other drug regimens are administered.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Compartment Syndromes; Cytokines; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Myoglobin; Myoglobinuria; Neoplasm Recurrence, Local; Recombinant Proteins; Rhabdomyolysis; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

To evaluate response rates and systemic and regional toxicity of hyperthermic isolated limb perfusion (ILP) for treatment of in-transit metastases of extremity melanoma using escalating-dose tumor necrosis factor (TNF) in conjunction with melphalan and interferon gamma (IFN).. All patients received IFN 0.2 mg2 for 2 days followed by a 90-minute ILP with TNF and IFN (0.2 mg) given at time 0 and melphalan (10 mg/L limb volume) given at 30 minutes. Twenty-six patients were treated with 4 mg of TNF and 12 patients received 6 mg of TNF. All patients had assessable disease in the perfusion field and all but two patients were assessable for response at 1 month after treatment.. Mean peak perfusate TNF levels in the 4-mg group were 4.8 micrograms/mL, compared with 7.4 micrograms/mL for the 6-mg group (P = .03). The complete response rate in the 4-mg TNF group was 76%, with an overall objective response rate of 92%, compared with 36% and 100% for the 6-mg group. Subgroup analyses showed that the lower complete response rate in the 6-mg TNF group was not explained by differences in disease burden or prior regional therapy. Systemic drug toxicity was short-lived, easily managed, and related to perfusate leak more than to TNF perfusate dose. Regional toxicity, particularly painful myopathy and neuropathy, was greater with the 6-mg dose level and was considered dose-limiting.. ILP with 4 mg TNF, IFN, and melphalan can lead to complete local responses in the majority of patients with extremity melanoma. Escalating the TNF dose to 6 mg did not increase the complete response rate and increased regional toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Interferon-gamma; Male; Melanoma; Melphalan; Middle Aged; Recombinant Proteins; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

Regionally advanced cancer is a common, often unresolved problem. Effective local control with chemotherapy is limited by the toxicity following systemic administration. Chemofiltration (CF) is a form of regional perfusion that enables the administration of cytotoxic drugs into one body area while limiting systemic toxicity. The drug is infused into the artery supplying the involved area. The venous effluent of the same organ is pumped out into a hemofiltration unit at a high flow rate. The drug is then filtered away and the blood returned to systemic circulation.. Forty-one patients underwent 45 CF. Twenty-four patients had CF of the pelvis for advanced rectal carcinoma (10), malignant melanoma (6), and cancers of the uterine cervix (3), ovary (2), vulva (1), endometrium (1), and anus (1). Seventeen patients underwent CF of the liver for metastatic colon (10), breast (4), pancreas (1), ovary (1), and unknown primary (1) cancer. 5-fluorouracil (1 g/m2) and mitomycin-C (30 mg/m2); cisplatinum (200 mg/m2) alone or combined with bleomycin (50 mg/m2) and mitomycin-C (20 mg/m2); or melphalan (1 mg/kg) were the combinations used.. Generally the procedure was well tolerated. Complications included transient leukopenia (18), paralytic ileus (2), hair loss (2), renal failure (1). Two patients died within 40 days following CF. Of 36 evaluable patients, 16 (44%) had partial response, 14 (38%) had stable disease, and 6 (18%) had disease progression. A decrease of at least 30% in carcinoembryonic antigen levels occurred in 12 of 24 patients (50%). Median time to progression was 7 months. Ten of 13 patients (77%) achieved good symptomatic palliation.. The results of CF in our study are not superior to alternative methods of drug delivery to the liver and pelvis. However, considering that previous systemic chemotherapy had failed two-thirds of the patients, some benefit may be attributed to this regional delivery modality. Furthermore, pelvic CF afforded very significant symptomatic relief which was definitely superior to other methods.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Renal Cell; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Digestive System Neoplasms; Female; Fluorouracil; Genital Neoplasms, Female; Hemofiltration; Humans; Kidney Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Mitomycin; Prognosis; Survival Rate

Hyperthermic isolated limb perfusion (ILP) with melphalan is well established as an effective form of treatment for recurrent melanoma confined to an extremity. High drug concentrations in the limb are readily achieved, without systemic side-effects. However, regional toxicity can lead to considerable morbidity and functional disturbance. This study was undertaken to evaluate factors which might contribute to acute regional toxicity following ILP. Melphalan concentrations in limb blood samples taken at regular intervals during 135 ILPs were measured by HPLC, allowing peak melphalan concentration and area under the curve (AUC) for each procedure to be determined. Acute regional toxicity associated with ILP was found to be significantly correlated with limb tissue temperatures > 40 degrees C, peak melphalan concentration and melphalan AUC, in decreasing order, but was not correlated with tourniquet time. Further studies are required to directly assess melphalan uptake by tumour tissue, and to relate this to both limb toxicity and tumour response.

Topics: Antineoplastic Agents, Alkylating; Arm; Body Temperature; Chemotherapy, Cancer, Regional Perfusion; Chromatography, High Pressure Liquid; Humans; Leg; Melanoma; Melphalan; Metabolic Clearance Rate; Tourniquets

The aim of this study was to assess whether isolated limb perfusion can be performed safely and whether it offers improved disease-free survival for patients with limb malignant melanoma. Between August 1983 and July 1993, 103 patients (78 female, 25 male) with recurrent limb melanoma were treated by isolated limb perfusion (ILP) in Glasgow, U.K. The mean age of the patients was 62 years; 95 had leg recurrence, 8 had arm recurrence. The mean time from original diagnosis to ILP was 48 months (range 1-290). 102 iliac, 5 femoral, 7 popliteal and 8 axillary perfusions were performed. All patients had stage II (local recurrence within 3 cm of primary site) or stage III (regional metastases; tissues excluding nodes, nodes or combination) disease according to the MD Anderson Cancer Centre Staging System. At a mean follow-up of 30.7 months, 68 patients had died of recurrent disease (mean time to death 22.5 months). The 2 and 5 year survival of the group was 50 and 26%, respectively and disease-free survival was 23 and 12%, respectively. At first perfusion, 76% of patients showed complete response and 23% showed partial response. With repeat perfusion, 47% showed complete response and 53% had partial response. In conclusion, ILP is safe and has an acceptable morbidity. It achieves highly satisfactory local disease control but long-term survival is the exception.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Extremities; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Middle Aged; Sex Factors; Skin Neoplasms; Survival Rate

Melphalan administered by isolated hyperthermic perfusion of the affected limb is an accepted treatment for malignant melanoma of the extremities. In contrast, pharmacologic and phase I studies suggest that, because of its high uptake, mitoxantrone may give even better local control, but data on survival, onset of metastases, and local and systemic toxicities have not yet been reported.. A matched-pairs comparison was performed to examine differences in the tolerability and effectiveness of isolated hyperthermic extremity perfusion with mitoxantrone (n = 44) and melphalan (n = 44) in high risk and locoregionally (P < 0.41) metastatic malignant melanoma. Criteria evaluated were local and systemic complications, and recurrence-free and overall survival.. Local complications, such as delayed wound healing, were more frequent in the mitoxantrone (27.9%) than in the melphalan group (9.8%) (P < 0.05). Systemic toxicity, in particular bone marrow toxicity, was also more severe with mitoxantrone (78.6% versus 15.4%, P < 0.001). Hepatotoxic effects were more frequent among patients in the melphalan group who were older and has lower tissue perfusion temperatures (P < 0.05). There was no difference between the two groups in overall or recurrence-free survival (P < 0.41).. Local and systemic toxicity seem to be higher with mitoxantrone. Survival rates were similar with both drugs. The data obtained suggest a randomized phase II study with an appropriate number of patients.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Child; Extremities; Female; Humans; Hyperthermia, Induced; Male; Matched-Pair Analysis; Melanoma; Melphalan; Middle Aged; Mitoxantrone; Survival Rate; Wound Healing

The tolerated systemic dose of recombinant tumor necrosis factor alpha (rTNF-alpha) is very limited, since its administration leads to a severe septic shock-like condition. Its implementation in isolated limb perfusion (ILP) for metastatic melanoma or advanced soft-tissue sarcoma confined to the limb facilitates doses of rTNF-alpha 10 times higher than the systemic tolerated dose. However, with the traditional high flow rate used in ILP, systemic leakage and side effects are not eliminated.. To determine if a lower perfusion flow rate would reduce leakage and consequently toxic effects.. Isolated limb perfusion was performed for melanoma and soft-tissue sarcoma confined to the limb using a flow rate of 869 +/- 122 mL/min in nine patients (group 1) and a lower rate of 286 +/- 62 mL/min in six patients (group 2).. The systemic leakage rate was 12.5% +/- 2.9% in group 1, compared with 2.3% +/- 1.0% in group 2 (P = .003). Peak TNF-alpha levels were 29,000 +/- 2700 pg/mL in group 1, higher than 1580 +/- 1355 pg/mL in group 2 (P = .02). The tachycardia, hypotension, increased cardiac output, decreased systemic vascular resistance, bilirubinemia, elevation of liver enzyme levels, hypocholestrolemia, thrombocytopenia, and prolongation of prothrombin and partial thromboplastin times all observed in group 1 were significantly attenuated or eliminated in group 2. The limb PO2, PCO2, pH, and viability remained similar in both groups. Also, the tumor response rate remained high and was unaffected by the decrease in flow rate.. Decreasing perfusion flow rate during ILP results in diminished leakage of TNF-alpha. Consequently, the systemic hemodynamic, metabolic, and hematologic toxic effects are virtually abolished.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Arm; Blood Cell Count; Chemotherapy, Cancer, Regional Perfusion; Cholesterol; Drug Administration Schedule; Female; Hemodynamics; Humans; Leg; Liver Function Tests; Male; Melanoma; Melphalan; Metabolism; Middle Aged; Recombinant Proteins; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

The matrix protein tenascin-C (TN-C) is present in the blood of healthy individuals at concentrations around 1 mg/l. Elevated serum levels have been reported in cancer patients. In this study we have measured the concentration of circulating TN-C in 40 patients with melanoma, soft-tissue sarcoma (STS) or squamous-cell carcinoma (SCC) of the limbs, and have found a minor increase in the mean concentration compared with healthy subjects. Only 10 patients had TN-C levels above the normal range. No correlation was observed between TN-C levels and tumor burden. Nineteen patients were treated by isolation limb perfusion (ILP) with TNF, IFN gamma, melphalan (11 melanoma, 2 SCC and I STS), melphalan alone (3 melanoma) or hyperthermia at 41.5 degrees C (2 melanoma). ILP with TNF, IFN gamma and melphalan induced a rapid increase in plasma TN-C levels, peaking in most patients between 24 or 48 hr after ILP. Two patients treated with hyperthermia only had a slow increase in TN-C concentration peaking at day 4, while the patients treated with melphalan alone had no significant change. In some cases elevated TN-C levels persisted for over 8 weeks after ILP. The early rise in TN-C concentration correlates with the increase in circulating C-reactive protein. Our findings suggest that circulating TN-C behaves, at least in part, as an acute-phase protein and that it may play a role in the inflammatory response.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; C-Reactive Protein; Carcinoma, Squamous Cell; Chemical and Drug Induced Liver Injury; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Extremities; Female; Humans; Interferon-gamma; Interleukin-6; Male; Melanoma; Melphalan; Middle Aged; Neoplasms; Recombinant Proteins; Sarcoma; Soft Tissue Neoplasms; Tenascin; Tumor Necrosis Factor-alpha

Isolated limb perfusion (ILP) with tumor necrosis factor (TNF), interferon gamma, and melphalan (M) has been reported to result in high response rates for extremity melanoma and sarcoma. We have evaluated the relationship of systemic TNF exposure to induction of several secondary mediators and incidence of systemic toxicity.. Nineteen patients with extremity melanoma (n = 16) or sarcoma (n = 3), underwent 90-minute ILP with TNF-alpha, interferon gamma (0.2 mg), and M (10 to 13 mg/L of limb volume) (TNF/IFN/M) (n = 12), or M alone (n = 7). Continuous intraoperative monitoring (CIM) for systemic leak from the perfusion circuit was performed using radioactive iodine-131 albumin. Cytokine levels in the perfusate and systemic circulation during and after ILP were measured by enzyme-linked immunosorbent assay.. Systemic leaks > or = 1% from the perfusion circuit occurred in six patients who received TNF/IFN/M and in four who received M alone. Hypotension that required vasopressor support occurred in six of six patients with evidence of a leak (> or = 1%) and zero of six patients without a leak (< 1%). These six patients had significantly higher peak systemic TNF levels during and after perfusion than patients without a leak (2.8 and 8.2 ng/mL v 0.7 and 2.0 ng/mL, respectively; P < .05). All patients who received TNF/IFN/M had significantly greater increases in systemic interleukin-6 (IL-6) levels than in patients with M alone (12,395 +/- 10,374 pg/mL v 79.4 +/- 7.2 pg/mL, respectively; P < .001). Intracellular adhesion molecule (ICAM), IL-8, and TNF-R levels were also increased after ILP with TNF/IFN/M.. ILP with TNF/IFN/M can be safely performed, as I131 albumin provides a sensitive measure of systemic leakage from the perfusion circuit. Patients with a measured leak of > or = 1% develop mild and transient postoperative hypotension with significantly higher systemic TNF levels and lower perfusate TNF levels than in patients without leaks.

Topics: Adult; Aged; Aged, 80 and over; Arm; Chemotherapy, Cancer, Regional Perfusion; Cytokines; Female; Histiocytoma, Benign Fibrous; Humans; Interferon-gamma; Interleukin-6; Interleukin-8; Leg; Leiomyosarcoma; Male; Melanoma; Melphalan; Middle Aged; Receptors, Tumor Necrosis Factor; Sarcoma, Ewing; Skin Neoplasms; Tumor Necrosis Factor-alpha

Isolated regional perfusion (IRP) of an extremity is a major operation. The therapeutic value for stage I melanoma is still controversial and is presently being investigated in a prospective, randomized study by the European Organization for Research and Treatment of Cancer. So far there are no reliable data available concerning the morbidity of IRP. Therefore, we performed a prospective, randomized study on this topic.. In a prospective study, a group of 97 patients with a stage I melanoma localized on an arm or leg were randomized for IRP with melphalan followed by wide excision (WE) and fasciotomy or for WE only. Morbidity was evaluated on the basis of the following parameters: duration of hospitalization, postoperative pain, postoperative performance, and grade of perfusion toxicity. At 12-month follow-up, a physical diagnostic examination was performed to measure the mobility of the joints, and the circumference and volume of the treated and untreated extremities.. All the parameters, including the physical diagnostic examination, could be evaluated in 83 of the 97 patients (8 patients died of metastatic disease and 1 patient died of another disease before they could be investigated; 2 patients were in too poor physical condition due to metastases to be examined, and 3 patients were unable to participate for nonmedical reasons). Age and sex distribution were comparable in the various patient groups. Treatment mortality was 0%. There were no complications except for urine retention (one patient) and wound dehiscence (one patient). After IRP + WE of the lower limb, the period of hospitalization was an average of 1.9 days longer (p = 0.01) than for WE on the limb only. This difference was absent for the arm. Naturally after perfusion, there was a significant difference in toxic reactions (edema and pain) between the IRP + WE patients and the WE-only patients. However, at 12-month follow-up, the difference in morbidity between IRP + WE and WE-only patients was no longer present: Morbidity of joints and circumference of the limb were the same. A number of subjective complaints were encountered fairly often after IRP + WE (e.g., pricking sensations or pain during changes in the weather), which can possibly be explained by fibrosis caused by perfusion. These complaints were not quantified further because they did not hinder the patients' functioning.. In a long term, IRP with fasciotomy does not cause any additional morbidity. Immediately after the operation, there was more morbidity as a result of the perfusion, which caused a 2-day-longer period of hospitalization in the patients with lower-limb perfusion compared with those who underwent WE only. These findings are in contrast to those in the literature, in which 25% limitation of motion in the ankle joint after perfusion is mentioned. One explanation may be that we always performed fasciotomy after perfusion to prevent (sub)clinical compression syndrome and avoid late fibrosis.

Topics: Adult; Aged; Arm; Chemotherapy, Cancer, Regional Perfusion; Fasciotomy; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Leg; Length of Stay; Male; Melanoma; Melphalan; Middle Aged; Morbidity; Pain, Postoperative; Prospective Studies; Skin Neoplasms; Time Factors

It has been reported that a double perfusion schedule shows a better complete remission rate than does the single procedure for recurrent melanoma of the limb. As more perfusion strategies approach the ideal of a 100% complete remission rate, the main issue now is to prolong the period of disease control in the limb, ie to reduce the limb recurrence rate. The follow up of 42 patients treated with a double perfusion schedule and of 45 patients treated with a single perfusion procedure was updated to compare the duration of limb disease control. Both treatment groups were well balanced with respect to patient and tumour characteristics. For patients treated with a double schedule, the dose of melphalan given in the first perfusion was low (6 mg/l limb volume; 1 h; normothermic) in order to make it possible to carry out a second perfusion (9 mg/l; 1 h; normothermic) with a planned short interval of 3-4 weeks. In the single perfusion group a normothermic perfusion with 10 mg melphalan/l was carried out. The acute tissue reactions and long-term side effects did not differ between the two treatment modalities. The response rate was significantly higher in the double perfusion group owing to a higher complete remission rate (76% vs 48%; P = 0.006). However, no significant difference was seen in limb disease control rates 3 years after perfusion (double schedule, 36%; single schedule, 30%), nor in overall 3-year survival (double schedule, 52%; single schedule, 45%). When evaluating perfusion regimens with equally high complete remission rates, attention should be focused on the duration of limb disease control.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Drug Administration Schedule; Extremities; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local

We report an update of a multi-centre pilot study previously published. Fifty-three patients (42 women, 11 men) were accrued between October 1988 and May 1992: 34 had stage IIIA, 15 had stage IIIAB, and four had stage IV melanoma. Most of them had more than five in-transit metastases; 50% had been previously treated by regional chemotherapy. Protocol included 90-min isolation perfusion at 40 degrees C with 2-4 mg rTNF-alpha, 0.2 mg rIFN-gamma and 10/13 mg/l melphalan. We prevented severe TNF systemic side effects by administration of dopamine and fluid loading. There has been no toxic death and the toxicity remained acceptable, with only one multi-organ failure (MOF) and no prolonged shock. Response rates remained very high, with 90% complete remission, 10% partial response and no failure. With a median follow-up time of 26 months, there were 12 regional recurrences, 15 distant metastases and nine local and distant recurrences. The median overall survival has been 28 months. We conclude that high-dose rTNF-alpha associated with melphalan in isolation perfusion is the therapy of choice for in-transit melanoma metastases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Extremities; Female; Humans; Interferon-gamma; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Pilot Projects; Recombinant Proteins; Tumor Necrosis Factor-alpha

Nine patients with soft tissue tumours of the lower limb not amenable to treatment other than by isolated limb perfusion (ILP) or amputation underwent ILP at the level of the superficial femoral vessels, using a combination of recombinant TNF-alpha and melphalan. In seven patients in whom tumours were superficial, sloughing and necrosis were apparent within 48 h of perfusion. All patients experienced a complete tumour response. There were no systemic side effects associated with the use of TNF-alpha, although local side effects, particularly oedema, were pronounced. Four patients ultimately required amputation, three because of large soft tissue defects resulting from necrosis of tumour and overlying skin and one because of tumour recurrence.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Pilot Projects; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

From December 1991 to July 1993, 22 consecutive patients with grade IIIA-IIIAB melanoma underwent isolation perfusion with TNF-alpha (0.5-4 mg), melphalan (10 mg/l perfused limb) and, in the first 12 cases, IFN-gamma (1.5 x 10(6) U). The first series of 12 patients received a total dosage TNF-alpha of 2-4 mg, and the second series of 10 cases received an escalating dosage of TNF-alpha (1.5-1.0-0.5 mg) and no IFN-gamma before or during surgery. The perfusion lasted 90 min and was conducted in mild hyperthermia (39-39.5 degree C muscle temperature). The results of the first series included seven patients in complete remission, four with stable disease and one case not evaluable for local toxicity. Fifty per cent of cases developed a regional relapse from 3 to 4 months after surgery. Presently with a median follow up of 10 months, five patients of this group have no evidence of disease, four are alive with disease, two died from melanoma and one died of complications likely due to treatment (multi-organ failure syndrome). In the second series, the immediate responses included seven patients in complete remission and three in partial remission; with a median follow up of 3 months, two patients developed a regional relapse, respectively, 3 and 5 months after surgery. So far our experience of perfusion with TNF-alpha has not reproduced the data reported by other investigators. Further clinical and biological findings and a longer follow-up period are needed to draw any conclusion, and a decreasing TNF-alpha dose should be carefully evaluated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dose-Response Relationship, Drug; Extremities; Female; Humans; Hyperthermia, Induced; Interferon-gamma; Male; Melanoma; Melphalan; Middle Aged; Neoplastic Cells, Circulating; Recombinant Proteins; Skin Neoplasms; Tumor Necrosis Factor-alpha

The Surgery Branch of the National Cancer Institute has initiated several clinical trials involving the use of high-dose TNF in isolated limb perfusions. A phase III trial compares the three drug combination of TNF, interferon-gamma (IFN-gamma) and melphalan with a standard melphalan-alone perfusion in a prospective randomized trial. Another protocol escalates the dose of TNF in the perfusate to define the maximally tolerated dose that can be administered in this regional manner. A third protocol adds systemic high-dose interleukin-2 postoperatively to a TNF, IFN, and melphalan limb perfusion for patients with stage IV melanoma with the bulk of the disease in the extremity. This brief review highlights the rationale and study design of these TNF limb perfusion protocols.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Dose-Response Relationship, Drug; Extremities; Humans; Interferon-gamma; Interleukin-2; Melanoma; Melphalan; Prospective Studies; Randomized Controlled Trials as Topic; Tumor Necrosis Factor-alpha

In the period 1978-1990, 49 patients with locally inoperable melanoma of the limbs were treated with regional isolated perfusion according to four different perfusion schedules. Perfusion resulted in a complete remission in 28 patients (57%), with a median duration of 10 (1-55+) months, and a partial remission in 10 (21%), with a median duration of 3 (1-9) months. In patients treated with a double (normothermic or sequential hyperthermic) perfusion schedule the complete remission rate was higher. Regional lymph node involvement reduced the chance of achieving complete remission. Twelve patients with complete remission (43%) showed a relapse in the perfused area. The corresponding 3-year limb recurrence-free interval was 46%. This interval was mainly influenced by the number of lesions at the moment of perfusion. Three of the patients who failed to respond eventually required amputation of the affected limb. The median follow-up of the surviving patients was 23 (5-142) months. At the time of analysis 23 patients were still alive, 12 of whom had no evidence of disease. Patients with complete remission had a slightly, though statistically not significant better 3-year survival rate than patients without complete remission (49% vs 33%). Regional isolated perfusion halted progression in all of these 49 patients and resulted in a complete remission for 57%. It is, therefore, an important modality in the management of patients with locally inoperable melanoma and provides a valuable alternative to amputation.

Topics: Adult; Aged; Aged, 80 and over; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Drug Administration Schedule; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged

Utilization of alpha-tumor necrosis factor (alpha-TNF) in clinical practice is limited by severe general side effects. Very promising results with low toxicity were reported with administration of alpha-TNF by isolation perfusion in extracorporeal circulation.. From December 1991 to November 1992, 14 patients underwent perfusion with alpha-TNF (2-4 mg, total dose), gamma-interferon (1.5 x 10(6) IU), and melphalan (10 mg/l/perfused limb). Twelve patients presented in-transit metastases of the limbs, one patient, a clear cell sarcoma of the hand, and one patient, a wide spindle cell carcinoma of the thigh. Perfusion lasted 90 minutes and was conducted in mild hyperthermia (38-40.5 degrees C, muscle temperature).. Nine complete regressions and four stable diseases were recorded. In one case, a reliable evaluation of response was not possible for diffused tissue necrosis. Five patients relapsed or progressed locally from 3 to 4 months after surgery, five presented distant localizations from 2 to 7 months after surgery, and one died of disease 6 months after perfusion. Twelve patients are alive, seven without evidence of disease. A septic-like shock syndrome was observed in all patients and required administration of dopamine, dobutamine, or noradrenaline. One patient died 30 days after perfusion from a multiorgan-failure syndrome, likely due to alpha-TNF. The follow-up time ranges from 4 to 15 months (median, 6).. The preliminary, impressive results reported in other series were not completely confirmed in this study adopting the same treatment scheme. Further clinical experience and biologic data are needed to state the real efficacy of the approach and to reduce the severe general toxicity consistently associated with this type of treatment.

Topics: Adult; Aged; Arm; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Interferon-gamma; Leg; Male; Melanoma; Melphalan; Middle Aged; Pilot Projects; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

One of the current international prospective clinical trials of the EORTC Melanoma Cooperative Group explores the usage of regional isolated perfusion as adjuvant in melanomas located on the extremities. In the design of the study it is necessary to define not only the extent of the surgery (perfusion+local excision versus local excision only), but also to ensure uniformity of surgery performed between surgeons and institutions. With on-site visits and general meetings with the participants, surgical protocol violations and misinterpretations of the protocol could be avoided. The conclusion is that accurate surgical quality control is time consuming, but not difficult.

Topics: Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melanoma; Melphalan; Prospective Studies; Quality Control; Skin Neoplasms; Surgical Procedures, Operative

To determine the toxicity and the therapeutic efficacy of the combination of the recombinant tumor necrosis factor alpha (rTNF alpha), recombinant interferon gamma (rIFN-gamma), and melphalan, we designed a protocol using isolation limb perfusion (ILP) with hyperthermia for in-transit metastases of melanoma and recurrent sarcoma. The triple combination was chosen because of the reported synergistic antitumor effect of rTNF alpha with IFN-gamma and of rTNF alpha with alkylating agents.. Twenty-three patients received a total of 25 ILPs with the triple combination. There were 19 females and four males with either multiple progressive in-transit melanoma metastases of the extremities (stage IIIa or IIIab; 19 patients) or recurrent soft tissue sarcoma (five). The rTNF alpha was injected as a bolus in the arterial line, and total dose ranged between 2 and 4 mg, under hyperthermic conditions (40 degrees C to 40.5 degrees C) for 90 minutes. The rIFN-gamma was given subcutaneously (SC) on days -2 and -1 and in the perfusate, with rTNF alpha at the dose of 0.2 mg. Melphalan (Alkeran; Burroughs Wellcome Co, London, England) was administered in the perfusate at 40 micrograms/mL.. Toxicity observed during three ILPs in a pilot study with rTNF alpha included only two severe toxicities: one severe hypotension with tachycardia and transient oliguria and one moderate hypotension for 4 hours followed by severe kidney failure with complete recovery on day 29. In all 18 ILPs performed in the triple combination protocol, the patients received continuous infusion dopamine at 3 micrograms/kg/min from the start of ILP and for 72 hours and showed only mild hypotension and transient chills and temperature. Regional toxicity attributable to rTNF alpha was minimal. There have been 11 cases with hematologic toxicity consisting of neutropenia (one grade 4 and one grade 3) and neutropenia with thrombocytopenia (one grade 4 and three grade 2). Twelve patients had been previously treated with melphalan in ILP (11) or with cisplatin (one). The 23 patients are assessable: there have been 21 complete responses (CRs; range, 4 to 29 months; 89%), two partial responses (PRs; range, 2 to 3 months), and no failures. Overall disease-free survival and survival have been 70% and 76%, respectively, at 12 months. In all cases, softening of the nodules was obvious within 3 days after ILP and time to definite response ranged between day 5 and 30.. This preliminary analysis of a phase II study suggests that high-dose rTNF alpha can be administered with acceptable toxicity by ILP with dopamine and hyperhydration. Tumor responses can be evidenced in melanoma and sarcoma. Furthermore, combination of rTNF alpha, rIFN-gamma, and melphalan seems to achieve high efficacy with minimal toxicity, even after failure of prior therapy with melphalan alone.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arm; Chemotherapy, Cancer, Regional Perfusion; Drug Evaluation; Female; Humans; Hyperthermia, Induced; Interferon-gamma; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Recombinant Proteins; Sarcoma; Survival Analysis; Tumor Necrosis Factor-alpha

A prospective randomized trial testing regional hyperthermic perfusion with melphalan has been conducted. Sixty-nine patients with recurrent malignant melanoma of the extremities were randomly allocated to surgery (36 patients) or surgery plus regional perfusion (33 patients). Prognostic variables concerning primary tumor as well as the recurrent disease were evenly distributed in the groups, excluding any bias in the randomization. Median tumor-free survival after randomization was 17 months in the perfusion group and 10 months in the control group. There were 15 locoregional recurrences in the perfusion group and 24 in the control group. The tumor-free survival curve was significantly (P = .044) better for the perfusion group than for the control group. Median survival time after randomization was 57 months in the perfusion group and 35 months in the control group. This difference was not significant. One patient died within 1 month after perfusion of pulmonary embolism. Regional hyperthermic perfusion after surgery of recurrent malignant melanoma should only be recommended in prospective and controlled trials, until its value has been proven in several randomized studies.

Topics: Adult; Aged; Arm; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Recurrence; Survival Rate

Ninety-three patients with stage I primary cutaneous malignant melanoma of the lower limb were treated by wide local excision and hyperthermic isolated regional perfusion with melphalan (L-phenylalanine dihydrochloride) in a prospective non-randomized study between 1976 and 1982. Eighteen patients (19.4%) developed recurrent melanoma. Nine had recurrent regional disease, one with in transit metastases and eight with positive regional nodes. Nine patients developed distant metastases. No patient had locally recurrent disease. This series confirmed the close correlation between tumour microstaging, melanoma recurrence and survival. Seventy-nine per cent of patients were disease-free at 5 years. Males had deeper lesions (mean 4.56 mm) and increased recurrence (33%) than females (mean 3.36 mm and 13%). Superficial spreading melanoma had the most favourable prognosis of the three histological types. Overall survival was 83% (female 86%; males 64%) at 5 years. Significant morbidity occurred in two patients with deep vein thrombosis. Adjuvant therapy using hyperthermic regional perfusion provides improved local and intransit control of limb melanoma.

Topics: Adult; Aged; Biopsy; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Prospective Studies; Skin; Skin Neoplasms

To evaluate the effectiveness of regional hyperthermic cytostatic perfusion in patients with malignant melanomas of the extremities, 107 patients were included in a prospective randomized study. In a control group (A, n = 54) the tumors were widely excised, and the regional lymph nodes were dissected. The patients in the perfusion group (B, n = 53) received additional hyperthermic (42 degrees C) perfusion with melphalan. The disease-free survival time was chosen as the criterion for success. An intermediate evaluation (average follow-up observation period of 550 days) revealed a highly significant difference between the groups (P = 0.0001): 21 recurrences in the control group versus four recurrences in the perfusion group. In a second analysis 3 1/2 years after premature discontinuation, 26 recurrences were diagnosed in Group A, whereas only six recurrences were noted in Group B (P = 0.0001). A retrospective analysis of the entire test group revealed the following figures. In Group A seven recurrences in Stage I were diagnosed, seven in Stage II, and 12 in Stage III. In Group B one was observed in Stage I, one in Stage II, and four in Stage III. The level of significance was calculated to be P = 0.05 in Stage I, P = 0.05 in Stage II, and P = 0.01 in Stage III. The results of the study show that additional perfusion in the treatment of extremity melanomas is superior to conventional methods.

Topics: Arm; Clinical Trials as Topic; Female; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Neoplasm Staging; Perfusion; Prospective Studies; Random Allocation; Retrospective Studies; Skin Neoplasms

Twenty-three patients with extremity malignant melanoma who fit the clinical and pathologic criteria for acral lentiginous melanoma were treated in a prospective, nonrandomized trial of wide local excision, regional lymphadenectomy, and hyperthermic isolation perfusion. There were 17 patients (73.9 percent) pathologically judged to be in stage I and 6 (26.1 percent) in stage II. Three patients entered the study with regional recurrence. Delay in diagnosis of the lesions averaged almost 3 1/2 years. Increasing awareness about the occurrence of acral lentiginous melanoma may result in earlier diagnosis, increased survival rates, and cure. Life table survival analysis revealed 5 and 10 year survival rates of 75 percent and 58 percent, respectively. This supports the findings of Krementz et al and suggests not only that a marked improvement in survival can be achieved through the use of hyperthermic isolation perfusion, but that the survival of patients with acral lentiginous melanoma is comparable with that of patients with other extremity malignant melanomas treated with aggressive multimodality therapy.

Topics: Actuarial Analysis; Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Combined Modality Therapy; Extremities; Female; Humans; Lymph Node Excision; Male; Melanoma; Melphalan; Middle Aged; Prospective Studies; Skin Neoplasms; Time Factors

To evaluate the effectiveness of regional hyperthermic cytostatic perfusion in patients with malignant melanomas of the extremities 107 patients were included in a prospective randomized study. In a control group (A, n = 54) the tumors were excised widely and the regional lymph nodes were dissected. The patients in the perfusion group (B, n = 53) received additional hyperthermic (42 degrees C) perfusion with Melphalan. We chose the disease-free-survival time as the criterion for success. An intermediate evaluation (mean follow-up observation period of 550 days) revealed a highly significant difference between the groups (p = 0.0001) of 21 resp. 4 recurrences. A second evaluation, 2 1/2 years after prematurely discontinuation, also shows a highly significant difference in favour of perfusion (p = 0.0001).

Topics: Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Combined Modality Therapy; Extremities; Follow-Up Studies; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Random Allocation; Skin Neoplasms

5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388), melphalan, and hydroxyurea were evaluated in a randomized clinical trial in which 35 patients with disseminated malignant melanoma were treated. Therapeutic results were not impressive. Objective remissions were noted in two of the 23 patients who received NSC-45388, none of the 21 who received melphalan, and none of the 24 who received hydroxyurea. Toxicity was significant but tolerable: gastrointestinal toxicity was noted in 23 of the 23 patients who received NSC-45388, 15 of the 21 who received melphalan, and 16 of the 24 who received hydroxyurea. Hematologic toxicity resulted in leukocyte counts less than 3000 cells/mm3 in seven of the 23 patients who received NSC-45388, six of the 21 who received melphalan, and 18 of the 24 who received hydroxyurea. Platelet depression, with cell counts less than 100,000 cells/mm3, was noted in five of the 23 patients who received NSC-45388, three of the 21 who received melphalan, and six of the 24 who received hydroxyurea.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; Dacarbazine; Female; Humans; Hydroxyurea; Leukocytes; Male; Melanoma; Melphalan; Middle Aged; Remission Induction; Treatment Outcome

Topics: Adolescent; Adult; Aged; Bone Marrow; Bone Neoplasms; Carcinoma; Child; Child, Preschool; Clinical Trials as Topic; Cyclophosphamide; Dactinomycin; Drug Synergism; Female; Fluorouracil; Gastrointestinal Neoplasms; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Mitomycins; Parotid Neoplasms; Sarcoma; Urogenital Neoplasms; Vincristine

Uveal melanoma accounts for 80% of all ocular melanomas, and 30-60% of patients have metastases to the liver. A few patients are candidates for liver resection, and this disease is associated with poor prognosis. There are few data on optimal management of metastatic uveal melanoma. Isolated hepatic perfusion is a perspective method for regional treatment of inoperable metastatic liver lesions with uveal melanoma. We present a patient with uveal melanoma who underwent previous enucleation of the eye. Cancer progressed 15 years later as an isolated inoperable metastatic liver lesion. The patient underwent isolated liver perfusion with melphalan, hyperthermia and oxygenation. Subsequently, the patient received systemic therapy with pembrolizumab. Partial response was achieved 1 month after the procedure. There was no progression for 20 months after surgery under systemic therapy with pembrolizumab. Thus, isolated liver chemoperfusion with melphalan is advisable in these patients.. Увеальная меланома составляет 80% всех глазных меланом, и 30—60% пациентов имеют метастазы, ограниченные только печенью. Немногие пациенты являются кандидатами на потенциально лечебную резекцию печени, поэтому это заболевание связано с плохим прогнозом. Опубликовано мало данных об оптимальном ведении и лечении метастатической увеальной меланомы. Перспективным методом регионального лечения неоперабельного метастатического поражения печени увеальной меланомой является метод изолированной химиоперфузии печени. Мультидисциплинарный коллектив НМИЦ радиологии и Костромского онкологического диспансера представил клинический случай больной с увеальной меланомой, перенесшей энуклеацию глаза, и прогрессированием спустя 15 лет в форме изолированного нерезектабельного метастатического поражения печени. Пациентке была проведена изолированная перфузия печени с мелфаланом, гипертермией и оксигенацией. В дальнейшем пациентке проводили системную терапию пембролизумабом. Достигнут частичный ответ через 1 мес после выполнения процедуры. Констатировано отсутствие прогрессирования на протяжении 20 мес после операции на фоне системной терапии пембролизумабом. На основании представленного клинического наблюдения этой категории пациентов целесообразно применение изолированной химиоперфузии печени мелфаланом в комбинации с иммунотерапией.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Humans; Liver Neoplasms; Melanoma; Melphalan; Perfusion

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melanoma; Melphalan; Skin Neoplasms

Topics: Humans; Melanoma; Melphalan; Uveal Neoplasms

Choroidal melanoma, a common intraocular malignant tumor, relies on local radiotherapy and enucleation for treatment. However, cancer recurrence and visual impairment remain important challenges. Here, a therapeutic artificial vitreous body (AVB) hydrogel based on tetra-armed poly(ethylene glycol) was developed to control the recurrence of choroidal melanoma and preserve vision after vitrectomy. AVB loaded with melphalan (Mel) and anti-programmed cell death ligand-1 (αPDL1), was injected after surgical resection in the choroidal melanoma mouse model. Afterwards, the sequentially released Mel and αPDL1 from AVB could achieve a synergistic antitumor effect to inhibit tumor recurrence. AVB with similar physical properties to native vitreous body could maintain the normal structure and visual function of eye after vitrectomy, which has been evidenced by standard examinations of ophthalmology in the mouse model. Thus, the immunotherapeutic AVB may be a promising candidate as an infill biomaterial to assist surgical treatment of intraocular malignant tumors.

Topics: Animals; Choroid Neoplasms; Hydrogels; Immunotherapy; Melanoma; Melphalan; Mice; Neoplasm Recurrence, Local; Vitrectomy; Vitreous Body

Prior to the advent of effective systemic therapy for melanoma, isolated limb perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma (ITM). However, many patients who are now treated by ILP will have received prior immunotherapy. We sought to compare response rates to ILP in patients who had previously received immunotherapy compared to immunotherapy naive patients.. All patients who underwent ILP for ITM between January 2015 and July 2020 for melanoma were identified retrospectively from two tertiary institutions. Surgical morbidity and oncologic outcomes were compared between immunotherapy naive and immunotherapy pre-treated patients.. 97 perfusions were performed for melanoma. Of those, 18 patients had undergone prior immunotherapy. There were no differences in clinicopathological characteristics or perioperative outcomes between cohorts. Surgical morbidity and local toxicity were similar between both cohorts. Patients who underwent immunotherapy prior to ILP had significantly decreased complete response (CR) rates compared with immunotherapy-naïve (6% vs 47%, p = 0.0018) and a significantly decreased overall survival (OS) and distant progression free survival (DPFS) (p = 0.0031 and p = 0.0006 respectively). There was no difference in overall response (OR), partial response (PR), stable disease (SD), progressive disease (PD) and local progression free survival (LPFS) between cohorts.. Oncological outcomes and complete response rates are worse in patients who have received immunotherapy prior to ILP compared with immunotherapy naïve patients. Despite this, ILP is still a valuable second line treatment for local control in patients who have multiple, bulky and/or recurrent ITM post immunotherapy.

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Immunotherapy; Melanoma; Melphalan; Neoplasms, Second Primary; Perfusion; Retrospective Studies; Skin Neoplasms; Tumor Necrosis Factor-alpha

Uveal melanoma, the most common primary ocular malignancy in adults, carries a poor prognosis: 50% of patients develop the metastatic disease with a 10-25% 1-year survival and no established standard of care treatment. Prior studies of melphalan percutaneous hepatic perfusion (M-PHP) have shown promise in metastatic uveal melanoma (mUM) patients with liver predominant disease but are limited by small sample sizes. We contribute our findings on the safety and efficacy of the procedure in the largest sample population to date. A retrospective analysis of outcome and safety data for all mUM patients receiving M-PHP was performed. Tumour response and treatment toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events v5.03, respectively. 250 M-PHP procedures were performed in 81 patients (median of three per patient). The analysis demonstrated a hepatic disease control rate of 88.9% (72/81), a hepatic response rate of 66.7% (54/81), and an overall response rate of 60.5% (49/81). After a median follow-up of 12.9 months, median overall progression-free (PFS) and median overall survival (OS) were 8.4 and 14.9 months, respectively. There were no fatal treatment-related adverse events (TRAE). Forty-three grade 3 (29) or 4 (14) TRAE occurred in 23 (27.7%) patients with a significant reduction in such events between procedures performed in 2016-2020 vs. 2012-2016 (0.17 vs. 0.90 per patient, P < 0.001). M-PHP provides excellent response rates and PFS compared with other available treatments, with decreasing side effect profile with experience. Combination therapy with systemic agents may be viable to further advance OS.

Topics: Adult; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Humans; Liver Neoplasms; Melanoma; Melphalan; Neoplasms, Second Primary; Perfusion; Retrospective Studies; Skin Neoplasms; Uveal Neoplasms

The aim of this study was to identify positive predictors for survival in uveal melanoma (UM) patients treated with percutaneous hepatic perfusion with melphalan (M-PHP), by retrospectively pooling data from three centers.. Retrospective analysis including patients ([Formula: see text] 18 years) treated with M-PHP between February 2014 and December 2019 for unresectable liver-dominant or liver-only metastases from UM. Predictors for OS were assessed using uni- and multivariate analyses. Other study outcome measures were response rate, progression-free survival (PFS), liver progression-free survival (LPFS), overall survival (OS) and complications according to CTCAEv5.0.. In total, 101 patients (47.5% males; median age 59.0 years) completed a minimum of one M-PHP. At a median follow-up time of 15.0 months, complete response (CR), partial response (PR), stable disease (SD) and progressive disease were seen in five (5.0%), 55 (54.5%), 30 (29.7%) and 11 (10.9%) patients, respectively, leading to a 89.1% disease control rate. Median PFS, LPFS and OS were 9.0, 11.0 and 20.0 months, respectively. Survival analyses stratified for radiological response demonstrated significant improved survival in patients with CR or PR and SD category. Treatment of the primary tumor with radiotherapy, ≥ 2 M-PHP and lactate dehydrogenase (LDH) < 248 U/L were correlated with improved OS. Thirty-day mortality was 1.1% (n = 2). Most common complication was hematological toxicity (self-limiting in most cases).. M-PHP is safe and effective in patients with UM liver metastases. Achieving CR, PR or SD is associated with improved survival. Primary tumor treatment with radiotherapy, normal baseline LDH and > 1 M-PHP cycles are associated with improved OS.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Perfusion; Retrospective Studies; Uveal Neoplasms

Hyperthermic Ιsolated Limb Perfusion using melphalan and TNFα (TM-HILP) is a regional chemotherapy method for advanced melanoma.. To explore the feasibility of the study of Circulating Melanoma Cells (CMCs) in the context of acute physiological changes induced by TM-HILP and their association with oncological outcomes.. The study included 20 patients undergoing TM-HILP for unresectable in-transit melanoma of the limbs, stage III(B/C/D). CMCs in the peripheral blood were analyzed at 5-time points from the preoperative day until day 7 from surgery using the following biomarkers: MITF, Tyrosinase mRNA, Melan-A and S100b, through quantitative RT-PCR.. No CMCs according to Tyrosinase and Melan-A biomarkers were found in any sample. Friedman test showed significant alterations perioperatively for MITF (. TM-HILP is associated with increased levels of CMCs, but there was no association of this increase with survival. Patients with complete response to HILP demonstrate higher values of MITF shortly after the operation.

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Feasibility Studies; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Perfusion; Tumor Necrosis Factor-alpha

The aim of the study was to evaluate pretreatment inflammatory markers as prognostic factors in patients with unresectable uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion.. 54 patients (44% male, median age: 61 years) were retrospectively assessed. A median of 3 (range: 1-11) treatment sessions were performed with melphalan (92%) or fotemustin (8%). Inflammatory indices were calculated as follows: neutrophils/nl to lymphocytes/nl ratio (NLR), systemic immune-inflammation index ([platelets/nl × neutrophils/nl]/[lymphocytes/nl]; SII), and platelets/nl to lymphocytes/nl ratio (PLR). The cut-off for dichotomization purposes was set at the median (inflammatory indices, hepatic tumor burden) or the upper level of normal. Kaplan Meier analysis was performed for median overall survival (OS) in months, and Cox proportional hazard model for uni(UVA) and multivariate (MVA) hazard ratio (HR, 95%CI) analyses were performed.. Median OS of the study cohort was 7.7 (6.3-10.9) months. In UVA OS was prolonged for low C reactive protein (CRP) (13.5. Pretreatment inflammatory markers (CRP, SII) and AST were independent prognostic survival markers in patients with uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. A combination of factors may help to identify patients potentially benefitting from treatment.

Topics: Adult; Aged; Aged, 80 and over; Alanine Transaminase; Antineoplastic Agents; Aspartate Aminotransferases; Biomarkers, Tumor; Blood Platelets; C-Reactive Protein; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Lymphocytes; Male; Melanoma; Melphalan; Middle Aged; Neutrophils; Nitrosourea Compounds; Organophosphorus Compounds; Prognosis; Proportional Hazards Models; Retrospective Studies; Tumor Burden; Uveal Neoplasms

Isolated limb perfusion (ILP) is widely accepted as treatment for recurrent melanoma limited to the limbs. The use of ILP has decreased in recent years with the introduction of potentially effective new systemic therapies. We evaluated retrospectively if ILP still may be a treatment option in locally advanced melanoma. In Finland, ILP is centralized to the Comprehensive Cancer Center of Helsinki University Hospital. We included all ILP patients treated at our hospital between 2007 and 2018. Clinical factors and treatment outcomes were retrospectively evaluated. Altogether 60 patients received ILP. Toxicity was mostly transient. The overall response rate was 77% with 35% complete responses and 42% partial responses. The median progression-free survival (PFS) was 6.1 months (range 0.6-116.5 months) and the median melanoma-specific survival (MSS) was 29.9 months (range 3.5-138.7 months). Patients with CR had superior median PFS (19.7 months, range 2.5-116.5 vs. 4.5 months, range 0.6-39.7 months, P = 0.00003) and median MSS (median MSS not reached vs. 25.9 months, range 3.5-98.7 months, P = 0.0005) compared to other responders. Younger patients (<69 years) had longer median MSS (47.2 months, range 3.5-138.7 vs. 25.9 months, range 8.4-125.4 months, P = 0.015) compared to patients over 69 years. Treatment outcomes of Finnish ILP patients were comparable to earlier studies and some long-term survivors were observed in the group of complete responders. Median PFS and OS were longer for patients achieving a CR. Treatment was well-tolerated also among older patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Finland; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Perfusion; Retrospective Studies; Skin Neoplasms; Survival Rate; Time Factors; Treatment Outcome

Treatment strategies for advanced cutaneous melanoma (CM) patients, resistant or not treatable with novel target and immunotherapeutic drugs, remain a significant challenge, particularly for patients with unresectable stage IIIC/D disease localized to inferior limbs and pelvis, for whom specific outcomes are rarely considered.. This is a prospective study of multidisciplinary treatments, including locoregional melphalan chemotherapy, in 62 BRAF wild-type CM patients with locoregional metastases in the inferior limbs and pelvis, including inguinal regions. Patients were either in progression following or ineligible for, or not treatable with novel immunotherapy. For exclusively inferior limb-localised disease, patients received locoregional melphalan chemotherapy performed by hyperthermic isolated limb perfusion (n = 19) or isolated limb infusion (n = 19), and for synchronous lesions localised to inferior limbs and pelvis, received hypoxic pelvic and limb perfusion (n = 24). Additional multidisciplinary therapy included local, locoregional and systemic treatments and the primary endpoint was tumour response.. The objective response rate following first cycle of locoregional chemotherapy was 37.1% at 3 mo and median progression-free survival was 4-mo, with 12.9% procedure-related complications, 30.6% low-grade haematological toxicity and 11.3% severe limb toxic tissue reactions. Multivariate logistic regression showed that the odds of response were significantly higher for patients ≤ 75 y of age and for patients with locoregional metastases exclusively located in the inferior limbs.. In this subgroup of CM patients with BRAF wild-type status, locoregional metastases localized to inferior limbs and pelvis, in progression following or ineligible for immunotherapy, melphalan locoregional chemotherapy demonstrated a safe and effective profile.. ClinicalTrials.gov Identifier NCT01920516; date of trial registration: August 6, 2013.

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Infusions, Intra-Arterial; Melanoma; Melphalan; Prospective Studies; Proto-Oncogene Proteins B-raf; Skin Neoplasms

To report treatment of vitreous seeding of choroidal melanoma with monthly injections of intravitreal melphalan.. Case report.. A 70-year-old white woman noted floaters in her left eye, and further examination revealed visual acuity of 20/30 in both eyes. Funduscopically, there was a mushroom-shaped choroidal melanoma in her left eye, measuring 9 mm in basal dimension and 4.8 mm in thickness. Notably, there was apical retinal invasion of melanoma with mild vitreous hemorrhage, without vitreous seeding. The tumor was treated with iodine-125 plaque radiotherapy using an apex dose of 70 Gy over 99 hours, designed to include the retinal invasion. The melanoma demonstrated complete regression into a nearly flat scar of 1 mm and remained stable over 4 years. Five years after radiotherapy, there were diffuse vitreous pigmented seeds of presumed melanoma origin, emanating from the site of retinal necrosis. This progressively worsened over the following 18 months, suspicious for viable melanoma cells, as visual acuity concurrently declined to 20/100. Treatment with intravitreal melphalan (10 μg/0.05 mL) was delivered on a monthly basis for 12 cycles, resulting in vitreous seeds regression, and preservation of the eye. Final visual acuity was 20/200. There were no treatment-related complications.. Intravitreal melphalan can be considered in cases of vitreous seeding from uveal melanoma.

Topics: Aged; Antineoplastic Agents, Alkylating; Choroid Neoplasms; Female; Fluorescein Angiography; Humans; Intravitreal Injections; Melanoma; Melphalan; Neoplasm Seeding; Retinal Neoplasms; Retrospective Studies; Tomography, Optical Coherence; Vitreous Body

Melanoma risk is increased after allogeneic hematopoietic cell transplantation (HCT), but specific risk factors are unknown.. Investigate risk factors for melanoma after allogeneic hematopoietic cell transplantation.. We conducted a nested case-control study of 140 melanoma cases and 557 controls (matched by age at HCT, sex, primary disease, survival time) through the Center for International Blood and Marrow Transplant Research.. Melanoma risk was significantly increased among HCT survivors who received total body irradiation-based myeloablative conditioning (multivariable adjusted odds ratio [OR] = 1.77; 95% confidence interval [CI] = 1.00-3.15) or reduced-intensity conditioning containing melphalan (OR = 2.60; 95% CI = 1.13-6.02) or fludarabine (OR = 2.72; 95% CI = 1.02-7.30) versus busulfan-based myeloablative regimens; were diagnosed with acute graft-versus-host disease (GVHD) with stage 2+ skin involvement (OR = 1.92; 95% CI = 1.19-3.10), chronic GvHD without skin involvement (OR = 1.91; 95% CI = 1.03-3.57), or keratinocytic carcinoma (OR = 2.37; 95% CI = 1.16-4.83); and resided in areas with higher ambient ultraviolet radiation (ORtertile3 = 1.64; 95% CI = 1.01-2.67).. Data on individual-level ultraviolet radiation exposure and clinical data on melanoma characteristics were lacking. Additionally, misclassification of melanoma is possible as not all pathology reports were available for review.. These results emphasize the importance of adherence to current surveillance guidelines (routine skin examination, photoprotection recommendations), particularly for HCT survivors at highest risk.

Topics: Adolescent; Adult; Age Factors; Aged; Busulfan; Case-Control Studies; Child; Child, Preschool; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Karnofsky Performance Status; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Risk Factors; Skin; Skin Neoplasms; Tissue Donors; Transplantation Conditioning; Ultraviolet Rays; Vidarabine; Whole-Body Irradiation; Young Adult

Cutaneous melanoma metastatic to the vitreous is very rare. This study investigated the clinical findings, treatment, and outcome of patients with metastatic cutaneous melanoma to the vitreous. Most patients received checkpoint inhibition for the treatment of systemic disease, and the significance of this was explored.. Multicenter, retrospective cohort study.. Fourteen eyes of 11 patients with metastatic cutaneous melanoma to the vitreous.. Clinical records, including fundus photography and ultrasound results, were reviewed retrospectively, and relevant data were recorded for each patient eye.. Clinical features at presentation, ophthalmic and systemic treatments, and outcomes.. The median age at presentation of ophthalmic disease was 66 years (range, 23-88 years), and the median follow-up from diagnosis of ophthalmic disease was 23 months. Ten of 11 patients were treated with immune checkpoint inhibition at some point in the treatment course. The median time from starting immunotherapy to ocular symptoms was 17 months (range, 4.5-38 months). Half of eyes demonstrated amelanotic vitreous debris. Five eyes demonstrated elevated intraocular pressure, and 4 eyes demonstrated a retinal detachment. Six patients showed metastatic disease in the central nervous system. Ophthalmic treatment included external beam radiation (30-40 Gy) in 6 eyes, intravitreous melphalan (10-20 μg) in 4 eyes, enucleation of 1 eye, and local observation while receiving systemic treatment in 2 eyes. Three eyes received intravitreous bevacizumab for neovascularization. The final Snellen visual acuity ranged from 20/20 to no light perception.. The differential diagnosis of vitreous debris in the context of metastatic cutaneous melanoma includes intravitreal metastasis, and this seems to be particularly apparent during this era of treatment with checkpoint inhibition. External beam radiation, intravitreous melphalan, and systemic checkpoint inhibition can be used in the treatment of ophthalmic disease. Neovascular glaucoma and retinal detachments may occur, and most eyes show poor visual potential. Approximately one quarter of patients demonstrated ocular disease that preceded central nervous system metastasis. Patients with visual symptoms or vitreous debris in the context of metastatic cutaneous melanoma would benefit from evaluation by an ophthalmic oncologist.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Eye Neoplasms; Female; Humans; Immunotherapy; Male; Melanoma; Melanoma, Cutaneous Malignant; Melphalan; Middle Aged; Retrospective Studies; Skin Neoplasms; Vitreous Body; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Humans; Hyperthermia, Induced; Interferons; Leukocytes, Mononuclear; Melanoma; Melphalan; Perfusion; Tumor Necrosis Factor-alpha

Isolated limb infusion (ILI) is used to treat in-transit melanoma metastases confined to an extremity. However, little is known about its safety and efficacy in octogenarians and nonagenarians (ON).. ON patients (≥ 80 years) who underwent a first ILI for American Joint Committee on Cancer seventh edition stage IIIB/IIIC melanoma between 1992 and 2018 at nine international centers were included and compared with younger patients (< 80 years). A cytotoxic drug combination of melphalan and actinomycin-D was used.. Of the 687 patients undergoing a first ILI, 160 were ON patients (median age 84 years; range 80-100 years). Compared with the younger cohort (n = 527; median age 67 years; range 29-79 years), ON patients were more frequently female (70.0% vs. 56.9%; p = 0.003), had more stage IIIB disease (63.8 vs. 53.3%; p = 0.02), and underwent more upper limb ILIs (16.9% vs. 9.5%; p = 0.009). ON patients experienced similar Wieberdink limb toxicity grades III/IV (25.0% vs. 29.2%; p = 0.45). No toxicity-related limb amputations were performed. Overall response for ON patients was 67.3%, versus 64.6% for younger patients (p = 0.53). Median in-field progression-free survival was 9 months for both groups (p = 0.88). Median distant progression-free survival was 36 versus 23 months (p = 0.16), overall survival was 29 versus 40 months (p < 0.0001), and melanoma-specific survival was 46 versus 78 months (p = 0.0007) for ON patients compared with younger patients, respectively.. ILI in ON patients is safe and effective with similar response and regional control rates compared with younger patients. However, overall and melanoma-specific survival are shorter.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Australia; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Female; Humans; Length of Stay; Lower Extremity; Male; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasm Staging; Neoplasm, Residual; Progression-Free Survival; Skin Neoplasms; Treatment Outcome; Tumor Burden; United States; Upper Extremity

Chemosaturation with percutaneous hepatic perfusion (CS-PHP; Hepatic CHEMOSAT® Delivery System; Delcath Systems Inc, USA) is a novel interventional procedure, which delivers high doses of melphalan directly to the liver in patients with liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. We have previously shown promising efficacy for patients with ocular melanoma (OM) and cholangiocarcinoma (CCA) within our single-center and multi-center experiences. The aim of this study was to analyze the safety and efficacy of CS-PHP after 141 treatments at Hannover Medical School, Germany.. Overall response rates (ORR) were assessed according to Response Evaluation Criteria In Solid Tumors (RECIST1.1). Median Overall survival (mOS), median progression-free survival (mPFS), and median hepatic PFS (mhPFS) were analyzed using the Kaplan-Meier estimation.. Overall, 60 patients were treated with CS-PHP in the salvage setting from October 2014 until January 2019 at Hannover Medical School with a total of 141 procedures. Half of the patients were patients with hepatic metastases of ocular melanoma (OM) (n = 30), 14 patients had CCA (23.3%), 6 patients had hepatocellular carcinoma (10%), and 10 patients were treated for other secondary liver malignancies (16.7%). In total, ORR and disease stabilization rate were 33.3% and 70.3% (n = 25), respectively. ORR was highest for patients with OM (42.3%), followed by patients with CCA (30.8%). Independent response-associated factors were normal levels of lactate dehydrogenase (odds ratio (OR) 13.7; p = 0.015) and diagnosis with OM (OR 9.3; p = 0.028). Overall, mOS was 9 months, mPFS was 4 months, and mhPFS was 5 months. Patients with OM had the longest mOS, mPFS, and mhPFS with 12, 6, and 6 months, respectively. Adverse events included most frequently significant, but transient, hematologic toxicities (80% of grade 3/4 thrombopenia), less frequently hepatic injury up to liver failure (3.3%) and cardiovascular events including two cases of ischemic insults (5%).. Salvage treatment with CS-PHP is safe and effective particularly in patients OM and CCA. Careful attention should be paid to possible, serious hepatic, and cardiovascular complications.

Topics: Aged; Antineoplastic Agents, Alkylating; Bile Duct Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Cholangiocarcinoma; Female; Humans; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Progression-Free Survival; Retrospective Studies; Salvage Therapy; Uveal Neoplasms

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Eye Neoplasms; Humans; Liver Neoplasms; Melanoma; Melphalan; Perfusion

Isolated limb infusion (ILI) is a minimally-invasive procedure for delivering high-dose regional chemotherapy to treat melanoma in-transit metastases confined to a limb. The aim of this international multi-centre study was to identify predictive factors for toxicity and response.. Data of 687 patients who underwent a first ILI for melanoma in-transit metastases confined to the limb between 1992 and 2018 were collected at five Australian and four US tertiary referral centres.. After ILI, predictive factors for increased limb toxicity (Wieberdink grade III/IV limb toxicity, n = 192, 27.9%) were: female gender, younger age, procedures performed before 2005, lower limb procedures, higher melphalan dose, longer drug circulation and ischemia times, and increased tissue hypoxia. No patient experienced grade V toxicity (necessitating amputation). A complete response (n = 199, 28.9%) was associated with a lower stage of disease, lower burden of disease (BOD) and thinner Breslow thickness of the primary melanoma. Additionally, an overall response (combined complete and partial response, n = 441, 64.1%) was associated with female gender, Australian centres, procedures performed before 2005, lower limb procedures and lower actinomycin-D doses. On multivariate analysis, higher melphalan dose remained a predictive factor for toxicity, while lower stage of disease and lower BOD remained predictive factors for overall response.. ILI is safe and effective to treat melanoma in-transit metastases. Predictive factors for toxicity and response identified in this study will allow improved patient selection and optimization of intra-operative parameters to increase response rates, while keeping toxicity low.

Topics: Age Factors; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Australia; Chemotherapy, Cancer, Regional Perfusion; Creatine Kinase; Dactinomycin; Dose-Response Relationship, Drug; Female; Humans; Ischemia; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Sex Factors; Skin Neoplasms; Time Factors; Tourniquets; United States; Upper Extremity

Isolated limb infusion (ILI) is a minimally invasive procedure for delivering high-dose chemotherapy to extremities affected by locally advanced or in-transit melanoma. This study compared the outcomes of melanoma patients treated with ILI in the United States of America (USA) and Australia (AUS).. Patients with locally recurrent in-transit melanoma treated with ILI at USA or AUS centers between 1992 and 2018 were identified. Demographic and clinicopathologic characteristics were collected. Primary outcomes of treatment response, in-field progression-free survival (IPFS), distant progression-free survival (DPFS), and overall survival (OS) were evaluated by the Kaplan-Meier method. Multivariable analysis evaluated whether availability of new systemic therapies affected outcomes.. More ILIs were performed in AUS (n = 411, 60 %) than in the USA (n = 276, 40 %). In AUS, more ILIs were performed for stage 3B disease than in the USA (62 % vs 46 %; p < 0.001). The reported complete response rates were similar (AUS 30 % vs USA 29 %). Among the stage 3B patients, AUS patients had better IPFS (p = 0.001), whereas DPFS and OS were similar between the two countries. Among the stage 3C patients, the USA patients had better OS (p < 0.001), whereas IPFS and DPFS were similar. Availability of new systemic therapies did not affect IPFS or DPFS in either country. However, the USA patients who received ILI after ipilimumab approval in 2011 had significantly improved OS (hazard ratio, 0.62; p = 0.013).. AUS patients were treated at an earlier disease stage than the USA patients with better IPFS for stage 3B disease. The USA patients treated after the availability of new systemic therapies had a better OS.

Topics: Antineoplastic Combined Chemotherapy Protocols; Australia; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Male; Melanoma; Melphalan; Skin Neoplasms; United States

In recent years, the incidence of malignant melanoma has rapidly increased worldwide. Among patients with recurrences, approximately 5% develop in-transit metastases, which can potentially be treated with isolated limb perfusion (ILP). However, little is known about patient experiences with this treatment. A more thorough understanding might guide future research and clinical care. In this study, we aimed to describe patients' experiences of ILP treatment.. This study included eight patients who participated in a semi-structed interviewed, conducted at one occasion between 3 and 11 months after their ILP treatment. The mean interview duration was 26 min. Data were analyzed using qualitative inductive content analysis according to the methods of Elo-Kyngäs and Graneheim and Lundman.. Our analysis yielded three categories, each built on two subcategories: positive experiences after ILP treatment emerged from the sub-categories reduced tumor burden and living a less restricted life; negative experiences after ILP was built on the subcategories fear of relapse and complications and side effects; and experiences of healthcare was founded on the subcategories need for correct information and being viewed as sicker then experienced.. Participants showed greater focus on the healthy parts of their lives, even when negative symptoms occurred after ILP treatment. They also described how healthcare workers focused on their illness. Based on these findings, we suggest the following means of providing good nursing care to ILP patients: give correct information, strive to reduce patients' negative symptoms, support their daily living needs, and provide emotional support to reduce fear of recurrence.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melanoma; Melanoma, Cutaneous Malignant; Melphalan; Middle Aged; Patient Satisfaction; Qualitative Research; Skin Neoplasms; Treatment Outcome

In patients undergoing percutaneous liver perfusion with melphalan (M-PHP), the presence of variant hepatic arteries (HAs) may require catheter repositioning and thus prolong procedure time. Coil-embolization of variant HAs may enable M-PHP with a single catheter position as occlusion of variant HAs results in redistribution of flow through preexisting intrahepatic arterial collaterals. We aimed to evaluate whether redistribution of flow has any negative effect on therapeutic response in ocular melanoma patients undergoing M-PHP.. We retrospectively analyzed pretreatment angiograms in all 32 patients that underwent M-PHP between January 2014 and March 2017 for unresectable liver metastases from ocular melanoma. Patients that underwent embolization of a variant left HA (LHA) or middle HA (MHA) during pretreatment angiography followed by at least one technically successful M-PHP were included for further analysis. Redistribution of arterial flow was evaluated on angiography and cone-beam computed tomography (CBCT) images. In each patient, tumor response in liver segments with redistributed blood flow was evaluated using RECIST 1.1 and mRECIST, and then compared with tumor response in segments without flow redistribution. Follow-up scans were reviewed to evaluate progression of liver metastases.. A total of 12 patients were included. Replaced LHA embolization resulted in redistribution of flow to segment(s) 2 (n=3), 2 and 3 (n=5), and 2, 3 and 4 (n=2). MHA embolization resulted in redistribution of flow to segment 4 (n=2). Successful redistribution was confirmed by angiography and/or CBCT in all patients. Tumor response was similar for redistributed and non-redistributed liver segments in 8 out of 9 patients (89%) according to RECIST 1.1, and in 7 out of 8 patients (88%) according to mRECIST. In three patients, tumor response was not evaluable according to RECIST 1.1 or mRECIST as metastases were too small to be categorized as target lesions (n=1), or target lesions were confined to non-redistributed segments (n=2). In one patient, tumor response was not evaluable according to mRECIST as target lesions in the redistributed segments were hypovascular. After a median follow-up time of 17.1 months (range, 9.1-38.5 months), hepatic progression was seen in 9 out of 12 patients with a median time to progression of 9.9 months (range, 2.5-17.7 months). Progression of liver metastases was never seen only in the redistributed liver segments.. Flow redistribution in liver segments by coil-embolization of variant HAs is a feasible technique that does not seem to compromise tumor response in patients undergoing M-PHP.

Topics: Adult; Aged; Angiography; Antineoplastic Agents, Alkylating; Cone-Beam Computed Tomography; Embolization, Therapeutic; Eye Neoplasms; Female; Hepatic Artery; Humans; Liver; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Perfusion; Regional Blood Flow; Retrospective Studies

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Infusions, Intravenous; Melanoma; Melphalan

Isolated limb perfusion (ILP) is a safe and well-established treatment for in-transit metastases of melanoma. In case of relapse or disease progression, ILP can be repeated (re-ILP). This study aimed retrospectively to analyze a large consecutive series of re-ILP and compare clinical outcomes with first-time ILP.. Between 2001 and 2015, 290 consecutive patients underwent 380 ILPs. Of these, 90 were re-ILPs including 68 second ILPs, 16 third ILPs, 4 fourth ILPs, and two fifth ILPs. The study evaluated response (using World Health Organization [WHO] criteria), local toxicity (using the Wieberdink scale), and complications (using Clavien-Dindo).. The results were compared between the first ILP, the second ILP, and the third to fifth ILP. The overall response rate was respectively 83%, 80% and 68%, with a complete response (CR) rate of 60%, 41%, and 59%. In the re-ILP group, the patients with a CR after the first ILP had a 65% CR rate after the second ILP compared with 8% for the patients without a CR (p = 0.001). The risk for local toxicity or complications was not increased after re-ILP. The median overall survival periods were respectively 34, 41, and 93 months (p = 0.02).. As a therapeutic option, ILP can be repeated safely for in-transit metastases of melanoma, achieving similar high response rates without increasing complications or toxicity. Re-ILP is mainly indicated for patients who already had a CR after the first ILP, whereas other treatment options should be considered for primary non-responders.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Extremities; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Retrospective Studies; Skin Neoplasms; Survival Rate; Young Adult

Isolated limb infusion (ILI) is a minimally invasive treatment for patients with locally advanced extremity melanoma. Most studies combine results of upper-limb ILI (UL-ILI) and lower-limb ILI (LL-ILI), leaving UL-ILIs relatively underreported as LL-ILIs comprise the vast majority in these reports. However, differences between the two procedures may be clinically important. The aim of this study was to evaluate the efficacy and toxicity of UL-ILI in an Australian multi-center setting.. 316 ILI procedures for melanoma performed between 1992 and 2008 in five Australian institutions were analyzed. In all institutions melphalan (±actinomycin D) was circulated in the isolated limb for 20-30 min.. Baseline patient characteristics for UL-ILI (n = 27) and LL-ILI (n = 289) were similar, except that more men underwent UL-ILI (66% vs. 38%; p = 0.007) and disease in LL-ILI was mostly located on the distal limb (p = 0.02). Median tourniquet times were shorter for UL-ILI (38 vs. 48 min; p = 0.04) and UL-ILI patients experienced less limb toxicity (Grade III/IV in 24% vs. 31%; p = 0.01). Complete response (CR) rates were similar: 33% after LL-ILI (p = 0.70), 30% after UL-ILI, while overall response (OR) rates were higher after LL-ILI: (76%) than UL-ILI (59%; p = 0.05). No difference in survival was seen.. UL-ILI is safe to perform and effective, resulting in low limb toxicity. CR rates were similar to those for LL-ILI, but OR rates were lower for UL-ILI. It may be possible to improve OR rates achieved by UL-ILI by optimizing perioperative factors, while maintaining low toxicity.

Topics: Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Australia; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Female; Humans; Lymph Node Excision; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Prospective Studies; Skin Neoplasms; Upper Extremity

To investigate the outcome and safety data of chemosaturation with percutaneous hepatic perfusion (CS-PHP) of melphalan in patients with liver-dominant metastatic uveal melanoma.. This is a HIPAA compliant, IRB approved, retrospective study. A total of 28 CS-PHPs were performed in 16 individual patients (six men and ten women, median age 63.1 years [range 49.1 to 78.7 years], one to six CS-PHP procedures per patient) for treatment of liver-dominant metastatic uveal melanoma between June, 2015 and December, 2018. All patients received cross-sectional imaging at baseline and during follow-up. CS-PHP was performed with the Hepatic CHEMOSAT® Delivery System (Delcath Systems, Inc., NY, USA) facilitating extracorporeal filtration of hepatic blood for melphalan removal. Ideal body weight-adjusted melphalan doses were administered into the hepatic arteries. Serious adverse events (SAE), progression-free survival based on response criteria in solid tumors, and overall survival were noted. Survival data were analyzed using Kaplan-Meier estimates.. Partial response after first CS-PHP was observed in nine patients (60%), stable disease in five patients (33%) and progressive disease in one patient (7%). Median overall survival was 27.4 months (95% CI 4.1 to 35.4 month) after first CS-PHP. Median progression-free survival was 11.1 months after first CS-PHP (95% CI 4.9 to 23.6 months). SAEs were observed in the majority of patients with most SAEs limited to grades one and two. Thirteen SAEs of grades three and four were observed in seven individual patients. No grade five SAE was observed.. CS-PHP is an efficacious and safe treatment for patients presenting with liver-dominant metastatic uveal melanoma.

Topics: Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Liver Circulation; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Uveal Neoplasms

1-O-alkylglycerols (AKG) are a class of natural ether lipids derived from 1-O-alkyl-2,3-diacyl-sn-glycerols by deacylation. In this study, 1-O-alkylglycerol (AKG) composition was investigated in the hepatopancreas lipids of the crab Paralithodes camtschaticus and the liver lipids of the squid Berryteuthis magister and the skate  Bathyraja parmifera. One of the principal AKG in marine organisms was 1-O-hexadecyl-sn-glycerol (AKG 16:0). To assess AKG influence on melanoma, we evaluated the cytotoxicity and antiproliferative actions of natural AKG 16:0 and synthetic 1-O-octyl-sn-glycerol (AKG 8:0) on three human melanoma cell lines SK-Mel-5, SK-Mel-28, and RPMI-7951. Natural AKG 16:0 in concentration up to 20 µM was not toxic to all cell lines. AKG 8:0 showed no toxicity to cells SK-Mel-5 and SK-Mel-28 in concentrations up to 20 µM but had moderate cytotoxicity to RPMI-7951 cells with an IC

Topics: Animals; Anomura; Decapodiformes; Glyceryl Ethers; Hepatopancreas; Humans; Immunoglobulin G; Liver; Melanoma; Melphalan; Skates, Fish

Isolated limb perfusion is the treatment of stage III melanoma with in-transit metastasis. This technique allows the administration of cytostatics at an effective concentration and temperature, which could not be administered systemically because of their toxicity. The toxicity due to leakage of the chemotherapy agent from the limb into the systemic circulation is the most serious short-term complication, and is manifested by a systemic inflammatory response syndrome in the immediate post-intervention period. Early detection of this complication and its peri-operative management requires a multidisciplinary approach, in which the anaesthesiologist plays a key role. A case of isolated lower limb perfusion is reported in which the procedure had to be interrupted due to the passage of tumour necrosis factor into the systemic circulation, with severe intra-operative haemodynamic repercussions.

Topics: Acid-Base Imbalance; Aged; Antineoplastic Combined Chemotherapy Protocols; Bicarbonates; Calcium; Chemotherapy, Cancer, Regional Perfusion; Epinephrine; Extravasation of Diagnostic and Therapeutic Materials; Female; Humans; Hyperthermia, Induced; Hypotension; Intraoperative Complications; Leg; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Melphalan; Methylene Blue; Norepinephrine; Skin Neoplasms; Tachycardia; Tumor Necrosis Factor-alpha

This study was designed to evaluate the efficacy of isolated limb infusion (ILI) treatment in Chinese patients with in-transit melanoma and to identify factors predictive of the outcome.. A total of 150 patients with in-transit melanoma who received a single ILI between 2007 and 2016 were identified from a prospectively collected database.. All patients had AJCC Stages IIIb, IIIc, and IV disease. Acral lentiginous melanoma (ALM) accounted for 79% of patients, and 59% had a high burden of disease (BOD). The complete response (CR) and partial response (PR) rates were 6 and 35%, respectively. Forty-five percent of patients experienced grade III-IV limb toxicities, but no grade V toxicity was observed. Patients with a low BOD, high limb temperature, high peak creatine phosphokinase (CK) level, and grade III-IV limb toxicity achieved higher response rates. Stage IV disease and high BOD were associated with worse infield progression-free survival (PFS) and overall survival (OS), whereas patients with CR or PR to ILI had better infield PFS and OS. Multivariate analyses showed that disease stage, BOD, and a CR were independent predictors of infield PFS, whereas disease stage and a response to ILI were independent predictors of OS.. ILI is well-tolerated but the response rate in Chinese patients was lower than that reported in US and Australian studies. The prevalence of the ALM histological type, advanced disease stages, and a high BOD may be the main reasons for this. A response to ILI, BOD, and disease stage are prognostic factors for survival.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; China; Dactinomycin; Extremities; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Middle Aged; Prospective Studies; Survival Rate; Treatment Outcome; Young Adult

Metastatic uveal melanoma (UM) carries a poor prognosis; liver is the most frequent and often solitary site of recurrence. Available systemic treatments have not improved outcomes. Melphalan percutaneous hepatic perfusion (M-PHP) allows selective intrahepatic delivery of high dose cytotoxic chemotherapy.. Retrospective analysis of outcomes data of UM patients receiving M-PHP at two institutions was performed. Tumor response and toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) v4.03, respectively.. A total of 51 patients received 134 M-PHP procedures (median of 2 M-PHPs). 25 (49%) achieved a partial (N = 22, 43.1%) or complete hepatic response (N = 3, 5.9%). In 17 (33.3%) additional patients, the disease stabilized for at least 3 months, for a hepatic disease control rate of 82.4%. After median follow-up of 367 days, median overall progression free (PFS) and hepatic progression free survival (hPFS) was 8.1 and 9.1 months, respectively and median overall survival was 15.3 months. There were no treatment related fatalities. Non-hematologic grade 3-4 events were seen in 19 (37.5%) patients and were mainly coagulopathic (N = 8) and cardiovascular (N = 9).. M-PHP results in durable intrahepatic disease control and can form the basis for an integrated multimodality treatment approach in appropriately selected UM patients.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Follow-Up Studies; Humans; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Rare Diseases; Retrospective Studies; Survival Rate; Uveal Neoplasms

Isolated limb perfusion (ILP) is used to treat in-transit metastases of melanoma of the extremities when surgical excision is not possible. The optimal setting concerning temperature and perfusion time is unknown. The purpose of this study was to analyze these factors concerning their effects on response, toxicity, and survival.. A retrospective analysis of 284 consecutive stage III melanoma patients treated with melphalan ILP for the first time in our institution, during a 31-year period (July 1986-May 2017), was performed. Our series was divided in four time periods, according to perfusion temperature and duration. Demographical data, stage, number, and size of lesions were retrieved from our prospective database.. Overall response (OR) rate 83% and a complete response (CR) rate of 59%. Significant predictive factors for CR in multivariate analysis were non-bulky tumor, fewer metastases, and a perfusion time of 120 min. Predictive factors for increased local toxicity were femoral ILP and higher perfusion temperatures. The median overall survival was 30 months, and the independent negative prognostic factors were lymph-node status, bulky tumors, response, upper limb perfusion, and 120 min perfusion at 39-40 °C.. Modern ILP uses diminished perfusion time and lower temperature, leading to a decrease in toxicity. However, our data also show a decrease in response, which indicates that optimal perfusion time and temperature regimen remain to be determined.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Male; Melanoma; Melanoma, Cutaneous Malignant; Melphalan; Middle Aged; Prognosis; Prospective Studies; Remission Induction; Retrospective Studies; Skin Neoplasms; Survival Rate; Temperature; Young Adult

Ocular melanoma has a predilection for liver metastases. Systemic treatment is ineffective and the optimal regional therapy approach is poorly defined. Isolated hepatic perfusion (IHP) with melphalan has emerged as a viable treatment option, however a subset of patients are not candidates for this treatment. We therefore sought to determine if melphalan could be safely administered via the hepatic artery for these patients.. A retrospective review of patients treated with hepatic artery infusion (HAI) of melphalan was undertaken. All patients had contraindications to IHP and were without other therapy options. Melphalan infusion was repeated every four weeks with consideration for dose escalation in the absence of toxicity or significant disease progression.. Fourteen patients were treated with HAI of melphalan from 2010 to 2015. All patients had hepatic dysfunction or prohibitive tumor volume precluding IHP. There were no procedure-related complications. Three patients (21%) died within 30 days and the median survival was 2.9 months. Elevated baseline bilirubin > 2.5 mg/dL was associated with worse overall survival (0.93 vs 6.3 months, P < 0.05).. HAI of melphalan is safe and feasible for patients with metastatic ocular melanoma. Further study to determine the optimal utilization of this treatment approach is warranted.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Eye Neoplasms; Female; Follow-Up Studies; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Retrospective Studies; Treatment Outcome

Isolated limb perfusion (ILP) is a well-established treatment for patients with advanced extremity malignancies unsuitable for limb-conserving surgery. However, little is known about the outcomes of this treatment in elderly patients. We sought to determine the effects of age on the tolerability and efficacy of ILP for advanced extremity malignancy.. Patients undergoing ILP at our institution between January 2005 and January 2018 were identified from a prospectively maintained database. Patients were stratified by pathology (melanoma, soft-tissue sarcoma, other) and age (<75 years and ≥75 years). Outcomes of interest were perioperative morbidity and mortality, locoregional toxicities, response rates and oncological outcomes.. During the study period, a total of 189 perfusions were attempted. Successful perfusions were performed in 179 patients, giving a technical success rate of 94.7%. No difference in perfusion success rates, severe locoregional toxicity and perioperative morbidity or mortality was noted between those aged <75 years and ≥75 years. The overall response rate in melanoma was 82.4%, and no difference in response rates or oncological outcomes between age groups was noted in these patients. The overall response rate in soft-tissue sarcoma was 63.5%, with no difference in response rates noted between age groups. However, patients aged <75 years with soft-tissue sarcoma had prolonged local recurrence-free survival compared with older patients (13 versus 6 months), possibly due to the prevalence of chemosensitive subtypes in the younger age group.. ILP is an effective treatment for advanced extremity malignancies in the elderly, with comparable response rates and toxicities to younger patients.

Topics: Age Factors; Aged; Chemotherapy, Cancer, Regional Perfusion; Databases, Factual; Disease Progression; Extremities; Female; Humans; Male; Melanoma; Melphalan; Neoplasm Recurrence, Local; Progression-Free Survival; Regional Blood Flow; Risk Factors; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Approximately 25% of melanoma patients with locoregional metastases are nonresponsive to new molecular target therapy and immunotherapy. When metastases are located in the pelvis, melphalan hypoxic perfusion can be an optional treatment. Because methylation of MGMT promoter increases the efficacy of alkylating agents, studies on melanoma outcome of patients treated with melphalan regional chemotherapy should consider this epigenetic change. This study aims to evaluate whether the survival of stage III melanoma patients treated with melphalan regional chemotherapy may be correlated with MGMT methylation status. The metastatic tissues of 27 stage III melanoma patients with locoregional metastases located in the pelvis subjected to melphalan hypoxic pelvic perfusion were examined. The methylation status of the MGMT promoter was investigated by MS-MLPA probes analysis and the presence of the BRAF V600E mutation was analyzed by CAST-PCR. The median survival times were estimated using the Kaplan-Meier curves and were stratified according to the clinicopathological characteristics of patients and lesions. The overall median survival time was 17 months. The 1-year, 3-year, and 5-year survival rates were 66.7, 18.5, and 7.4%, respectively. Disease stage, burden, and percentage of MGMT methylation significantly affected survival. We estimated an MGMT promoter methylation cut-off of at least 14%, which was significantly associated with a longer survival after melphalan regional chemotherapy. Our data suggest that MGMT promoter methylation could be an important factor in determining which melanoma patients should receive melphalan regional chemotherapy, but its prognostic significance in the routine clinical setting needs to be clarified in a larger study.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Pelvic Neoplasms; Pilot Projects; Prognosis; Promoter Regions, Genetic; Retrospective Studies; Survival Analysis; Tumor Suppressor Proteins

Isolated limb infusion (ILI) offers a minimally invasive treatment option for locally advanced extremity melanoma.. The aim of the current study was to evaluate the safety and efficacy of ILI in elderly patients in an Australian multicenter setting.. The results of 316 first ILI procedures, performed between 1992 and 2008 in five Australian institutions, were identified and analyzed, with the main focus on elderly patients (≥75 years of age). All institutions used the same protocol: melphalan was circulated in the isolated limb for 20-30 min (±actinomycin D), and toxicity, responses, and survival were recorded.. Characteristics of patients aged ≥75 years (n = 148) were similar to those aged <75 years (n = 168), except that older patients had more melanoma deposits (median 4 vs. 5; p = 0.035) and lower limb volumes (5.4 vs. 6.5 L; p = 0.001). Median drug circulation times were lower in the older group (21 vs. 24 min; p = 0.04), and older patients experienced less limb toxicity (grade III/IV in 22 and 37% of patients, respectively; p = 0.003). A complete response (CR) was seen in 27% of patients aged ≥75 years and in 38% of patients aged <75 years (p = 0.06), while overall response rates were 72 and 77%, respectively (p = 0.30). No difference in survival was seen (p = 0.69).. The ILI technique proved safe and effective in elderly patients. When present, toxicity was localized, and lower compared with younger patients, possibly due to shorter drug circulation times. CR rates were higher in younger patients, although not significantly, while overall response and survival were equal. Optimization of perioperative factors in elderly patients may allow response rates to be raised further, while maintaining low toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Australia; Chemotherapy, Cancer, Regional Perfusion; Extracorporeal Circulation; Female; Follow-Up Studies; Humans; Lower Extremity; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Skin Neoplasms; Survival Rate

Pelvic Melanoma relapse occurs in 15% of patients with loco regional metastases, and 25% of cases do not respond to new target-therapy and/or immunotherapy. Melphalan hypoxic pelvic perfusion may, therefore, be an option for these non-responsive patients. Overall median survival time (MST), stratified for variables, including BRAF V600E mutation and eligibility for treatments with new immunotherapy drugs, was retrospectively assessed in 41 patients with pelvic melanoma loco regional metastases. They had received a total of 175 treatments with Melphalan hypoxic perfusion and cytoreductive excision. Among the 41 patients, 22 (53.7%) patients exhibited a wild-type

Topics: Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Cohort Studies; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Pelvic Neoplasms; Pelvis; Proto-Oncogene Proteins B-raf; Retrospective Studies; Survival Analysis

Percutaneous isolated hepatic perfusion (PIHP) with Melphalan has been developed as a treatment for patients with isolated hepatic metastases of uveal melanoma. We discuss patient outcome and safety in a retrospective multi-centre study.. Between 2012 and 2016 18 patients with un-resectable isolated hepatic metastases of uveal melanoma received single or repeated PIHP with Melphalan (n = 35) at seven sites. Progression-free time, overall survival time (OS) and tumour response by means of RECIST 1.1 criteria were evaluated. Peri- and post-procedural adverse events (AE) were registered. Patients' life quality was assessed using four-point scale questionnaires.. Of 18 patients, initial PIHP treatment resulted in partial response (PR) in eight, stable disease (SD) in seven and progressive disease (PD) in three cases. Nine patients underwent second PIHP with PR in eight cases and PD in one case. Six patients were evaluated after third PIHP with PR in five patients and SD in one patient. Two patients received fourth PIHP with PD in both cases. Median OS was 9.6 months (range 1.6-41.0 months). Median progression-free survival time was 12.4 months (range 0.9-41.0 months) with 1-year survival of 44%. Most common post-procedural AE grade 3 and 4 were temporary leukopenia (n = 11) and thrombocytopenia (n = 8). Patients' self-assessments showed good ratings for overall health and quality of life with only slight changes after PIHP, and a high degree of satisfaction with PIHP treatment.. PIHP with Melphalan proved to be a relatively safe, minimal-invasive and repeatable treatment for patients with non-resectable hepatic metastases of uveal melanoma.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Female; Follow-Up Studies; Humans; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Quality of Life; Retrospective Studies; Survival Rate; Uveal Neoplasms

Data on isolated limb perfusion (ILP) in elderly melanoma patients are scarce. We aimed to evaluate the efficacy and safety of ILP in our institutional cohort of melanoma patients.. We performed retrospective analysis of stage IIIB/C melanoma patients who underwent ILP for melanoma in-transit metastases (ITMs) in our institution between 2000 and 2016. Normothermic ILP was performed with either melphalan or melphalan and tumor necrosis factor. Baseline and treatment characteristics, locoregional progression-free survival (LPFS) and melanoma-specific survival (MSS) were assessed and prognostic factors for response, recurrence, and survival were analyzed using univariable and multivariable analysis.. Overall, 91 patients were included in this study. Based on the median age of 70 years, we split patients into younger and elderly groups. No differences in response rates were observed between age groups, with an overall response rate of 81% and complete response (CR) rate of 47%. LPFS did not differ between age groups, and median LPFS was 16 months for patients with a CR. Median MSS was 38 months and differed between younger (45 months) and elderly patients (18 months). Toxicity was generally mild and did not differ between age groups. Two patients (2.2%) suffered Wieberdink IV toxicity, while no patients required amputation because of severe toxicity. CR was prognostic for improved LPFS and MSS, while patients >70 years of age and patients with stage IIIC disease had a higher risk of melanoma-specific death.. Because of its safety profile and high CR rates, ILP is a viable option for patients with bulky or multiple melanoma ITMs, including elderly (>70 years of age) patients.

Topics: Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Patient Safety; Retrospective Studies; Survival Rate; Treatment Outcome

Despite advances in cross-sectional imaging, chemotherapeutic dosing for isolated limb infusion (ILI) in melanoma is currently calculated through cumbersome and potentially imprecise manual measurements. The primary objective of this study was to examine the feasibility of using computed tomography (CT) to calculate limb volume, its concordance with manual measurement, and its ability to predict clinical response and toxicity in patients undergoing ILI.. A retrospective analysis of all patients undergoing lower extremity ILI at Duke University Medical Center between 2003 and 2014 was performed. Data pertaining to manually measured limb volume, chemotherapeutic dosing, and patient outcome was obtained. CT-based measurements of limb volume were performed in all patients for whom imaging was available and subsequently compared with manually measured values.. CT data were sufficient for measurement in 73 patients. The mean measurement time was 4.61 ± 2.13 min. Although average CT-based measurements were 1.20 L higher in the case of lower limbs, they correlated well with those obtained manually (r (2) = 0.90). Unlike manual measurement, patients with complete responses to chemotherapy had smaller limb volumes than those with disease progression as measured by CT (9.3 vs. 10.7 L; p = .038). Patients suffering grade 3 and 4 toxicities also had statistically lower limb volumes as measured by CT than those who did not (p < .05).. CT-based limb volume measurement is feasible for chemotherapy dosing in patients undergoing ILI for melanoma and has predictive value with respect to clinical response and toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Disease Progression; Feasibility Studies; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Lower Extremity; Melanoma; Melphalan; Neoplasm Staging; Prognosis; Retrospective Studies; Skin Neoplasms; Tomography, X-Ray Computed

Isolated limb infusion (ILI) offers a less invasive alternative to isolated limb perfusion (ILP) for the treatment of locally advanced extremity melanoma. In Australia, ILI has essentially completely replaced ILP. The aim of this study was to collect and evaluate the results of ILI in an Australian multicenter setting.. The results of 316 first ILI procedures, performed between 1992 and 2008 in five Australian institutions, were collectively analyzed, with all five institutions using the same protocol. Melphalan was circulated in the isolated limb for 20-30 min (±actinomycin D). Response was determined using the World Health Organization criteria, and limb toxicity was assessed using the Wieberdink scale.. The median patient age was 74 years (range 28-100) and 59 % of patients were female. Overall response rate was 75 % (complete response [CR] 33 %; partial response 42 %). Stable disease was seen in 18 % of patients and progressive disease in 7 %. Wieberdink grade III or higher was seen in 30 % of the cases. No toxicity-related amputations occurred, and median survival was 44 months. In patients with a CR, median survival was 80 months (p = 0.014). On multivariate analysis, Breslow thickness, lower-limb ILI, and a procedure performed at the Melanoma Institute Australia remained significant predictors for response, although not for survival.. This Australian multicenter study of ILI is the largest reported to date. ILI is a useful technique that can be safely and effectively performed across tertiary referral centers for the successful management of advanced extremity melanoma. Increased optimization of perioperative factors might allow response rates to be raised further, while maintaining acceptable toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Australia; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Female; Follow-Up Studies; Humans; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Prospective Studies; Skin Neoplasms; Survival Rate

This report describes the outcomes and long-term follow-up data from all isolated hepatic perfusions (IHPs) performed at a single institution in Sweden between the years 1989 and 2013 for patients with isolated uveal melanoma metastases.. A total of 68 patients (median age, 61 years) were treated consecutively at Sahlgrenska University Hospital. Of the 68 patients, 67 % had fewer than 10 tumors. The median diameter of the largest lesion was 2.5 cm. The patients underwent IHP with either melphalan alone or the addition of either tumor necrosis factor-alpha or cisplatin. The response was assessed after 8-12 weeks by computed tomography or magnetic resonance imaging.. The overall response rate was 67 and 20 % of the patients had a complete response. The median times to local and systemic progression were respectively 10 and 14 months. The prognostic factors for time to local recurrence were response and number of tumors. The median survival time was 22 months. The prognostic factors for survival were response, largest tumor diameter, and number of tumors. Five patients (7 %) died within 30 days, and six patients (9 %) experienced major complications (Clavien-Dindo 3/4).. Isolated hepatic perfusion is a treatment option with high response rates and tolerable mortality and morbidity. Whether IHP has a survival benefit compared with other treatment options currently is being investigated in a randomized trial.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Extracorporeal Circulation; Female; Follow-Up Studies; Humans; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Prognosis; Survival Rate; Tumor Necrosis Factor-alpha; Uveal Neoplasms; Young Adult

The incidence of malignant melanoma is increasing, and up to 5 % of patients will experience in-transit metastases. Normally, the initial treatment is surgical excision, but when not possible, locoregional treatment options such as isolated limb perfusion (ILP) are an alternative. This study aimed to assess health-related quality of life (HRQoL) prospectively for patients whose in-transit metastases is treated with ILP. More specifically, the study aimed to describe HRQoL for patients with in-transit extremity melanoma metastases, to describe changes in HRQoL after ILP, and to correlate HRQoL with local toxicity and clinical response after ILP.. The Functional Assessment of Cancer Therapy-Melanoma (FACT-M) consists of 51 items comprising the Functional Assessment of Cancer Therapy-General (FACT-G), the melanoma subscale , and the melanoma surgery scale. Forty-five patients answered the FACT-M questionnaire before ILP (52 procedures) and at 3, 6 and 12 months after ILP. Response and toxicity were analyzed and correlated with the changes in the HRQoL of the patients.. Patients with in-transit metastasis have an HRQoL mainly influenced by tumor burden, defined as more or <10 tumors (FACT-M: 142.5 vs. 128.4 points; p = 0.02). After ILP, there was a trend toward a decrease in FACT-G (+0.1 vs. -7.3 points; p = 0.05) and FACT-M (+1.6 vs. -8.9 points; p = 0.08) when Wieberdink classifications 1-2 and 3-4 were compared at 3 months. A significant difference in FACT-G (+1.0 vs. -13.0 points; p = 0.04) was observed 12 months after ILP as well as a trend for FACT-M (+1.7 vs. -14.6 points; p = 0.08) when the patients who had a complete response were compared with those who did not.. This study found that patients with in-transit metastases have an HRQoL mainly influenced by tumor burden. After ILP, there is an initial decrease in HRQoL due to local toxicity. After 12 months, the patients with a complete response maintained an HRQoL at baseline level, strengthening the use of ILP as a palliative treatment.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Quality of Life; Remission Induction; Skin Neoplasms

Isolated limb perfusion (ILP) and infusion (ILI) are therapeutic modalities for the treatment of in transit melanoma.. A retrospective review of all patients undergoing first-time ILI or ILP for in-transit melanoma metastases between 2007 and 2015 was performed. Demographic and clinical characteristics included age, sex, nodal status at the time of ILI/ILP (N-stage), and burden of disease (BOD). Regional toxicity was categorized by the Wieberdink classification. Clinical response was evaluated at 3 months after treatment.. A total of 203 patients were reviewed (ILI = 94, ILP = 109). There were no differences in age, sex, or N-stage between groups; however, BOD was higher for the ILI group (high BOD 58 vs. 44 %, p = 0.04). Regional toxicity was minimal (Grade IV < 1 % in ILI and 2 % in ILP, p = 0.40). Overall response rate (ORR) was 53 % for ILI versus 80 % for ILP (p < 0.001). Median overall survival (OS) was 46 months for ILI versus 40 months for ILP (p = 0.31). A high BOD [hazard ratio (HR) 3.02, 95 % confidence interval (CI) 1.85-4.93, p < 0.001] and N3 disease (HR 1.58, 95 % CI 1.01-2.48, p = 0.04) were associated with worse OS, whereas there was no difference in OS by procedure (p = 0.20).. ILP offers an improved ORR, but this does not translate into improved local PFS or OS. Both procedures are well tolerated with minimal regional toxicity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Prognosis; Retrospective Studies; Skin Neoplasms; Survival Rate

Hyperthermic isolated limb perfusion (HILP) can be performed as an alternative to amputation for soft tissue sarcomas and melanomas of the extremities. Melphalan and tumor necrosis factor-alpha are used at a dosage that depends on the volume of the limb. Regional tissue volume is traditionally measured for the purposes of HILP using water displacement volumetry (WDV). Although this technique is considered the gold standard, it is time-consuming and complicated to implement, especially in obese and elderly patients.. The aim of the present study was to compare the different methods described in the literature for calculating regional tissue volume in the HILP setting, and to validate an open source software.. We reviewed the charts of 22 patients (11 males and 11 females) who had non-disseminated melanoma with in-transit metastases or sarcoma of the lower limb. We calculated the volume of the limb using four different methods: WDV, tape measurements and segmentation of computed tomography images using Osirix and Oncentra Masterplan softwares.. The overall comparison provided a concordance correlation coefficient (CCC) of 0.92 for the calculations of whole limb volume. In particular, when Osirix was compared with Oncentra (validated for volume measures and used in radiotherapy), the concordance was near-perfect for the calculation of the whole limb volume (CCC = 0.99). With methods based on CT the user can choose a reliable plane for segmentation purposes. CT-based methods also provides the opportunity to separate the whole limb volume into defined tissue volumes (cortical bone, fat and water).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Drug Dosage Calculations; Female; Humans; Hyperthermia, Induced; Image Processing, Computer-Assisted; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Organ Size; Positron Emission Tomography Computed Tomography; Sarcoma; Soft Tissue Neoplasms; Tomography, X-Ray Computed; Tumor Necrosis Factor-alpha

High heparanase expression is associated with enhanced tumor growth, angiogenesis, and metastasis in many types of cancer. However, the mechanisms driving high heparanase expression are not fully understood. In the present study, we discovered that drugs used in the treatment of myeloma upregulate heparanase expression. Frontline anti-myeloma drugs, bortezomib and carfilzomib activate the nuclear factor-kappa B (NF-κB) pathway to trigger heparanase expression in tumor cells. Blocking the NF-κB pathway diminished this chemotherapy-induced upregulation of heparanase expression. Activated NF-κB signaling was also found to drive high heparanase expression in drug resistant myeloma cell lines. In addition to enhancing heparanase expression, chemotherapy also caused release of heparanase by tumor cells into the conditioned medium. This soluble heparanase was taken up by macrophages and triggered an increase in TNF-α production. Heparanase is also taken up by tumor cells where it induced expression of HGF, VEGF and MMP-9 and activated ERK and Akt signaling pathways. These changes induced by heparanase are known to be associated with the promotion of an aggressive tumor phenotype. Importantly, the heparanase inhibitor Roneparstat diminished the uptake and the downstream effects of soluble heparanase. Together, these discoveries reveal a novel mechanism whereby chemotherapy upregulates heparanase, a known promoter of myeloma growth, and suggest that therapeutic targeting of heparanase during anti-cancer therapy may improve patient outcome.

Topics: Antineoplastic Agents; Bortezomib; Cell Line, Tumor; Doxorubicin; Enzyme Induction; Gene Expression Regulation, Neoplastic; Glucuronidase; Humans; Melanoma; Melphalan; Oligopeptides; Phenotype

Previous NMR studies demonstrated that lonidamine (LND) selectively diminishes the intracellular pH (pHi) of DB-1 melanoma and mouse xenografts of a variety of other prevalent human cancers while decreasing their bioenergetic status (tumor βNTP/Pi ratio) and enhancing the activities of melphalan and doxorubicin in these cancer models. Since melphalan and doxorubicin are highly toxic agents, we have examined three other nitrogen (N)-mustards, chlorambucil, cyclophosphamide and bendamustine, to determine if they exhibit similar potentiation by LND. As single agents LND, melphalan and these N-mustards exhibited the following activities in DB-1 melanoma xenografts; LND: 100% tumor surviving fraction (SF); chlorambucil: 100% SF; cyclophosphamide: 100% SF; bendamustine: 79% SF; melphalan: 41% SF. When combined with LND administered 40 min prior to administration of the N-mustard (to maximize intracellular acidification) the following responses were obtained; chlorambucil: 62% SF; cyclophosphamide: 42% SF; bendamustine: 36% SF; melphalan: 10% SF. The effect of LND on the activities of these N-mustards is generally attributed to acid stabilization of the aziridinium active intermediate, acid inhibition of glutathione-S-transferase, which acts as a scavenger of aziridinium, and acid inhibition of DNA repair by O6-alkyltransferase. Depletion of ATP by LND may also decrease multidrug resistance and increase tumor response. At similar maximum tolerated doses, our data indicate that melphalan is the most effective N-mustard in combination with LND when treating DB-1 melanoma in mice, but the choice of N-mustard for coadministration with LND will also depend on the relative toxicities of these agents, and remains to be determined.

Topics: Alkylating Agents; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Chlorambucil; Cyclophosphamide; Doxorubicin; Drug Synergism; Humans; Indazoles; Male; Mechlorethamine; Melanoma; Melphalan; Mice; Mice, Nude; Mice, SCID; Xenograft Model Antitumor Assays

We investigate the mechanism through which N-cadherin disruption alters the effectiveness of regional chemotherapy for locally advanced melanoma.. N-cadherin antagonism during regional chemotherapy has demonstrated variable treatment effects.. Isolated limb infusion (ILI) with melphalan (LPAM) or temozolomide (TMZ) was performed on rats bearing melanoma xenografts after systemic administration of the N-cadherin antagonist, ADH-1, or saline. Permeability studies were performed using Evans blue dye as the infusate, and interstitial fluid pressure was measured. Immunohistochemistry of LPAM-DNA adducts and damage was performed as surrogates for LPAM and TMZ delivery. Tumor signaling was studied by Western blotting and reverse-phase protein array analysis.. Systemic ADH-1 was associated with increased growth and activation of the PI3K (phosphatidylinositol-3 kinase)-AKT pathway in A375 but not DM443 xenografts. ADH-1 in combination with LPAM ILI improved antitumor responses compared with LPAM alone in both cell lines. Combination of ADH-1 with TMZ ILI did not improve tumor response in A375 tumors. ADH-1 increased vascular permeability without effecting tumor interstitial fluid pressure, leading to increased delivery of LPAM but not TMZ.. ADH-1 improved responses to regional LPAM but had variable effects on tumors regionally treated with TMZ. N-cadherin-targeting agents may lead to differential effects on the AKT signaling axis that can augment growth of some tumors. The vascular targeting actions of N-cadherin antagonism may not augment some regionally delivered alkylating agents, leading to a net increase in tumor size with this type of combination treatment strategy.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Blotting, Western; Cadherins; Capillary Permeability; Cell Line, Tumor; Chemotherapy, Cancer, Regional Perfusion; Dacarbazine; Melanoma; Melphalan; Neoplasm Transplantation; Oligopeptides; Peptides, Cyclic; Phosphatidylinositol 3-Kinases; Protein Array Analysis; Proto-Oncogene Proteins c-akt; Rats; Rats, Nude; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Skin Neoplasms; Temozolomide

Isolated limb infusion (ILI) with melphalan is a minimally invasive, effective treatment for in transit melanoma. We hypothesized that burden of disease (BOD) would correlate to treatment response.. We retrospectively analyzed a prospectively collected database from two academic centers. BOD was stratified as high or low (low ≤ 10 lesions, none >2 cm). Response rates were measured 3 months post-ILI. Multivariable analysis (MV) was used to evaluate the association between the response and BOD. Kaplan-Meier methods with log-rank tests and MV Cox proportional hazard models were used to analyze overall survival (OS) and progression free survival (PFS).. Sixty (38 %) patients had low and 100 (62 %) high BOD. Patients with low BOD had an overall response rate (ORR) of 73 % with 50 % CR, compared with an ORR of 47 % with 24 % CR in patients with high BOD (p = 0.002). MV analysis of preoperative, intraoperative, and postoperative parameters showed no significant impact on 3-month response. Patients with a CR at 3 months demonstrated improved PFS over the remainder of the cohort, but OS was similar. Low BOD patients had an increased median PFS of 6.9 versus 3.8 months (p = 0.047) and a increased median OS of 38.4 versus 30.9 months (p = 0.146).. Lower BOD is associated with an increased ORR and CR rate with statistically significantly improved PFS in patients undergoing ILI for in transit extremity melanoma. BOD provides useful prognostic information for patient counseling and serves as a marker to stratify patient risk groups.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Female; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Multivariate Analysis; Neoplasm Seeding; Retrospective Studies; Skin Neoplasms

Melphalan represents the reference drug for locoregional chemotherapy of melanoma; nevertheless, treatment failure may occur because of resistance to chemotherapy. Refractory melanoma cells show either an increased capability of drug inactivation, which is known to be associated with elevated intracellular levels of glutathione (GSH), or a decreased melphalan uptake. The aim of this study was to explore a biochemical and a biophysical strategy, and their combination, to overcome melphalan resistance in melanoma cells. The biochemical strategy was based on the treatment of melanoma cells with DL-buthionine (S,R)-sulfoximine (BSO) to deplete the GSH levels, thus reducing melphalan inactivation. In the biophysical strategy, cell membrane electroporation was used to increase melphalan uptake. The SK-MEL 28-resistant human melanoma cell line was pretreated with 50 μmol/l BSO for 24 h and then treated with increasing melphalan doses, with or without electroporation. Spectrophotometric quantification of cell viability was used to determine melphalan cytotoxicity. Intracellular total GSH was measured using a kinetic enzymatic assay. BSO induced 3.50-fold GSH depletion in untreated cells and a similar reduction was also maintained in melphalan-treated cells. BSO pretreatment produced a 2.46-fold increase in melphalan cytotoxicity. Electroporation increased melphalan cytotoxicity 1.42-fold. The combination of both BSO pretreatment with melphalan plus electroporation led to a 4.40-fold increase in melphalan cytotoxicity compared with melphalan alone. Pretreatment with BSO and cell membrane permeabilization by electroporation enhanced the cytotoxic activity of melphalan in melanoma cells. Their rational combination deserves further investigation and may improve the efficacy of locoregional chemotherapy of melanoma.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Electroporation; Glutathione; Humans; Melanoma; Melphalan

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic agent melphalan. Briefly, the procedure starts with the setup of a percutaneous veno-venous bypass from the femoral vein to the external jugular vein. Via a laparotomy, catheters are then inserted into the proper hepatic artery and the caval vein. The portal vein and the caval vein, both supra- and infrahepatically, are then clamped. The arterial and venous catheters are connected to a heart lung machine and the liver is perfused with melphalan (1 mg/kg body weight) for 60 min. This way it is possible to locally perfuse the liver with a high dose of a chemotherapeutic agent, without leakage to the systemic circulation. In previous studies including patients with isolated liver metastases of uveal melanoma, an overall response rate of 33-100% and a median survival between 9 and 13 months, have been reported. The aim of this protocol is to give a clear description of how to perform the procedure and to discuss IHP as a treatment option for liver metastases of uveal melanoma.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extracorporeal Circulation; Heart-Lung Machine; Hepatic Artery; Humans; Liver Neoplasms; Melanoma; Melphalan; Portal Vein; Uveal Neoplasms; Vascular Access Devices

We seek to exploit the natural tendency of melanomas and other tumors to convert glucose to lactate as a method for the selective intracellular acidification of cancer cells and for the potentiation of the activity of nitrogen-mustard antineoplastic agents. We performed this study to evaluate whether the induction of hyperglycemia (26 mM) could enhance the effects of lonidamine (LND, 100 mg/kg; intraperitoneally) on the induction of intracellular acidification, bioenergetic decline and potentiation of the activity of melphalan (LPAM) against DB-1 melanoma xenografts in mice. Intracellular pH (pHi ), extracellular pH (pHe ) and bioenergetics (β-nucleoside triphosphate to inorganic phosphate ratio, β-NTP/Pi) were reduced by 0.7 units (p < 0.001), 0.3 units (p > 0.05) and 51.4% (p < 0.05), respectively. The therapeutic response to LPAM (7.5 mg/kg; intravenously) + LND (100 mg/kg; intraperitoneally) was reduced by about a factor of three under hyperglycemic conditions relative to normoglycemia, producing a growth delay of 7.76 days (tumor doubling time, 5.31 days; cell kill, 64%) compared with LND alone of 1.70 days and LPAM alone of 0.29 days. Under normoglycemic conditions, LND plus LPAM produced a growth delay of 17.75 days, corresponding to a cell kill of 90% at the same dose for each of these agents. The decrease in tumor cell kill under hyperglycemic conditions correlates with an increase in tumor ATP levels resulting from increased glycolytic activity. However, hyperglycemia substantially increases lactic acid production in tumors by a factor of approximately six (p < 0.05), but hyperglycemia did not increase the effects of LND on acidification of the tumor, most probably because of the strong buffering action of carbon dioxide (the pKa of carbonic acid is 6.4). Therefore, this study demonstrates that the addition of glucose during treatment with LND diminishes the activity of this agent.

Topics: Acids; Animals; Cell Line, Tumor; Cell Proliferation; Energy Metabolism; Humans; Hydrogen-Ion Concentration; Hyperglycemia; Indazoles; Intracellular Space; Magnetic Resonance Spectroscopy; Male; Melanoma; Melphalan; Mice, Nude; Organ Specificity; Xenograft Model Antitumor Assays

Systemic chemotherapy generally has been considered immunosuppressive, but it has become evident that certain chemotherapeutic drugs elicit immunogenic danger signals in dying cancer cells that can incite protective antitumor immunity. In this study, we investigated whether locoregionally applied therapies, such as melphalan, used in limb perfusion for melanoma (Mel-ILP) produce related immunogenic effects. In human melanoma biopsies, Mel-ILP treatment upregulated IL1B, IL8, and IL6 associated with their release in patients' locoregional sera. Although induction of apoptosis in melanoma cells by melphalan in vitro did not elicit threshold levels of endoplasmic reticulum and reactive oxygen species stress associated with danger signals, such as induction of cell-surface calreticulin, prophylactic immunization and T-cell depletion experiments showed that melphalan administration in vivo could stimulate a CD8(+) T cell-dependent protective antitumor response. Interestingly, the vaccination effect was potentiated in combination with exogenous calreticulin, but not tumor necrosis factor, a cytokine often combined with Mel-ILP. Our results illustrate how melphalan triggers inflammatory cell death that can be leveraged by immunomodulators such as the danger signal calreticulin.

Topics: Animals; Antigens, Surface; Antineoplastic Agents, Alkylating; Apoptosis; Calreticulin; Cells, Cultured; Cytokines; Endoplasmic Reticulum Stress; Humans; Inflammation Mediators; Melanoma; Melphalan; Mice; Reactive Oxygen Species; Skin Neoplasms

Isolated limb perfusion (ILP) is indicated in locally advanced melanoma and soft tissue sarcoma of the extremities. This series reports the outcome of patients undergoing ILP with melphalan and tumour necrosis factor α (TNFα) at a single centre.. All patients undergoing ILP from January 2005 to January 2015 were identified from a prospectively maintained database. Those undergoing ILP for in-transit melanoma (ITM) were grouped according to disease burden: low volume and bulky (>2 cm diameter).. A total of 143 perfusions were attempted: 9 and 134 in the upper and lower limbs, respectively. A response was assessable in 129 patients with overall response rates for ITM and sarcoma of 81.8 and 61.1 %, respectively. No difference was found in response rates between low-volume and bulky ITM. Limb salvage rates in these cohorts were 97 and 62 %. Regional toxicity following ILP was minimal with 7 grade III (5.4 %), and 1 grade V (0.8 %) reactions. Median progression-free survival was 11 months in the ITM cohort and 12 months in the sarcoma cohort. In the ITM cohort, complete responses were significantly more durable than partial responses (p = 0.0004). Median disease-specific survival was 21 months in the ITM cohort and was not reached in the sarcoma cohort.. TNFα-based ILP is safe and provides excellent palliation of ITM due to rapid progression of systemic disease. It is less effective in sarcoma due to lower initial response rates and a lower incidence of disease dissemination.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Cohort Studies; Drug Therapy, Combination; Extremities; Female; Follow-Up Studies; Humans; Limb Salvage; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Prognosis; Sarcoma; Survival Rate; Tumor Necrosis Factor-alpha

Topics: Animals; Antigens, Surface; Antineoplastic Agents, Alkylating; Calreticulin; Humans; Melanoma; Melphalan; Skin Neoplasms

Topics: Animals; Antigens, Surface; Antineoplastic Agents, Alkylating; Calreticulin; Humans; Melanoma; Melphalan; Skin Neoplasms

The study of pharmacokinetics of melphalan in the perfusate and blood plasma during isolated limb regional perfusion (ILRP) was carried out in patients with melanoma (n=21) and soft tissue sarcoma (n = 24). Melphalan was administered as 10 mg/l for a lower extremity and 13 mg/l for a upper extremity. Quantification of melphalan in perfusate and blood samples was performed by means of liquid chromatography/tandem mass spectrometry. 30 samples of the perfusate and 27 venous blood samples were analyzed. During the first 5 minutes of ILRP concentration of melphalan in the perfusate decreased to 13.2% of the initial value, and by the end of perfusion (60 minutes) it was 3.3%. The amount of melphalan in the blood plasma of the patients by the end of ILRP wasn't higher than 1.6% from the administered dose. That demonstrates minor systemic absorption of the drug during ILRP. Moreover melphalan concentration in the blood plasma during the perfusion was in average 0.015-0.223 mg/l which is significantly lower compared to the blood plasma concentrations after intravenous administration of melphalan. Thus ILRP procedure provided 97% of the melphalan dose accumulation in the soft tissues of a limb and in tumor tissues. Also pharmacokinetic advantage of melphalan over systemic administration of the drug was shown.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Chromatography, Liquid; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Melanoma; Melanoma, Cutaneous Malignant; Melphalan; Middle Aged; Sarcoma; Skin Neoplasms; Tandem Mass Spectrometry

There is increasing evidence that tumor hypoxia plays a significant role in the chemoresistance of melanoma, but to our knowledge, real-time tumor oxygenation during isolated limb infusion (ILI) has not been studied. We sought to demonstrate the feasibility of measuring real-time alterations in tissue oxygenation.. Consecutive patients with histologically confirmed in-transit melanoma were enrolled onto a prospective single-arm pilot study and administered the hypoxia marker drug EF5. All patients were treated with ILI. Optical spectroscopy readings were obtained at three locations: two discrete target lesions and one normal skin control. Measurements were taken at 11 predefined time points during ILI.. A total of six patients were enrolled onto this pilot study. Intratumor and normal skin optical spectroscopy readings were found to have discrete inflection points throughout the duration of therapy, corresponding with established time points. Baseline hypoxia as measured by both optical spectroscopy and EF5 immunofluorescence was variable, but on the basis of optical spectra, tumors appeared to become more hypoxic compared to normal skin after tourniquet application. The optical hypoxia signature was variable between patients while hemoglobin absorption increased.. To our knowledge, this is the first use of real-time optical spectroscopy to evaluate oxygenation and perfusion within melanoma lesions during regional chemotherapy. We report our development of this new noninvasive means of assessing tumor vascular function, which has the potential to be a powerful tool for noninvasive examination of the melanoma tumor microenvironment.

Topics: Aged; Antineoplastic Agents, Alkylating; Etanidazole; Feasibility Studies; Female; Follow-Up Studies; Humans; Hydrocarbons, Fluorinated; Hypoxia; Indicators and Reagents; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Pilot Projects; Prognosis; Prospective Studies

Isolated limb infusion (ILI) is a limb-preserving treatment for in-transit extremity melanoma. The benefit of resecting residual disease after ILI is unclear.. A multi-institutional experience was analyzed comparing patients who underwent ILI plus resection of residual disease (ILI + RES) versus ILI-alone.. A total of 176 patients were included, 154 with ILI-alone and 22 with ILI + RES. There were no differences between the groups with respect to gender, age, extremity affected, or time from diagnosis to ILI. All surgical resections were performed as an outpatient procedure, separate from the ILI. Within the ILI + RES group, 15 (68%) had a partial response (PR), 2 (9%) stable disease (SD), and 5 (23%) progressive disease (PD). The ILI-alone group had 52 (34%) CR, 30 (19%) PR, 15 (10%) SD, and 46 (30%) PD. Eleven (7%) ILI-alone patients did not have 3-month response available for review. Evaluating overall survival (OS) from date of ILI, the ILI-alone group had a median OS of 30.9 months, whereas the ILI + RES group had not reached median OS, p = 0.304. Although the ILI + RES group had a slightly longer disease-free survival (DFS) compared to those with a CR after ILI-alone (12.4 vs. 9.6), this was not statistically significant, p = 0.978. Within the ILI + RES group, those with an initial PR after ILI had improved DFS versus those with SD or PD after ILI, p < 0.0001.. Resection of residual disease after ILI offers a DFS and OS similar to those who have a CR after ILI-alone. It may offer a treatment strategy that benefits patients undergoing ILI.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dactinomycin; Extremities; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Neoplasm, Residual; Prognosis; Remission Induction; Retrospective Studies; Survival Rate

Src kinase inhibition has been shown to augment the efficacy of chemotherapy. Dasatinib, a dual Src/Abl kinase inhibitor approved for the treatment of CML, is under investigation as monotherapy for tumors with abnormal Src signaling, such as melanoma. The goal of this study was to determine if Src kinase inhibition using dasatinib could enhance the efficacy of regionally administered melphalan in advanced extremity melanoma.. The mutational status of c-kit and patterns of gene expression predictive of dysregulated Src kinase signaling were evaluated in a panel of 26 human melanoma cell lines. The effectiveness of dasatinib was measured by quantifying protein expression and activation of Src kinase, focal adhesion kinase, and Crk-associated substrate (p130(CAS)), in conjunction with in vitro cell viability assays using seven melanoma cell lines. Utilizing a rat model of regional chemotherapy, we evaluated the effectiveness of systemic dasatinib in conjunction with regional melphalan against the human melanoma cell line, DM443, grown as a xenograft.. Only the WM3211 cell line harbored a c-kit mutation. Significant correlation was observed between Src-predicted dysregulation by gene expression and sensitivity to dasatinib in vitro. Tumor doubling time for DM443 xenografts treated with systemic dasatinib in combination with regional melphalan (44.8 days) was significantly longer (p = 0.007) than either dasatinib (21.3 days) or melphalan alone (24.7 days).. Systemic dasatinib prior to melphalan-based regional chemotherapy markedly improves the efficacy of this alkylating agent in this melanoma xenograft model. Validation of this concept should be considered in the context of a regional therapy clinical trial.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Blotting, Western; Cell Proliferation; Dasatinib; Female; Humans; Melanoma; Melphalan; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyrimidines; Rats; Rats, Nude; Real-Time Polymerase Chain Reaction; src-Family Kinases; Thiazoles; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Primary cutaneous CD30-positive T-cell lymphoproliferative disorders (CD30(+) LPD), including primary cutaneous anaplastic large cell lymphoma (CALCL) and lymphomatoid papulosis (LyP), comprise the second most common group of cutaneous T-cell lymphomas (CTCL). The etiology of these disorders is not known. Isolated limb perfusion (ILP) and isolated limb infusion (ILI) are forms of regional chemotherapy used to treat recurrent tumors of the extremity, most commonly, melanoma. Secondary malignancy following regional therapy is rarely reported.. We identified two cases of CD30(+) LPD arising in the affected limbs of patients treated with ILP/ILI. We subsequently performed CD30 immunohistochemical stains on 11 pre- and post-treatment skin specimens from melanoma patients treated with ILP/ILI and found that 5 of the 11 cases showed an increase in CD30(+) lymphocytes following ILP/ILI.. We hypothesize that ILP/ILI causes upregulation of CD30 expression in the extremities of treated patients, and suggest that this may be a marker of treatment response. However, a rare but long-term effect may be an increased risk of T-cell cutaneous lymphoproliferative disease in the affected limb.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Immunohistochemistry; Ki-1 Antigen; Lymphocytes; Lymphoma, Large-Cell, Anaplastic; Lymphomatoid Papulosis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Skin Neoplasms

To investigate anti-proliferatory activity of a selected N,N-[(8-hydroxyquinoline)methyl]-substituted benzylamine (JLK1486) on melanoma cells and to characterize its mechanism of cell population growth inhibition.. In vitro cultures of B16F10 (mouse melanoma) cells were used as a model to characterize anti-proliferatory activity of JLK1486 using MTT growth assay, trypan blue viability assessment, cell cycle analysis, melanin production, β-galactosidase and acridine orange staining.. Proliferating B16F10 and also MeWo (human melanoma) cells were strongly growth inhibited by JLK1486, displaying IC50 values of 196 nm and 110 nm respectively. Anti-proliferatory effects were independent of cell death and were characterized by a distinct accumulation of cells in G0 /G1 phase. Tyrosinase activity and relative melanin content remained unchanged indicating that the anti-proliferatory activity was not due to phenotype differentiation. Although treated B16F10 cells stained strongly positive for senescence marker β-galactosidase, cells regained near normal proliferatory activity after removal of JLK1486. Increased acridine orange staining and presence of perinuclear vacuoles suggested induction of autophagy in B16F10 cells. Furthermore, JLK1486 pre-treatment completely abolished melphalan and antimycin A-induced apoptosis.. JLK1486 provides a promising chemical scaffold to develop new anti-melanoma drugs or combination therapies, due to its potent inhibition of cell proliferation and induction of autophagy, at pharmacologically relevant concentrations.

Topics: Animals; Anti-Bacterial Agents; Antimycin A; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Autophagy; beta-Galactosidase; Cell Differentiation; Cell Division; Cell Line, Tumor; Cellular Senescence; HeLa Cells; Humans; Hydroxyquinolines; MCF-7 Cells; Melanins; Melanoma; Melphalan; Mice; Monophenol Monooxygenase; S Phase Cell Cycle Checkpoints

Preprocedure clinical and pathologic factors have failed to consistently differentiate complete response (CR) from progressive disease (PD) in patients after isolated limb infusion (ILI) with melphalan for unresectable in-transit extremity melanoma.. Multiplex immunobead assay technology (Milliplex MAP Human Cytokine/Chemokine Magnetic Bead Panel, Millipore Corp., Billerica, MA; and Magpix analytical test instrument, Luminex Corp., Austin, TX) was performed on pre-ILI plasma to determine concentrations of selected cytokines (MIP-1α, IL-1Rα, IP-10, IL-1β, IL-1α, MCP-1, IL-6, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1β) on a subset of patients (n = 180) who experienced CR (n = 23) or PD (n = 24) after ILI. Plasma from normal donors (n = 12) was also evaluated.. Of 180 ILIs performed, 28 % (95 % confidence interval 22-35, n = 50) experienced a CR, 14 % (n = 25) experienced a partial response, 11 % (n = 21) had stable disease, 34 % (n = 61) had PD, and 13 % (n = 23) were not evaluable for response. Tumor characteristics and pharmacokinetics appeared similar between CR (n = 23) and PD (n = 24) patients who underwent cytokine analysis. Although there were no differences in cytokine levels between CR and PD patients, there were differences between the melanoma patients and controls. MIP-1α, IL-1Rα, IL-1β, IL-1α, IL-17, EGF, IL-12p40, VEGF, GM-CSF, and MIP-1β were significantly higher in normal controls compared to melanoma patients, while IP-10 was lower (p < 0.001) in controls compared to melanoma patients.. Patients with unresectable in-transit melanoma appear to have markedly decreased levels of immune activating cytokines compared to normal healthy controls. This further supports a potential role for immune-targeted therapies and immune monitoring in patients with regionally advanced melanoma.

Topics: Adult; Aged; Case-Control Studies; Chemotherapy, Cancer, Regional Perfusion; Cytokines; Extremities; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Prognosis; Prospective Studies; Skin Neoplasms; Survival Rate

Cutaneous melanoma displays high morbidity and mortality rates. Isolated limb perfusion with melphalan (Mel) is used for the treatment of non-resectable, locally advanced extremity melanomas. When combined with tumor necrosis factor alpha (TNF-alpha) treatment, the complete response varies between 70% and 90%. The mechanisms underlying the effects of Mel and TNF-alpha are not completely understood. We evaluated the impact of systemic Mel and TNF-alpha administration on tumor growth, analyzed the morphological changes promoted by each treatment, and identified early expressed genes in response to Mel and TNF-alpha treatment, either alone or in combination, in a murine melanoma model.. Six- to eight-week-old male mice were subcutaneously inoculated with B16F10 melanoma cells and then intravenously injected with TNF-alpha, melphalan or a combination of both drugs when the tumors reached 1.0 cm(2). Tumor growth was monitored every other day, and histological analysis was performed when the tumors reached 3.0 cm(2). Total RNA was extracted from the resected tumors and submitted to amplification, labeling and hybridization on an oligonucleotide microarray (Fox Chase Cancer Center). Tumor growth and histological parameters were compared using ANOVA. Survival curves were calculated using the Kaplan-Meier method. Two-way ANOVA was used to identify differentially expressed genes among the various treatments, and Dunn's test was used for pair-wise comparisons.. Systemic administration of Mel impaired tumor growth (p<0.001), improved animal survival (p<0.001), and decreased mitotic rate (p=0.049). Treatment with TNF-alpha alone had no impact, neither on tumor growth, nor on survival, but it increased necrosis (p<0.024) and decreased mitotic rates (p=0.001) in the tumors. Combined treatment with Mel and TNF-alpha had similar effects in tumor growth, survival, necrosis and mitotic rate as observed with individual treatments. Moreover, 118 genes were found differentially expressed by microarray analysis and 10% of them were validated by RT- real time PCR. In our model we found that the treatments regulate genes that play important roles in tumorigenesis such as cell adhesion (Pard3, Pecam1, Ilk, and Dlg5), proliferation (Tcfe3 and Polr1e), cell motility (Kifap3, Palld, and Arhgef6), apoptosis (Bcl2l11), and angiogenesis (Flt1 and Ptprj).. Our data reproduces, in mice, some of the features observed in melanoma patients treated with the combination of Mel and TNF-alpha. The identification of genes with altered expression by these drugs both individually and in combination might help in the understanding of their mechanism of action and, as a consequence, improved strategies that could impact their clinical application.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Gene Expression Profiling; Male; Melanoma; Melphalan; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neovascularization, Pathologic; Treatment Outcome; Tumor Necrosis Factor-alpha

Although approximately 30% to 50% of patients experience a complete response after regional chemotherapy for in-transit melanoma, a subset of patients will develop rapidly progressive disease. In the current era of an expanding armamentarium, including both regional and systemic options for treating advanced melanoma, identifying perioperative factors that predict disease progression may obviate unnecessary morbidity associated with regional therapy and avoid delays in systemic therapy.. To identify patient-related clinical and pathological variables, as well as procedural factors, that correlate with disease progression.. Using a prospectively maintained database, we identified patients who either underwent first-time melphalan-based isolated limb infusion (ILI) or first-time hyperthermic isolated limb perfusion (HILP) for in-transit melanoma. Response was defined using modified Response Evaluation Criteria in Solid Tumors for cutaneous disease at 3 months after treatment. Survival analyses were performed using the Kaplan-Meier method, with the differences in survival curves compared using a log-rank test. Potential preoperative and procedural predictors of in-field progressive disease were analyzed using logistic regression.. Of the 258 patients included in the database, 215 were identified as having undergone first-time regional therapy. Of these 215 patients, 134 underwent ILI, and 81 underwent HILP.. Regional therapy (ILI or HILP).. Complete response or progressive disease.. Of 134 patients who underwent ILI, 43 (32.1%) experienced in-field progressive disease. Of 81 patients who underwent HILP, 9 (11.1%) experienced in-field progressive disease. The median survival for patients with in-field progressive disease was 20.3 months for the ILI cohort and 15.0 months for the HILP cohort. In general, patients with progressive disease were younger, with advanced-stage melanoma and increased tumor burden. Compared with patients who experienced a complete response, patients with in-field progressive disease after ILI were younger (odds ratio, 1.06 [95% CI, 0.90-0.98]; P = .002). For patients who underwent HILP, no clinically relevant preoperative predictors of in-field progressive disease were identified. Procedural variables, including chemotherapeutic dosing, degree of acidosis or base deficit achieved, and peak temperature attained, were not predictors of in-field progressive disease after ILI or HILP.. Patient, clinical, and procedural factors are unreliable predictors of in-field progressive disease after regional therapy in patients with in-transit melanoma. Defining the potential utility of molecular markers in predicting response or failure of regional therapy should be the focus of future research efforts.

Topics: Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Female; Humans; Kaplan-Meier Estimate; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Treatment Outcome

The aim of the present study is to describe our experience with isolated limb perfusion (ILP) in the treatment of in-transit metastases of malignant melanoma and to determine prognostic factors for response, local progression, survival and toxicity.. A retrospective follow-up of all patients (n = 163) treated between January 1984 and December 2008 using data collected from individual patient records and the Swedish National Patient Register.. Clinical response was evaluable in 155 patients, 65% had a complete response (CR) and 20% had a partial response (PR). Local progression occurred in 63% of the patients after a median time of 16 months. Negative prognostic factors in univariate analyses were proximal location of the primary tumour, >10 in-transit metastases and if there was no CR after ILP. In multivariate analysis, proximal location of the primary tumour and no CR after ILP were significant prognostic factors. Median cancer-specific survival was 30 months, and negative prognostic factors in univariate analyses were male gender, positive lymph node status, systemic metastases, bulky tumour, >10 in-transit metastases and if there was no CR after ILP. In multivariate analysis, positive lymph node status, bulky tumour and no CR after ILP were significant prognostic factors. A majority (97%) of the patients had a Wieberdink grade II-III local toxicity. Four patients underwent limb amputation after a median of 19 months, none because of toxicity.. We found that ILP is a safe method with a high response rate for the treatment of patients with in-transit metastases of malignant melanoma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Perfusion; Skin Neoplasms; Tumor Necrosis Factor-alpha; Young Adult

L-type amino acid transporter 1 (LAT1), an isoform of amino acid transport system L, transports branched or aromatic amino acids essential for fundamental cellular activities such as cellular growth, proliferation and maintenance. This amino acid transporter recently has received attention because of its preferential and up-regulated expression in a variety of human tumors in contrast to its limited distribution and low-level expression in normal tissues. In this study, we explored the feasibility of using LAT1 inhibitor as a new therapeutic agent for human malignant melanomas (MM) using canine spontaneous MM as a model for human MM. A comparative study of LAT expression was performed in 48 normal tissues, 25MM tissues and five cell lines established from MM. The study observed LAT1 mRNA levels from MM tissues and cell lines that were significantly (P<0.01) higher than in normal tissues. Additionally, MM with distant metastasis showed a higher expression than those without distant metastasis. Functional analysis of LAT1 was performed on one of the five cell lines, CMeC-1. [(3)H]l-Leucine uptake and cellular growth activities in CMeC-1 were inhibited in a dose-dependent manner by selective LAT1 inhibitors (2-amino-2-norbornane-carboxylic acid, BCH and melphalan, LPM). Inhibitory growth activities of various conventional anti-cancer drugs, including carboplatin, cyclophosphamide, dacarbazine, doxorubicin, mitoxantrone, nimustine, vinblastine and vincristine, were significantly (P<0.05) enhanced by combination use with BCH or LPM. These findings suggest that LAT1 could be a new therapeutic target for MM.

Topics: Amino Acids, Cyclic; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dogs; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Large Neutral Amino Acid-Transporter 1; Melanoma; Melphalan; Neoplasm Metastasis; Pilot Projects

In vivo (31) P MRS demonstrates that human melanoma xenografts in immunosuppressed mice treated with lonidamine (LND, 100 mg/kg intraperitoneally) exhibit a decrease in intracellular pH (pH(i) ) from 6.90 ± 0.05 to 6.33 ± 0.10 (p < 0.001), a slight decrease in extracellular pH (pH(e) ) from 7.00 ± 0.04 to 6.80 ± 0.07 (p > 0.05) and a monotonic decline in bioenergetics (nucleoside triphosphate/inorganic phosphate) of 66.8 ± 5.7% (p < 0.001) relative to the baseline level. Both bioenergetics and pH(i) decreases were sustained for at least 3 h following LND treatment. Liver exhibited a transient intracellular acidification by 0.2 ± 0.1 pH units (p > 0.05) at 20 min post-LND, with no significant change in pH(e) and a small transient decrease in bioenergetics (32.9 ± 10.6%, p > 0.05) at 40 min post-LND. No changes in pH(i) or adenosine triphosphate/inorganic phosphate were detected in the brain (pH(i) , bioenergetics; p > 0.1) or skeletal muscle (pH(i) , pH(e) , bioenergetics; p > 0.1) for at least 120 min post-LND. Steady-state tumor lactate monitored by (1) H MRS with a selective multiquantum pulse sequence with Hadamard localization increased approximately three-fold (p = 0.009). Treatment with LND increased the systemic melanoma response to melphalan (LPAM; 7.5 mg/kg intravenously), producing a growth delay of 19.9 ± 2.0 days (tumor doubling time, 6.15 ± 0.31 days; log(10) cell kill, 0.975 ± 0.110; cell kill, 89.4 ± 2.2%) compared with LND alone of 1.1 ± 0.1 days and LPAM alone of 4.0 ± 0.0 days. The study demonstrates that the effects of LND on tumor pH(i) and bioenergetics may sensitize melanoma to pH-dependent therapeutics, such as chemotherapy with alkylating agents or hyperthermia.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Drug Synergism; Energy Metabolism; Hydrogen-Ion Concentration; Indazoles; Magnetic Resonance Spectroscopy; Melanoma; Melphalan; Mice; Phosphorus Radioisotopes; Protons; Treatment Outcome

Circulating endothelial progenitor cells (cEPCs) as recruited to the angiogenic vascular system of malignant tumors have been proposed as a biomarker in malignancies. The effect of antitumor chemotherapy on cEPCs is not fully understood. We examined the level of cEPCs, vascular endothelial growth factor (VEGF), and angiopoietin-2 in the blood of sarcoma and melanoma patients before and after isolated limb perfusion (ILP) with or without recombinant human tumor necrosis factor-α (rhTNF-α).. Twenty-two patients, 11 each with soft tissue sarcoma or recurrent melanoma of the limb, were recruited. ILP was performed with rhTNF-α/melphalan (TNF) or melphalan only (no TNF). Fifteen healthy volunteers served as control subjects. Blood was sampled before and up to 6 weeks after ILP. Peripheral blood mononuclear cells were isolated by density gradient centrifugation, and annexin V-negative cells were characterized as cEPCs by triple staining for CD133(+), CD34, and VEGFR-2(+).. Before treatment, cEPC numbers were significantly increased in sarcoma (0.179 ± 0.190 %) and melanoma patients (0.110 ± 0.073 %) versus healthy controls (0.025 ± 0.018 %; P < 0.01), but did not differ significantly between sarcoma and melanoma patients. cEPC decreased significantly after ILP in patients with no TNF compared to pretreatment values (P < 0.05) and were significantly lower at 4 h, 48 h, and 1 week compared to ILP with TNF (P < 0.05). Values 6 weeks after ILP were significantly lower than before ILP in both investigated groups (P < 0.01).. ILP with TNF results in activation of bone marrow-derived EPCs compared to ILP without TNF. Alteration of cEPCs and angiopoietin-2 by rhTNF-α might account for the cytotoxicity and hemorrhagic effects on tumor vessels during limb perfusion procedures.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Case-Control Studies; Cells, Cultured; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Combined Modality Therapy; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Extremities; Female; Flow Cytometry; Follow-Up Studies; Healthy Volunteers; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Recombinant Proteins; Sarcoma; Stem Cells; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor Receptor-2; Young Adult

Resveratrol (RESV) is a naturally occurring compound that possesses anti-cancer capabilities. The goal of this study was to evaluate the potential of RESV as an adjunct to chemotherapy in melanoma treatment.. The in vitro and in vivo cytotoxic activity of RESV with or without chemotherapy was tested using cellular assays and a xenograft model. Two Duke melanoma cell lines (DM738, DM443) were used for both in vivo and in vitro experiments, and two nonmalignant human fibroblast lines (NHDF, HS68) were used for in vitro cellular assays. Xenografts were randomized to treatment arms and tumors measured to evaluate response. Results were analyzed using a Student's t-test and ANOVA. Western blots were performed on in vivo tissue.. In vitro RESV significantly decreased melanoma cell viability in all lines tested (all P < 0.0001). Treatment of fibroblast cell lines revealed that RESV selectively spared NHDF and HS68 cells compared with its cytotoxic effects on melanoma cells (P < 0.0001). Treatment of malignant cells with 50 μM RESV and temozolomide (TMZ) for 72 h significantly enhanced cytotoxicity compared with treatment with TMZ alone (P < 0.0001). In vivo, however, there was no significant difference between any treatment arms (P = 0.65).. RESV shows promise as a novel therapeutic in the management of melanoma for its selective anti-tumor activity in vitro. Translating in vitro results to in vivo models has proven difficult. Barriers thought to prevent such translation are identified, and a rationale for overcoming them is discussed.

Topics: Animals; Antineoplastic Agents; Cell Line; Cell Line, Tumor; Chemotherapy, Adjuvant; Dacarbazine; Disease Models, Animal; Drug Therapy, Combination; Humans; In Vitro Techniques; Melanoma; Melphalan; Mice; Mice, Nude; Mice, SCID; Resveratrol; Skin Neoplasms; Stilbenes; Temozolomide; Treatment Outcome; Xenograft Model Antitumor Assays

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Humans; Lower Extremity; Melanoma; Melphalan; Mitomycin; Neoplasm Recurrence, Local; Skin Neoplasms; Upper Extremity

Hyperthermic isolated limb perfusion (HILP) or isolated limb infusion (ILI) are well-accepted regional chemotherapy techniques for in-transit melanoma of extremity. The role and efficacy of repeat regional chemotherapy for recurrence and which salvage procedure is better remains debatable. We aimed to compare toxicities and clinical outcomes by procedure types and the sequence.. Data from 44 patients, who underwent repeat HILPs or ILIs from 3 institutions beginning 1997 to 2010, were retrospectively reviewed. Regional toxicity assessed by Wieberdink grade, systemic toxicity assessed by serum creatine phosphokinase level, length of hospital stay (LOS), response rates at 3 months after the procedure, and time to in-field progression (TTP) were analyzed.. Of 44 patients, 46% were men and 54% women with a median age of 66 (range 29-85) years at diagnosis. The median follow-up was 21.4 (range 4-153) months. Of 70 ILIs and 28 HILPs, the following groups were identified: group A, ILI → ILI (n = 25); group B, ILI → HILP (n = 10); group C, HILP → ILI (n = 12); and group D, HILP → HILP (n = 3). The comparison of Wieberdink grade, serum creatine phosphokinase level, LOS, and response rate between procedures (HILP vs. ILI), between sequence (initial vs. repeat), and among their interactions showed no statistically significant differences. TTP after initial procedure did not differ between HILP and ILI (P = 0.08), and no survival difference was seen (P = 0.65) when TTP after repeat procedure was compared.. Most patients tolerated repeat regional chemotherapy without increased toxicity or LOS. No statistical difference in clinical outcomes was noted when comparing repeat procedures, even though repeat HILPs showed higher complete response compared to repeat ILIs.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Drug Administration Schedule; Female; Humans; Length of Stay; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Retrospective Studies; Skin Neoplasms; Treatment Outcome

The aim of the study is to evaluate the limb salvage rate achieved by treating locally advanced extremity sarcoma and melanoma by hyperthermic isolated limb perfusion with melphalan and TNF-α (ILP-MT).. A retrospective study was conducted on patients suffering from locally advanced soft tissue sarcoma and melanoma of the limb and treated by means of ILP-MT between November 2001 and February 2010. The response rate, toxicity, complications, disease free intervals, overall survival and limb salvage rate were evaluated.. A total of 30 patients (19 females and 11 males) with a median age of 60 years (14-82) were treated by this technique. The overall response rate was 93.4% (complete, 46.7%; partial 46.7%); the mean follow-up was 23 months. The median duration of response was 5 months (0-62), The median overall survival was 13.5 months (range 1 - 62). Limb salvage rate was 86.7%. Eleven patients are currently alive (5 without disease, 2 with residual disease on treatment, 2 with local progression and 2 with systemic progression).. With the use of ILP-MT we have avoided the amputation of 26 limbs affected by locally advanced sarcoma or melanoma. ILP-MT is feasible and safe in a multidisciplinary environment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Arm; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Hyperthermia, Induced; Leg; Limb Salvage; Male; Melanoma; Melphalan; Middle Aged; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha; Young Adult

Isolated limb infusion (ILI) for the treatment of in-transit melanoma was originally described more than 10 years ago. Response rates of 45-53% have been reported in U.S. series. Long-term quality of life outcomes after this procedure have not been described. We hypothesized that ILI is rarely associated with long-term limb morbidity.. ILIs performed at our institution between July 2005 and June 2009 were reviewed. Patients were contacted cross-sectionally at 2 time points. During these interviews, response to treatment and postoperative limb function were assessed.. Thirty-two ILIs were performed during the time period. Twenty-seven patients were treated for in-transit melanoma; 5 were treated for recurrent Merkel cell carcinoma. The 30-day mortality was 0%. Three patients (9%) required fasciotomy. Durable complete responses were achieved in 41% of patients, with mean follow-up time of 19.4 ± 9.6 months after infusion; after this period, 53% reported progression of disease. The most common postprocedure symptoms were edema (88%), numbness (59%), and pain (59%). By 3 months and at the time of last follow-up, the most common symptoms were edema (82%), numbness (65%), and stiffness (35%). No patients reported impaired limb function at the time of last follow-up compared to baseline. Median survival was 19.2 ± 4.2 months after infusion.. ILI for melanoma and Merkel cell carcinoma is associated with postprocedure symptoms in most patients, most commonly edema, color change, and numbness. At last follow-up, no ILI patients had residual functional impairment in the treated limb.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Arm; Carcinoma, Merkel Cell; Cross-Sectional Studies; Dactinomycin; Edema; Female; Follow-Up Studies; Humans; Hypesthesia; Infusions, Intravenous; Leg; Length of Stay; Male; Melanoma; Melphalan; Neoplasm Recurrence, Local; Quality of Life; Skin Neoplasms; Survival Rate

Isolated limb perfusion combined with melphalan is an accepted treatment for obtaining locoregional control in advanced melanoma of the extremities and other malignant neoplasias restricted to the limb. This study aims to examine the factors associated with toxicity caused by the regional method. We considered the technical aspects of severe complications associated with the procedure in an attempt to diminish the patient morbidity that occurs during the learning curve.. We conducted a retrospective analysis of the records of patients who underwent perfusion at the AC Camargo Hospital in São Paulo, Brazil between January 2000 and January 2009. The Wieberdink scale was applied to classify local toxicity and its relation to clinical and laboratory variables.. Fifty-eight perfusions were performed in 55 patients. Most patients (86.2%) presented a toxicity level between I and III. Grade V toxicity was seen in five cases (8.6%), four of which occurred in the first 2 years. Creatine phosphokinase, an important predictive factor for toxicity, had an average value of 231.8 for toxicity grades I-III and 1286.2 for toxicity grades IV-V (p = 0.001). There was a relationship between the melphalan dose and toxicity, which was 77 mg (25 to 130 mg) for toxicity grades I-II and 93.5 mg (45 to 120 mg) for toxicity grades IV-V (p = 0.0204).. It is possible to prevent the toxicity associated with melphalan by adjusting the dose according to the patient's body weight (especially for women and obese patients) and the creatine phosphokinase values in the postoperative period.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Chemotherapy, Cancer, Regional Perfusion; Creatine Kinase; Drug Dosage Calculations; Female; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Retrospective Studies; Risk Factors; Skin Neoplasms; Statistics, Nonparametric; Young Adult

Even after complete response (CR) to regional chemotherapy for in-transit melanoma, many patients develop recurrence. Understanding the probability, location, and timing of recurrences can optimize management strategies for this patient population.. A prospective database identified patients who underwent 81 first-time hyperthermic isolated limb perfusions (HILPs) and 133 first-time isolated limb infusions (ILIs). Response was defined using the response evaluation criteria in solid tumors; recurrence was defined as development of new disease after in-field CR.. HILP exhibited a significantly higher CR rate than ILI (44 vs. 28 %, p = .01). Among 36 HILP-CRs and 37 ILI-CRs, the 3-year recurrence rate was 65 % (95 % confidence interval [95 % CI]: 43-79 %) and 85 % (95 % CI: 63-94%), respectively. Median time to first recurrence was longer for HILP-CR than ILI-CR (23 vs. 8 months, p = .02). There was no statistically significant difference in median time to in-field recurrence between HILP-CR and ILI-CR (46 vs. 25 months, p = .15), but HILP-CR showed a longer median time to out-of-field recurrence (42 vs. 14 months, p = .02). Finally, the overall survival (OS) difference between HILP-CR and ILI-CR (3-year survival: 77 vs. 54 %) did not achieve statistical significance (p = .10).. In the largest series comparing patterns of recurrence, we demonstrate that out-of-field recurrence after CR to HILP occurs later than after CR to ILI, though control of in-field disease remains similar. There remains no statistically significant difference in overall survival after CR to the 2 procedures.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dactinomycin; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Prospective Studies; Remission Induction; Survival Rate

Despite recent advances in melanoma therapy, disseminated melanoma still lacks effective treatment, and recurrence of the tumor frequently occurs, even after high-dose chemotherapy. The mechanisms responsible for this chemoresistance or for the formation of new relapses remain poorly understood. Using a human 'model', in which the isolated limb is perfused with high doses of the chemotherapeutic melphalan (ILP), we identified a five-gene set (ATF3, CYR61, IER5, IL6, and PTGS2) of stress-induced genes that was consistently upregulated after ILP in all in-transit metastatic melanoma samples as well as in three melphalan-treated melanoma cell lines. Early post-ILP relapses retained these elevated expressions, whereas the expression of these genes returned to their original levels in late post-ILP recurrences. In addition, we identified upregulation of these genes in the A375 cell line's side population (SP) and melanospheres, established methods to enrich for candidate cancer stem cells (CSCs), which are considered chemoresistant and tumorigenic, and thus proposed to be responsible for tumor relapse. Our data identify an immediate and short-term upregulation of early stress-responsive genes that are potentially linked to chemoresistance and CSCs.

Topics: Aged; Aged, 80 and over; Cell Line, Tumor; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Extremities; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Oligonucleotide Array Sequence Analysis; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Side-Population Cells; Skin Neoplasms

Isolated limb perfusion (ILP) for extremity melanoma has been used clinically for over half a century. Mouse modeling of ILP may offer significant experimental advantages compared with existing models. We propose a novel mouse model and report our initial experience.. We injected female C57BL/6 mice (22-25 g) with 1 × 10(6) B16 melanoma cells subcutaneously in the distal right thigh. After 7 d of tumor establishment, we cannulated the superficial femoral artery (inflow) and vein (outflow) of anesthetized mice and placed a proximal tourniquet. Non-oxygenated perfusate included low-dose or high-dose melphalan and saline (control). We analyzed endpoints of cannulation time, procedural complications, morbidity, toxicity, and tumor response.. We performed 11 superficial femoral vessel cannulations. Median cannulation time was 19 min (range, 15-32 min). Intact perfusion models were obtained in 10 of 11 cases (91%); one case failed owing to superficial femoral vein dissection. Morbidity rate was 20% (one wound dehiscence and one hematoma). Both high- and low-dose melphalan perfusion groups (4 mice/group) trended to growth delay and regression compared with saline-perfused groups. Toxicity was greater in the high-dose melphalan-treated mice.. We have established the first reproducible mouse model of ILP for melanoma. Future experiments will take advantage of the large number of established mouse knockout models and reagents to dissect the precise mechanisms of tumor control after ILP, and examine to novel agents.

Topics: Animals; Antineoplastic Agents, Alkylating; Catheterization, Peripheral; Cell Line, Tumor; Disease Models, Animal; Female; Femoral Artery; Hindlimb; Melanoma; Melphalan; Mice; Mice, Inbred C57BL; Morbidity; Neoplasm Transplantation; Skin Neoplasms; Tourniquets

To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM).. After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evan's blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO(2) were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues.. Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO(2) decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively (P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation.. Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Capillary Permeability; Cell Line, Tumor; Chemotherapy, Cancer, Regional Perfusion; Drug Delivery Systems; Female; Humans; Melanoma; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Oxygen Consumption; Rats; Rats, Nude; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Isolated limb infusion (ILI), introduced in 1992, is a technique used to deliver regional chemotherapy to treat advanced melanoma confined to a limb. Adjusting melphalan dose according to ideal body weight (IBW) has been proposed as a method of decreasing limb toxicity without compromising outcome. The current study analyzed this proposed dose adjustment.. We reviewed 99 consecutive patients with lower extremity melanomas treated by ILI at our institution between May 1998 and February 2009. Toxicity and outcomes were tested for correlation with differences between administered dose and calculated adjusted dose, both in mg and mg/L, and with differences between actual limb volume and calculated adjusted limb volume.. The median actual body weight was 71 kg, whereas the calculated median IBW was 57 kg (p < .001). Median administered melphalan dose was 7.7 mg/L. The median calculated adjusted dose was 6.5 mg/L (range 3.2-9.3 mg/L, p < .001). None of the three aforementioned parameters correlated with either Wieberdink toxicity grade or outcome. BMI did not correlate with toxicity either. Interestingly, a higher total melphalan dose did not only correlate with higher toxicity, but also with a lower response rate.. Adjusting the melphalan dose for IBW does not appear to reduce toxicity following ILI for melanoma. The effect on outcome remains uncertain. More research is needed to optimize melphalan concentrations in individual patients during ILI to limit toxicity without compromising the response.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Body Mass Index; Body Weight; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Organ Size; Retrospective Studies; Skin Neoplasms; Treatment Outcome

Although studies of melphalan-based isolated limb infusion (ILI) combine data from upper extremity (UE) treatments with those from lower extremity (LE) treatments, differences between the 2 may be clinically important.. Candidates for UE ILI (n = 51) and LE ILI (n = 192) were identified from prospective databases at 2 institutions. The Response Evaluation Criteria in Solid Tumors and Wieberdink toxicity scale were used as appropriate.. The following patients had indications for UE ILI: melanoma, 36 of 47 patients (77%); sarcoma, 5 of 47 patients (11%); Merkel cell sarcoma, 3 of 47 patients (6%), and squamous cell carcinoma, 3 of 47 patients (6%). The patients who underwent UE ILI, as expected, had lower limb volumes (mean, 2.5 L vs 8.6 L; P < .001) and lower mean melphalan doses (20.7 mg vs 49.5 mg; P < .001). On perfusate blood gas analysis, the mean base excess at 30 minutes (-13.9 vs -9.1; P < .001) and the mean pH at 30 minutes (7.06 vs 7.15; P < .001) were lower for UE procedures than for LE procedures, although the mean ischemic time was longer in LE procedures (67.2 minutes) than in UE procedures (61.6 minutes; P = .03). The rate of regional toxicity grade ≥3 for UE ILI was 7% compared with 24% (P = .005) for LE ILI. There was no difference in the complete response rate for melanoma UE procedures (28%; 95% confidence interval, 16%-44%) compared with LE ILI procedures (32%; 95% confidence interval, 25%-39%).. ILI for UE disease was associated with similar complete response rates but lower toxicity than ILI for LE disease and with different physiologic sequelae despite comparable methods. The UE appears relatively resistant to toxic effects of melphalan-based ILI as currently performed, which suggests a potential for further optimization of drug dosing for UE ILI.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Follow-Up Studies; Humans; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Prospective Studies; Sarcoma; Survival Rate; Upper Extremity; Young Adult

Topics: Aged; Biopsy, Needle; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Foot; Humans; Immunohistochemistry; Male; Melanoma; Melphalan; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Obesity, Morbid; Risk Assessment; Skin Neoplasms; Time Factors; Treatment Outcome

We present the case of a 79-year-old patient with extensive metastatic malignant melanoma (MM) of the scalp. Cutaneous MM of the head and neck often presents a therapeutic challenge. Radical surgical procedures and conventional chemotherapy are often unfeasible and contraindicated because of the difficult anatomy, the extent of the tumour process, and systemic toxicity. In our patient, selective intra-arterial perfusion with pegylated liposomal doxorubicin (PLD) and melphalan was performed after catheterization of both bilateral external carotid arteries with an arterial port system. PLD 4.5 mg/m(2) and melphalan (1.35 mg/m(2), followed by 2.7 mg/m(2) after reaching tolerance) were given as short-term infusions at two-weekly intervals into the right and left external carotid arteries, respectively. After eight applications with tolerable side-effects, no MM cells were detected; however, infiltrates of lymphocytes and melanophages were seen. This case suggests that intra-arterial chemotherapy may be a useful treatment for metastatic melanoma of the scalp.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carotid Artery, External; Chemotherapy, Cancer, Regional Perfusion; Doxorubicin; Female; Head and Neck Neoplasms; Humans; Melanoma; Melphalan; Polyethylene Glycols; Scalp; Skin Neoplasms

Hyperthermic isolated limb perfusion (HILP) with TNF-α and melphalan has high response rates in patients with soft tissue sarcomas (STS) or melanomas of the limbs. Its effectiveness is based on the destructive effect of TNF-α on the blood supply of the tumours. Shedding of soluble TNF-receptor (sTNF-R) negatively modulates the effects of TNF-α, whereas hyperthermia (HT) induces shedding. Here, we investigated whether sTNF-R shedding in response to HT occurs during HILP.. The serum levels of sTNFR-1 were measured in 23 patients with HILP by obtaining serum from the extracorporeal and central circuits. The samples were taken from the patients under normothermic (37°C) and hyperthermic (39°C) conditions. Additionally, cell cultures of HUVEC, human fibrosarcoma cells and peripheral blood cells were used to confirm the effects of HT on sTNF-R1 shedding by ELISA and western blot.. Under HT, levels of sTNF-R1 increased 23.5% in the extracorporeal circuit, but this increase was not observed in the systemic circuit. However, we could not confirm this effect using the cell culture model, where cellular TNF-R1 and sTNF-R1 of culture supernatants, respectively, were not significantly different between NT and HT conditions.. HT is associated with an increase of sTNF-R1 in the extracorporeal circuit of perfused limbs. Interestingly, HT does not exhibit the same effect on cells cultured in vitro. Additional studies will be aimed at determining whether our findings have an impact in the clinic by analysing the relationship between TNF-R1 shedding and tumour response to HILP.

Topics: Aged; Cells, Cultured; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Receptors, Tumor Necrosis Factor; Sarcoma; Soft Tissue Neoplasms; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Our initial results with isolated limb perfusion (ILP) using melphalan ± TNF alpha in patients with unresectable melanoma of the limb were analyzed.. 15 ILPs were performed between 2001 and 2006. Indications for ILP were stage III or IV metastatic melanoma. Complete and partial response rates, time to local and systemic tumour progression rates, disease free and overall survival rates were retrospectively analyzed.. Overall response rate was 93%, with a 67% complete response and a 26% partial response rate. In eight cases grade II, while in six cases grade III local toxicity was detected. However, one mortality was detected in the early postoperative phase due to a grade V complication. With a mean follow-up period of 2.7 years, eight patients had local progression and in four of those, systemic progression was detected.. ILP was generally well tolerated and limb salvage was achieved in all cases.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha; Upper Extremity

After ilioinguinal radical lymph node dissection (RLND), the therapy for lymph fistulas constitutes a challenge. Risk factors for the genesis of lymph fistulas have not been sufficiently evaluated. We investigated possible factors that could influence the development of lymph fistulas in patients suffering from malignant melanoma after iloinguinal RLND.. The analysis was related to patients with intransit and lymphonodal metastasised malignant melanoma of the lower limb, who underwent RLND and isolated limb perfusion (ILP). Prospective data acquisition from patients undergoing ilioinguinal RLND and ILP in a one-step approach was performed. The association of lymph fistulas to risk factors was calculated using chi-squared, linear-by-linear test and ROC curves. As possible risk factors we investigated the presence of prior surgery and diabetes mellitus type II in the medical history, chemotherapeutics, patient age and the body mass index (BMI).. Postoperative lymph fistula occurred in 11 of 108 patients (10.2%). A significant association to lymph fistulas was found in BMI (30.2± 7.0 kg/m (2), p<0.02). Other parameters, such as prior surgery (82% vs. 71%), diabetes mellitus type II (9% vs. 11.7%), chemotherapeutics and patient age (mean 67.8 vs. 62.4 years) showed no influence.. Our results indicate that the incidence of lymph fistulas after RLND and ILP of malignant melanoma of the lower limb was associated with an increased BMI. Thus, for the prevention of lymph fistulae, an initially alternative wound-closure dressing like vacuum assisted closure (V.A.C.) dressing could be of clinical relevance for obese patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Female; Fistula; Humans; Inguinal Canal; Leg; Lymph Node Excision; Lymphatic Diseases; Male; Melanoma; Melphalan; Middle Aged; Negative-Pressure Wound Therapy; Neoplasm Staging; Obesity; Postoperative Complications; Retrospective Studies; Risk Factors; Skin Neoplasms; Tumor Burden; Tumor Necrosis Factor-alpha

The cavitational effects of ultrasound (US) exposure induce transient pores on the cell membrane (sonoporation). Sonoporation have been applied in the field of cancer therapy by promoting delivery of extracellular molecules such as drugs and genes into cytoplasm. In addition, it is known that using US together with microbubbles (MB) elevates permeability of these agents. In this study, by applying the US-MB strategy for melanoma chemotherapy, we evaluated the antitumor effect of melphalan combined with US-MB on a melanoma cell line (C32) in vitro and in vivo. The in vitro cytotoxic effect of the melphalan with US-MB was greater than that of melphalan alone or melphalan in combination with US. In vivo experiments using xenografts, intratumoral injection of melphalan and MB with US exposure led to a greater degree of tumor regression than did the intratumoral injection of the melphalan alone or melphalan in combination with US. These results suggest that US-MB promotes the antitumor effect of melphalan by increasing delivery of molecules into cells and that this strategy may become an effective method of adjuvant therapy against malignant melanoma.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell Enlargement; Cell Line, Tumor; Female; Humans; Melanoma; Melphalan; Mice; Mice, Inbred BALB C; Microbubbles; Ultrasonic Therapy

Hyperthermic isolated limb perfusion (HILP) is a standardized method of treatment in selected patients with in-transient locoregional recurrence/methastasis of melanoma or, some other soft tissue tumors (incl. sarcoma etc.) Authors present history and current status of this treatment modality in General University Hospital in Prague. During one year period (7/2009-6/2010) 10 patients were indicated for this procedure. We performed 13 procedures (3x redo), 11 in lower extremity and 2 in upper extremity. There was no serious complication in this cohort of patiens. Multidisciplinar approach is indicated in melanoma patients care.

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Tumor Necrosis Factor-alpha

This study was conducted to assess the safety and efficacy of our modified ILP treatment with borderline true hyperthermia and high melphalan concentration in stage III lower limb melanoma.. Between March 1990 and December 2006, 91 consecutive patients were given ILP treatment. Forty three patients were treated with double L-PAM bolus combined with D-actinomicin; 48 patients were treated with additional L-PAM bolus alone.. The mean follow-up period is 68.5 months. The acute regional toxicity occurred with grade II (54%), III (38%), IV (2.1%). The systemic toxic effects were present with transitory hematological disorders. Complete response (CR) rate was observed in 89.2% of stage IIIA-IIIAB unexcised IT-mets. The overall limb recurrent disease in stage III was 39%. In patients with CR recurrent rate occurred in 44% with a mean limb recurrence-free interval (LRFI) of 23.8 months. Distant metastases was attained with a mean time of 29.2 months. After CR, the interval was 32.1 months. The 5-year survival rate was 45%; in patients with CR, was 48%.. Our procedure is an important therapeutic option. The results suggest a marked local control of the recurrent disease. The LRFI is longer than for those treated with other treatment schedules.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Skin Neoplasms; Survival Analysis

The use of tumour necrosis factor (TNF) α in isolated limb perfusion (ILP) for in-transit melanoma metastasis is not uniformly accepted. This article reports the long-term results of adding TNF-α to standard melphalan-based ILP (TM-ILP) for treatment of melanoma in-transit metastases.. Data for patients treated between 1991 and 2005 were retrieved from a prospectively maintained database. Hyperthermic ILP was performed with 1-4 mg TNF-α. With a median potential follow-up of 13 years, response rates, time to local progression and disease-specific survival were analysed in relation to standard baseline factors.. Some 118 TM-ILPs were analysed in 105 patients, 54 for stage IIIA, 50 for stage IIIAB and 14 for stage IV disease. The overall response rate was 93·2 per cent; the response was complete in 67·8 per cent and partial in 25·4 per cent. The response rate was significantly influenced by stage of disease (IIIA versus IIIAB; P = 0·006). The complete response was maintained until the end of follow-up in 35 patients (33·3 per cent), and local control was achieved with one additional intervention in 12 others (11·4 per cent). Local progression occurred after 66 ILPs (55·9 per cent). Number of in-transit metastases (P = 0·008) and complete response after ILP (P < 0·001) were strong prognostic factors for time to local progression. The 5-year disease-specific survival rate was 27·3 per cent; survival was positively influenced by age, stage of disease, previous ILP and complete response after ILP.. ILP with TNF-α may obtain long-term local control in selected patients with in-transit metastases from melanoma.

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Disease-Free Survival; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

NGR-TNF is a derivative of TNF-α that targets tumor blood vessels and enhances penetration of chemotherapeutic drugs. Because of this property, NGR-TNF is being tested in combination with chemotherapy in various phase II and III clinical trials. Here we report that chromogranin A (CgA), a protein present in variable amounts in the blood of normal subjects and cancer patients, inhibits the synergism of NGR-TNF with doxorubicin and melphalan in mouse models of lymphoma and melanoma. Pathophysiologically relevant levels of circulating CgA blocked NGR-TNF-induced drug penetration by enhancing endothelial barrier function and reducing drug extravasation in tumors. Mechanistic investigations done in endothelial cell monolayers in vitro showed that CgA inhibited phosphorylation of p38 MAP kinase, disassembly of VE-cadherin-dependent adherence junctions, paracellular macromolecule transport, and NGR-TNF-induced drug permeability. In this system, the N-terminal fragment of CgA known as vasostatin-1 also inhibited drug penetration and NGR-TNF synergism. Together, our results suggest that increased levels of circulating CgA and its fragments, as it may occur in certain cancer patients with nonneuroendocrine tumors, may reduce drug delivery to tumor cells particularly as induced by NGR-TNF. Measuring CgA and its fragments may assist the selection of patients that can respond better to NGR-TNF/chemotherapy combinations in clinical trials.

Topics: Antineoplastic Agents; Cell Membrane Permeability; Chromogranin A; Doxorubicin; Drug Synergism; Humans; Lymphoma; Melanoma; Melphalan; Recombinant Fusion Proteins; Tumor Necrosis Factor-alpha

Isolated limb infusion (ILI) is a novel, minimally invasive technique for delivering high-dose regional chemotherapy in patients with recurrent and in-transit melanoma. The aim of this study was to review our single-centre experience in treating eleven patients. We emphasize the role of radiologists in setting up this service, including pre-treatment workup and placement of vascular catheters.. A retrospective analysis of 11 patients who underwent 12 procedures between 2005 and 2009 was performed. Pre-procedural staging computed tomography (CT), CT angiography, and duplex studies were performed. All patients received a cytotoxic combination of melphalan and actinomycin-D via radiologically placed arterial and venous catheters in the affected limb under mild hyperthermic conditions. The outcome measures include response rates, limb toxicity, complications, and survival.. All patients were female with a mean age of 72 years. Three patients had American Joint Committee on Cancer (AJCC) stage IIIB melanoma, seven had stage IIIC melanoma, and one had a stage IIIB Merkel cell tumour. Complete response was seen in five patients (46%), partial response in four (36%), and progressive disease in two (18%). One patient developed grade 4 toxicity requiring a fasciotomy and another experienced systemic toxicity.. These outcomes are comparable to previous studies and shows that ILI is effective in locoregional control of unresectable melanoma. It is a relatively safe procedure but not without risk. Our experience shows the importance of radiological input to ensure safe and effective delivery of services.

Topics: Aged; Angiography; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Infusion Pumps; Melanoma; Melphalan; Neoplasm Staging; Postoperative Care; Preoperative Care; Prognosis; Retrospective Studies; Skin Neoplasms; Survival Analysis; Tomography, X-Ray Computed; Treatment Outcome

To assess the survival of patients with hepatic uveal melanoma metastases undergoing sequential transarterial hepatic chemoperfusion.. 61 patients (mean age, 60.3 ± 13.8 y) underwent a total of 249 hepatic chemoperfusion procedures (mean: 4 chemoperfusion procedures; range, 1-7 chemoperfusion procedures; standard deviation, 2.3 chemoperfusion procedures). All patients started with melphalan. In the case of progressive disease, melphalan was replaced by a different chemoperfusion agent. 38 patients were treated with melphalan only, 23 patients were treated with a combination of melphalan and other drugs. The median overall survival time was calculated for the overall population and several sub-groups. Differences in the survival rate between the sub-groups were assessed for statistical significance. The complication rate was assessed.. The median overall survival of the entire population was 10 months. The patients in the subgroups with a maximum number of 9 hepatic metastases as well as the patients in the subgroup without extrahepatic metastases at the beginning of therapy survived significantly longer than patients with more than 9 metastases/extrahepatic metastases (p = 0.019, p = 0.008). One patient (0.4%) died from liver failure after initial infusion of melphalan.. Intraarterial sequential hepatic chemoperfusion offers a minimally invasive treatment in patients with hepatic uveal melanoma metastases with good survival times and an acceptable major complication rate.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Humans; Infusions, Intra-Arterial; Liver Failure; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Retrospective Studies; Survival Rate; Uveal Neoplasms

In-transit melanoma metastases develop within regional dermal and subdermal lymphatics before reaching the regional lymph nodes. The prognosis is poor and comparable to multiple nodal metastases. Isolated limb infusion (ILI) or perfusion (ILP) are effective treatments for unresectable, in-transit melanoma, with response rates reaching 95%. Although ILI and ILP are more effective than systemic therapy, most patients will recur, thus highlighting the need for newer strategies to improve durable response rates.. We review historical and current literature from 1958 to 2009 regarding regional therapy for melanoma, with focus on the ILI and ILP techniques, pharmacokinetics and resistance mechanisms of melphalan. Alternative therapies, adjunct strategies and new targeted therapies aimed at improving response rates and long-term remission are also discussed.. The reader will gain a comprehensive review on regional pharmacotherapy for melanoma, including alternative therapies, adjunct strategies and new targeted therapies.. Regional chemotherapy is a viable, evolving treatment for patients with in-transit melanoma and a springboard for ongoing research aimed at improving therapies for malignant melanoma.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Humans; Hyperthermia, Induced; Infusions, Intra-Arterial; Lymphatic Metastasis; Melanoma; Melphalan; Neoplasm Recurrence, Local; Skin Neoplasms; Soft Tissue Neoplasms

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Infusion Pumps; Infusions, Intra-Arterial; Male; Melanoma; Melphalan; Neoplasm Metastasis

The aim is to analyse a modified standardised HILP procedure regarding the response rates, local recurrences and complication rates.. 152 patients (101 females, 51 males) with an average age of 62 years and locoregionally metastasised malignant melanoma underwent HILP using melphalan and dactinomycin between 1992 and 2007. Using M.D. Anderson's classification at the time of the perfusion 51 patients presented in stage IIIA, 43 patients in stage IIIAB and 58 patients in stage IV. If indicated, lymph node dissection was performed simultaneously just before perfusion of the extremity.. Complete remission was observed in 91 (62.7%) of 145 patients, partial remission in 26 (17.9%) patients. 28 (19.3%) patients showed no response. The overall response rate was 80.7% (117 of 145 patients). Severe complications (Wieberdink IV/V) were seen in eight cases. The average recurrence-free survival was 17 months. The median survival was 39 months; the five-year overall survival rate was 38%. The overall survival rate was significantly influenced by the stage of the disease.. HILP is an efficient therapy for multiple or recurrent in-transit metastases of malignant melanoma of the lower extremities. The efficiency increased by improving the technique of the perfusion. Long-term survival can be observed in patients without regional lymph node metastases or distant metastases.

Topics: Adult; Aged; Aged, 80 and over; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Hyperthermia, Induced; Kaplan-Meier Estimate; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Skin Neoplasms; Treatment Outcome

Hyperthermic isolated limb perfusion with TNF-alpha and melphalan (TM-HILP) is a complicated surgical procedure. Herein, we present the experience of the Hellenic collaborating centers with TM-HILP for inoperable in-transit melanoma and soft tissue sarcoma (STS) of the extremities to examine safety and feasibility of collaborating as a multi-institutional group for future research studies. From 2001 to 2009, twenty patients (median age 63.5 years) underwent TM-HILP for locally advanced in-transit melanoma (n=14) or unresectable STS (n=6). All patients underwent a 90-min isolated limb perfusion with melphalan (10 mg/l limb volume) and TNF-alpha (1-2 mg) under mild hyperthermia (39-40 degrees C). No major intra-operative complications occurred and all patients completed the procedure successfully. One patient developed postoperative ischemic necrosis of the limb necessitating amputation. All melanoma patients showed a response to TM-HILP with 7 (62%) of them experiencing complete response. All STS patients attained complete response after excision of residual tumor. The median disease specific and limb-relapse-free survival was 15 and 12 months, respectively. TM-HILP can be safely applied even in low volume tertiary hospitals provided that technology to minimize intraoperative systemic leakage is available. Future prospective studies can be performed reproducibly by this multi-institutional collaborative group.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Feasibility Studies; Female; Greece; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Reproducibility of Results; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

Patients with ocular melanoma liver metastases have a poor prognosis, treatment options are limited, and median survival is less than 1 year. In this study, we characterized the early molecular changes that occur in tumors immediately after vascular isolation perfusion with melphalan with hyperthermia in patients with hepatic metastases from ocular melanoma.. Patients underwent treatment on a clinical trial using a 60-min hyperthermic isolated hepatic perfusion (IHP) with melphalan. Microarray analysis was performed in 28 tumor samples obtained intraoperatively of which 12 were pre- and 16 were post-IHP. Various statistical analyses were performed to identify differentially expressed genes and gene categories between the groups.. Median survival of 17 treated patients was 11.9 months. Unsupervised hierarchical clustering of all tumors resulted in separation of pre and post-IHP samples into two distinct groups. Analysis of genes showed that the Ras GTPase activator, ecotropic viral integration site 5 (EVI5), and several other melanoma-associated genes were overexpressed in pre-IHP tumors. In post-IHP samples the overexpression of a DNA replication associated gene, replication factor C (RFC5), was significantly associated with shortened survival (P < 0.003). Other major gene ontology categories identified in the post-IHP tumor samples were DNA-directed RNA polymerase activity and chromatin remodeling, both important categories involved in DNA replication and repair.. These results demonstrate that acute changes in gene expression patterns occur in tumors immediately after treatment with melphalan administered via hyperthermic IHP. Rapid activation of DNA synthesis and repair pathways may be a mechanism of acquired tumor resistance in patients with ocular melanoma.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Chemotherapy, Cancer, Regional Perfusion; Cohort Studies; Eye Neoplasms; Female; Gene Expression Profiling; Humans; Hyperthermia, Induced; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Rate; Treatment Outcome

In-transit metastatic melanoma, which typically presents as multifocal lesions, provides a unique setting to evaluate the utility of gene signatures for defining optimal regional therapeutic strategies and assessing the efficacy of treatment. The goal of this study was to determine whether a single multifocal lesion is representative of residual tumor burden in terms of gene expression signatures predictive of response to therapy. Using microarray-based gene expression profiling, we examined 55 in-transit melanoma lesions across 29 patients with multifocal disease. Principal component analysis, unsupervised hierarchical clustering, one-way ANOVA, binary regression analysis, and gene signatures predictive of oncogenic pathway activation were used to compare patterns of gene expression across all multifocal lesions from a patient. Patterns of gene expression were highly similar (P < 0.006; average r = 0.979) across pretreatment lesions from a single patient compared with the significantly different patterns observed across patients (P < 0.05). The findings presented in this study show that individual melanoma tumor nodules in patients with multifocal disease harbor similar patterns of gene expression and a single lesion can be used to predict response to chemotherapy, evaluate the activation status of oncogenic signaling pathways, and characterize other aspects of the biology of an individual patient's disease. These results will facilitate the use of gene expression profiling in melanoma regional therapy clinical trials to not only select optimal regional chemotherapeutic agents but to also allow for a more rational identification of candidates for specific targeted therapies and evaluation of their therapeutic efficacy. Mol Cancer Ther; 9(4); 779-90. (c)2010 AACR.

Topics: Aged; Aged, 80 and over; Cell Line, Tumor; Dacarbazine; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Intracellular Space; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Regression Analysis; Signal Transduction; Temozolomide; Transcription, Genetic

The aims of the study were: (1) to determine toxicity, response rate, local-regional control, and survival in the entire population of the perfused patients; (2) to compare toxicity, response, and survival among patients who underwent melphalan-based perfusion with or without low-dose tumor necrosis factor (TNF); and (3) to identify factors that predict a complete response and survival.. A total of 53 patients with extensive in-transit metastases (47%) underwent perfusion with melphalan, and 59 (53%) also received low-dose TNF.. No difference was observed between the 2 drug regimens for what concerns local toxicity (P = 1.0). The tumor complete response rate was higher in patients treated with TNF (60.3% versus 41.5%, P = .036), in particular in the case of locally advanced tumors (66.7% versus 30%, P = .049). The presence of lymph node metastases had a negative influence on the tumor response rate (P = .003). Median time to local progression and survival were 19.6 and 34.5 months, respectively. Long-term complete response was achieved in 68% of the patients with initial CR (39 of 57 patients). The tumor response after perfusion was the only prognostic factor for local control and survival (P < .0001 and P = .002, respectively).. In the case of locally advanced disease, the addition of low-dose TNF to melphalan-based isolated limb perfusion appears safe and particularly useful. The presence of lymph node metastases is associated with decreased response rates. A sustained complete response was obtained in about one-third of the patients.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Remission Induction; Skin Neoplasms; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha

Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 micromol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzenesulfonates; Blotting, Western; Butadienes; Cell Line, Tumor; Cell Survival; Dacarbazine; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Melanoma; Melphalan; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Niacinamide; Nitriles; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-bcl-2; Pyridines; Rats; Rats, Nude; Sorafenib; Temozolomide; Tumor Burden; Xenograft Model Antitumor Assays

Isolated limb infusion (ILI) for recurrent or in-transit melanoma is an accepted technique that allows high-dose chemotherapy to be delivered to an extremity with minimal systemic toxicity. Current infusion systems have relied on manual delivery of drugs and circulation of blood during the treatment. Herein, we document our initial results with an automated circuit for ILI as an alternative to the manual technique.. Patients undergoing ILI with an automated circuit for recurrent or advanced malignancy were identified. ILI was performed utilizing a Sarns 8000 roller pump attached to a Cobe 4:1 cardioplegia set with heat exchanger with a total priming volume of 80 ml. Melphalan (7.5 mg/L) and Dactinomycin (75 μg/L) doses which were corrected for ideal body weight were delivered via the infusion circuit after limb temperature reached 38 °C.. Fourteen lower extremity infusion procedures were performed in 10 patients. Successful infusion procedures were completed in all patients using the automated circuit. Constant flow rates of 50-70 cc/minute were achievable with the automated circuit. Acute toxicity and clinical results were similar to that reported with manual delivery systems.. ILI for advanced malignancy utilizing an automated circuit is feasible and safe. This automated system offers a safe and reliable alternative to the manual infusion technique.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Female; Heart Arrest, Induced; Humans; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Treatment Outcome

Ocular melanoma prefers to metastasize to the liver and the liver is the sole site of metastatic disease in 80% of patients. Until now there has been no standard treatment available and these patients have a very poor prognosis (median survival 2-5 months). Isolated hepatic perfusion may be an option in patients with irresectable hepatic ocular melanoma metastases. The aim of this study was to evaluate applicability, toxicity and response in this selected group of ocular melanoma patients by treatment with isolated hypoxic hepatic perfusion with retrograde outflow (IHHP) with melphalan.. From September 2002 until July 2006 eight consecutive patients were included in this study. IHHP was performed with inflow via the hepatic artery and retrograde outflow via the portal vein during 25 min with 1mg/kg melphalan. The perfusion was followed by a complete wash-out procedure.. The median total operation time was 4h with a median blood/fluid loss of 1100 ml. No postoperative mortality was observed. Median hospital stay was 9.5 days. Toxicity was moderate: WHO grade 3 leukocytopenia in 3 patients, grade 3 hepatic toxicity in 1 patient. In 37% of patients (3/8) a partial response could be demonstrated 3 months after IHHP. Stable disease was found in 3 patients and progressive disease in 2 patients. Median time to local progression was 6 months and the median survival was 11 months.. Melphalan-based IHHP with retrograde outflow is a safe treatment option for patients with irresectable ocular melanoma metastases. Survival benefit seems to be comparable to classical IHHP.

Topics: Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Eye Neoplasms; Female; Humans; Liver Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Treatment Outcome

This study aims to determine what effect correcting melphalan dosing for ideal body weight (IBW) has on toxicity and response in isolated limb infusion (ILI) in patients with advanced extremity melanoma.. This was an open observational study examining whether correcting the melphalan dose for IBW will influence response and toxicity in patients undergoing ILI for advanced extremity melanoma in 41 patients undergoing 42 procedures (13 without correction for IBW; and 29 with correction for IBW). Melphalan pharmacokinetics, limb toxicity, serologic toxicity, and response at 3 months were compared.. The corrected group had a lower estimated limb volume (V (esti)) to melphalan volume at steady state (V (ss)) (P < .0001) ratio as well as lower incidence of grade > or =3 regional toxicity, serologic toxicity, and compartment syndrome (P = .0249, P = .027, P = .02). There was a positive correlation of V (esti)/V (ss) to toxicity (P = .0127, r = .382). No significant difference in response (P = .3609) between the groups was found, although there was a trend of association between V (esti)/V (ss) and response (P = .051, r = .3383).. Correcting for IBW in ILI lowers toxicity without significantly altering response rates.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Body Weight; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms

In the treatment of patients with advanced limb melanoma a major treatment dilemma can arise when distant metastases are present also. Isolated limb infusion (ILI) has proved to be a useful limb-saving treatment and could potentially be of palliative value in patients with American Joint Committee on Cancer (AJCC) stage IV melanoma.. We identified 37 patients with advanced symptomatic limb disease as well as documented distant metastases at the time of their ILI. In all patients a drug combination of melphalan and actinomycin D was used.. Fifty one percent had visceral distant metastases and 49% had cutaneous distant metastases only. The overall response rate in the treated limb was 76% [complete response (CR) rate 22%, partial response (PR) rate 54%]. Median response duration was 11 months (28 months for patients with CR; p = 0.08). Median survival after CR was 22 months, 17 months after PR, and only 4 months for those with stable or progressive disease (p = 0.002). Patients with visceral distant metastases had a significantly decreased survival compared with those with cutaneous distant metastases only (8 and 21 months, respectively; p = 0.03). Limb salvage was achieved in 86% of the patients. The procedure was well tolerated, with only one patient developing Wieberdink grade IV toxicity (threatened/actual compartment syndrome) and none requiring amputation as a result of the procedure (grade V toxicity).. Minimally invasive ILI can effectively be used as palliative treatment to provide local tumor control and limb salvage in stage IV melanoma patients with advanced, symptomatic limb disease.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Palliative Care; Skin Neoplasms

Isolated limb infusion (ILI) with cytotoxic drugs is a low-flow isolated limb perfusion (ILP) performed via percutaneous catheters without oxygenation to treat metastatic melanoma confined to a limb. Response rates and duration of response following ILI are similar to those after ILP. Previously we have shown that more significant limb toxicity is not associated with a higher response rate or improved patient outcome. In this study we sought to determine factors predicting toxicity following ILI.. From our prospective database 185 patients with advanced metastatic melanoma of the limb treated with a single ILI between 1992 and 2007 were identified. In all patients a cytotoxic combination of melphalan and actinomycin D was used. Drug circulation time was 20-30 min under mild hyperthermic conditions (38-39 degrees C). Limb toxicity was assessed using the Wieberdink scale.. The average patient age was 74 years (range 29-93 years) and 62% were female. Most patients (134/185) had MD Anderson stage III disease (satellites and in-transit metastases). Toxicity grade I (no reaction) occurred in 3 patients, grade II (slight erythema and edema) in 105 patients, grade III (considerable erythema and edema +/- blistering) in 72 patients, and grade IV (threatened or actual compartment syndrome) in 5 patients. No patient developed grade V toxicity (requiring amputation). On univariate analysis high peak and high final melphalan concentrations were found to be predictive factors for grade III/IV limb toxicity as well as the area under the curve of the melphalan concentration. Surprisingly, a greater rise in the CO(2) level during the procedure was associated with lower toxicity in the univariate analysis. Increased serum creatine phosphokinase (CK) postoperatively was related to higher toxicity score. In the multivariate analysis high final melphalan concentration and shorter tourniquet time were independent predictive risk factors for developing grade III/IV limb toxicity.. ILI is a safe alternative to the more invasive and laborious ILP technique to treat melanoma confined to a limb. Regional acute toxicity following ILI is mild to moderate in most patients. Based on the predictive factors found in this series, altering melphalan dose and tourniquet time may allow further reductions in post-ILI toxicity without compromising effectiveness.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms

: Isolated limb infusion (ILI) is an effective and minimally invasive treatment option for delivering regional chemotherapy in patients with metastatic melanoma confined to a limb. Recurrent or progressive disease after an ILI, however, presents a challenge for further treatment. The value of repeat ILI in this situation has not been well documented.. : Forty-eight patients were identified who had been treated with a repeat ILI. In all patients, a cytotoxic combination of melphalan and actinomycin D was used.. : The median time between the 2 procedures was 11 months. The complete response (CR) rate after repeat ILI was 23%, compared with 31% after the initial ILI (P = .36). The overall response was 83%, compared with 75% after the first procedure (P = .32). The median duration of response was 11 months (10 months for patients with CR; P = .80), and median survival was 38 months. In those patients achieving a CR, the median survival was 68 months (P = .003). Toxicity after repeat ILI was increased, with 20 patients experiencing Wieberdink grade III limb toxicity (considerable erythema and edema with blistering) and 5 patients experiencing grade IV toxicity (threatened or actual compartment syndrome), whereas after the initial ILI these toxicity grades occurred in 14 patients and 1 patient, respectively (P = .03). No patient experienced grade V toxicity (requiring amputation).. : Repeat ILI is an attractive treatment option to achieve limb salvage in patients with inoperable recurrent or progressive melanoma after a previous ILI. It can be associated with significant short-term regional toxicity, but is well tolerated by most patients, with satisfactory response rates. Cancer 2009. (c) 2009 American Cancer Society.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Disease Progression; Female; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Recurrence; Skin Neoplasms; Survival Analysis; Time Factors; Treatment Outcome

Topics: Antineoplastic Agents, Alkylating; Bone Density Conservation Agents; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Diphosphonates; Humans; Imidazoles; Male; Melanoma; Melphalan; Positron-Emission Tomography; Skin Neoplasms; Tibia; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult; Zoledronic Acid

Isolated limb infusion (ILI) is a minimally invasive approach for treating in-transit extremity melanoma, with only two US single-center studies reported. Establishing response and toxicity to ILI as compared with hyperthermic isolated limb perfusion is important for optimizing future regional chemotherapeutic strategies in melanoma.. Patient characteristics and procedural variables were collected retrospectively from 162 ILIs performed at 8 institutions (2001 to 2008) and compared using chi-square and Student's t-test. ILIs were performed for 30 minutes in patients with in-transit melanoma. Melphalan dose was corrected for ideal body weight (IBW) in 42% (n = 68) of procedures. Response was determined at 3 months by Response Evaluation Criteria in Solid Tumors; toxicity was assessed using the Wieberdink Limb Toxicity Scale.. In 128 evaluable patients, complete response rate was 31%, partial response rate was 33%, and there was no response in 36% of patients. For all patients (n = 162), 36% had Wieberdink toxicity grade >or=3 with one toxicity-related amputation. On multivariate analysis, smaller limb volumes were associated with better overall response (p = 0.021). Use of papaverine in the circuit to achieve cutaneous vasodilation was associated with better response (p < 0.001) but higher risk of grade >or=3 toxicity (p = 0.001). Correction of melphalan dose for ideal body weight did not alter complete response (p = 0.345), but did lead to marked reduction in toxicity (p < 0.001).. In the first multi-institutional analysis of ILI, a complete response rate of 31% was achieved with acceptable toxicity demonstrating this procedure to be a reasonable alternative to hyperthermic isolated limb perfusion in the management of advanced extremity melanoma.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Drug Therapy, Combination; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Multivariate Analysis; Papaverine; Retrospective Studies; Skin Neoplasms; Treatment Outcome; United States; Young Adult

The treatment of malignant melanoma or sarcomas on a limb using extremity perfusion with tumour necrosis factor (TNF-alpha) and melphalan can result in a high degree of systemic toxicity if there is any leakage from the isolated blood territory of the limb into the systemic vascular territory. Leakage is currently controlled by using radiotracers and heavy external probes in a procedure that requires continuous manual calculations. The aim of this work was to develop a light, easily transportable system to monitor limb perfusion leakage by controlling systemic blood pool radioactivity with a portable gamma camera adapted for intraoperative use as an external probe, and to initiate its application in the treatment of MM patients.. A special collimator was built for maximal sensitivity. Software for acquisition and data processing in real time was developed. After testing the adequacy of the system, it was used to monitor limb perfusion leakage in 16 patients with malignant melanoma to be treated with perfusion of TNF-alpha and melphalan.. The field of view of the detector system was 13.8 cm, which is appropriate for the monitoring, since the area to be controlled was the precordial zone. The sensitivity of the system was 257 cps/MBq. When the percentage of leakage reaches 10% the associated absolute error is +/-1%. After a mean follow-up period of 12 months, no patients have shown any significant or lasting side-effects. Partial or complete remission of lesions was seen in 9 out of 16 patients (56%) after HILP with TNF-alpha and melphalan.. The detector system together with specially developed software provides a suitable automatic continuous monitoring system of any leakage that may occur during limb perfusion. This technique has been successfully implemented in patients for whom perfusion with TNF-alpha and melphalan has been indicated.

Topics: Disease-Free Survival; Equipment Design; Extremities; Gamma Cameras; Humans; Melanoma; Melphalan; Monitoring, Intraoperative; Neoplasm Metastasis; Radionuclide Imaging; Reproducibility of Results; Sarcoma; Survival Analysis; Technetium; Tumor Necrosis Factor-alpha

Isolated limb infusion (ILI) is a minimally invasive technique delivering regional chemotherapy to treat in-transit extremity melanoma. Determining perioperative factors that could predict toxicity is important to optimize strategies to improve clinical outcomes after regional chemotherapy in melanoma.. Perioperative factors from 171 ILI patients performed at eight centers from 2001 to 2008 were reviewed. The Wieberdink limb toxicity scale and creatine phosphokinase (CK) levels were used to measure toxicity. Logistic regression analysis was used to estimate the association between toxicity and perioperative parameters.. Mild (grades I-II) and severe (grades >or=III) limb toxicity developed in 68% and 32% of patients, respectively. Melphalan adjusted for ideal body weight (aIBW) and papaverine were used in 47% and 63% of patients, respectively. Median peak CK for all patients was 563 U/l, and median peak occurred at postoperative day 4. On univariate analysis, papaverine and high CK levels (>563 U/l) were significantly associated with higher toxicity. On the contrary, aIBW was significantly associated with a lower risk of severe toxicity. Perfusate blood gas at 30 min [pH, PaO(2), and base excess (BE) ], limb temperature, and ischemia time were not predictive of limb toxicity. On multivariate analysis, severe toxicity was associated with female sex (P = 0.01), papaverine (P = 0.01), and high peak CK levels (P < 0.01). Independent predictors of high CK levels included younger age, unadjusted melphalan dose, and low PaO(2) at 30 min.. ILI can be performed with an acceptable morbidity. Papaverine use, female gender, and high peak CK were associated with higher limb toxicity. CK levels can be diminished significantly with aIBW.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Creatine Kinase; Drug Therapy, Combination; Female; Humans; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Papaverine; Phosphodiesterase Inhibitors; Prognosis; Retrospective Studies; Survival Rate; Treatment Outcome; Young Adult

We present the case of a 72-year-old female presenting to our unit with locally recurrent malignant melanoma of the lower limb almost entirely confined to a fasciocutaneous free flap. The flap (lateral arm donor site) had been used several years previously to reconstruct a wide local excision defect following the excision of recurrent disease. The striking difference about this case is that the recurrence observed after isolated limb perfusion (ILP) was almost entirely confined to the flap rather than the affected limb. Several possible explanations for this phenomenon are discussed--considering factors such as altered flap lymphatics, neuronal factors, and differential flap-versus-normal tissue response to the tumour necrosis factor used in ILP. The case highlights interesting questions about the mechanism of action of ILP--especially with regard to free flap tissue--and unknowns regarding tumour spread across wound scar boundaries.

Topics: Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Melanoma; Melphalan; Neoplasm Recurrence, Local; Skin Neoplasms; Surgical Flaps; Wound Healing

Isolated limb infusion (ILI) is a minimally invasive technique for delivering regional chemotherapy in patients with advanced and metastatic melanoma confined to a limb. It is essentially a low-flow isolated limb perfusion (ILP) performed via percutaneous catheters without oxygenation.. From our prospective database 185 patients with advanced metastatic melanoma of the limb treated with a single ILI between 1993 and 2007 were identified. In all patients a cytotoxic drug combination of melphalan and actinomycin-D was used. Drug circulation time was 20-30 min under mild hyperthermic conditions (38-39 degrees C).. The majority of patients (62%) were female. Their average age was 74 years (range 29-93 years). Most patients had MD Anderson stage III disease (134/185). The overall response rate was 84% [complete response (CR) rate 38%, partial response rate 46%]. Median response duration was 13 months (22 months for patients with CR; P = 0.01). Median follow-up was 20 months and median survival was 38 months. In those patients with a CR, the median survival was 53 months (P = 0.005). CR rate and survival time decreased with increasing stage of disease. On multivariate analysis significant factors for a favorable outcome were achievement of CR, stage of disease, thickness of primary melanoma, the CO(2 )level in the isolated circuit, and a Wieberdink limb toxicity score of III (considerable erythema and edema).. The response rates and duration of response after ILI are comparable to those achieved by conventional ILP. ILI is a minimally invasive alternative to the much more complex and morbid conventional ILP technique for patients with advanced metastatic melanoma confined to a limb.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Prospective Studies; Skin Neoplasms; Survival Rate; Time Factors; Treatment Outcome

The alkylating peptide PSF shows very promising results in vitro on different cancer cells but its efficacy in animals has not been assessed. Here we evaluate the efficacy of PSF in human melanoma-bearing nude mice and examine the underlying mechanism. In melanoma-bearing nude mice, escalating doses of PSF showed dose-dependent responses and reached tumor regression with an optimal dose of 20 mg/kg for 1 month. A comparison of PSF with its free moiety m-sarcolysin and melphalan showed a highly significant advantage of PSF. Furthermore, dose fractionation yielded an even better control of tumor regrowth. In vitro studies unraveled an original delivery mechanism based on the rapid binding of PSF mainly due to red blood cells to form a pro-drug complex and the subsequent release of active metabolites by tumor-associated proteolytic enzymes. Blood kinetics showed one major metabolite partially released over time, while in the presence of melanoma cells three additional metabolites are generated. Interestingly, tumor-shed proteases also induce the production of these metabolites and varying combinations of enzyme inhibitors indicate the involvement of metallo- and other families of proteases in the delivery process. This particular transport and delivery of such an alkylating agent may have several benefits, mainly lowering the drug-free moiety in plasma and at the same time increasing its concentration in protease rich areas such as tumors.

Topics: Animals; Antineoplastic Agents; Dipeptides; Drug Delivery Systems; Drug Stability; Humans; Melanoma; Melphalan; Mice; Mice, Nude; Models, Biological; p-Fluorophenylalanine; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Metastatic cutaneous melanoma is highly resistant to cytotoxic drugs, and this contributes to poor prognosis. In vivo studies on the chemosensitivity of metastatic melanoma are rare and hampered by poor response rates to systemic chemotherapeutics. Patients who undergo isolated limb infusion (ILI) with cytotoxic drugs show high response rates and are, therefore, a good cohort for studying chemosensitivity in vivo. We used tumors from patients who underwent ILI to study the role of melanoma tumor-suppressor genes and oncogenes on melanoma chemosensitivity. Prospectively acquired tumors from 30 patients who subsequently underwent ILI with melphalan and actinomycin-D for metastatic melanoma were investigated for mRNA expression levels of p14(ARF), p16(INK4a), and MITFm. The mutation status of B-RAF, N-RAS, and PTEN were also determined. A high percentage of tumors had activating mutations in either B-RAF (15/30) or N-RAS (10/30) and only two tumors carried altered PTEN. High expression of p16(INK4a) and absence of an activating B-RAF mutation independently predicted response to treatment. Further, inducible expression of p16(INK4a) sensitized a melanoma cell line to death induced by melphalan or actinomycin-D. This study shows that high expression of p16(INK4a) or the absence of activated B-RAF correlates with in vivo response of melanoma to cytotoxic drugs.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Cell Cycle; Cyclin-Dependent Kinase Inhibitor p16; Dactinomycin; Female; Gene Expression Regulation, Neoplastic; Genes, p16; Genes, ras; Humans; Male; Melanoma; Melphalan; Microphthalmia-Associated Transcription Factor; Middle Aged; Mutation; Polymorphism, Single-Stranded Conformational; Proto-Oncogene Proteins B-raf; PTEN Phosphohydrolase; Reverse Transcriptase Polymerase Chain Reaction; Statistics, Nonparametric; Tumor Suppressor Protein p14ARF

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Sarcoma

Tumor necrosis factor (TNF)-based isolated limb perfusion (ILP) yields high tumor response rates in patients with in-transit melanoma metastases. However, most patients will ultimately experience disease recurrence. The aim of this pilot study was to test the hypothesis that systemic low-dose interferon alpha-2b (LDI) might consolidate the therapeutic effect of ILP.. A total of 12 patients with in-transit melanoma metastases not amenable to surgical excision were given LDI subcutaneously (3 million IU/day, 7 days/week for 12 months) after TNF-based ILP (TNF 1 mg + melphalan (L-PAM) 10 mg/L) (group A). The clinical outcome of these patients was historically compared with that of 19 patients with similar anthropometric and disease characteristics who underwent TNF-based ILP alone (group B).. In group A, LDI was well tolerated, only grade 2 systemic toxicity being recorded in 50% of patients. The progression-free survival analysis showed a statistically significant advantage for group A patients as compared with group B (median time to progression: 26 and 17 months, respectively; log-rank test P-value: 0.037). This survival benefit was confirmed at multivariate analysis, where treatment was the only prognostic factor retained by the prediction model. The analysis of the risk of disease progression over time suggested that this survival benefit appears to vanish after LDI discontinuation, which further strengthens the hypothesis that LDI might consolidate the therapeutic effect of TNF-based ILP.. These preliminary findings support the conduction of larger trials to formally assess the ability of LDI to improve the clinical outcome of melanoma patients with in-transit metastases undergoing TNF-based ILP.

Topics: Adult; Aged; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Male; Melanoma; Melphalan; Middle Aged; Pilot Projects; Recombinant Proteins; Skin Neoplasms; Tumor Necrosis Factor-alpha

The objective was to analyze the outcome of three treatment strategies using isolated hyperthermic liver perfusion (IHP) with melphalan for liver metastases of malignant melanoma. It was designed as an exploratory study. The setting was a single-center study in a university hospital. The study was carried out on 27 patients. IHP was used with modifications during three different time periods (IHP I, IHP II and IHP III), in technique and temperature (amount of melphalan: 0.5, 1.0 and 2 mg/kg body weight in the perfusate; 41, 40 and 40 degrees C). Tumor response was estimated according to WHO criteria with computed tomography or MRI. Mortality and morbidity were secondary measures. Six of 11 patients in the IHP I cohort experienced a partial response (PR). In the IHP II cohort, two patients of 11 experienced a complete response and five a PR. In the IHP III cohort, five of five patients experienced a PR. Six postoperative deaths were reported (27%) (three in the IHP I and three in the IHP II series), secondary to liver insufficiency and multiorgan failure. Treatment of liver metastases of malignant melanoma with isolated hyperthermic melphalan perfusion has shown an impressive tumor response rate, which seems to be higher than the response rates reported for other systemic chemotherapy regimens. The maximum tolerated dose for melphalan in the perfusate was surpassed with a 2 mg/kg body weight. By modifying the technique and restricting the allowed tumor burden, the response rate remained high and the mortality was reduced.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Humans; Liver Neoplasms; Melanoma; Melphalan; Middle Aged; Skin Neoplasms

Malignant transformation in melanoma is characterized by a phenotype "switch" from E- to N-cadherin, which is associated with increased motility and invasiveness of the tumor and altered signaling, leading to decreased apoptosis. We hypothesized that the novel pentapeptide (ADH-1), which disrupts N-cadherin adhesion, could sensitize melanoma tumors to the cytotoxic effects of chemotherapy. N-cadherin-expressing human melanoma-derived cell lines were used to generate xenografts in animal models to study isolated limb infusion with melphalan and systemic chemotherapy with temozolomide. We report here that melphalan in combination with ADH-1 significantly reduced tumor growth up to 30-fold over melphalan alone. ADH-1 enhancement of response to melphalan was associated with increased formation of DNA adducts, increased apoptosis, and intracellular signaling changes associated with focal adhesions and fibroblast growth factor receptors. Targeted therapy using an N-cadherin antagonist can dramatically augment the antitumor effects of chemotherapy and is a novel approach to optimizing treatment for melanoma.

Topics: Animals; Antineoplastic Agents, Alkylating; Cadherins; Dacarbazine; DNA Adducts; Humans; Immunotherapy; Melanoma; Melphalan; Models, Biological; Neoplasm Transplantation; Phenotype; Rats; Rats, Nude; Temozolomide

Isolated limb perfusion (ILP) with melphalan is used in the treatment of advanced in-transit melanoma but has no real efficacy for irresectable soft tissue sarcomas arising in the extremities. The addition of tumor necrosis factor (TNF)-alpha may increase response rates for bulky melanoma and for sarcoma, but the potential for major systemic toxicity has limited its use.. Between October 2000 and April 2004, 49 ILPs were performed with melphalan and TNF-alpha. All procedures were performed with continuous leakage monitoring and regional hyperthermia.. Forty-nine ILPs were performed for melanoma (n = 30), sarcoma (n = 16), or other tumors (n = 3). The most common indications were widespread in-transit disease for melanoma (n = 29) and irresectable primary disease for sarcoma (n = 9). Complete and partial responses for melanoma were 40% and 37%, and for sarcoma they were 20% and 33%. At a median follow-up of 14 months, 66% of melanoma patients who responded had not experienced local progression, compared with only 37% of sarcoma patients. Progression-free survival was significantly less for patients with sarcoma than melanoma (P = .0476). Four of 16 patients with sarcoma subsequently required amputation for progressive disease.. ILP with melphalan and TNF-alpha is a valuable treatment for advanced in-transit melanoma. Significant response rates were also seen in irresectable sarcoma, although the duration of response was limited.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Sarcoma; Skin Neoplasms; Tumor Necrosis Factor-alpha

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Data Interpretation, Statistical; Extremities; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Randomized Controlled Trials as Topic; Research Design; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

To determine the bioactivation and uptake of prolidase-targeted proline prodrugs of melphalan in six cancer cell lines with variable prolidase expression and to evaluate prolidase-dependence of prodrug cytotoxicity in the cell lines compared to that of the parent drug, melphalan.. Hydrolysis, cell uptake, and cell proliferation studies of melphalan and the L: - and D: -proline prodrugs of melphalan, prophalan-L: and prophalan-D: , respectively, were conducted in the cancer cell lines using established procedures.. The bioactivation of prophalan-L: in the cancer cell lines exhibited high correlation with their prolidase expression levels (r (2) = 0.86). There were no significant differences in uptake of melphalan and its prodrugs. The cytotoxicity of prophalan-L: (GI(50)) in cancer cells also showed high correlation with prolidase expression (r (2) = 0.88), while prophalan-D: was ineffective at comparable concentrations. A prolidase targeting index (ratio of melphalan to prophalan-L: cytotoxicity normalized to their uptake) was computed and showed high correlation with prolidase expression (r (2) = 0.82).. The data corroborates the specificity of prophalan-L: activation by prolidase as well as prolidase-targeted cytotoxicity of prophalan-L: in cancer cell lines. Hence, prophalan-L: , a stable prodrug of melphalan, exhibits potential for efficiently targeting melanoma with reduced systemic toxicity.

Topics: Antineoplastic Agents, Alkylating; Biological Transport; Biotransformation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chlorambucil; Dipeptidases; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Hydrolysis; Inhibitory Concentration 50; Melanoma; Melphalan; Prodrugs; Proline; Protease Inhibitors; RNA, Messenger; Stereoisomerism

To review the long-term duration of limb tumor complete remission (CR) and patient survival following therapeutic hyperthermic isolated limb perfusion (ILP) with cytotoxic drugs for melanoma.. A retrospective case series of 124 ILPs performed in 111 patients.. There were 120 assessable ILPs. Patient staging (M.D. Anderson system) was stage II 11.7%, stage IIIA 44.2%, stage IIIAB 33.3%, and stage IV 10.8%. CR was initially attained after 83 ILPs (69.2%) and partial remission (PR) after 19 ILPs (15.8%). Limb CR was maintained in 28 (33.7%) of the 83 cases. Disease recurred in the perfused limb after an initial CR in the remaining 55 cases (median time to recurrence, 11 months); in 19 of these cases, the limb was disease-free at last follow-up after further locoregional treatment. A long-term CR was achieved, with or without further treatment, in 47 (56.6%) of the 83 cases in which an initial CR had occurred (mean follow-up, 97 months; median, 65 months). There was no significant difference in long-term local remission for stage IIIA and IIIAB patients. Five-year survival for those who had a partial or no response to ILP was 7%. Ten-year survival for those who had a long-term CR was 49%.. ILP, with or without further locoregional treatment, achieved long-term control of recurrent and metastatic limb disease in 56.6% of cases in which an initial CR was achieved. A complete response to ILP was a positive prognostic indicator for survival, probably reflecting more favorable tumor biology in this subset of patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Remission Induction; Retrospective Studies; Skin Neoplasms; Treatment Outcome

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Multicenter Studies as Topic; Patient Selection; Randomized Controlled Trials as Topic; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha; United States

Five different human melanoma xenografts were used in a xenograft model of extremity melanoma to evaluate the variability of tumor response to regionally administered melphalan or temozolomide and to determine if various components of pertinent drug resistance pathways for melphalan [glutathione S-transferase (GST)/glutathione] and temozolomide [O(6)-alkylguanine DNA alkyltranferase (AGT)/mismatch repair (MMR)] could be predictive of tumor response. Xenograft-bearing rats underwent regional isolated limb infusion with either melphalan (90 mg/kg) or temozolomide (2,000 mg/kg). The levels of AGT activity, GST activity, glutathione level, and GST/AGT expression were examined in this group of xenografts and found to be quite heterogeneous. No correlation was identified between melphalan sensitivity and the GST/glutathione cellular detoxification pathway. In contrast, a strong correlation between the levels of AGT activity and percentage increase in tumor volume on day 30 (r = 0.88) was noted for tumors treated with temozolomide. Regional therapy with temozolomide was more effective when compared with melphalan for the xenograft with the lowest AGT activity, whereas melphalan was more effective than temozolomide in another xenograft that had the highest AGT activity. In three other xenografts, there was no significant difference in response between the two chemotherapy agents. This study shows that AGT activity may be useful in predicting the utility of temozolomide-based regional therapy for advanced extremity melanoma tumors. Our observations also point out the limited ability of analysis of the GST/glutathione pathway to predict response to chemotherapies like melphalan whose resistance is primarily mediated through a complex mechanism of detoxification.

Topics: Animals; Antineoplastic Agents; Base Pair Mismatch; Cell Line, Tumor; Dacarbazine; Female; Gene Expression Regulation, Neoplastic; Glutathione; Humans; Infusions, Intravenous; Melanoma; Melphalan; Neoplasm Transplantation; Rats; Rats, Nude; Skin Neoplasms; Temozolomide

We have recently demonstrated that cytolysis of human melanoma cells by immune effectors (both NK and T cells) is associated with release of the nuclear chromatin protein, high mobility group box I (HMGB1). Extracellular HMGB1 mediates a number of important functions including endothelial cell activation, stromagenesis, recruitment and activation of innate immune cells, and also dendritic cell maturation that, in the setting of cancer, lead to a chronic inflammatory response. This reparative inflammatory response promotes tumor cell survival, expansion, and metastases. Release of HMGB1 after chemotherapy-induced cytotoxicity has not been well characterized. We measured the release of HMGB1 after chemotherapy or immune cytolysis and demonstrated that this did not correlate with conventional markers of apoptosis and necrosis in several human colorectal, pancreatic, and melanoma tumor cell lines. Rather, we observed that tumor cells incubated with the platinating agent oxaliplatin, retained HMGB1 within the nucleus for significantly longer periods than other agents used at comparable cytotoxic concentrations or even with potent cytolytic cells. Thus, release of HMGB1 from dying tumor cells treated with chemotherapy or cells with lymphokine activated killer cell activity is not dependent solely on the mode of cell death. Sequestration of the damage associated molecular pattern molecule, HMGB1, may play a role in the clinical efficacy of platinating agents and suggests this as a superior agent for coupling with immunotherapeutic strategies, possibly enhancing their effectiveness.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Nucleus; Colonic Neoplasms; Combined Modality Therapy; HMGB1 Protein; Humans; Immunotherapy; Killer Cells, Lymphokine-Activated; Melanoma; Melphalan; Microscopy, Confocal; Necrosis; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

To analyse results with a standardized HILP procedure in terms of response rate, recurrence pattern and complication rate.. From 1992 to 2003 HILP with melphalan and dactinomycin was performed in 101 patients with loco-regional metastases of malignant melanoma of the limbs. Among these were 66 women and 35 men with a median age of 62 years. Forty patients were in M. D. Anderson stage IIIA, 51 patients in stage IIIAB and 9 had stage IV disease at the time of perfusion. If not been done before, regional lymph node dissection preceded limb perfusion in the same setting.. A complete response (CR) was observed in 58 out of 87 evaluable patients. Twenty-one patients achieved a partial response (PR) and eight patients were non-responders. The overall response rate was 90.8%. The median recurrence-free interval after CR was 21 months. Severe toxicity (Wieberdink IV/V) was observed in five patients necessitating fasciotomy in four of them and above knee amputation in one patient. All further cases presented with grade II-III toxicity. The overall survival was 42 months, with a 5-year survival rate of 38%. Survival significantly differed according to stage of disease.. HILP is an effective treatment for loco-regional tumour relapse of malignant melanoma of the extremities and has improved by modification of technique. In the absence of regional lymph node and distant metastases long-term survival can be achieved in responders.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Postoperative Complications; Surgical Procedures, Operative; Survival Analysis; Treatment Outcome

Both patients with soft tissue sarcoma (STS) and patients with melanoma have limited treatment possibilities once the tumor has metastasized systemically. In patients with extremity STS or bulky melanoma in-transit metastases, the local tumor burden may be so problematic that, even in patients with systemically metastasized disease, an amputation may be inevitable. Isolated limb perfusion (ILP) has proven to be an excellent, local, limb-saving treatment option in patients with locally advanced extremity tumors. In this study, the authors investigated the palliative value of the ILP procedure to avoid amputation in patients who had Stage IV STS and melanoma.. From 1991 to 2003, of 339 tumor necrosis factor alpha (TNF)-based ILPs, 51 procedures were performed for either Stage IV STS (n = 37 patients) or Stage IV melanoma (n = 14 patients). All patients underwent an ILP with TNF and melphalan of the upper limb (n = 4 patients) or the lower limb (n = 47 patients) with 26-140 mg melphalan and 2-4 mg TNF.. The overall response in patients with Stage IV STS was 84%, and their median survival was 12 months after ILP. Limb salvage was achieved in 36 of 37 patients, with 1 patient undergoing amputation due to treatment toxicity. In the patients with Stage IV melanoma, the complete response rate was 43%. All patients with melanoma preserved their limb during a median survival of 7 months.. TNF-based ILP is an excellent procedure that provided tumor control and limb salvage for the short survival of patients with metastasized, very bulky, limb-threatening tumors of the extremity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Agents, Alkylating; Arm; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Palliative Care; Recombinant Proteins; Sarcoma; Tumor Necrosis Factor-alpha

To assess the effectiveness of isolated limb perfusion (ILP) with tumour necrosis factor-alpha (TNFalpha) and melphalan for recurrent or persistent melanoma lesions after previous ILP.. Between 1978 and 2001, 21 patients (mean age 65, range 29-83 years) underwent repeat ILP for recurrent or persistent melanoma after a previous ILP. First ILPs had been performed with melphalan alone in 13 patients and with addition of TNFalpha in eight, for a median of nine lesions (interquartile (IQ) range 2-23 lesions). Repeat ILP was performed with TNFalpha and melphalan in all 21 patients for a median of nine lesions (IQ range 5-25 lesions). Median follow-up after repeat ILP was 18 months (IQ range 6-36 months).. Thirteen patients attained a complete response (CR) after repeat ILP compared to 11 of 17 with measurable lesions after the first ILP. Nine patients relapsed after CR. Median limb recurrence-free survival was 13 months. Fourteen patients had mild acute regional toxicity after repeat ILP compared to 18 after the first ILP (n.s.). One patient underwent amputation for critical limb ischemia 10 months following repeat ILP. The limb salvage rate was 95%. Overall median survival was 62 months after CR compared to 13 months for those without CR (P=0.05).. Repeat ILP with TNFalpha and melphalan is feasible after previous ILP with mild regional toxicity. The CR rate is relatively high and comparable to the first procedure with good limb recurrence-free survival and high limb salvage rate.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Drug Therapy, Combination; Extremities; Female; Follow-Up Studies; Humans; Limb Salvage; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

The present study presents the author's modification of the method, which aims to create proper parameters of the treatment. The selected group consisted of 15 women and eight men, with a mean age of 57.2 years (range from 26 to 72 years). The patients were divided into two groups, depending on whether they were given epidural bupivacaine (group I - 13 patients treated between the years 2001 and 2004) or not [group II (control) - 10 patients treated earlier, between the years 1997 and 2000]. We observed a significant change in the temperature of thigh muscles (P=0.009) and shank muscles (P=0.006). In the control group II, there was a statistically significant difference (P=0.048) in the temperatures between the muscles and subcutaneous tissue on the one hand and the shank skin on the other. That difference was mean 0.67 degrees Celsius (from 0.4 to 0.9) during the perfusion after applying the cytostatic. The temperature of the skin was lower than the temperature of the deeper tissues of the shank and did not exceed 39.9 degrees Celsius. Such a difference in the temperatures was not observed in case of the group I patients who were given bupivacaine into the extrameningeal space before applying the cytostatic. The difference in the temperatures was on average 0.26 degrees Celsius and was not statistically significant (P=0.99), whereas the shank skin temperature was 40.0-40.6 degrees Celsius. The attained results imply that despite the noticeable improvement in the heating of the limb muscles after application of bupivacaine, the improvement in the heating of the skin and subcutaneous tissue is still not satisfactory, although the growing tendency implies such a possibility.

Topics: Adult; Aged; Bupivacaine; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Injections, Epidural; Lower Extremity; Male; Melanoma; Melphalan; Middle Aged; Perfusion

A 43-year-old woman presented with a nodular melanoma treated with wide excision, split skin graft, and sentinel node biopsy. At 2-year follow up, she was noted to have clinical recurrence at the excision site. FDG PET/CT demonstrated in-transit metastasis in her left thigh in addition to disease at the site of the sentinel node biopsy. Isolated limb infusion was performed with melphalan and dactinomycin. PET/CT at 5 weeks demonstrated resolution of the in-transit metastasis and the disease at the excision site. This report of PET/CT demonstrates the effectiveness of chemotherapy for malignant melanoma delivered by isolated limb infusion.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dactinomycin; Fluorodeoxyglucose F18; Infusions, Intra-Arterial; Lymphatic Metastasis; Melanoma; Melphalan; Positron-Emission Tomography; Radiopharmaceuticals; Skin Neoplasms; Tomography, X-Ray Computed; Treatment Outcome

The aim of this study was to analyse indications and results of amputation for intractable extremity melanoma after failure of isolated limb perfusion (ILP).. Between 1978 and 2001, 451 patients with loco-regional advanced extremity melanoma underwent 505 ILPs. Amputation of the affected extremity had to be carried out for intractable recurrent disease in 11 of these patients.. The indications for amputation were uncontrollable pain (n=2), extensive loco-regional tumour progression (n=4), loss of ankle function due to local tumour growth (n=1), and ulcerating and fungating lesions, not responding to other treatments (n=4). Four patients developed stump recurrence after amputation. Ten patients died of melanoma metastases after a median of 11 months (range 2-110 months). Two patients survived more than 5 years after amputation.. Major amputation is rarely indicated for intractable extremity melanoma but long-term survival can be achieved in selected patients.

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Treatment Failure

Multifunctional effects of flavonoids are reported to be markedly connected with their structure and the functional groups in the molecule. The important role in the activity play C2-C3 double bond, hydroxyl group at C3 and the number of hydroxyl groups at phenyl ring (B). In this paper, the DNA protective free radical scavenging potential of quercetin (QU) and luteolin (LU) against H2O2 and their clastogenic effect alone and in combination with melphalan (MH) were investigated in human melanoma HMB-2 cells. Elevated frequency of chromosomal aberrations induced by MH, that at high doses have shown a variety of toxic side effects, was statistically decreased by studied flavonoids regarding to control (QU at the concentration of 50 microM and LU already at the concentration of 20 microM). The results concerning DNA protective potential against free radicals in HMB-2 cells demonstrated that QU and LU have significant effect in dose dependent manner. The percentage of QU protective effect is 40% at the concentration 20 microM, resp. 80% at the concentration 100 microM. Comparable values were obtained with LU. Results are correlated to their structural arrangement and organization of the hydroxyl groups.

Topics: Animals; Antineoplastic Agents, Alkylating; Antioxidants; Cell Line, Tumor; Chromosome Aberrations; Comet Assay; DNA; Free Radical Scavengers; Humans; Hydrogen Peroxide; Luteolin; Melanoma; Melphalan; Molecular Structure; Oxidants; Quercetin

Isolated limb perfusion (ILP) is an effective treatment modality for multiple in-transit melanoma metastases confined to the limb. Recurrences after ILP, however, occur in approximately 50% of patients and are a challenge for further treatment. The efficacy of repeat ILPs to prolong local control in this patient category is evaluated in this article.. We used a prospective database in a tertiary referral center. Out of 100 tumor necrosis factor (TNF)-based ILPs with TNF and melphalan (TM-ILPs) in melanoma patients between March 1991 and July 2003, 25 repeat ILP procedures were performed in 21 patients in whom prior ILP treatment failed. All patients had bulky and/or numerous lesions and were treated with mild hyperthermic TM-ILP by using 2 to 4 mg of TNF and 10 to 13 mg/L of limb volume for the leg and arm, respectively.. The complete response rate was 76%, a partial response occurred in 20%, and no change was recorded in 4%. There was no difference in the complete response rate or local toxicity between first and repeat perfusions. Local recurrence occurred in 72%; the median time to local progression was 14 months. The 5-year survival rate was 47%, which compares favorably with known survival rates of stage IIIA/AB patients. The median follow-up of the patients was 26 months.. Patients who experience treatment failure after previous ILP treatment respond very well to repeat perfusion, and prolonged local control can thus be obtained. The subgroup of patients qualifying for repeat ILP represents a relatively favorable biological behavior of the melanoma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Arm; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Drug Therapy, Combination; Female; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Seeding; Retreatment; Skin Neoplasms; Treatment Failure; Tumor Necrosis Factor-alpha

Two to three percent of the patients with extremity melanoma develop in-transit metastases in the course of their disease. When local treatments fail, isolated limb perfusion (ILP) is a reasonable option, but is generally only applied to patients without evidence of distant metastases. We assessed the value of ILP in stage IV melanoma patients with symptomatic unresectable limb melanoma at our institutions.. A computerized database, containing all patient, tumor, ILP, and follow-up data of 505 ILPs performed in 451 patients between 1978 and 2001, allowed the selection of eight (1.8%) stage IV patients who underwent a palliative ILP for unresectable melanoma lesions on the limbs. All patients had high tumor burden limb disease, according to the combined Fraker and Rossi criteria.. The overall tumor response rate was 88%, with 13% complete and 75% partial response rates. One patient did not respond to ILP. Three partial responding patients attained a complete remission (CR) after excision of the remaining limb lesions. The median duration of hospital stay was 12 days and acute regional toxicity was mild with slight erythema and edema in six and no signs of reaction in two patients. The median limb recurrence-free interval after CR was 6 months and the median duration from the time of distant metastases to death was 15 months. Overall ILP leads to the desired palliative effect in six patients (75%).. ILP should be considered as a palliative treatment in selected stage IV melanoma patients with symptomatic advanced limb disease.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Catheter Ablation; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Humans; Length of Stay; Lung Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Palliative Care; Remission Induction; Skin Neoplasms; Soft Tissue Neoplasms; Tourniquets; Tumor Burden; Tumor Necrosis Factor-alpha

Isolated limb perfusion with TNF and melphalan (TM-ILP) is highly effective in the local treatment of advanced sarcoma and melanoma of the limb. The optimal dose of TNF for this procedure is not well established. The aim of this study was to assess the efficacy and toxicity of TM-ILPs with reduced TNF dose.. Largest single institution prospective database on TNF-based ILP. Out of 339 TM-ILPs performed between 1991 and 2003, 64 procedures were performed with reduced TNF dose (<3 mg in arm perfusions, <4 mg in leg perfusions). Response rates and toxicity of the procedure and outcome of the patients are evaluated.. Complete response in melanoma patients after reduced-dose ILP was 75 vs 69% after standard-dose ILPs (overall response 94 vs 95%, respectively); overall response in non-melanoma patients was 69 (reduced) vs 74% (standard). Response rates and outcome were comparable with the procedures performed with standard-dose TNF (p=NS for response, local/systemic progression and survival after multivariate analysis, both in melanoma and in non-melanoma patients). Systemic and local toxicity did not differ statistically between reduced- and standard dose TM-ILPs.. Provided doses at 1mg or higher are used, TM-ILP with TNF dose reduction for both melanoma and non-melanoma patients seems to be as effective as the standard dose procedure in terms of response rate and patient outcome. Numbers to formally confirm or reject this hypothesis are too large for such a non-inferiority trial to be conducted in patients with these rare conditions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Arm; Chemotherapy, Cancer, Regional Perfusion; Child; Female; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Sarcoma; Skin Neoplasms; Survival Rate; Tumor Necrosis Factor-alpha

Isolated limb perfusion with the administration of cytotoxic drugs has been successfully used to treat melanomas of the extremity since it was first introduced in 1958. The use of hyperthermia (40 degrees C) combined with chemotherapy agents, primarily melphalan, has resulted in greater cytotoxicity in laboratory studies, which led to the application of hyperthermia in clinical studies during the 1960s. The effectiveness of this regional technique and the absence of any good systemic therapy made hyperthermic-isolated limb perfusion (HILP) the main treatment for patients with regionally advanced melanoma. HILP involves open surgical dissection and cannulation of the peripheral vessels and is associated with moderate morbidity rates. Blood transfusions, systemic drug leak, infection, and damage to the blood vessels and nerves are all potential hazards associated with this technique. Recently, however, there has been increased interest in an alternative technique termed isolated limb infusion (ILI), which was first reported in 1994 from the Sydney Melanoma Unit in Australia. Based on a few single institution experiences, it was found that there are fewer morbidities associated with HILP than with ILI but no compromise in patient outcomes. ILI is a less invasive procedure involving the use of angiographically placed catheters inserted percutaneously through the femoral vessels that does not require blood donor exposure or use of a heart lung machine. Preliminary data suggest that the resultant local hypoxia and acidosis induced by this procedure potentiates the cytotoxic effects of melphalan. Response rates comparing ILI to HILP seem similar, and both are markedly better than systemic chemotherapy. ILI may be a more desirable option because morbidity is greatly reduced and outcomes appear similar. There is a potential role for the perfusionist in the application of ILI, an evolving area of cancer therapy.

Topics: Antineoplastic Agents, Alkylating; Extremities; Heart Arrest, Induced; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Perfusion

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Humans; Melanoma; Melphalan; Skin Neoplasms; Tumor Necrosis Factor-alpha

Perfusate acidification with dilute hydrochloric acid augments tumor response rates in a rodent model of isolated limb perfusion (ILP). This study investigates the combination of metaiodobenzylguanidine (MIBG), a mitochondrial inhibitor, and systemic hyperglycemia as a strategy to selectively acidify tumors and thereby sensitize them to ILP.. Human melanoma xenografts were implanted into the hind limbs of athymic rats. When tumors reached 12 to 15 mm in diameter, animals were randomized to ILP with or without melphalan, with or without systemic MIBG, and hyperglycemia of 485 +/- 35 mg/dL. Intratumoral pH was measured during MIBG and glucose treatment by using magnetic resonance spectroscopy.. MIBG at 30 mg/kg plus hyperglycemia decreased intracellular pH by.6 units and extracellular pH by.8 units. MIBG at 22.5 mg/kg plus hyperglycemia decreased intracellular and extracellular pH by.4 and.5 units, respectively. Tumor growth was unaffected by systemic MIBG and hyperglycemia alone. When MIBG at 30 mg/kg and hyperglycemia were combined with ILP, tumor growth was delayed for 33 days after control ILP and for 44 days after melphalan ILP. However, this dose of MIBG was complicated by a 40% mortality rate after ILP. MIBG at 22.5 mg/kg, in combination with MIBG in the perfusate, did not cause mortality and delayed tumor growth by 51 days after melphalan ILP.. MIBG and hyperglycemia improve tumor response rates after ILP in a rodent model of human melanoma. Selective tumor acidification with MIBG and hyperglycemia may offer added benefit to current regional perfusion strategies.

Topics: 3-Iodobenzylguanidine; Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Disease Models, Animal; Drug Interactions; Female; Glucose; Humans; Hydrogen-Ion Concentration; Hyperglycemia; Intracellular Fluid; Melanoma; Melphalan; Random Allocation; Rats; Skin Neoplasms

The presence of resistance to chemotherapy is associated with poor tumor response and patient survival in a variety of tumors. Attempts to modulate resistance in conjunction with systemic chemotherapy have been limited by the toxicity of combined therapy, particularly gastrointestinal or hematopoetic toxicity. This study explored systemic modulation of resistance in conjunction with intra-arterial regional therapy to determine if tumor responses to melphalan could be improved with acceptable toxicity.. Using a nude rat human xenograft model of extremity melanoma,we analyzed tumors for glutathione (GSH), the main protein in the melphalan resistance pathway. Modulation of GSH was performed with intraperitoneal buthionine sulfoximine (BSO). In parallel, BSO-modulated and nonmodulated animals underwent survival studies after regional intra-arterial perfusion with melphalan or saline. Rats were monitored daily for tumor growth and toxicity.. BSO depleted tumor GSH levels by 71.8% with minimal toxicity. Survival studies using increasing melphalan concentrations demonstrated similar tumor growth. The combined use of modulator and chemotherapeutic agent showed a significant tumor growth delay as compared to control and drug-alone group without enhanced toxicity.. Modulation of resistance in conjunction with regional chemotherapy allows for improved tumor responses with minimal toxicity. These results demonstrate that BSO can potentiate the cytotoxic effects of regional melphalan therapy in the setting of extremity melanoma.

Topics: Animals; Buthionine Sulfoximine; Chemotherapy, Cancer, Regional Perfusion; Drug Resistance, Neoplasm; Female; Glutathione; Melanoma; Melphalan; Rats

Regional perfusion treatments for melanoma, using the alkylating agent melphalan, show variable responses in magnitude and duration. Surprisingly, the potential contribution of alkylating-agent resistance mechanisms to diminish tumor responses, especially the crucial cellular detoxifying system formed by glutathione (GSH) and its associated enzyme glutathione-S-transferase (GST), has remained unexplored. Objectives of this study were to characterize GSH levels and GST activity in melanoma of patients undergoing regional perfusion and examine the effect of melphalan concentration in both an in vitro human melanoma cell line and in the extremity melanoma of an in vivo rodent limb infusion model.. Human in-transit melanoma, muscle, subcutaneous tissue, and skin (n = 9) and metastatic regional lymph nodes (n = 7) were evaluated for GSH level and GST activity. Effects of increasing melphalan exposure on GSH and GST were studied in an in vitro human melanoma cell line. A survival human melanoma xenograft model of isolated limb infusion using increasing dosages of melphalan was used, with evaluation of GSH and GST in the recurrent tumor.. GSH levels in human in-transit lesions and muscle were significantly higher than that of skin and subcutaneous tissue. Four of 9 patients had tumor-to-muscle GSH ratio > 1. A strong correlation was seen between in vitro melphalan dose and resultant GSH level and GST activity. In vivo recurrent tumor GSH levels correlated with increasing melphalan infusion dose.. A GSH-based resistance pathway may play a role in effecting response and toxicity to regional melphalan perfusion.

Topics: Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Drug Resistance, Neoplasm; Female; Glutathione; Glutathione Transferase; Humans; Inactivation, Metabolic; Lymphatic Metastasis; Melanoma; Melanoma, Experimental; Melphalan; Rats; Rats, Nude; Transplantation, Heterologous; Tumor Cells, Cultured

Hypoxic antiblastic stop-flow perfusion (SFP) has recently been proposed as a therapeutic option for patients with locally advanced tumors. We report on the clinical and pharmacological results of our prospective study of limb SFP for the treatment of in transit melanoma metastases. Twenty-three patients with limb-sited melanoma metastases were treated with melphalan (10 mg/l) based pelvic (n=11, group A) or femoral (n=12, group B) SFP under hypoxic conditions. Systemic and locoregional toxicity, tumor response rate, and local progression-free survival were analyzed. Melphalan concentrations were measured in the perfusate and systemic circulation during SFP, and after 30-min hemofiltration. Perfusate-to-plasma leakage was assessed using a scintigraphic method. No postoperative deaths occurred. Mild locoregional toxicity was observed in 5 patients (18%), and systemic toxicity was mild to severe in 8 patients (30%), the incidence being higher in group A. Tumor response rate (complete + partial response) and time to local disease progression were significantly different in group A and B (9% vs 58% and 7 vs 13 months, respectively). The pharmacokinetic study showed that pelvic SFP was associated with a higher leakage rate and a lower area under the curve ratio than femoral SFP (44% vs 31% and 5.6 vs 9.8, respectively). Limb SFP is a feasible and relatively simple procedure. Toxicity and tumor response rates strictly depend upon drug leakage control. Further efforts should be made to exploit the potential anti-tumor activity of this novel locoregional drug delivery system.

Topics: Aged; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Extremities; Female; Humans; Hypoxia; Male; Melanoma; Melphalan; Middle Aged; Prospective Studies; Skin Neoplasms; Treatment Outcome

In patients with truly unresectable melanoma of the extremities, results after isolated limb perfusion (ILP) are absent in the literature. Complete response rates are probably lower than the reported 54% for locoregional recurrent melanoma. In these patients, ILP with melphalan and tumor necrosis factor alpha (TNF-alpha) could be superior to ILP with melphalan alone.. Retrospective analysis with a median follow-up period of 21 months (interquartile range, 9-40 months).. Two tertiary care cancer centers in the Netherlands.. We assessed all 130 consecutive patients who underwent ILP for unresectable melanoma of the extremities, performed between 1978 and 2001. Of these patients, 38% had stage IIIA melanoma and 45% had stage IIIAB melanoma according to criteria of the MD Anderson Cancer Center. Lesions were considered unresectable on the basis of their size, number, or localization.. Forty ILPs were performed with melphalan, and 90 were done with TNF-alpha and melphalan.. Response rate, disease-free survival, limb salvage rate, and overall survival.. In 45% of the patients, a complete response was attained after ILP with melphalan (95% confidence interval, 29%-61%) compared with 59% after ILP with TNF-alpha and melphalan (95% confidence interval, 49%-69%; P = .14). The time to complete response was 3 months (interquartile range, 2-6 months) vs 2 months (interquartile range, 1-3 months; P = .01), respectively. The recurrence rate and median limb recurrence-free survival were not significantly different for both ILP types. The overall limb salvage rate was 96%. Overall 5-year survival was 29% (95% confidence interval, 20%-38%). The ILP type was not an independent prognostic factor for complete response, nor was limb recurrence-free survival, whereas stage IIIA was a favorable prognostic factor (P = .01 and P = .02, respectively). Favorable prognostic factors for improved survival were complete response (P<.001) and a tumor size of 3 cm or less (P = .01).. In more than half of the patients with truly unresectable melanoma of the extremities, a complete response was obtained after ILP with melphalan with or without TNF-alpha. The ILP type was not an independent prognostic factor for complete response, limb recurrence-free survival, or overall survival.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Limb Salvage; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Retrospective Studies; Skin Neoplasms; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha

Regional infusion therapy with melphalan (LPAM) is an accepted treatment for advanced extremity melanoma. However, much room exists for improving the therapeutic index of this type of therapy.. Isolated limb infusion (ILI) with temozolomide (TMZ), a novel methylating agent, was performed using a nude rat bearing human melanoma xenograft. Additional rats were treated systemically with TMZ, or regionally with LPAM or 10% dimethyl sulfoxide (DMSO; control) using ILI.. Rats that received systemic TMZ showed a poor tumor response and no tumor regression. In contrast, intra-arterial TMZ demonstrated a prolongation of tumor growth delay in a dose-responsive manner. In comparison with LPAM of equitoxic dose, TMZ provided both longer tumor growth delay and a greater number of tumor regressions.. These data suggest that ILI with TMZ is an effective treatment for advanced extremity melanoma and may be better than LPAM in this setting.

Topics: Analysis of Variance; Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Dacarbazine; Disease Models, Animal; Dose-Response Relationship, Drug; Extremities; Female; Infusions, Parenteral; Melanoma; Melphalan; Probability; Random Allocation; Rats; Rats, Nude; Reference Values; Sensitivity and Specificity; Severity of Illness Index; Skin Neoplasms; Survival Rate; Temozolomide; Transplantation, Heterologous; Treatment Outcome

The aim of this study is to describe the experience with 100 TNF-based ILP for locally advanced melanoma and to determine prognostic factors for response, time to local progression, and survival.. One hundred TNF-based ILPs were performed between 1991 and 2003 in 87 patients for whom local control by surgery of in-transit melanoma metastases was impossible. In total, 62 iliac, 33 femoral, and 5 axillary ILPs were performed in mild hyperthermic conditions with 2 to 4 mg of TNF and 10 to 13 mg of melphalan per liter of limb volume.. Overall response was 95%, with 69% complete response, 26% partial response, and 5% no change. Complete response rate differed significantly for patients with IIIA disease versus IIIAB and IV. Local and systemic toxicity was mild to moderate in almost all cases, with no treatment-related death and one treatment-related amputation. Five-year overall survival was 32%; local progression occurred in 55% after a median of 16 months. In complete response patients, 5-year survival was 42% with local progression in 52% at a median of 22 months. Response rate and survival were significantly influenced by stage of disease; (local progression free) survival was influenced by response rate.. TNF-based ILP results in excellent response rates in this patient population with unfavorable characteristics. Response on ILP predicts outcome in patients and reflects aggressiveness of the tumor.

Topics: Antineoplastic Agents, Alkylating; Axillary Artery; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Femoral Artery; Humans; Iliac Artery; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Prognosis; Skin Neoplasms; Survival Rate; Time Factors; Tumor Necrosis Factor-alpha

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Arm; Carboplatin; Chemotherapy, Cancer, Regional Perfusion; Female; Follow-Up Studies; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Soft Tissue Neoplasms; Time Factors

In 3 patients over 75 years of age with a malignancy, limb salvage was achieved through the application of isolated limb perfusion with melphalan with or without tumour necrosis factor alpha: an 82-year-old woman with extensive locoregional melanoma metastases on her lower leg, a 78-year-old woman with a large, ulcerating recurrence of melanoma on her lower leg and an 83-year-old woman with recurrent sarcoma of the lower arm. There were no complications and the women recovered well. Isolated limb perfusion can be effectively and safely used in older patients with irresectable tumours of the extremities, offering them limb salvage for the remainder of their lives.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Limb Salvage; Melanoma; Melphalan; Neoplasm Recurrence, Local; Sarcoma

Isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF) and melphalan for advanced extremity malignancies achieves significant complete response rates. To study molecular mechanisms underlying this response, a nude rat ILP model with a human melanoma xenograft was developed.. NIH1286 human melanoma was grown subcutaneously in the hind limb of nude rats. Anesthetized rats underwent a 10-minute ILP via femoral vessels with hetastarch, heparin, and melphalan, TNF, or TNF plus melphalan. The tumors and ulcers were measured and viable tumor area was calculated. Post-ILP tumors were analyzed by electron microscopy for vascular damage and also by liquid chromatography atmospheric pressure chemical ionization tandem mass spectrometry (LC/APCI/MS/MS) for free melphalan levels. Colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-dephenyltetrazolium bromide (MTT) assays were performed on NIH1286 cells and human dermal microvascular endothelial cells (HDMVEC) to test for direct cytotoxicity to TNF and melphalan. Post-ILP tumors sections were also examined by electron microscopy.. The mean maximal decrease in viable tumor area after ILP for control, TNF, melphalan, and TNF + melphalan groups were 0%, 22 +/- 13%, 61 +/- 14%, and 100 +/- 0%, respectively. LC/APCI/MS/MS revealed no difference in the free tumor melphalan concentration between melphalan alone and TNF + melphalan groups. The percent cytotoxicity in MTT assays using TNF, melphalan, and TNF + melphalan against NIH1286 were 0%, 51-59%, and 74-81%, respectively, and against HDMVEC were 28%, 16-23%, and 6-13%, respectively. Electron microscopic analyses showed that addition of TNF to the perfusate caused erythrostasis in tumor blood vessels.. We developed a human melanoma nude rat ILP model with tumor responses very similar to the human ILP trials. This model will allow further investigation of the synergistic mechanism of TNF and melphalan in human melanoma in a preclinical setting, and extension of this study to current clinical trials.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Disease Models, Animal; Female; Hindlimb; Humans; Melanoma; Melphalan; Perfusion; Rats; Rats, Nude; Skin Neoplasms; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

Hyperthermic isolated limb perfusion (HILP) with melphalan as treatment for locally recurrent or in-transit malignant melanoma is frequently performed but the principle for calculating drug dosage remains poorly understood.. This study examined the pharmacokinetic profile of 14 consecutive patients to determine what variables were associated with toxicity and tumor responses.. Marked fourfold variability was noted in patient plasma melphalan concentrations. We defined a factor--the ratio of estimated limb volume (Vesti) to melphalan volume of distribution (Vss), Vesti/Vss--that was much more strongly correlated with acute regional toxicity than either area under concentration-time curve or peak plasma concentration. In addition, we found that AUX2 was the best correlate of tumor response.. Pharmacokinetic evaluation of prospective HILP trials is critical to not only understand response and toxicity outcomes but also to potentially improve the therapeutic index of regional perfusion.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms

Risk factors were determined for mortality within 1 year after isolated limb perfusion (ILP).. All of 439 patients who underwent ILP for melanoma of the extremities were studied. Ninety percent of the patients had MD Anderson stage IIB or III disease at the time of ILP. ILP was performed with melphalan with or without TNFalpha under mild hyperthermic (38-40 degrees C) or normothermic (37-38 degrees C) conditions in 80% of the cases.. Sixty-nine patients died within this period, 64 of metastatic melanoma. The indication for ILP was an unresectable primary (n=3), a local recurrence (n=24) or adjuvant to excision of primary lesions (n=17) in patients with stage IIIB regional lymph node metastases. These patients or patients with stage IIIAB melanoma with satellites and/or in-transit metastases with regional lymph node metastases had a relative risk of 4.6 (95% CI 2.0-6.6) and 3.6 (95% CI 2.1-10) of dying within 1 year from ILP, respectively (p<0.001). In patients with stage IV disease (distant metastases), the relative risk was 22 (95% CI 3.8-127, p=0.001).. Patients with advanced limb melanoma have an increased risk of death within 1 year after ILP when regional lymph node or distant metastases are present.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Logistic Models; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Risk Factors; Skin Neoplasms; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha

To enhance affinity for malignant cartilaginous tumors (chondrosarcomas), quaternary ammonium (QA) conjugates of chlorambucil and melphalan were prepared by linking the QA moiety to nitrogen mustards via an amide bond. They exhibited closely similar and sometimes more favorable values than their parent compounds. In the cell lines tested, the two QA conjugates displayed appreciable cytotoxicity, the QA conjugate of chlorambucil even showing an enhanced efficiency against chondrosarcoma compared with chlorambucil.

Topics: Animals; Antineoplastic Agents; Chlorambucil; Chondrosarcoma; Drug Screening Assays, Antitumor; Humans; Melanoma; Melphalan; Mice; Quaternary Ammonium Compounds; Structure-Activity Relationship; Tumor Cells, Cultured; Tumor Stem Cell Assay

Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor alpha and melphalan is a highly effective treatment for advanced soft tissue sarcoma (STS) and locoregional metastatic malignant melanoma. Multidrug resistance (MDR)-associated genes are known to be inducible by heat and drugs; expression levels of the major vault protein (MVP), MDR1, and MDR-associated protein 1 (MRP1) were determined sequentially before, during, and after ILP of patients.. Twenty-one STS or malignant melanoma patients were treated by ILP. Tumor tissue temperatures were recorded continuously and ranged from 33.4 degrees C initially to peak values of 40.4 degrees C during ILP. Serial true-cut biopsy specimens from tumor tissues were routinely microdissected. Expression analyses for MDR genes were performed by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry.. In 83% of the patients, MVP expression was induced during hyperthermic ILP. MVP-mRNA inductions often paralleled the increase in temperature during ILP. Increased MVP protein expressions either were observed simultaneously with the MVP-mRNA induction or were delayed until after the induction at the transcriptional level. Inductions of MDR1 and MRP1 were observed in only 13% and 27% of the specimens analyzed. Temperatures and drugs applied preferentially led to an induction of MVP and were not sufficient to induce MDR1 and MRP1 in the majority of tumors.. This study is the first to analyze the expression of MDR-associated genes sequentially during ILP of patients and demonstrates that treatment might lead to increased levels of MVP, whereas enhanced levels of MDR1 and MRP1 remain rare events.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Child; Female; Fungal Proteins; Genes, MDR; Humans; Hyperthermia, Induced; Immunohistochemistry; Male; Melanoma; Melphalan; Middle Aged; Multidrug Resistance-Associated Proteins; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; Saccharomyces cerevisiae Proteins; Sarcoma; Soft Tissue Neoplasms; Statistics, Nonparametric; Treatment Outcome; Tumor Necrosis Factor-alpha; Vault Ribonucleoprotein Particles

Isolated limb perfusion (ILP) with melphalan is an accepted treatment for intransit melanoma of the extremities. Using an ILP human melanoma xenograft model, we tested the hypothesis that acidosis augments the antitumor effect of melphalan and that nitric oxide (NO) induction mediates tumor regression.. NIH1286 human melanoma tumor bearing athymic nude rats underwent a 10-minute ILP. Group C was perfused at physiologic pH without acid or melphalan, group M received melphalan at physiologic pH (7.2), group A received 0.2 N of HCl at pH 6.8, and group A/M received melphalan and HCl at pH 6.8. Groups 1400W + A and 1400W + A/M were injected with 1400W, a specific inhibitor of inducible NO synthase, 1 hour pre-ILP. Tumor response was followed for up to 60 days in all survival experiments. In 4 to 6 animals from groups C, M, A, and A/M, tumor NO was measured pre- and post-ILP, and tumor and thigh muscle from 2 additional animals in each group were collected at 20 minutes and 24 hours post-ILP and processed for terminal deoxynucleotidyl transferase dUTP nick end labeling staining.. Maximum mean reduction in tumor size after ILP in the different groups was as follows: C = 0%, M = 55%, A = 99.6% (3 of 4 complete responses), A/M = 100% (all complete responses), 1400W + A = 0%, and 1400W + A/M = 25%. Median tumor NO was 0.87 +/- 0.74 (SD) micromol/L before ILP and increased significantly (Mann-Whitney rank sum test, P <.001) after ILP (C = +6.9%, n = 4; M = +7.5%, n = 5; A = +66.0%, n = 6; A/M = +35.9%, n = 6). Also, minimal apoptotic cell death was seen in C and M, whereas A and A/M showed evidence of widespread apoptosis.. Acidosis enhances the antitumor effect of melphalan. NO induction appears to play a role in tumor regression.

Topics: Acidosis; Amidines; Animals; Antineoplastic Agents, Alkylating; Apoptosis; Benzylamines; Disease Models, Animal; Enzyme Inhibitors; Female; Hindlimb; Humans; Melanoma; Melphalan; Nitric Oxide; Rats; Rats, Nude; Regional Blood Flow; Skin Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Older patients are assumed to have a higher risk of complications from isolated limb perfusion (ILP). A study was performed evaluating the safety and efficacy of ILP in patients older than 75 years with advanced melanoma of the limbs.. A total of 218 therapeutic ILPs with melphalan with or without tumor necrosis factor alpha were performed in 202 patients with advanced measurable melanoma and were analyzed retrospectively. Fifty-three patients (28%) were 75 years or older.. Complete response rates were 56% for those older than 75 years and 58% for the younger group (P =.79). Locoregional relapse occurred in 56% of the older group versus 51% in the younger group (P =.61). Limb toxicity, systemic toxicity, local complications, and long-term morbidity were similar in both age groups. Perioperative mortality was low, with one procedure-related death in the older group. Older patients stayed in the hospital for a median of 23 days (younger patients, 19 days; P <.01).. ILP results in similar response rates in the elderly with recurrent melanoma, without increased toxicity, complications, or long-term morbidity compared with younger patients. Older age in itself is not a contraindication for ILP.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Extremities; Female; Humans; Length of Stay; Linear Models; Male; Melanoma; Melphalan; Multivariate Analysis; Netherlands; Retrospective Studies; Skin Neoplasms; Survival Rate; Tumor Necrosis Factor-alpha

Isolated limb perfusion (ILP) with cytotoxic agents is a remarkably effective but complex technique used to treat locally recurrent and metastatic melanoma confined to a limb. Isolated limb infusion (ILI), essentially a low-flow ILP performed without oxygenation via percutaneous catheters, has been developed as a simpler alternative.. The outcome in 135 patients treated by ILI was reviewed.. The overall response rate in the treated limb was 85% (complete response [CR] rate 41%, partial response rate 44%). Median response duration response was 16 months (24 months for patients with CR). Median patient survival was 34 months. In those with a CR, the median survival was 42 months. CR rate and survival time decreased with increasing disease stage. Patients aged >70 years had a better overall response than younger patients. On multivariate analysis, factors associated with an improved outcome were a lower stage of disease, a final limb temperature >37.8 degrees C, and a tourniquet time >40 minutes.. The frequency and duration of responses after ILI were comparable to those achieved by conventional ILP. The ILI technique is particularly useful for older patients who might not be considered suitable for conventional ILP.

Topics: Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Extremities; Female; Humans; Male; Melanoma; Melphalan; Multivariate Analysis; Neoplasm Recurrence, Local; New South Wales; Proportional Hazards Models; Prospective Studies; Skin Neoplasms; Survival Rate

The aim of this study was to analyze the value of continuous leakage monitoring with radioactive iodine-131-labeled human serum albumin (RISA) in patients treated with hyperthermic isolated limb perfusion with tumor necrosis factor-alpha (TNF alpha) and melphalan.. Forty-eight patients with melanoma (n = 14) or soft tissue sarcoma (n = 34) of an extremity underwent 51 perfusions. Perfusion was performed at the iliac level in 22 cases, at the popliteal level in 16 cases, at the femoral level in 7 cases, and at the axillary level in 6 cases. Leakage rates and perfusion circuit and systemic levels of TNF alpha, interleukin-6, and C-reactive protein were determined, as were systemic hematological and metabolic profiles and tumor response.. The mean isotopically measured leakage was 2.9%. Systemic leakage was < or = 2% in 28 perfusions and >2% in 23 perfusions. The correlation between the maximal monitored leakage and maximal systemic TNF alpha levels was.7114. The area under the curve for TNF alpha in the perfusion circuit, indicating the exposure of the perfused limb to TNF alpha, was 18.7% lower in the >2% leakage group. No significant differences in tumor response were found between groups. The area under the curve for systemic TNF alpha, indicating the exposure of the patient to TNF alpha, was 18.1 times higher in the >2% leakage group, resulting in a significant decrease in leukocyte and platelet count, hyperbilirubinemia, hypocholesterolemia, and proteinemia. No beneficial effect of the systemically leaked TNF and melphalan was seen on the occurrence of distant metastasis during follow-up. There was a significant difference between perfusions performed at the iliac and femoral levels compared with leakage values at the popliteal level.. A good correlation between RISA leakage measurement and TNF alpha exposure during and after hyperthermic isolated limb perfusion with TNF alpha and melphalan was demonstrated. RISA leakage measurement serves as a good guide for the effectiveness of isolation during perfusion. If leakage exceeds the 2% limit during perfusion, less exposure of the tumor-bearing limb to TNF alpha, increased exposure of the patient systemic circulation to TNF alpha, and more systemic side effects can be expected.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Area Under Curve; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hypothermia, Induced; Iodine Radioisotopes; Male; Melanoma; Melphalan; Middle Aged; Monitoring, Physiologic; Organotechnetium Compounds; Radiopharmaceuticals; Sarcoma; Serum Albumin; Skin Neoplasms; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

To describe initial experience with the new technique of isolated limb infusion (ILI) for in-transit melanoma.. A prospective case series.. The major tertiary care oncology centre for the state of Victoria, Australia.. Nine patients having for extensive in-transit limb melanoma. All patients received ILI (13 treatments).. Patient survival, response to treatment and complications of treatment.. There were no perioperative deaths and morbidity was limited to deep venous thrombosis and pulmonary embolism in 1 patient. Control of the in-transit metastases was achieved to some degree in all patients and was complete in 4.. ILI is an alternative treatment modality for patients suffering from multiple, advanced in-transit melanoma metastases. It provides effective palliation with limited morbidity and offers a safe, quick, inexpensive alternative to isolated limb perfusion with comparable results.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Humans; Infusions, Intra-Arterial; Leg; Melanoma; Melphalan; Skin Neoplasms

To determine whether the addition of high-dose tumour necrosis factor-alpha (TNF alpha) to isolated limb perfusion (ILP) with melphalan increases acute regional tissue toxicity compared to ILP with melphalan alone.. A retrospective, multivariate analysis of toxicity after normothermic (37--38 degrees C) and 'mild' hyperthermic (38--40 degrees C) ILPs for melanoma was undertaken. Normothermic ILP with melphalan was performed in 294 patients (70.8%), 'mild' hyperthermic ILP with melphalan in 71 patients (17.1%) and 'mild' hyperthermic ILP with melphalan combined with TNF alpha in 50 patients (12.0%). Toxicity was nil or mild (grades I--II according to Wieberdink et al.) in 339 patients (81.7%), and more severe acute regional toxicity (grades III--V) developed in 76 patients (18.3%). A stepwise logistic regression procedure was performed for the multivariate analysis of prognostic factors for more severe toxicity.. On univariate analysis, 'mild' hyperthermic ILP with melphalan plus TNF alpha significantly increased the incidence of more severe acute regional toxicity compared to normothermic and 'mild' hyperthermic ILP with melphalan alone (36% vs 16% and 17%; P=0.0038). However, after ILP using TNF alpha no grade IV (compartment compression syndrome) or grade V (toxicity necessitating amputation) reactions were seen. Significantly more severe toxicity was seen after ILPs performed between 1991 and 1994 compared with earlier ILPs (33%vs 14%P=0.0001). Also, women had a higher risk of more severe toxicity than men (22% vs 7%; P=0.0007). After multivariate analysis, prognostic factors which remained significant were: sex (P=0.0013) and either ILP schedule (P=0.013) or treatment period (P=0.0003).. Regional toxicity after 'mild' hyperthermic ILP with melphalan and TNF alpha was significantly increased compared to ILP with melphalan alone. This may be caused by increased thermal enhancement of melphalan due to the higher tissue temperatures (39--40 degrees C) at which the melphalan in the TNF alpha-ILPs was administered or by an interaction between high-dose TNF alpha and melphalan.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Blister; Chemotherapy, Cancer, Regional Perfusion; Compartment Syndromes; Edema; Erythema; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Multivariate Analysis; Retrospective Studies; Severity of Illness Index; Sex Factors; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

Isolated limb infusion (ILI) is an attractive, less complex alternative to isolated limb perfusion (ILP). It has a lower morbidity in treating localized recurrences and in transit metastases of the limb for tumours such as melanoma, Merkel cell tumour and Kaposi's sarcoma, allowing administration of high concentrations of cytotoxic agent to the affected limb under hypoxic conditions. Melphalan is the preferred cytotoxic agent for the treatment of melanoma by ILP or ILI. We report pharmacokinetic data from 12 patients treated by ILI for tumours of the limb in Brisbane. The kinetics of drug distribution in the limb was calculated using a two-compartment vascular model, where both tissue and infusate act as well-stirred compartments. Analysis of melphalan concentrations in the perfusate during ILI showed good agreement between the values measured and the concentrations predicted by the model. Recirculation and wash-out flow rates, tissue concentrations and the permeability surface area product (PS) were calculated. Correlations between the PS value and the drug concentrations in the perfusate and tissue were supported by the results. These data contribute to a better understanding of the distribution of melphalan during ILI in the limb, and offer the opportunity to optimize the drug regimen for patients undergoing ILI.

Topics: Aged; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Dose-Response Relationship, Drug; Female; Humans; Infusion Pumps; Leg; Male; Melanoma; Melphalan; Middle Aged; Models, Biological; Neoplasm Recurrence, Local; Sarcoma, Kaposi; Skin Neoplasms; Time Factors

In the treatment of cancer, isolated limb perfusion (ILP) allows what would be a lethal systemic dose of cytotoxic drugs to be administered directly to a tumour site of an extremity. Unfortunately, ILP is a complex, expensive, time-consuming treatment that requires general anaesthesia, vascular surgery and expertise with extracorporeal circuits that may not be available outside a cardiac centre. By streamlining the traditional ILP protocols and eliminating the oxygenator from the circuit, an equally safe and effective technique of hypoxic hyperthermic isolated limb perfusion has been developed.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Clinical Protocols; Extracorporeal Circulation; Extremities; Humans; Hyperthermia, Induced; Hypoxia; Melanoma; Melphalan; Oxygenators, Membrane

Continuous measurement of perfusate leakage into the systemic circulation is of the utmost importance and can be performed with the help of radioactive tracers. The purpose of this study was to assess changes in the perfusion leakage rate between two periods: 1977-1990 and 1991-2000, and to determine the factors responsible for these changes.. During the 1991-2000 period, 119 patients underwent HILP mainly for locally recurrent melanoma or locally advanced soft tissue sarcoma. HILP was performed with melphalan (33%) or in combination with TNFalpha (65%). There were 67 iliacal, 12 femoral, 25 popliteal, and 15 axillary perfusions performed. Leakage into the systemic circulation was monitored continuously with the help of 131I-albumin and a stationary scintillation detector placed above the heart.. The median maximum leakage was 2.7% (range 0%-21%) which is significantly less than the previous period (1977-1990) where leakage of 8% (range 0%-30%) was reported (P < .05). A statistical difference in leakage was detected among perfusion locations where the iliac and femoral vessels showed more leakage than the axillary and popliteal vessels (P < .05). Furthermore, there appeared to be significantly less leakage when TNFalpha was used than when melphalan was the sole drug (P < .05).. Nowadays leakage from isolated perfusions into the systemic circulation is further minimized compared with the days when melphalan was the sole drug used. Increased awareness about TNFalpha leakage, continuous external monitoring with 131I-albumin as the main isotope, flow rate regulation in the perfusion circuit, and regulation of the patient's systemic blood pressure have all been major contributors to this improvement.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Retrospective Studies; Sarcoma; Sex Factors; Skin Neoplasms; Tumor Necrosis Factor-alpha

Isolated limb perfusion (ILP) with high-dose chemotherapy and tumor necrosis factor is being tested in clinical trials as a treatment for locally advanced extremity melanoma. The authors investigated the ability of F-18 fluorodeoxyglucose positron emission tomography (FDG PET) to determine the true extent of disease in patients with this condition, whose distribution of lesions differs from that seen in previous studies.. Nine patients with locally advanced melanoma were selected for imaging of the entire body and extremities using FDG PET from a group of participants in a clinical trial of ILP with melphalan +/- tumor necrosis factor. Scans were obtained without attenuation correction. Post-treatment scans were obtained in three patients 1 month after ILP. The findings in the FDG-PET scans were compared with those of a standard protocol (SP) that included anatomic images and physical examinations.. Eighty lesions (74 malignant, 6 benign) were detected with FDG PET and the SP combined. Only malignant lesions were detected by both methods in the perfused limbs. Of the malignant lesions, FDG PET detected 65 lesions (sensitivity rate, 88%). In contrast, 48 lesions were detected with the SP (sensitivity rate, 65%). Twenty-six malignant lesions were seen only with FDG PET (35%), whereas nine malignant lesions were seen only with SP (12%). The six benign lesions included three false-positive mediastinal lymph nodes in one patient. The accuracy rates of FDG PET and the SP were 83% and 65%, respectively. These results are comparable to those seen in previous studies with patients who had disease confined primarily to the torso. All post-therapy FDG-PET scans showed a reduction in the number of visualized limb lesions, and diffuse uptake throughout the perfused limbs. The diffuse uptake correlated with post-therapy limb inflammation.. Non-attenuation-corrected FDG PET is more sensitive than the SP in detecting the extent of disease in candidates for ILP. The FDG uptake associated with post-therapy inflammation may reduce the contrast resolution of this technique and must be evaluated further.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Drug Therapy, Combination; Female; Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Likelihood Functions; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Radiopharmaceuticals; Sensitivity and Specificity; Tomography, Emission-Computed; Tumor Necrosis Factor-alpha; Whole-Body Counting

Nude rats bearing melanomas on their hindlimbs were treated by isolated limb infusion (ILI) with increasing doses (7.5-400 microg/ml) of melphalan. The response of tumours to treatment at the end of the observation period was graded, according to diameter, as complete response (CR), partial response (PR), no change (NC) or progressive disease (PD). No linear relationship between the dose of melphalan and the tumour response was observed. All doses above a threshold of 15 microg/ml achieved a PR or CR. The achievement of CR was not related to increased dose. Two major implications arise from this work. Firstly, the typically two- to three-fold increase in cytotoxic drug concentration given in high dose chemotherapy compared with standard drug concentration may not be sufficient to produce the expected increase in tumour response and possibly survival, and the controversial results of high dose chemotherapy in different studies may thus be explained. Secondly, since an increase in melphalan dose above a certain threshold does not greatly increase tumour response, the use of combination therapies would seem to be more likely to be effective than increased chemotherapeutic drug doses in achieving better tumour responses.

Topics: Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Disease Models, Animal; Dose-Response Relationship, Drug; Hindlimb; Humans; Melanoma; Melphalan; Neoplasm Transplantation; Rats; Rats, Inbred Strains; Rats, Nude; Skin Neoplasms; Treatment Outcome

The aim of the present work was to investigate the origin and half-life of endogenous S100B protein reported by many investigators as a useful melanoma serum marker. Within cells, S100B protein exists in homo- or heterodimer form containing mainly Ca(++), having a substantial fraction bound to membranes. As such, S100B is believed to be involved in the regulation of cytoskeleton. Also, a role in the cell cycle progression has been suggested. Although S100B appears having important intracellular functions, proofs of its secretion, at least at concentrations such as the ones measured in melanoma patients, are still lacking. Consistent with this view is the fact that immunohistology for S100 protein reported by numerous authors clearly indicate an exclusive intracellular staining. For these reasons, it was of a major interest to investigate how and when S100B is shed to the blood. Knowing that significant S100B levels are seen only in stage IV patients, we hypothesized that cell death may be the major source of circulating S100B protein in these patients. This hypothesis was studied in an in vitro model simulating cell death and in vivo in melanoma and other cancer patients undergoing highly cytotoxic regional immunochemotherapy using isolated limb perfusion with tumor necrosis factor and melphalan, as well as in tumor exudates and pleural fluids. Our results strongly suggest melanoma and endothelial cell death and subsequent continuous drainage to the blood as the major mechanism behind S100B release to the blood circulation. We estimated the endogenous S100B protein half-life to be about 30 min.

Topics: Biomarkers, Tumor; Calcium; Calcium-Binding Proteins; Cell Death; Dimerization; Endothelium, Vascular; Hemangiosarcoma; Humans; Kinetics; Melanoma; Melphalan; Necrosis; Nerve Growth Factors; Perfusion; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Sarcoma; Time Factors; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Umbilical Veins

Isolated limb perfusion (ILP) results in complete response (CR) rates of 60% to 90% in patients with regionally advanced melanoma. Survival after a CR may be influenced by various factors, particularly out-of-field disease in iliac lymph nodes (ILN) identified during lower-extremity ILP. We examined clinical and pathological parameters, including ILN status and outcome, for patients with in-transit melanoma who had a CR to ILP.. From May 1992 to July 1997, 50 patients (16 men and 34 women; median age, 57 years) with stage IIIA or IIIAB melanoma had a CR to a 90-minute hyperthermic iliac ILP with melphalan (10 mg/L limb volume, n = 20) or melphalan and tumor necrosis factor (4-6 mg+/-200 microg interferon; n = 30). Clinical and pathological parameters were analyzed by univariate and Cox proportional hazards models to determine which were associated with survival or in-field recurrence.. The median in-field recurrence-free survival in the cohort of 50 patients after a CR to ILP was 1.4 years, and the actuarial 5-year in-field recurrence-free survival was 30%. By univariate analysis, there was a trend for improved outcome with female sex and stage IIIA (vs. IIIAB) at initial diagnosis was associated with improved survival after a CR to ILP (P = .056 and .012, respectively). Eleven (22%) of 50 patients had positive ILNs identified and resected at ILP. The probability of overall in-field recurrence was 70% after 4 years, and there was no difference between those with or without positive ILNs; median time to in-field recurrence was 13 and 19 months, respectively (P = .62). Similarly, overall survival was not influenced by positive ILN status (median [months]: +ILN, 69 vs. -ILN, 58; P = .68). Of note, Cox models identified that the risk of death was significantly greater in those with a history of prior systemic therapy (hazard ratio: 2.67 [95% confidence interval, 1.17-6.11]; P = .02) and those with an in-transit lesion size > or =1.4 cm2 (hazard ratio, 3.12 [95% confidence interval, 1.30-7.5]; P = .011). When these two variables were combined, there was a highly significant association with shortened survival (P = .002 by log-rank test).. These data indicate that for patients undergoing ILP and in whom positive ILNs are found and resected, ILP is justified. In addition, patients who have a CR after ILP and have a history of prior treatment or larger lesions should be considered for adjuvant systemic therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Extremities; Female; Humans; Hyperthermia, Induced; Interferons; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Skin Neoplasms; Tumor Necrosis Factor-alpha

Hyperthermic isolated limb perfusion with cytostatic drugs (HILP) is indicated in locoregional recurrences of malignant melanoma of the limbs. As a neoadjuvant treatment it is also used for non-curatively resectable soft tissue sarcoma or their recurrences on the extremities. Up to now, melphalan is still the standard drug in HILP for malignant melanoma. With melphalan, complete response can be achieved in 65-80% for clinically detectable in transit metastases (+/- regional lymph node metastases). The combination of tumor necrosis factor (TNF) alpha with melphalan has considerably improved response rates of HILP in sarcoma. In more than 80% of the patients the otherwise necessary amputation of the limb can be avoided. The combination of TNF with other drugs than melphalan could possibly further improve results of HILP in sarcoma patients. The high rate of local recurrences of malignant melanoma after HILP poses an unsolved problem yet.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Hyperthermia, Induced; Lymphatic Metastasis; Melanoma; Melphalan; Neoplasm Recurrence, Local; Neoplasm Staging; Skin Neoplasms; Tumor Necrosis Factor-alpha

Isolated limb perfusion (ILP) with melphalan is used to treat recurrent melanoma. This study aimed to develop a microdialysis technique for melphalan tissue concentration measurement during ILP. The effects of melphalan concentration (50-600 microg/ml), microdIalysis flow rate (0.55-17.5 microl/min), probe length (5-50 mm) and temperature (25-41.5 degrees C) on in vitro recovery were studied. In addition, in vivo recovery was measured in rat hindlimbs perfused with melphalan using 50 mm microdialysis probes implanted subcutaneously and into muscle. Both dialysate and tissue sample melphalan concentrations were determined by high performance liquid chromatography. The in vitro recovery of melphalan was not affected by melphalan concentration or temperature, but increased with probe length and decreased with flow rate. The melphalan concentrations in subcutaneous and muscle dialysates were not significantly different. A linear relationship was found between tissue dialysate concentrations and actual tissue concentrations of melphalan (r2 = 0.97). Microdialysis is a potential method for tissue drug monitoring which may assist in the efficacious use of cytotoxics in human ILP.

Topics: Animals; Chemotherapy, Cancer, Regional Perfusion; Drug Monitoring; Hindlimb; Male; Melanoma; Melphalan; Microdialysis; Neoplasms, Muscle Tissue; Rats; Rats, Wistar; Time Factors

Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and melphalan is a highly effective treatment for locoregional metastases of malignant melanoma and for advanced soft tissue sarcoma of the limb. The major systemic side effects are characterized by the induction of a systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), a serum marker of bacterial sepsis, was investigated with respect to its role in SIRS after ILP.. University surgical oncology division with an integrated eight-bed intensive care unit.. Thirty-seven patients were treated by ILP with rhTNF-alpha and melphalan (n = 26) or with cytostatics alone (n = 11) for soft tissue sarcoma or malignant melanoma.. The course of serum PCT, interleukin (IL)-6, and IL-8 was analyzed intra- and postoperatively. Hemodynamic variables including heart rate, mean arterial pressure, cardiac index, pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary and systemic vascular resistance were recorded in parallel.. PCT was significantly elevated over baseline after ILP with a maximum between 8 hrs (peak level 16.0+/-18.8 (SD) ng/mL) and 36 hrs (13.8+/-15.7 ng/mL) (p < .001). The increase in serum PCT was significantly more pronounced after ILP with rhTNF-alpha/melphalan than after ILP with cytostatics alone (p < .001). IL-6 and IL-8 were also significantly increased after ILP (p = .001), reaching peak concentrations at 1 hr and 4 hrs postoperatively. Significant changes in heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance were observed during and after ILP; however, PCT levels could not be correlated to these variables. Pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary vascular resistance showed no significant changes.. Serum procalcitonin is induced as part of the SIRS after ILP with rhTNF-alpha/melphalan. It may be induced directly by rhTNF-alpha or other cytokines, because serum peaks of IL-6 and IL-8 precede the peak of PCT. Because there is no correlation between serum levels of PCT and hemodynamic variables, this marker cannot be applied to assess the severity of SIRS reaction after ILP.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Calcitonin; Calcitonin Gene-Related Peptide; Cardiovascular Physiological Phenomena; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Extremities; Female; Glycoproteins; Humans; Interleukin-6; Interleukin-8; Male; Melanoma; Melphalan; Middle Aged; Protein Precursors; Recombinant Proteins; Sarcoma; Time Factors; Tumor Necrosis Factor-alpha

Since the introduction of high-dose tumor necrosis factor-alpha (TNFalpha) in the setting of isolated limb perfusion (ILP) in the clinic, prevention of leakage to the body of the patient is monitored with great precision for fear of TNF-mediated toxicity. That we observed remarkably little toxicity in patients with and without leakage prompted us to determine patterns of cytokines and acute phase proteins in patients with high leakage and in patients without any leakage.. TNFalpha, interleukin (IL)-6, IL-8, C-reactive protein, and secretory (s)-phospholipase A2 were measured at several time points during and after (until 7 days) ILP in 10 patients with a leakage to the systemic circulation varying in percentage from 12% to 65%. As a control, the same measurements, both in peripheral blood and in perfusate, were performed in nine patients without systemic leakage.. In patients with systemic leakage, levels of TNFalpha increased during ILP, reaching values to 277 ng/ml. IL-6 and IL-8 peaked 3 hours after ILP with values significantly higher compared with patients without systemic leakage. C-reactive protein and s-phospholipase A2 peaked at day 1 in both patient groups, s-phospholipase A2 with significant higher levels and C-reactive protein, in contrast, with lower levels in the leakage patients.. High leakage of TNFalpha to the systemic circulation, caused by a complicated ILP, led to 10-fold to more than 100-fold increased levels of TNFalpha, IL-6, and IL-8 in comparison with patients without leakage. The increase of the acute phase proteins was limited. Even when high leakage occurs, this procedure should not lead to fatal complications. The most prominent clinical toxicity was hypotension (grade III in four patients), which was easily corrected. No pulmonary or renal toxicity was observed in any patient. It is our experience that, even in the rare event of significant leakage during a TNFa-based ILP, postoperative toxicity is usually mild and can be easily managed by the use of fluid and, in some cases, vasopressors.

Topics: Acute-Phase Proteins; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Cytokines; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Sarcoma; Tumor Necrosis Factor-alpha

Topics: Adult; Anesthetics, Inhalation; Capillary Leak Syndrome; Chemotherapy, Cancer, Regional Perfusion; Desflurane; Hemodynamics; Humans; Hyperthermia, Induced; Isoflurane; Leg; Male; Melanoma; Melphalan

Irradiation of human melanoma (MeWo, Be11) and squamous cell carcinoma (4451, 4197) cells induces cell cycle blocks from which the cells recover to re-enter mitosis after 40-60 h. In the TP53 mutant cell lines, MeWo and 4451, irradiation induces a G(2)-phase block, where the fraction of cells in G(2) phase reaches a maximum after 18-20 h. In the TP53 wild-type cell lines, 4197 and Be11, a G(1)- and G(2)-phase block is reached 12 and 16 h postirradiation, respectively. Addition of pentoxifylline after irradiation at the time when the number of cells in G(2) phase has reached a maximum shortens the normal recovery from G(2)-phase block to approximately 7 h. Addition of daunorubicin, melphalan and cisplatin under these conditions markedly enhanced drug toxicity. In the TP53-mutated cell lines MeWo and 4451, the survival ratio at 7 Gy measured by colony formation was 2.3-2.8, 8.6-85 and 52-74 for daunorubicin, melphalan and cisplatin, respectively. In the TP53 wild-type cell lines, the corresponding survival ratios were found to be 1.3-1.4, 2.3-3.0 and 1.2-2.6, respectively. The survival ratios are for clonogenic survival after 7 Gy and 2 mM pentoxifylline and measure the influence of drug doses that ensure 95% survival in nonirradiated controls. The results indicate that the G(2)-phase block is a crucial event in the damage response that can be manipulated to achieve a significant enhancement of drug toxicity. These effects are particularly pronounced in TP53 mutant cells and are observed at drug doses well below the clinical range.

Topics: Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Count; Cell Cycle; Cell Survival; Cisplatin; Daunorubicin; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Flow Cytometry; G2 Phase; Humans; Melanoma; Melphalan; Mitosis; Mutation; Pentoxifylline; Tumor Cells, Cultured; Tumor Suppressor Protein p53

PET with L-[1-11C]-tyrosine (TYR) was investigated in patients undergoing hyperthermic isolated limb perfusion (HILP) with recombinant tumor necrosis factor alpha (rTNF-alpha) and melphalan for locally advanced soft-tissue sarcoma and skin cancer of the lower limb.. Seventeen patients (5 women, 12 men; age range 24-75 y; mean age 52 y) were studied. TYR PET studies were performed before HILP and 2 and 8 wk afterwards. The protein synthesis rates (PSRs) in nanomoles per milliliter per minute were calculated. After final PET studies, tumors were resected and pathologically examined. Patients with pathologically complete responses (pCR) showed no viable tumors after treatment. Those with pathologically partial responses (pPR) showed various amounts of viable tumors in the resected tumor specimens.. Six patients (35%) showed a pCR and 11 patients (65%) showed a pPR. All tumors were depicted as hot spots on PET studies before HILP. The PSR in the pCR group at 2 and 8 wk after perfusion had decreased significantly (P < 0.05) in comparison to the PSR before HILP. A significant difference was found in PSR between the pCR and pPR groups at 2 and at 8 wk (P < 0.05). Median PSR in nonviable tumor tissue was 0.62 and ranged from 0.22 to 0.91. With a threshold PSR of 0.91, sensitivity and specificity of TYR PET were 82% and 100%, respectively. The predictive value of a PSR > 0.91 for having viable tumor after HILP was 100%, whereas the predictive value of a PSR < or = 0.91 for having nonviable tumor tissue after HILP was 75%. The 2 patients in the pPR groups with a PSR < 0.91 showed microscopic islets of tumor cells surrounded by extensive necrosis on pathological examination.. Based on the calculated PSR after HILP, TYR PET gave a good indication of the pathological outcome. Inflammatory tissue after treatment did not interfere with viable tumor on the images, suggesting that it may be worthwhile to pursue TYR PET in other therapy evaluation settings.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Hypothermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Radiopharmaceuticals; Recombinant Proteins; Sarcoma; Sensitivity and Specificity; Skin Neoplasms; Soft Tissue Neoplasms; Tomography, Emission-Computed; Tumor Necrosis Factor-alpha; Tyrosine

The optimal toxic reaction of the normal tissues in perfused limbs after isolated limb perfusion (ILP) is unknown. Theoretically, more severe limb toxicity could reflect a concomitant increased toxic effect to the tumor and improved outcomes. We determined whether there is a relation between limb toxicity and treatment outcomes after ILP for recurrent limb melanoma.. Among 252 patients with recurrent melanoma of the limbs, treatment outcomes in 192 patients (76%) with no or mild acute limb toxicity were compared with those in 60 (24%) with more severe reactions. Multivariate analysis was used to identify prognostic factors for complete response, limb recurrence-free interval, and survival.. Among 112 patients with measurable disease, 65 patients (58%) had a complete response and 27 (42%) experienced a relapse in the perfused limb. For complete response, uninvolved regional lymph nodes (p = 0.0025) and ILP using tumor necrosis factor-alpha (p = 0.0076) appeared to be favorable prognostic factors in multivariate analysis. There was no evidence of a relation between limb toxicity and complete response either in univariate (p = 0.16) or multivariate analysis (p = 0.46). For limb recurrent-free interval, only the number of lesions was a significant prognostic factor (p = 0.047); limb toxicity was not (p = 0.095). In 140 patients with recurrent melanoma excised before or at the moment of ILP, independent prognostic factors for survival were gender, the number of positive nodes, and stage of disease. There was no relation between limb toxicity and survival in either univariate (p = 0.53) or multivariate analysis (p = 0.94). Forty-eight (34%) of the 140 patients had a relapse in the perfused limb. No prognostic factors for limb recurrent-free interval could be identified; limb toxicity was not related to relapse time in univariate or multivariate analyses (p = 0.16 and p = 0.14, respectively).. More severe acute limb toxicity is not associated with improved outcomes. One should aim at grade II toxicity (slight erythema or edema, compatible with complete recovery) at the most to increase the therapeutic ratio of ILP.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Edema; Erythema; Extremities; Female; Humans; Hyperthermia, Induced; Interferon-gamma; Male; Melanoma; Melphalan; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Prognosis; Retrospective Studies; Skin Neoplasms; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha

Despite high rates of complete responses (CRs) to isolated limb perfusion (ILP) for patients with in-transit melanoma (60% to 90%), extremity recurrences are common. We evaluated our experience with managing these recurrences to determine how best to treat these patients.. Between April 1992 and April 1998, 72 patients experienced CRs after hyperthermic ILP using Melphalan, with (n = 46) or without (n = 26) tumor necrosis factor. Of these, 25 patients (35%) experienced initial recurrences in the extremities, and they form the basis of this study.. Three patients who underwent repeat ILP for treatment of their recurrences experienced a second CR and recurrence in the extremity (at 9, 15, and 16 months), allowing analysis of 28 cases. For 5 of 20 recurrences managed with excision, 2 of 6 managed with repeat ILP, and 0 of 2 managed with systemic treatment, the patient was free of disease at the last follow-up examination (median follow-up period, 11 months).. Isolated extremity recurrences after CRs to ILP occurred in 35% of patients. Initially, these could be managed successfully by excision or repeat ILP for the majority of patients (92%). We recommend excision of small-volume recurrent disease, reserving repeat ILP for patients with increasing numbers of lesions or increasing rapidity of in-field recurrences.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Retreatment; Tumor Necrosis Factor-alpha

The treatment of bulky recurrent melanotic lesions of extremities with isolated limb perfusion with high dose chemotherapy offers palliation in a number of patients. However, the question is raised whether these major surgical procedures are too risky to warrant performing them in elderly patients.. Sixty-seven limbs were perfused in 60 patients with various drugs from 1976 through 1996 (35, imidazole carboxamide; 7, cisplatin; 20, carboplatin; 5, thiotepa). Among the 67 perfusions, 20 were in patients aged 70 years and older. Perfusion was performed for 16 upper extremities and 51 lower extremities by using the pump oxygenator for 1 hour.. A total of 19 complications were noted after a total of 14 of the 67 perfusions (21%) (postoperative edema, 5; seroma, 4; wound separation or infection, 9; nonfatal pulmonary embolus, 1). The complications in 4 of 20 perfusions in the older patients (20%) were less than in 15 of 47 perfusions in the younger patients (32%). Among the 17 patients older than 70 years of age who were treated with perfusions for recurrent disease, four patients (24%) are alive with no evidence of disease (NED) for a median of 29 months (range, 16 to 80 months); one patient is now more than 6 years with NED after her third perfusion for repeated in-transit disease. Another 2 of 17 patients (12%) are alive with disease for a median of 89 months (range, 54 to 123 mos). The remaining 11 patients (64%) are dead of their disease. These data are comparable to the control rates in the group of younger patients in the study. Overall, half of all the patients (14 of 28) who died of their disease in both groups had maintained local control of their involved extremities.. Aggressive treatment in selected patients with regional isolated perfusion of limbs for melanoma can lead to significant palliation of symptoms and salvage of limbs with adequate disease-free control and occasional survival benefit. This series of patients was associated with meaningful disease control and with few serious complications. Perfusions are tolerated well by patients in their 70s and 80s; therefore advanced age is not a contraindication to this procedure in carefully selected patients.

Topics: Adult; Age Factors; Aged; Antineoplastic Agents; Dacarbazine; Edema; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Outcome Assessment, Health Care; Perfusion; Recurrence; Skin Neoplasms

TNF (tumour necrosis factor) is a new immunological anti-cancer agent which is too toxic for systemic use and relatively ineffective when used alone, but remarkably effective when used in closed circuit perfusion techniques together with other anti-cancer agents. Several studies have shown that when TNF is used with melphalan in closed circuit perfusion treatment for multiple melanoma metastases confined to a limb, a response rate of 80% can be achieved compared to a best response rate of 40% with melphalan alone. These findings confirm the difference in tumour responses which can be achieved with the appropriate use of regional chemotherapy in treatment of locally advanced tumours and the importance of surgical oncologists and vascular radiologists in maintaining and developing skills in integrated regional cancer treatment.

Topics: Chemotherapy, Cancer, Regional Perfusion; Humans; Melanoma; Melphalan; Neoplasms; Tumor Necrosis Factor-alpha

We evaluated the cytotoxic effects of a cell-permeable ceramide (Cer), N-hexanoyl-D-sphingosine (C6-Cer) and of two related sphingoid bases, sphingosine (So) and dihydrosphingosine (sphinganine; Sa) on human melanoma cell lines and on soft tissue sarcoma lines recently established from fresh surgical biopsy specimens. These cell lines ranged from high susceptibility (939 melanoma) to strong resistance (A2058 melanoma and all three sarcomas) to tumour necrosis factor (TNF), an inducer of elevated intracellular Cer levels. However, all the cell lines demonstrated a dose-dependent susceptibility to C6-Cer with protracted cytotoxic kinetics, with the C8161 melanoma being the most sensitive and A2058 the least. Protein kinase C (PKC) antagonizes Cer-dependent apoptosis, and chelerythrine chloride, So and Sa, which inhibit PKC, caused extremely rapid cytotoxicity of melanoma cell lines, irrespective of their relative sensitivity to C6-Cer. So-mediated cytotoxicity was extensive even after only 90 min of treatment, within the time frame of limb perfusion. So and Sa only slightly potentiated the cytotoxic responses to TNF, C6-Cer or melphalan. Sphingolipid-driven intracellular pathways may offer opportunities for therapy of these tumours.

Topics: Alkaloids; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzophenanthridines; Carboxylic Acids; Cell Survival; Ceramides; Dose-Response Relationship, Drug; Fumonisins; Histiocytoma, Benign Fibrous; Humans; Lung Neoplasms; Melanoma; Melphalan; Phenanthridines; Protein Kinase C; Sarcoma; Signal Transduction; Sphingosine; Time Factors; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor alpha (TNFalpha) is effective for advanced melanoma and sarcoma of the limbs. Ten patients undergoing HILP with TNFalpha were evaluated by neurological examinations, nerve conduction studies (NCS), sympathetic skin responses (SSR) and conventional and quantitative electromyography (EMG), performed before, 7 days and 6 weeks following HILP. Seven patients showed minimal clinical signs of peripheral nerve damage following HILP; in two the injury was evident electrophysiologically: 7 days following HILP five patients had paresthesias and/or hypoesthesia, one had a mild foot drop and one had autonomic disturbances in the affected limb. SSR was low in two patients in the affected limb, sensory nerve action potentials were not elicited in one, with normal motor NCS and EMG. At 6 weeks, four patients continued to have mild paresthesias and one had dysautonomia of the perfused limb. Sensory responses and SSR did not change, motor abnormalities were not found. These findings show that HILP with TNFalpha induces a mild, mainly sensory neuropathy in perfused limbs, not disturbing functionality and improving over time.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Arm; Autonomic Nervous System Diseases; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Electromyography; Female; Humans; Hyperthermia, Induced; Immunologic Factors; Leg; Male; Melanoma; Melphalan; Middle Aged; Neural Conduction; Paresthesia; Peripheral Nervous System Diseases; Prognosis; Reflex, Abnormal; Sarcoma, Kaposi; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

L-buthionine-S,R-sulfoximine (L-S,R-BSO) was enriched for the active L-buthionine-S-sulfoximine (L-S-BSO) diastereomer. Comparative analysis was performed to determine if this enriched form possessed an increased capacity to deplete glutathione (GSH), and to inhibit the proliferation of tumor cell lines and fresh human tumor samples. Increased activity was observed for the enriched preparation of L-S-BSO in direct proportion to its increased L-S-diastereomeric percentage. Significant antitumor activity towards melanoma, breast and ovarian carcinoma specimens was noted, with the greatest activity directed against malignant melanoma. The activity of BSO on melanoma specimens was found to be correlated with their melanin content, suggesting that free radicals generated during melanin synthesis may become cytotoxic after GSH-dependent scavenging has been eliminated by BSO treatment. The antimelanoma activity of melphalan and BCNU were found to be significantly enhanced in combination with L-S-BSO. With respect to the mechanism of L-S-BSO synergy with alkylators, L-S-BSO treatment of M14 and ZAZ human melanoma cell lines resulted in decreased GSH levels and glutathione S-transferase (GST) activity. Western and Northern blot analyses indicated that GST-mu was the predominant isozyme downregulated after L-S-BSO treatment. Both M14 and ZAZ cell lines selected for resistance to L-S-BSO also showed decreased levels of GST-mu expression. However, in drug free media GST enzyme activity returned to pre-treatment levels without altering the BSO-resistance status of the cell lines. We conclude that L-S-BSO may be an active agent in the treatment of melanoma, and that it may enhance alkylator activity on melanoma through depletion of GSH and down-regulation of GST expression. Purified L-S-BSO should be explored clinically as an active agent for the treatment of melanoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Buthionine Sulfoximine; Carmustine; Down-Regulation; Drug Resistance; Enzyme Inhibitors; Female; Glutamate-Cysteine Ligase; Glutathione Transferase; Humans; Melanins; Melanoma; Melphalan; Ovarian Neoplasms; Tumor Cells, Cultured

Two patients presenting with a stage I melanoma of the sole of the foot (Clark's level IV, Breslow's 2.8 mm, and Clark's level IV, Breslow's 3.2 mm) underwent a 3-cm tumor free-margin skin resection, followed by microanastomosed muscle flap reconstruction (serratus anterior and latissimus dorsi). Immediately after primary wound healing, an elective inguino-iliac lymph-node dissection, followed by hyperthermic isolated regional chemotherapy with Melphalan, was carried out. Only moderate swelling of both free flaps was observed after these procedures, and this resolved rapidly. The patients returned to ambulation after 2 weeks. No other side effects of the hyperthermic isolated regional chemotherapy were observed in the previously microanastomosed flaps.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Foot Diseases; Humans; Hyperthermia, Induced; Lymph Node Excision; Melanoma; Melphalan; Middle Aged; Muscle, Skeletal; Surgical Flaps

Treatment of stage IIIA/B melanoma patients by isolated limb perfusion (ILP) with a combination of tumor necrosis factor-alpha (TNF-alpha) and melphalan induces a complete response in 80-90% of the cases. The mechanism of tumor regression induced by the combination of TNF-alpha and melphalan is not precisely understood. Previous studies focused on the immediate (ie., within a few days) clinico-pathological changes after perfusion involving hemorrhagic necrosis. However, clinical data clearly indicate that complete tumor remission frequently requires a period of a few weeks to as much as months after ILP. Because the mechanism underlying this delayed-type reaction is completely unknown, we studied the clinico-pathological events in patients with such slowly regressing melanoma lesions. For this purpose, 94 biopsies of in-transit melanoma metastasis that were taken sequentially from 11 patients between 1 week and 9 months after ILP were analyzed by light and electron microscopy and immunohistochemistry. Clinical data included patient sex, age, anatomical localization and size of the tumor, and follow-up. All of the 11 patients ultimately responded to perfusion treatment (9 complete, 1 partial, 1 stable disease). Serial biopsies showed scattered individual tumor cell necrosis without hemorrhage. Most of the lesions with this delayed-type reaction pattern were less than 0.5 cm in diameter. They contained varying amounts of histologically viable-looking tumor cells and tumor-infiltrating melanophages. In addition, a marked but transient infiltrate of peritumoral eosinophils and moderate interstitial edema and dermal fibrosis were encountered. Only small numbers of lymphocytes were present. In comparison with the reaction pattern after treatment with melphalan alone, the delayed-type reaction pattern was similar but more intense. The scattered tumor cell necrosis in the latter type may be explained by a TNF-alpha-induced increase in permeability of the tumor vascular bed, which results in higher intratumoral concentrations of melphalan or in a prolongation of its effect. Subsequently, degenerated tumor cells are cleared by macrophages, and, finally, repair by fibrosis occurs. Because the immediate reaction type is evoked by hyperpermeability of the tumor vessels as well, quantitative differences seem to determine which reaction type ensues. We suggest that the extent of tumor vasculature that is sensitive to TNF-alpha determines the onset and histopathological

Topics: Aged; Aged, 80 and over; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Necrosis; Tumor Necrosis Factor-alpha

Malignant melanoma presenting as an inflammatory skin metastasis has been described but is an exceedingly rare phenomenon. We report an unusual case of a patient who developed right leg lesions that were initially thought to be infectious in origin. There was no resolution of these lesions with antibiotic therapy, and the patient subsequently underwent an incisional biopsy that showed atypical S-100 positive cells within dermal vessels. On further questioning, the patient revealed that 20 years earlier she had a pigmented lesion removed from her right posterior calf. Review of that material revealed malignant melanoma, approximately 3.2 mm in depth. Although the patient was subsequently treated with a right groin lymph node dissection and isolated limb perfusion chemotherapy, she has continued to develop locally recurrent disease. This case is unusual both in terms of clinical presentation and interval of disease progression.

Topics: Aged; Antineoplastic Agents, Alkylating; Biopsy; Chemotherapy, Cancer, Regional Perfusion; Diagnosis, Differential; Disease Progression; Female; Humans; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Melphalan; Neoplasm Recurrence, Local; Panniculitis; S100 Proteins; Skin Diseases, Infectious; Skin Neoplasms; Vimentin

Topics: Adult; Antineoplastic Agents, Alkylating; Humans; Leg Ulcer; Male; Melanoma; Melphalan; Middle Aged; Perfusion; Sarcoma; Scleroderma, Localized

Severe limb toxicity following isolated limb perfusion (ILP) can lead to compartmental compression syndrome and severe rhabdomyolysis, occasionally necessitating amputation of the affected limb. We determined whether laboratory tests for muscle damage and inflammation could predict impending limb toxicity.. All 184 consecutive ILPs performed in our institute from 1988 to 1994 were included in this study. Creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (ASAT) and white blood cell (WBC) counts were determined on post-ILP days 1-4, 6, 8, and 15.. "Late peak" CK patterns, characterised by a peak on or after the 5th post-perfusion day, were strongly associated with severe limb toxicity (p < 0.001). Severe toxicity did develop in 40% of the limbs when CK values exceeded 1000 IU/L on the 2nd to 5th post-ILP day (p < 0.001). There was a correlation between the peak CK and the individual grades of toxicity (r = 0.6, p < 0.001). Serum LDH and ASAT values peaked 2.9 and 3.4 days after the CK peak respectively. Severe limb toxicity was statistically significantly associated with higher WBC counts from the 2nd post-ILP day onwards.. CK values exceeding 1000 IU/L after the 1st and WBC counts increasing after the 2nd post-ILP day could be predictors of impending limb toxicity. These patients should be observed closely for signs of compartmental compression syndrome and severe rhabdomyolysis.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Biomarkers; Chemotherapy, Cancer, Regional Perfusion; Compartment Syndromes; Creatine Kinase; Drug Monitoring; Extremities; Female; Humans; Interferon-gamma; L-Lactate Dehydrogenase; Leukocyte Count; Linear Models; Male; Melanoma; Melphalan; Middle Aged; Predictive Value of Tests; Rhabdomyolysis; Sarcoma; Toxicity Tests; Tumor Necrosis Factor-alpha

Regional limb perfusion with antineoplastic agents stresses the local vasculature in a variety of ways. However, by monitoring the perfusates from limbs treated with melphalan alone or with melphalan plus tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma), we were able to distinguish the effect of the cytokines on the observed coagulant and fibrinolytic responses. We collected samples of effluent from a series of lower extremities that were perfused with the cytokines and/or melphalan as treatment for localized melanoma. Both regimens produced statistically significant evidence of coagulant and fibrinolytic activation. However, limbs receiving cytokines in addition to the melphalan responded with a sharper rise in tissue plasminogen activator (tPA) and plasmin (plasmin-antiplasmin complexes [PAP]) than limbs treated with melphalan alone. Evidence of thrombin formation (prothrombin fragment 1 + 2 [F1 + 2], thrombin-antithrombin complexes [TAT]) was also greater when the cytokines were included, although the response was delayed and less consistent than the fibrinolytic activation.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Extremities; Female; Humans; Interferon-gamma; Male; Melanoma; Melphalan; Middle Aged; Perfusion; Tumor Necrosis Factor-alpha

We have established a surviving model of isolated limb perfusion using xenografts of the human melanoma cell line MM 96L injected subcutaneously into the hindlimb of a nude rat. The femoral artery and vein were cannulated via the left renal artery and vein and the hind limb was isolated using tourniquets. The limb was perfused with Krebs Heinseleit buffer at 37 degrees C containing 4.7% bovine serum albumin at a constant flow rate of 4 ml per min for 30-60 min with 100% survival of the animals. Tumour vascularization and blood flow were demonstrated using vascular casts and [51Cr]-microspheres. Following the addition of melphalan (15 or 100 micrograms/ml), drug concentrations in the perfusate, tissues and systemic circulation were determined using high pressure liquid chromatography (HPLC). Systemic leakage, assessed using [125I]albumin and melphalan and detected by a gamma-counter and HPLC respectively, was < 0.5%. The melphalan concentration and tissue flow rate in the tumour deposits were 40 and 30% respectively, when compared with the surrounding subcutaneous tissue. At a dose of 15 micrograms/ml, melphalan caused a reduction in tumour growth after 60 min perfusion, and a significant reduction in tumour size was seen when the melphalan dose was 100 micrograms/ml. The surviving nude rat model of isolated limb perfusion for recurrent melanoma will allow examination of optimal perfusion conditions, along with the pharmacokinetics, pharmacodynamics and efficacy of melphalan and other drugs.

Topics: Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Disease Models, Animal; Hindlimb; Humans; Melanoma; Melphalan; Neoplasm Transplantation; Rats; Rats, Nude; Transplantation, Heterologous

To analyse a personal series of cases of malignant melanoma of a limb with regional metastasis treated by isolated cytostatic perfusion of both recombinant human tumour necrosis factor (rhTNF-alpha) and melphalan, reported to produce a response rate of up to 100%.. 23 isolated hyperthermic regional perfusions were performed between 1993 and 1995 in 21 patients (17 women, four men) with proven regionally metastatic malignant melanoma of the limb, using rhTNF-alpha and melphalan in combination. Perfusion time was 90 min, at a tissue temperature of 38 degrees to 40 degrees C and a perfusion pressure 10-15 mm Hg below mean arterial.. All systemic effects of the limb perfusions were easily manageable under intensive care monitoring. There were no severe disturbances (WHO grade 3/4) of cardiovascular or pulmonary functions. One patient, who had sustained a marked leak during the perfusion, died two days after the perfusion of severe pneumonia and pulmonary emboli from a femoral vein thrombosis. Two further perfusions were terminated because of a leakage rate of more than 10%. A rise in bilirubin and the transaminases occurred in 11 of the 23 perfusions up to WHO grade 2 (n = 9) and 3 (n = 2). Renal functions were temporarily impaired in three of the 21 patients (WHO grade 1). Complete tumour regression was obtained in 13 patients, a partial one in three (response rate 80%). After a median follow-up period of 15 months five of the 13 patients developed a regional recurrence.. The observed response rate is higher than that with melphalan alone as reported in the literature. To clarify this difference a randomized phase III study comparing the two methods has been initiated.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Monitoring, Physiologic; Neoplasm Recurrence, Local; Recombinant Proteins; Remission Induction; Tumor Necrosis Factor-alpha

An isolated rat hindlimb perfusion model carrying xenografts of the human melanoma cell line MM96 was used to study the effects of perfusion conditions on melphalan distribution. Krebs-Henseleit buffer and Hartmann's solution containing 4.7% bovine serum albumin (BSA) or 2.8% dextran 40 were used as perfusates. Melphalan concentrations in perfusate, tumour nodules and normal tissues were measured using high-performance liquid chromatography (HPLC). Increasing the perfusion flow rates (from 4 to 8 ml min(-1)) resulted in higher tissue blood flow (determined with 51Cr-labelled microspheres) and melphalan uptake by tumour and normal tissues. The distribution of melphalan within tumour nodules and normal tissues was similar for both Krebs-Henseleit buffer and Hartmann's solution; however, tissue concentrations of melphalan were significantly higher for a perfusate containing 2.8% dextran 40 than for one containing 4.7% BSA. The melphalan concentration in the tumour was one-third of that found in the skin if the perfusate contained 4.7% BSA. In conclusion, this study has shown that a high perfusion flow enhances the delivery of melphalan into implanted tumour nodules and normal tissues, and a perfusate with low melphalan binding (no albumin) is preferred for maximum uptake of drug by the tumour.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell Transplantation; Chromatography, High Pressure Liquid; Glucose; Hindlimb; Humans; Isotonic Solutions; Male; Melanoma; Melphalan; Organ Preservation Solutions; Perfusion; Rats; Rats, Nude; Ringer's Lactate; Transplantation, Heterologous; Tromethamine; Tumor Cells, Cultured

Tumor necrosis factor alpha (TNF-alpha) is thought to have a key role in metabolic changes of muscle tissue during inflammatory diseases. It is unknown whether TNF-alpha affects muscle metabolism directly or whether these changes are mediated by secondary mediators. We studied 6 patients undergoing isolated limb perfusion with TNF-alpha for irresectable soft-tissue sarcoma or in-transit melanomas. Glucose, lactate, ammonia and amino-acid consumption or production were measured in the perfusate during 3 perfusion periods: before, after TNF-alpha and after the combined administration of TNF alpha and melphalan. Arterial glucose, lactate, ammonia and amino-acid concentrations were monitored to detect metabolic effects of TNF-alpha after it entered the systemic circulation. Glucose uptake and lactate release by the limb remained unchanged after the injection of TNF-alpha alone, as well as after the combination of TNF-alpha and melphalan. Furthermore, glutamine, alanine, phenylalanine, tyrosine and total amino-acid release into the perfusate did not increase during TNF-alpha and melphalan treatment, indicating that muscle metabolism was not changed. After the isolated limb perfusion, TNF-alpha entered the systemic circulation and induced metabolic changes resulting in a doubling of arterial lactate concentrations, decreased arterial glucose concentrations and decreased arterial amino-acid concentrations. Our study shows that regional administration of TNF-alpha alone or in combination with melphalan does not directly affect muscle glucose and protein metabolism. The data suggest that systemic metabolic changes induced by TNF-alpha are mediated through secondary, centrally produced, factors.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amino Acids; Ammonia; Antineoplastic Agents, Alkylating; Blood Glucose; Drug Therapy, Combination; Female; Glucose; Humans; Lactic Acid; Male; Melanoma; Melphalan; Middle Aged; Muscle, Skeletal; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

High doses of tumor necrosis factor-alpha (TNF) seem to be effective in the treatment of solid tumors in the extremities. By applying current intensive care technology, systemic administration of high doses of TNF levels might be feasible for the treatment of cancer in other localizations. To establish the early and late effects of high systemic TNF levels on the lungs, we determined lung function parameters in 12 patients before and after hyperthermic isolated limb perfusion (HILP) with TNF and melphalan. Because of leakage during perfusion, mean maximum systemic TNF levels of 60.0 ng/ml (range, 0.3-356 ng/ml) were obtained. Significant alterations in the vital capacity (VC), the capillary blood volume (Vc), the diffusing capacity of the alveolocapillary membrane (Dm), and the transfer capacity of the lungs for carbon monoxide per unit alveolar volume (KCO) were observed 1 week after HILP. Eight weeks after HILP, they returned to pretreatment value. Alterations in lung functions were not related to the maximum systemic TNF level. In conclusion, disturbances in pulmonary functions are observed in patients after HILP with TNF and melphalan. These disturbances, which are probably partly caused by high systemic TNF levels, are reversible and would not preclude administration of systemic TNF in high doses.

Topics: Adult; Aged; Arm; Breast Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Hyperthermia, Induced; Leg; Male; Mastectomy; Melanoma; Melphalan; Middle Aged; Respiratory Function Tests; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

The optimal dosing schedule for melphalan therapy of recurrent malignant melanoma in isolated limb perfusions has been examined using a physiological pharmacokinetic model with data from isolated rat hindlimb perfusions (IRHP). The study included a comparison of melphalan distribution in IRHP under hyperthermia and normothermia conditions. Rat hindlimbs were perfused with Krebs-Hen-seleit buffer containing 4.7% bovine serum albumin at 37 or 41.5 degrees C at a flow rate of 4 ml/min. Concentrations of melphalan in perfusate and tissues were determined by high performance liquid chromatography with fluorescence detection. The concentration of melphalan in perfusate and tissues was linearly related to the input concentration. The rate and amount of melphalan uptake into the different tissues was higher at 41.5 degrees C than at 37 degrees C. A physiological pharmacokinetic model was validated from the tissue and perfusate time course of melphalan after melphalan perfusion. Application of the model involved the amount of melphalan exposure in the muscle, skin and fat in a recirculation system was related to the method of melphalan administration: single bolus > divided bolus > infusion. The peak concentration of melphalan in the perfusate was also related to the method of administration in the same order. Infusing the total dose of melphalan over 20 min during a 60 min perfusion optimized the exposure of tissues to melphalan whilst minimizing the peak perfusate concentration of melphalan. It is suggested that this method of melphalan administration may be preferable to other methods in terms of optimizing the efficacy of melphalan whilst minimizing the limb toxicity associated with its use in isolated limb perfusion.

Topics: Animals; Antineoplastic Agents, Alkylating; Area Under Curve; Chemotherapy, Cancer, Regional Perfusion; Disease Models, Animal; Dose-Response Relationship, Drug; Hindlimb; Male; Melanoma; Melphalan; Neoplasm Recurrence, Local; Rats; Rats, Wistar; Tissue Distribution

Isolated hyperthermic cytostatic limb perfusion has been established as an efficient procedure for the treatment of malignant melanoma of the limbs. However, perfusions of the upper extremities are generally carried out much less frequently than would be expected given the distribution pattern of malignant melanoma and sarcoma. Thus, isolated descriptions of treatment results for perfusion of the upper extremities are not available. Between 1991 and 1994, arm perfusions using melphalan 1.0 mg/kg body weight were given to 14 patients with malignant melanoma, using the standardized method of perfusion described herein. Within an average observation period of 34.9 months (range, 12-65 months), 11 (78.7%) of the 14 patients who had M.D. Anderson stage II-IV melanoma remained free of local recurrence. In fact, 10 (71.6%) of the patients were still alive at the end of the observation period. None of the 14 patients showed any systemic adverse effects, although 1 patient developed a lymphedema 32 months after perfusion and 2 patients showed a postoperative temporary neurologic deficit. These results demonstrate that isolated perfusion of the upper limb with heat and melphalan under standardized conditions remains the treatment of choice for melanoma of the arm, as for melanoma of the leg, without a higher rate of complications.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Arm; Chemotherapy, Cancer, Regional Perfusion; Extracorporeal Circulation; Female; Humans; Hypothermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Treatment Outcome

During isolated limb perfusion (ILP) severe metabolic impairment with a subsequent alteration in oxygen consumption can be observed. The mechanisms responsible for this may be extracorporeal circulation, hyperthermia, and application of cytostatic drugs and cytokines. Thirty-three patients underwent ILP with rhTNF alpha and melphalan for melanoma or soft-tissue sarcoma. Cardiopulmonary monitoring consisted of arterial and mixed venous blood-gas analysis and a Swan-Ganz catheter was inserted after induction of general anesthesia prior to any surgical intervention. Arterial (SaO2) and mixed venous (SvO2) oxygen saturation, serum lactate and end-expiratory CO2 concentration were determined peri- and postoperatively for 72 h. Oxygen supply and consumption rates were measured systemically (DO2I, VO2I) and in the extracorporeal circuit ('DO2I, 'VO2I). For statistical analysis we used the t-test. During extracorporal circulation an increase of DO2I and VO2I was observed. A slight increase of lactate values began during the wash-out phase. Immediately after reperfusion. DO2I, VO2I and lactate increased significantly with normalization until the 2nd postoperative day. SaO2 and SvO2 remained unchanged. A significant correlation between regional toxicity and the postoperative maximum of serum lactate values was found. The increase of DO2I and VO2I in the tissues during ILP and after reperfusion was achieved by a significant increase in cardiac output while the oxygen extraction rate was not altered. Elevation of lactate values after reperfusion and the increase in oxygen utilization might be due to oxygen depletion in the perfused limb. This could contribute to the development of lactacidosis or rhabdomyolysis. Therefore, to minimize toxicity it seems to be mandatory to measure adequate tissue oxygen supply during ILP.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Carbon Dioxide; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Humans; Hyperthermia, Induced; Lactic Acid; Male; Melanoma; Melphalan; Middle Aged; Oxygen; Oxygen Consumption; Reperfusion Injury; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

We have characterized the relative dispersion of vascular and extravascular markers in the limbs of three patients undergoing isolated limb perfusions with the cytotoxic melphalan for recurrent malignant melanoma both before and after melphalan dosing.. A bolus of injectate containing [51Cr] labelled red blood cells, [14C]-sucrose and [3H]-water was injected into an iliac or femoral artery and outflow samples collected at 1 s intervals by a fraction collector. The radioactivity due to each isotype was analysed by either gamma [51Cr] or beta [14C and 3H] counting. The moments of the outflow fraction-time profiles were estimated by a nonparametric (numerical integration) method and a parametric model (sum of two inverse Gaussian functions).. The availability, mean transit time and normalised variance (CV2) obtained for labelled red blood cells, sucrose and water were similar before and after melphalan dosing and with the two methods of calculation but varied between the patients.. The vascular space is not well-stirred but characterized by a CV2 similar that reported previously for in situ rat hind limb and rat liver perfusions. A flow-limited blood-tissue exchange was observed for the permeating indicators. Administration of melphalan did not influence the distribution characteristics of the indicators.

Topics: Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local

This retrospective study evaluated the benefit of using tumor necrosis factor (TNF) and melphalan administered via an isolated limb perfusion (ILP) in a series of patients with metastatic melanoma who failed initial ILP with chemotherapeutics.. Seventeen patients with extremity melanoma who underwent prior ILP with conventional chemotherapeutics (10 with melphalan; 4 with platinum; 2 with platinum, dacarbazine, thiotepa, actinomycin D, and nitrogen mustard; and 1 with thiotepa, actinomycin D, and nitrogen mustard) and had local recurrences were treated with a 90-minute isolated hyperthermic limb reperfusion with melphalan (10 mg/L limb volume) plus TNF (2-6 mg). Five prior ILPs were adjuvant and 12 were therapeutic.. Reperfusion was associated with an overall 94% response rate and a 65% complete response (CR) rate. Of the patients who failed an initial ILP with melphalan alone the overall response rate was 90% after the reperfusion with TNF and melphalan. In patients who failed an initial ILP with agents other than melphalan the CR rate was 100% after ILP with TNF and melphalan. TNF/melphalan isolated limb reperfusion was found to be more effective in terms of CR after initial ILP regimens that did not utilize melphalan (100% CR after nonmelphalan ILP vs. 50% CR after melphalan ILP [P = 0.04]). Regional toxicity was comprised of mild skin blistering and peeling in 47% of patients. One patient developed Grade 3 (based on National Cancer Institute Common Toxicity Criteria) skin necrosis, and one developed Grade 5 muscle and nerve toxicity, requiring an amputation.. Isolated limb reperfusion with TNF and melphalan can be performed safely with response rates similar to those of other trials of single perfusions. Repeat ILP using TNF and melphalan in patients with melanoma who have failed prior ILP with chemotherapeutics is justified. The utility of TNF (vs. melphalan alone) will be defined in ongoing Phase III trials.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Arm; Female; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Perfusion; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

The therapy of advanced melanoblastomas of the lower extremities is limited. Surgery alone is insufficient due to the extent of the tumor, the radicality of mutilating surgery is questionable because of the existing or suspected subclinical metastasis. To avoid amputation, regional chemoperfusion and simultaneous hemofiltration may be the choice of treatment. Between 1993 and 1995 the authors performed surgical chemotherapy on 21 occasions in 14 patients with advanced melanoblastoma of the lower limb. Partial remission of 4 to 11 months developed in 10 patients, 3 patients achieved subjective improvement for 3 to 6 months, 1 patient had disease progression. Simultaneous application of surgical regional chemotherapy and hemofiltration offers an alternative approach in the management of patients suffering from advanced melanoblastoma.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Doxorubicin; Follow-Up Studies; Hemofiltration; Humans; Infusions, Intra-Arterial; Leg; Lymphatic Metastasis; Melanoma; Melphalan; Remission Induction; Skin Neoplasms; Soft Tissue Neoplasms

The most promising developments in the field of isolated limb perfusion have centred around the use of the recombinant cytokine tumour necrosis factor-alpha (rTNF-alpha) in combination with melphalan. While the results of clinical trials are impressive, the exact antitumour mechanisms of rTNF-alpha and its role in combination with melphalan remain unclear. Our aim was to study the antitumour activity of human rTNF-alpha with or without the combination of melphalan in a nude mouse human melanoma xenograft system. In a first attempt to define the maximal tolerated single dose of rTNF-alpha in this setting, 15 animals were exposed to increasing doses of rTNF-alpha (60-2500 microg/kg intraperitoneally). All but one animal survived and tumour growth was not influenced by these single dose applications of rTNF-alpha even at the very high doses. Anti-tumour activity of repeated application of melphalan (three times 9 mg/kg in group 2 and three times 6 mg/kg in group 3), of rTNF-alpha alone (nine doses of 50 microg/kg in group 4), and of rTNF-alpha in combination with melphalan (nine doses of 50 microg/kg rTNF-alpha and three times 6 mg/kg melphalan in group 5) was further compared with non-treated animals (group 1). Tumour growth was significantly inhibited in all animals treated with melphalan (group 2, 3 and 5), but was not decreased in animals treated with rTNF-alpha alone (group 4). Mean final tumour volumes and mean tumour weight were not different in group 2 (789 +/- 836 mm3, 0.38 +/- 0.20 g), group 3 (1173 +/- 591 mm3, 0.55 +/- 0.29 g) and group 5 (230 +/- 632 mm3, 0.37 +/- 0.29 g), but significant lower than group 1 (3156 +/- 1512 mm3, 2.35 +/- 0.90 g) and group 4 (3228 +/- 1990 mm3, 2.00 +/- 1.16 g). There were no significant differences between high and low dose melphalan treatment and between melphalan treatment in combination with rTNF-alpha. Histological examination did not show differences between treated and non-treated animals besides slightly inhibited mitotic activities of tumour cells in melphalan-treated animals. While tumour growth of human xenotransplanted melanoma in nude mice could be inhibited by melphalan, we failed to demonstrate any antitumour effect of rTNF-alpha. The combination of melphalan and rTNF-alpha did not enhance the antiproliferative effect of melphalan alone. Human xenotransplanted tumours on nude mice might not be the ideal experimental setting for studies of potential direct antineoplastic activity of rTNF-alpha, and th

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Humans; Male; Melanoma; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Recombinant Proteins; Transplantation, Heterologous; Tumor Necrosis Factor-alpha

Melanoma recurring locoregionally after isolated limb perfusion (ILP) constitutes a therapeutic dilemma. Major amputation is a deterrent option for local control and palliation in these patients who have a rather poor prognosis. Little is known about the feasibility and efficacy of repeat ILP in these situations.. From 1978 to 1993, 28 patients with recurrent melanoma after ILP were retreated with various ILP procedures using melphalan. Eighteen patients underwent reperfusion by a single and four by a multiple normothermic schedule. Hyperthermia was applied in six repeat ILP procedures.. A complete remission was achieved in 14 (74 percent) of 19 patients with measurable disease, with a median limb recurrence-free interval of 11 months. A partial remission was obtained in one patient (5 percent). Two patients had no change of disease and two patients had progressive disease. In the remaining nine patients, all macroscopic tumor tissue was excised before or during the repeat ILP procedure. The median limb recurrence-free interval of these nine patients was 15 months. After a median follow-up period of 30 months after repeat ILP, seven (25 percent) of the 28 total patients were alive without disease. Acute regional tissue toxicity was more severe after repeat ILP than after the first procedure (p < 0.05). Long-term regional morbidity occurred in 11 percent of the patients.. A high complete remission rate can be obtained with repeat ILP using melphalan. However, the high limb recurrence rate and relatively short limb recurrence-free interval need improvement. Increased acute regional toxicity after repeat ILP can be explained by the use of more intensive schedules.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Feasibility Studies; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Palliative Care; Skin Neoplasms; Survival Rate

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Disease-Free Survival; Extremities; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Neoplasm Recurrence, Local; Reoperation; Skin Neoplasms; Survival Rate

Controversy exists concerning the optimal pO2 of the perfusate during isolated limb perfusion (ILP) with melphalan. Therefore we studied the implications of hyperbaric oxygen tensions in the perfusate. In 12 consecutive patients, subcutaneous pO2 (Continucath 1000), tissue and tumor pH, and blood gas values were monitored throughout the ILP procedure. ILP started with an oxygen flow through the bubble oxygenator which was set routinely at one half of the flow of the perfusate; 30 min before the end of ILP, the oxygen flow was tripled. Mean arterial pO2 before and during ILP (before and after increasing the oxygen supply) was 19.4, 25.5 and 49.4 kPa, respectively. Mean subcutaneous pO2 values before, during (before and after increasing the oxygen supply), and post-ILP, were 7.4, 10.1, 16.3, and 9.1 kPa, respectively. Tissue pH values in the subcutis and muscle decreased during routine oxygen supply (p = 0.001); muscle pH moved towards starting values after increase of the oxygen supply (p = 0.011). In 4 patients, tumor pH was recorded showing a rise after increasing the oxygen supply (from 7.10 to 7.22; p = 0.11). In conclusion, high pO2 in the perfusate improves muscle pH during ILP. However, a concomitant rise in tumor pH may unfavorably influence the therapeutic effect of ILP, as it has been shown that low pH increases the cytotoxicity of melphalan.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Gases; Humans; Hyperbaric Oxygenation; Lactates; Lactic Acid; Male; Melanoma; Melphalan; Middle Aged; Muscles; Oxygen Consumption; Pilot Projects; Sarcoma; Skin

Loco-regional or pelvic metastases from malignant melanoma (MM) of the lower limbs or pelvis are usually refractory to systemic chemotherapy, the limiting factor being systemic toxicity. An attempt to improve this low response rate using a novel loco-regional approach involving intra-arterial high dose chemotherapy with concomitant hemofiltration of the venous effluent of the pelvis, hence chemofiltration, was studied. Chemofiltration was performed in seven MM patients. The arterial catheter and the venous cannula were placed in the aorta and the inferior vena cava just distal to the renal vessels. High-dose melphalan (1 mg/kg) or cis-platinum (200 mg/m2) was injected into the arterial catheter. Blood was pumped out into the hemofiltration unit at a rate of 500-700 ml/min. The filtered blood was returned via a catheter placed in the superior vena cava. Despite the extensive fluid exchange (9,700-15,000 ml), the procedure was well tolerated. Out of six patients who remained with measurable disease, three had a partial response lasting 5-12 months, two had stabilization of their disease for 3 months, and one developed a rapid progression. Chemofiltration is feasible in MM patients and is a viable option in locally advanced or metastatic malignant melanoma confined to the limb or pelvis.

Topics: Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Cisplatin; Dose-Response Relationship, Drug; Female; Hemofiltration; Humans; Infusions, Intra-Arterial; Male; Melanoma; Melphalan; Middle Aged; Pelvic Neoplasms

The aim of the present study was to potentiate the cytotoxic effects of melphalan through pharmacological and physical modulators. The combination of the cytotoxic agent with ethacrynic acid, a glutathione-S-transferase pi (GST pi) inhibitor, or topotecan, a topoisomerase I inhibitor, or mild hyperthermia was investigated. The selected cell lines exhibited variable levels of expression of GST pi, DNA topoisomerase I and heat-shock proteins. Mild hyperthermia (42 degrees C) alone potentiated melphalan cytotoxicity, especially in the two cell lines exhibiting low basal levels of HSP70 expression. The combination of the GST inhibitor with melphalan resulted in a potentiation of drug cytotoxicity only in JR8 cells, one of the two cell lines which expressed high levels of GST pi mRNA and which were the less responsive to ethacrinic acid alone. A synergistic interaction between topotecan and melphalan was observed only in the cell lines expressing low levels of topoisomerase I even if all cell lines exhibited a comparable sensitivity to this agent. The results support an involvement of GST and DNA topoisomerase in cell defense and response to the alkylating agent. However, the variable potentiation of the cytotoxic effects of melphalan achieved in different cell systems suggests that factors other than the level of expression of the modulation target are responsible of such potentiation.

Topics: Antineoplastic Agents, Alkylating; Blotting, Northern; Camptothecin; Drug Interactions; Enzyme Inhibitors; Ethacrynic Acid; Humans; Melanoma; Melphalan; Temperature; Topoisomerase I Inhibitors; Topotecan; Tumor Cells, Cultured

Side effects and results of isolated hyperthermic extremity perfusion in malignant melanoma at the University of Cologne were reviewed: Severe local and systemic side effects (WHO grade III, IV) occurred in 3%, 5-year survival rates were 100% in TNM stage I patients (n = 27), 88.7% in TNM stage II patients (n = 123), 46.4% in TNM stage III patients (n = 169) and 36.3% in TNM stage IV patients (n = 22). 5-year recurrence free survival rates were 100% in TNM stage I, 73.4% in TNM stage II, 20.8% in TNM stage III and in TNM stage IV 9.1%. Indication for extremity perfusion remains locoregional recurrent disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Child; Combined Modality Therapy; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Skin Neoplasms; Survival Rate

Hyperthermic isolated limb perfusion (ILP) with melphalan is an accepted method of treatment for advanced or recurrent melanoma on a limb. In a review of 124 patients who underwent 130 ILPs at the Sydney Melanoma Unit, the anaesthetic considerations are summarized. All patients received general anaesthesia. The level of monitoring is discussed and monitoring of the limb venous pressure is important to minimize major fluid shifts between the systemic vasculature and the vascular compartment of the isolated limb and extracorporeal circuit.

Topics: Adult; Aged; Aged, 80 and over; Analgesia; Antineoplastic Agents, Alkylating; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Perfusion

Systemic exposure to melphalan is minimized during isolated limb perfusion (ILP) by isolating a limb from the rest of the body. Consequently, there should be no toxicity to vital organs. At present systemic toxicity after ILP has not been studied in detail. Therefore, the incidence, nature and risk factors of systemic toxicity was retrospectively studied in 368 patients who underwent a single ILP with melphalan between 1978-1990. Some form of systemic toxicity occurred in 98 patients (27%). Nausea and vomiting after the 1st post-ILP day was seen in 73 patients (20%), and in seven (2%) treatment was required. Bone marrow depression was encountered in seven patients (2%): WHO grade II in five, and grade III in two. Miscellaneous systemic side-effects, including fever and minimal scalp hair loss, occurred in 19 patients (5%). Leakage from the isolated circuit to the systemic circulation was measured with radioactive tracers. Mean cumulative leakage during ILP was 0.9%. Systemic toxicity was not increased in patients with leakage greater than 1% or 5%. Female sex was associated with an increased incidence of systemic toxicity (P<0.05). Age over 60 years (P<0.05) and more severe acute regional toxicity (P<0.05) were correlated with nausea and vomiting. The miscellaneous systemic side-effects were more frequently encountered in women than in men (P<0.05). In conclusion, systemic toxicity was rarely severe, with nausea and vomiting being the most frequently encountered side-effects. Age over 60 years, female sex and more severe acute regional toxic reactions were correlated with an increased incidence of systemic side-effects. Systemic leakage during ILP was not associated with toxicity, probably due to the low incidence of significant leakage.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Sex Factors

Tumor necrosis factor (TNF) induces rapid necrosis in a variety of experimental neoplasms. However, its clinical application is limited by life-threatening systemic toxicity. Isolated limb perfusion (ILP) enables administration of large doses of TNF and cytotoxic drugs directly to the affected limb, avoiding systemic toxicity. We describe our experience in 20 consecutive patients (10 with melanoma and 10 with soft tissue sarcoma) treated with high-dose TNF and melphalan via ILP. ILP was performed via the external iliac (10 cases), femoral (2), popliteal (5) or brachial (3) vessels. Patients received 3-4 mg TNF to an upper, and 1-1.5 mg/kg to a lower extremity. Isolation efficiency was determined by injection of radiolabelled albumin. The procedure was successful in all 20 patients. Local complications included wound infection in 6 cases and hematoma in 2. 1 patient developed sepsis secondary to extensive necrosis of a large, secondarily infected tumor. The first 6 patients who underwent high-flow perfusion experienced systemic side-effects, mainly hypotension. These side-effects were eliminated when low-flow perfusion was introduced. The response rate was 100%. In the sarcoma group, 5/10 had complete response, and 5 partial response. Amputation or mutilating surgery was avoided in 9/10. Of the 10 with melanoma, 7 had complete, and 3 partial response. We conclude that administration of TNF via ILP is a safe and effective modality for treating advanced neoplasms of the limbs.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melanoma; Melphalan; Middle Aged; Recombinant Proteins; Sarcoma; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Oxygen; Partial Pressure; Polarography; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

We previously reported that combined treatment with melphalan and mild hyperthermia (1 h at 42 degrees C) caused a synergistic cytotoxic effect in JR8 melanoma cells, paralleled by a stabilisation of a melphalan-induced G2-phase cell block. In this study, we investigated the effect of melphalan and hyperthermia on proteins that regulate G2-M transition. Neither hyperthermia nor melphalan at a concentration of 2.5 micrograms ml-1, which had no antiproliferative effect at 37 degrees C, interfered with cyclin B1 expression or p34cdc2 kinase activity. At a concentration of 8.5 micrograms ml-1, which reduced cell growth by 50% at 37 degrees C, melphalan inhibited p34cdc2 kinase activity as a consequence of an increased tyrosine phosphorylation of the protein. A similar inhibitory effect on p34cdc2 kinase was obtained when the lowest melphalan concentration (2.5 micrograms ml-1) was used under hyperthermic conditions. Our results indicate that thermal enhancement of melphalan cytotoxicity could be mediated at least in part by an inhibition of p34cdc2 kinase activity, which prevents cell progression into mitosis.

Topics: Antineoplastic Agents, Alkylating; CDC2 Protein Kinase; Cell Division; Combined Modality Therapy; Cyclin B; Cyclin B1; Cyclins; G2 Phase; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Tumor Cells, Cultured

The three dosimetric schedules currently used in isolated limb perfusion with melphalan for malignant melanoma of the lower limb were compared in a series of 51 patients. The doses prescribed by each of the three methods (based on total body weight (TBW), limb tissue volume (LTV) and total blood volume in the perfusion circuit (TBV)) were calculated for all patients and were then compared using Wilcoxon's signed-rank test. This revealed that the method based on TBV consistently prescribed much lower doses of drug than either of the other two methods. Pharmacokinetic profiles of melphalan obtained by HPLC analysis of blood samples during the procedure also showed that the method did not reliably predict the concentration of melphalan achieved in the perfused limb. The dosimetric schedule based on LTV prescribed slightly higher doses than that based on TBW. However, the technique is more difficult to practise due to the problems of measuring the limb volume by immersion. We conclude that the dosimetric schedule based on TBW is the most appropriate by virtue of its simplicity, the high doses of melphalan which it prescribes, and the well-controlled toxicity which it produces.

Topics: Antineoplastic Agents, Alkylating; Blood Volume; Body Weight; Chemotherapy, Cancer, Regional Perfusion; Drug Administration Schedule; Humans; Leg; Melanoma; Melphalan; Skin Neoplasms

Isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan was carried out in 21 patients with regionally metastatic malignant melanoma of the limbs. The observed response rate was 65% complete and 15% partial remission. These results warrant further investigation of ILP with TNF and melphalan vs ILP with melphalan alone in a prospective randomised multicenter trial.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Extremities; Female; Humans; Male; Melanoma; Melphalan; Neoplasm Recurrence, Local; Neoplasm Staging; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

Chemotherapy for melanoma results in low response and must be reinforced with sensitizer compounds. We believed that azelaic acid (AZA) could modulate melanomas' resistance to antineoplastics. Therefore we tried to compare in vitro treatment with antineoplastics alone versus AZA treatment followed by antineoplastics. We carried out MTT assays to evaluate the cytotoxicity of melphalan, lomustine (CCNU), fotemustine, and 4-Hydroxyanisole (4-HA) on three melanoma lines (B16F10, SK-MEL-28, and SK-MEL-1), and the modulating effect of pretreatment with AZA (1 mM). AZA showed a dose-dependent antineoplastic activity on the three lines. Melphalan was the most active drug followed by CCNU, fotemustine, and 4-HA. The most sensitive line was B16F10 and the least sensitive was SK-meL-1. Previous treatment with AZA of B16F10 reinforced the effect of melphalan (2.5 times), CCNU (10 times), and fotemustine (14 times); whereas for SK-MEL-28 and SK-MEL-1, only the cytotoxicity of CCNU and fotemustine increased. An antagonist effect was produced by 4-HA on all three lines. We concluded that AZA enhances in vitro cytotoxicity of CCNU and fotemustine.

Topics: Animals; Anisoles; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Cell Differentiation; Cell Division; Dicarboxylic Acids; Dose-Response Relationship, Drug; Drug Synergism; Humans; Lomustine; Melanoma; Melphalan; Mice; Microscopy, Electron, Scanning; Monophenol Monooxygenase; Tumor Cells, Cultured; Vacuoles

Subungual melanoma is rare and experience in treating this condition with isolated limb perfusion is limited. Between 1985 and 1990, 24 patients were treated by digital amputation and isolated limb perfusion with melphalan and mild hyperthermia. The disease was staged according to the M.D. Anderson classification: stage I (17 patients), stage IIIA (one), stage IIIB (two) and stage IIIAB (four). Thirteen lesions were on the foot and 11 on the hand. Seven patients have developed locoregional recurrence. The estimated overall 2- and 5-year probabilities of survival were 77 and 46 per cent respectively, while for disease-free survival the rates were 58 and 51 per cent. When these results were compared retrospectively with those in 111 patients treated by amputation alone, no significant difference in survival was demonstrated. This experience suggests that isolated limb perfusion with melphalan and mild hyperthermia confers no additional survival benefit over appropriate surgery.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Nail Diseases; Neoplasm Recurrence, Local; Neoplasms; Proportional Hazards Models; Prospective Studies; Survival Rate

Topics: Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Humans; Melanoma; Melphalan; Neoplasms, Multiple Primary; Recombinant Proteins; Skin Neoplasms; Tumor Necrosis Factor-alpha

Topics: Animals; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Humans; Interferon-gamma; Melanoma; Melphalan; Mice; Models, Biological; Recombinant Proteins; Sarcoma; Treatment Outcome; Tumor Necrosis Factor-alpha

Twenty-nine stage IIIA/B melanoma patients treated by isolated limb perfusion (ILP) with a high dose of recombinant human tumour necrosis factor alpha (rHuTNF alpha), interferon gamma (IFN gamma), and melphalan were histologically documented with emphasis on therapy-induced changes of the tumour vasculature. Sequential biopsies were taken at various intervals before and after the treatment to compare the morphological change. In order to visualize microvascular changes, immunostaining was performed for von Willebrand factor (VWF), type IV collagen, alpha-smooth muscle actin, endothelial antigen PAL-E, tissue factor, CD41 (thrombocyte marker), and fibrin. In biopsies prior to perfusion, necrosis, haemorrhage, and fibrin thrombi were not found. Within 3 h following triple combination therapy, a change in the distribution of VWF staining occurred, from a discrete endothelial pattern in the untreated lesions to a fuzzy perivascular and subepidermal pattern in the treated lesions. Within 24 h, this was accompanied by intravascular thrombocyte aggregation and erythrostasis, in the absence of tissue factor and fibrin deposits. These findings indicate that the thrombocyte aggregation observed is not caused by local procoagulant activity, but is rather the result of the therapy-associated vascular damage or haemostasis. Although it is difficult to derive the dynamics of this process from static images, we assume that TNF alpha induced endothelial cell damage, leading to VWF release. Release VWF may play a role in the adhesion between thrombocytes and the damaged endothelium or the denuded subendothelium. As a consequence, the blood flow is impaired, leading to congestion and oedema, compatible with an early stage of haemorrhagic infarction.

Topics: Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Humans; Interferon-gamma; Melanoma; Melphalan; Platelet Aggregation; Recombinant Proteins; Skin Neoplasms; Tumor Necrosis Factor-alpha; von Willebrand Factor

The aim of this study was to investigate the role of mild hyperthermia (39-40 degrees C) in isolated cytostatic perfusion for patients with recurrent melanoma of the extremities. A total of 218 patients treated with mild hyperthermic perfusion was compared to 166 patients perfused under controlled normothermic conditions (37-38 degrees C). Only patients whose lesions had been excised before or at the moment of perfusion were eligible for this study. A variety of prognostic factors was controlled for in a Cox proportional hazards analysis. The application of mild hyperthermia did not influence limb recurrence-free interval nor survival (corrected P values 0.46 and 0.18, respectively). In this retrospective comparative study, no benefit for mild hyperthermia in regional isolated perfusion could be identified.

Topics: Adolescent; Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Retrospective Studies

To describe the systemic effects of high-dose recombinant tumor necrosis factor alpha (rTNF-alpha), recombinant interferon gamma (rIFN-gamma), and melphalan administered through hyperthermic isolation perfusion of the limbs (IPL) in patients with melanoma and malignant soft-tissue tumors.. The clinical, hemodynamic, and biologic parameters were recorded after IPL during the postoperative period.. Surgical intensive care service of a 1,000-bed tertiary university medical center.. Nineteen patients referred to a pluridisciplinary Center for Oncology after relapse of regionally advanced melanoma or soft-tissues tumors, included in a phase 2 therapeutic study.. Major systemic and hemodynamic changes were observed after IPL in all patients. Ninety-four percent (17/18) of the evaluable patients presented a shock unresponsive to fluid challenge, requiring the continuous perfusion of vasopressors, inotropic agents, or both. Analysis of hemodynamic data showed two distinctive patterns: a pure distributive shock in nine patients requiring norepinephrine, and a mixed distributive and cardiogenic shock in eight patients requiring vasopressor and inotropic agents. The oxygen parameters were characterized by an increase in both the delivery and the uptake of oxygen, with a prolonged reduced oxygen extraction ratio for most patients. The other observed effects were as follows: transient bilateral or mixed pulmonary infiltrates in all patients; some hematologic disturbances in 83% of patients; infection requiring a modification of the antibiotic prophylaxis in 61% of patients; and some liver toxic reactions in 50% of patients. Very high systemic TNF-alpha serum bioactivity was found in 12 patients for whom serum samples were available, indicating an early and important rTNF-alpha leakage from the IPL. No correlations could be found between the levels of TNF-alpha and the observed systemic effects. Despite the severity of the hemodynamic disturbance, no patient died.. Major systemic effects, consisting mainly in cardiovascular, respiratory, and hematologic disturbances, were observed in patients after IPL with high-dose of rTNF-alpha. The likely explanation for these observations is an early rTNF-alpha leakage related to inadequate IPL technique. These data show that the iatrogenic administration of high circulating TNF levels lead to a "septic shock-like" syndrome without resulting in lethal organ dysfunction.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials, Phase II as Topic; Extremities; Hemodynamics; Humans; Interferon-gamma; Melanoma; Melphalan; Recombinant Proteins; Retrospective Studies; Sarcoma; Shock, Septic; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

We evaluated the in vitro cytotoxic effects of combined human tumour necrosis factor alpha (TNF), human interferon gamma (IFN-gamma), melphalan (L-PAM) and hyperthermia (HTX) on human melanoma cell lines using the crystal violet assay. HTX (40 degrees C, 1 h) alone had no effect. The responses of the cell lines to TNF were in the rank order of 939 cells > 987 > 284 > C8161 > 852 > A2058 approximately 0, and all displayed shallow dose-response curves; no significant thermal enhancement of TNF cytotoxicity was apparent with this heat dose. All cell lines were sensitive to L-PAM, with 284 cells being the most sensitive; HTX caused only slightly increased sensitization to L-PAM. The combination of TNF and L-PAM resulted in generally subadditive or additive cytotoxicity, with or without HTX. The response to IFN-gamma alone was heterogeneous; the 939, 284 and 852 cell lines were sensitive to a dose as low as 20 ng/ml, whereas the 987 line was resistant to 2.0 micrograms/ml, even with HTX. IFN-gamma enhanced the response to TNF only of the TNF-resistant A2058 cell line, but there was no enhancement of the response to L-PAM for any line. Thus, this tetramodality combination achieved generally subadditive or additive cytoxicity in vitro.

Topics: Cell Survival; Combined Modality Therapy; Dose-Response Relationship, Drug; Humans; Hyperthermia, Induced; Interferon-gamma; Melanoma; Melphalan; Skin Neoplasms; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

An established human melanoma cell line was treated with several concentrations of three antineoplastic drugs: melphalan (0.016, 0.032, 0.16 microns), CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea) (0.04, 0.21, 0.42 microM), and 4-OHA (4-hydroxyanisole) (4.01 x 10(-4), 1.20 x 10(-3), 2.4 x 10(-3) microM), and the effects on cell growth and viability were compared. 24 hours after treatment, 4-OHA (ID50 = 2.4 x 10(-3) microM) was more cytotoxic than melphalan (ID50 = 0.016 microM) and CCNU (ID50 = 0.21 microM). However, after 96 hours exposure, the most effective drug was CCNU (growth rate = -1.277), which caused the death of the culture. This was followed by melphalan (growth rate = -1.024) and finally 4-OHA (growth rate = -0.69). Similar ultrastructural cell injuries were observed after the use of the three drugs: the dilation of endoplasmic reticulum vesicles and the nuclear membrane; mitochondria swelling; and the existence of lamellar structures and cytoplasmic vacuoles.

Topics: Anisoles; Antineoplastic Agents; Cell Division; Cell Line; Cell Survival; Drug Screening Assays, Antitumor; Humans; Lomustine; Melanocytes; Melanoma; Melphalan; Microscopy, Electron; Tumor Cells, Cultured

To determine the influence of acute regional toxic reactions on the incidence and characteristics of long-term morbidity after regional isolated perfusion with melphalan.. Retrospective study.. The Amsterdam and Rotterdam perfusion centers, the Netherlands.. All patients with melanoma who were treated between 1978 and 1990 and had a minimum follow-up of 1 year after perfusion (n = 367).. Fifty-four patients (15%) had perfusion of the upper limb, 313 (85%) had perfusion of the lower limb, and 164 patients (45%) underwent regional lymph node dissection at the time of perfusion.. Incidence and characteristics of morbidity 1 year after perfusion and the influence of acute regional toxic reactions on long-term morbidity.. One hundred sixty patients (44%) showed some degree of objective or subjective morbidity; most (104 [28%]) had lymphedema. Other long-term morbidity consisted of muscle atrophy or fibrosis (42 [11%]), limb malfunction (55 [15%]), neuropathy (13 [4%]), pain (28 [8%]), and recurrent infection (11 [3%]). Miscellaneous complications were seen in 14 patients (4%). Seventy-one patients (19%) had more than one complication. Acute regional toxic reactions had a statistically significant effect on the incidence of long-term morbidity (P < .01). Moderate to severe acute regional toxic reactions were strongly linked to the occurrence of muscle atrophy or fibrosis (P < .001) and limb malfunction (P < .001). Regional lymph node dissection was statistically significantly related to lymphedema (P = .05).. Improvement of the perfusion technique should be pursued in an effort to reduce acute regional toxic reactions, and thereby long-term morbidity, without compromising the therapeutic effect.

Topics: Adult; Aged; Aged, 80 and over; Chemotherapy, Cancer, Regional Perfusion; Drug Hypersensitivity; Extremities; Female; Humans; Lymphedema; Male; Melanoma; Melphalan; Middle Aged; Morbidity; Muscular Atrophy; Skin Neoplasms

Recombinant tumor necrosis factor alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the effective dose in animals. Isolated perfusion of the limbs (ILP) allows the delivery of high-dose rTNF alpha in a closed system with acceptable side effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In patients with melanoma-in-transit metastases (stage IIIA or AB), we obtained a 91% complete response rate compared with 52% after ILP with melphalan alone. In unresectable soft tissue sarcomas, this protocol was found to produce a 50% complete response with 87.5% limb salvage, since most tumors became removable. Release of nanograms levels of TNF alpha in the systemic circulation was evident, but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells, while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Clinical Protocols; Dose-Response Relationship, Drug; Extremities; Humans; Interferon-gamma; Melanoma; Melphalan; Pilot Projects; Recombinant Proteins; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

This paper reports clinical results of hyperthermal (41.5 degrees C) isolated perfusion of the lower limb for melanoma treatments in association with cytostatic drugs (L-PAM) in 10 consecutive patients. Attention is focussed on the toxicity effects in the search for a possible correlation between the treatment variables and toxicity. Careful heat administration techniques and thorough and accurate temperature monitoring have resulted in a uniform and closely controlled temperature distribution, allowing us to approach the limiting temperature value for possible damage both of the limb tissues and of the perfusate. Care was taken to avoid perfusate overheating (42 degrees C maximum). Local toxicity was observed between grades II and III. Systemic toxicity was of insignificant level. The clinical results show that high-temperature treatments with simultaneous administration of the cytostatic are feasible with acceptable toxicity. Further clinical investigations are recommended to ascertain the efficacy of the method.

Topics: Antineoplastic Agents, Alkylating; Blood Cell Count; Chemotherapy, Cancer, Regional Perfusion; Edema; Erythema; Female; Humans; Hyperthermia, Induced; Kidney; Leg; Liver; Male; Melanoma; Melphalan; Middle Aged; Temperature

We have investigated the effect of mild hyperthermia (42 degrees C) on the cytotoxic activity of a 1 h melphalan exposure in human melanoma cell lines. Hyperthermia did not affect cell growth of any culture, but it increased, to a different extent, melphalan cytotoxicity in all cell lines, with a reduction in the IC50 of 1.7 to 2.6-fold. Flow cytometric analysis showed that in normal temperature conditions melphalan caused S phase cell accumulation, which was evident only at 24 h in JR8, M14 and 2/21 cell lines and was still persistent at 72 h in 2/60 cells. Moreover, in all cell lines, the delay in S phase was paralleled, or followed, by an accumulation of cells in G2+M, which was transient in JR8 and M14 cells and persisted until 72 h in 2/21 and 2/60 melanoma clones. Hyperthermia caused a stabilization and prolongation of melphalan induced G2+M accumulation in JR8 and M14 cells. Conversely, in 2/21 and 2/60 clones, cell cycle perturbations induced by the drug were similar under normothermic or hyperthermic conditions. Specifically, in JR8, for which the maximum enhancement by hyperthermia on melphalan cytotoxicity was observed, cell accumulation in G2+M was still present 120 h after treatment. The accumulation was accompanied by an inhibition in the G2-M transition, as demonstrated by the significant reduction in the mitotic index of cells exposed to combined treatment compared to controls. Moreover, a bivariate distribution of cells stained for DNA and cyclin B1 showed that, following melphalan and hyperthermia treatment, the fraction of cyclin B1-expressing cells paralleled the fraction of G2+M phase cells, thus indicating that the inability of cells to enter mitosis was not ascribable to a reduction of cyclin B1 expression. On the whole, our results indicate that hyperthermia can stabilize the G2 accumulation induced by melphalan in human melanoma cells. Such a stabilization could contribute to the enhancement of melphalan cytotoxicity by heat, even though a strict correlation was not observed between the magnitude and persistence of the cell cycle perturbations and the extent of melphalan activity.

Topics: Cell Cycle; Cell Survival; Cyclin B; Cyclin B1; Cyclins; DNA; Flow Cytometry; G2 Phase; Hot Temperature; Humans; Kinetics; Melanoma; Melphalan; Mitosis; Multivariate Analysis; S Phase; Tumor Cells, Cultured

Regional isolated perfusion using tumor necrosis factor (TNF) shows significant promise for treatment of cancer which is limited to limbs or organs. The high toxicity of TNF requires very sensitive real time monitoring of leakage in order to avoid serious patient complications. Human serum albumin labeled with iodine-131 is used with an externally mounted and collimated NaI(Tl) detector to track the leakage of blood from the isolated perfusion blood circuit into the general systemic vascular space. Blood activity levels measured using the monitor demonstrated a very good correlation with blood serum samples taken concurrently with external monitoring. External monitoring can reduce the risks of perfusion leakage intraoperatively with the precision necessary to safely perform isolated perfusion using TNF.

Topics: Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Humans; Interferon-gamma; Liver Neoplasms; Melanoma; Melphalan; Monitoring, Intraoperative; Sarcoma; Serum Albumin, Radio-Iodinated; Tumor Necrosis Factor-alpha

Incidence, nature and cause of severe acute regional toxicity were studied in 181 patients who underwent normothermic (37-38 degrees C) or 'mild' hyperthermic (38-40 degrees C) isolated limb perfusion (ILP) with melphalan. The known risk factors for toxicity (sex, tissue temperature, blood gas values, isolation level and melphalan peak concentration) were analysed. Severe acute regional toxicity occurred in 30 patients (16%). The limb was painful, swollen, red and warm in 19, often with a smooth and glistening aspect. Blistering scattered over the extremity was seen in 11 cases. In another 11 patients, late blistering limited to the footsole or handpalm developed. Twenty-six patients with severe toxicity had undergone ILP at the iliac isolation level (p < 0.05). Sex and tissue temperature did not predict toxicity. Venous perfusate blood gas values were severely deteriorated in four patients; high calculated melphalan peak concentrations occurred in nine patients. Irreversible long-term morbidity as a sequence of severe toxicity occurred in 10 of the 30 patients. Only one of the 11 patients with late blisters limited to sole or palm developed long-term morbidity (p < 0.05). Thus, the only risk factor for severe acute regional toxicity that could be identified was iliac isolation level. However, in 27 of the 30 patients two or more risk factors were found.

Topics: Adult; Aged; Aged, 80 and over; Blister; Blood Gas Analysis; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Edema; Erythema; Extremities; Female; Humans; Hyperthermia, Induced; Incidence; Male; Melanoma; Melphalan; Middle Aged; Retrospective Studies; Risk Factors; Skin Neoplasms; Skin Temperature

Isolated limb perfusion with melphalan is a long-standing treatment for melanoma but the clinical conditions have not been subjected to a systematic evaluation. In order to establish optimal conditions for perfusion, three human melanoma cell lines were cultured with melphalan in vitro under conditions comparable to in vivo therapy. The most important findings were that: (a) 41.5 degrees C was synergistic for melphalan killing of three human melanoma cell lines; (b) prolonging the treatment time beyond 1 h had little additional toxicity; and (c) varying the initial pH of the culture medium had no effect. After 1 h of treatment, cells accumulated more melphalan at 41.5 degrees C than at 37 degrees C, relative to the extracellular concentration. A cell line (MM418) derived from a primary tumour was the most resistant of the three lines; pigmented or non-pigmented sublines were equally resistant. The A2058 line showed the lowest level of synergism with hyperthermia, and displayed a marked plateau at 10% of controls in the dose-response for survival, yet no melphalan-resistant subpopulation could be isolated. The implications of this work are that (a) enhanced cellular uptake of melphalan may account for hyperthermic synergism of melphalan; (b) varying conditions other than treatment time will be necessary to deal with the variation in resistance between tumours; and (c) repeated cycles of treatment may be needed for phenotypes such as A2058 where melphalan resistance appears to be based on an epigenetic mechanism.

Topics: Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Resistance; Drug Synergism; Extremities; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Skin Neoplasms; Temperature; Tumor Cells, Cultured

The authors present their 35-year experience with intra-arterial chemotherapeutic regional perfusion of 1139 patients with melanomas, using an extracorporeal oxygenated circuit and heart-lung apparatus.. Intra-arterial chemotherapy produces improved responses in many tumors. By isolating and sustaining the area with extracorporeal oxygenated circulation, high doses can be delivered to the tumor area, limited only by local toxicity. Drug levels up to 10 times those achieved by systemic administration are obtained.. Techniques for hyperthermic perfusion were developed for limbs, pelvis, head, neck, and skin of the breast. Melphalan (Burroughs Wellcome, Research Triangle Park, NC) was used in 753 patients. Combinations with melphalan or other drugs were used in remaining cases at temperature of 38 to 40 C for 30 to 60 minutes.. Chemotherapy perfusion followed by tumor excision or node dissection, was performed where indicated. The cumulative 10-year survival for patients with localized melanomas was 70%. For patients with local recurrences or satellites within 3 cm, survival was 61%. For those with regionally confined intransit tumors, survival was 30%; for those with regional node involvement, 38%; for those with intransit and nodal metastases, 16%; for those with distant metastases and perfusion--mainly to save functional limbs--survival was 7%. Multiple perfusions were performed in 158 patients with recurrent disease on 366 occasions. Patients with indolent regionally confined melanomas were benefited by prolongation of useful life.. Safe perfusion techniques are available for most anatomic regions. Increased chemotherapeutic doses are delivered to isolated areas limited only by local toxicity. Adjunct perfusion in poor prognosis stage I cases is useful in reducing local recurrence, and intransit or lymph node metastases. Regional perfusion reduces the need for major amputation. Multiple perfusion can be useful in treating recurrent chronic melanoma.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials as Topic; Combined Modality Therapy; Extracorporeal Membrane Oxygenation; Female; Humans; Lymphatic Metastasis; Male; Mechlorethamine; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Skin Neoplasms; Survival Analysis; Survival Rate; Thiotepa; Time Factors

The incidence of long-term (> or = 3 months) neuropathy in 350 melanoma patients treated with single normothermic or 'mild' hyperthermic perfusion with melphalan in the period 1978 to 1990 was studied. Long-term neuropathy was encountered in 14 patients; in 10/51 patients (20%) after perfusion at the axillary level and in 4/247 patients (2%) after perfusion at the iliac level. After brachial and femoro-popliteal perfusions no long-term neuropathy was observed. Neuropathy, mainly consisting of paresis/paralysis of the hand and/or fingers, anaesthesia, and/or paraesthesiae, improved over a mean period of 16 (3-43) months in eight patients, but three patients still had serious neuropathy one year after perfusion. In another six patients little improvement was seen and four died with permanent neuropathy. Acute regional toxicity after perfusion and the application of 'mild' hyperthermia did not seem to influence the incidence of long-term neuropathy. This complication is probably a result of the isolating Esmarch rubber bandage being applied too tightly during perfusion at a proximal level. At the axillary level, where the brachial plexus lacks the protection from enveloping tissues, nerve damage is especially prone to occur. We recommend applying this bandage no tighter than is necessary to maintain the isolation of the circuit. This implies meticulous surgical isolation of the vascular system and accurate monitoring of leakage.

Topics: Adolescent; Adult; Aged; Arm; Chemotherapy, Cancer, Regional Perfusion; Female; Fever; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Paralysis; Paresis; Peripheral Nervous System Diseases; Retrospective Studies; Sensation Disorders; Skin Neoplasms; Time Factors

In 14 consecutive patients with recurrent melanoma of the lower limb a total of 35 biopsies were taken at the end of perfusion treatment to assess melphalan tissue concentrations in tumour, skin/subcutis and muscle tissue. In tumour tissue (n = 12) the mean melphalan concentration was 6.8 micrograms g-1, which was significantly higher than that of healthy skin/subcutis (3.2 micrograms g-1; n = 10), but equal to that of muscle tissue (6.5 micrograms g-1; n = 13). The correlation between melphalan concentration in the tissues and the concentration in the perfusate was studied. The latter was assessed in the form of melphalan peak concentration and the area under the curve (AUC0-->60) of the melphalan concentration-time curve. Tumour concentration proved to be correlated linearly with AUC0-->60 (R = 0.6, P = 0.002) and muscle concentration with melphalan peak concentration (R = 0.8, P = 0.04). There was no relation between skin/subcutis concentrations and the perfusate parameters. Further research is warranted to study the relationship between melphalan tissue concentration, tumour response and regional toxicity.

Topics: Chemotherapy, Cancer, Regional Perfusion; Chromatography, High Pressure Liquid; Female; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Muscles; Skin; Skin Neoplasms

To date, little is known about prognostic factors for limb recurrence-free interval and survival in patients with recurrent melanoma of the limbs treated with regional isolated perfusion. Therefore, 216 such patients treated with normothermic perfusion using melphalan during the period 1978 to 1990 were analyzed for patient and tumor related variables using a Cox proportional hazard model. The five year limb recurrence-free interval was 52 percent. For stage II (n = 67), IIIA (n = 71) and IIIAB and IIIB (n = 78) disease separately, these percentages were 53, 56 and 47 percent. In stage II disease, patients with a local recurrence adjacent to scar or skin graft had a significantly better five year limb recurrence-free interval than patients with satellites (75 versus 33 percent; p = 0.0009). Prognostic factors for limb recurrence-free interval were--in order of importance--tumor tissue left in situ, number of previous limb recurrences and total tumor surface area. The overall five year survival rate was 42 percent. For stages II, IIIA and IIIAB and IIIB disease, these percentages were 57, 45 and 25 percent, respectively. There was no survival benefit for patients with a local recurrence. Prognostic factors for survival were, in order of importance, stage of disease, gender, age, Breslow thickness, Clark level of infiltration of the primary melanoma and the number of lesions forming the indication for perfusion. The results of this study will eventually further delineate indications for perfusion.

Topics: Adult; Arm; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Proportional Hazards Models; Survival Analysis; Texas; Time Factors

In order to gain some insight into the cause of acute regional toxicity after isolated perfusion using melphalan, 15 patient-related and perfusion-technique-related factors were tested in a logistic regression model. Acute toxicity was graded according to Wieberdink's grading system. In a group of 425 patients, 362 (85%) encountered no or slight toxicity with a grade I or II reaction, and 63 (15%) patients encountered more severe toxicity with a grade III, IV, or V reaction. Most patients were treated with a standard dose of 10 or 13 mg melphalan per liter of perfused tissue for leg and arm perfusions, respectively. Factors associated with a more severe toxicity reaction proved to be tissue temperatures of 40 degrees C or higher, female gender, a deterioration of the gas values of the venous perfusate during perfusion, and perfusion at a proximal level of isolation. Consideration of these prognostic factors may lead to a further decrease of acute regional toxicity in perfusion.

Topics: Adult; Analysis of Variance; Arm; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Hyperthermia, Induced; Leg; Logistic Models; Male; Melanoma; Melphalan; Middle Aged; Risk Factors; Skin Neoplasms

Four alpha-MSH drug conjugates have been synthesized, 2 C-terminal (Pep 3 and 4) and 2 central fragments (Pep 1 and 2), the latter being the 4-10 sequence known to be the main alpha-MSH-receptor-recognition site. Melphalan was introduced into each sequence at different locations. Their ability to recognize alpha-MSH receptors as well as their cytotoxic effects were compared in 3 cell lines: melanoma, carcinoma and fibroblast cells. Pep 1 and 2 were able to specifically bind to MSH receptors on melanoma cells by displacing labelled alpha-MSH from its binding sites at concentrations similar to the 4-10 heptapeptide sequence known to contain the main receptor-recognition site. They subsequently penetrate the cell, most probably by a receptor internalization mechanism, since about half of their effect could be inhibited by competition at the receptor level. Significant and selective cytotoxic effects to melanoma cells could be observed after only 2 hr exposure to the drug conjugates. Interestingly, these 2 conjugates, differing only in melphalan position, showed completely different cytotoxicity in terms of IC50 values, Pep 1 being 24 times more toxic to all cells; but the 2 were equally specific to melanoma cells. However, they both were less toxic to all cells than melphalan itself. Furthermore, Pep 1 and 2 were able to block the receptor and, unlike Pep 3 and 4, their cytotoxic effect could be significantly inhibited by an alpha-MSH agonist. Pep 3 and 4 were 5 to 10 times less toxic than melphalan to melanoma and carcinoma cells and 50 times less to fibroblast cells, and did not show any cell-type selectivity. They were less toxic than Pep 1 to melanoma and carcinoma cells by a factor of 2, but equally toxic to fibroblasts. In contrast, they were more toxic than Pep 2 to fibroblasts, melanoma and carcinoma by a factor of 3, 10 and 24 respectively. Our data strongly suggest a receptor-mediated cytotoxicity mechanism occurring with alpha-MSH central fragments in human melanoma cells due to the presence of alpha-MSH-specific receptors. This mechanism appeared to be both peptide- and cell-type-specific.

Topics: alpha-MSH; Carcinoma, Squamous Cell; Cells, Cultured; Drug Combinations; Drug Screening Assays, Antitumor; Fibroblasts; Humans; Melanoma; Melphalan; Molecular Sequence Data; Receptors, Pituitary Hormone; Skin Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured

At this time little is known about prognostic factors for tumor response and subsequent limb recurrence-free interval in patients suffering from advanced melanoma of the limbs who were treated with regional isolated perfusion.. A retrospective analysis was done, with a logistic regression model and a Cox proportional hazard analysis, looking at possible patient-, tumor-, and treatment-related prognostic factors in all 120 patients with advanced melanoma of the limbs who were treated with regional isolated perfusion with melphalan in the period 1978 to 1990 at our institutions.. Complete remission was achieved in 65 patients (54%) with a median duration of 9+ months (range, 1 to 97+ months), and partial remission was seen in 30 patients (25%). Prognostic factors for complete remission were multiple versus single perfusion schedule, the absence of regional node involvement, and leg versus other tumor sites. The 3-year limb recurrence-free interval was 38%. Factors associated with this interval were one as opposed to more than one lesion, complete remission after perfusion, and female sex. Patients exhibiting complete remission after perfusion had a better overall 3-year survival rate than had patients without complete remission (60% vs 35%; p = 0.0012).. In the present study prognostic factors for tumor response and limb recurrence-free interval could be determined. A multiple perfusion schedule may be more effective in providing complete remission in patients undergoing regional isolated perfusion than single perfusions are.

Topics: Adult; Aged; Aged, 80 and over; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Prognosis; Retrospective Studies; Survival Rate

Glutathione transferases (GSTs) are enzymes involved in the resistance of tumor cells to bifunctional alkylating cytostatic drugs. We investigated the melphalan sensitivity together with activity and cellular concentration of GST isoenzymes of human melanoma cell line RPMI 8322 in different phases of the cell cycle. By centrifugal elutriation three cell fractions containing different proportions of cells in the G1 phase were isolated. Melphalan sensitivity was estimated by the colony formation assay. The cell fraction with the largest proportion of G1 cells was more sensitive to the drug than the fractions enriched in S and G2 cells. The GST activity of the cell fractions was measured with 1-chloro-2,4-dinitrobenzene (CDNB) as substrate and the concentrations of GST P1-1, GST M1-1 and GST A1-1 were quantitated by use of isoenzyme-specific ELISA. The results show that there were less GST activity and lower GST P1-1 and A1-1 concentrations in the G1 cell enriched fraction, demonstrating a cell cycle dependence of GST expression. Thus, the cell fraction most sensitive to melphalan had the highest proportion of G1 cells and displayed the lowest GST activity, suggesting that the cell cycle dependent sensitivity to melphalan may at least partially depend on the expression of GSTs.

Topics: Cell Cycle; Cell Fractionation; Centrifugation; Drug Screening Assays, Antitumor; Glutathione Transferase; Humans; Isoenzymes; Melanoma; Melphalan; Subcellular Fractions; Tumor Cells, Cultured

94 patients with malignant melanoma or soft tissue sarcoma of the extremities were submitted to isolated cytostatic limb perfusion. With palliative indication for treatment of malignant melanoma, the 5 year survival rate was 25% after perfusion with methotrexate and 50% after perfusion with melphalan. The adjuvant perfusion showed very good results, too. Furthermore, the authors report on their first experiences in regional cytostatic perfusion of soft tissue sarcoma and bone sarcoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dose-Response Relationship, Drug; Doxorubicin; Extremities; Follow-Up Studies; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Methotrexate; Palliative Care; Sarcoma; Sarcoma, Ewing; Skin Neoplasms; Soft Tissue Neoplasms; Survival Rate; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Combined Modality Therapy; Dacarbazine; Dactinomycin; Evaluation Studies as Topic; Extremities; Humans; Hyperthermia, Induced; Incidence; Melanoma; Melphalan; Neoplasm Metastasis; Osteosarcoma; Rhabdomyolysis; Skin Neoplasms; Treatment Outcome

In order to avoid complications after regional chemotherapy (isolated hyperthermic perfusion) of the extremities, rapid measurement of blood leakage from the extracorporeal to the systemic circulation is important. A method using technetium-99m in vivo red blood cell (RBC) labelling is reported that provides results within 3 min. Blood samples drawn from the systemic and the extracorporeal circulation were measured for 99mTc activity using a mobile well counter, and the leakage values calculated. The mean result was 7.6% +/- 6.5%/15 min (n = 209). The corresponding flow rate was 100.2 +/- 85.7 ml/15 min (mean +/- SD). The values for isolation perfusion of the upper and the lower extremities are compared. The leakage results using 99mTc RBC labelling were correlated with other blood pool markers. Iodine-125 human serum albumin and indium-113 m transferrin were administered in subgroups of 4 and 19 patients simultaneously. Using linear regression, the coefficient of correlation was 0.72 for 99mTc/113mIn and 0.58 for 99mTc/125I. Comparison with the alternatives suggests that the rapid method of leakage measurement after 99mTc RBC labelling can be considered one of the most practicable and reliable methods available.

Topics: Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Erythrocytes; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Radionuclide Imaging; Skin Neoplasms; Sodium Pertechnetate Tc 99m; Time Factors

Topics: alpha-MSH; Animals; Humans; Iodine Radioisotopes; Liver Neoplasms; Melanoma; Melanoma, Experimental; Melphalan; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Pilot Projects; Radionuclide Imaging; Receptors, Pituitary Hormone

Topics: alpha-MSH; Amino Acid Sequence; Cell Division; Fibroblasts; Humans; Kinetics; Melanoma; Melphalan; Molecular Sequence Data; Receptors, Pituitary Hormone; Structure-Activity Relationship; Thymidine; Tumor Cells, Cultured

From 1985 to 1990 43 patients with measurable locally inoperable or recurrent melanoma of the lower limb were treated according to a double perfusion schedule. The dose of melphalan given in the first perfusion was low (6 mg/l; 1 h; normothermic) in order to make it possible to carry out a second perfusion (9 mg/l; 1 h; normothermic) with a planned short interval of 3-4 weeks. The toxicity after the first perfusion was slight; after the second it was higher with a Wieberdink grade III reaction in 15 patients. A clinical complete remission (CR) was seen in 33 patients (77%) and a partial one in 6 patients. 16 of the 33 patients with a CR recurred in the perfused area after 5 months (range 1-29); the others remained limb recurrence-free (7-44+ months). The overall 3-year survival rate is 50%, 19 patients are alive with no evidence of disease. The double perfusion schedule shows a high CR rate, an acceptable toxicity and is technically feasible.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Remission Induction; Time Factors

A hazard of regional perfusion for melanoma is incomplete isolation, resulting in leakage of the cytostatic drug into the systemic circulation. Data were analysed retrospectively on 438 melphalan perfusions performed for melanoma of the extremities during the period 1978-1990; continuous isotopic measurement of systemic leakage was carried out. The cumulative systemic leakage after 60 min perfusion was 0.9 per cent (95 per cent confidence interval 0.7-1.1 per cent). Systemic leakage of > or = 1 per cent was detected in 12.6 per cent of perfusions, > or = 5 per cent in 6.2 per cent and > or = 10 per cent in 1.4 per cent. In 2.3 per cent of patients, systemic side-effects in the form of mild transient bone marrow depression occurred. Six variables related to the perfusion technique were assessed by multivariate analysis for their influence on systemic leakage. The level of isolation and diameter of the venous cannula emerged as significant factors. In addition, ligation of the internal iliac vein provided optimal isolation during iliac perfusion.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Marrow; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Retrospective Studies

From 1978 to 1990, 24 patients with subungual melanoma (MD Anderson Stage I, 17, Stage III, 7 patients) were treated with amputation of a digit and regional isolated perfusion with melphalan. The lesions were located on the big toe in 14 (58%) patients. Median delay in definitive treatment was 21 months, while 14 patients (58%) had been subjected to some form of inadequate treatment before correct diagnosis was made. Median follow-up for the living patients was 48 months. Overall 5-year survival was 54% (Stage I, 68%, Stage III, 19% (log-rank P = 0.003)). Sex and site of the lesion did not influence survival. Compared to literature data of patients treated by amputation alone, no improvement in survival could be demonstrated despite perfusion treatment. Moreover, two limb and 7 regional node recurrences were seen. The benefit of adjuvant perfusion in the treatment of Stage I subungual melanoma has not been demonstrated in this study. The results of prospective randomized trials in primary high-risk extremity melanoma have to be awaited.

Topics: Aged; Amputation, Surgical; Chemotherapy, Cancer, Regional Perfusion; Female; Fingers; Follow-Up Studies; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Nail Diseases; Neoplasm Staging; Survival Rate; Toes

The risk of cardiocirculatory disorders was investigated in 23 consecutive patients with high-risk melanomas, who had been treated with hyperthermal limb perfusion. Postoperatively, there was a rise in the pulmonary vascular resistance. In addition, 14 patients with vascular occlusive diseases (1-2b, Fontaine) showed intraoperatively an increasing amount of leakage of the extracorporeal circulation. Elevations of thromboxane and prostacyclin in excess of the norm caused by mechanical and thermic traumatization of blood in the heart lung machine were detected in 8 patients investigated during and after the perfusion procedure. Significant increase of cisplatin, one of the two cytostatic agents injected extracorporeally, could not be demonstrated in the blood of the systemic circulation by atomic absorption spectroscopy. Increased pulmonary and arterial pressure disorders were observed in the group with occlusive vascular diseases, caused by a rising rate of vascular collaterals to the body and the rising rate of thromboxane and prostacyclin in the body blood flow. We believe that it is necessary to monitor pulmonary arterial pressure during isolated limb perfusion, especially in patients with vascular occlusive disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arm; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Dose-Response Relationship, Drug; Female; Hemodynamics; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Regional Blood Flow; Sarcoma; Soft Tissue Neoplasms

The results of hyperthermic isolated limb perfusion therapy in 36 patients with stage II-IV malignant melanoma of the extremities are presented. With the technique employed, neither severe complications nor functional deficiencies attributable to the perfusion therapy were observed. The findings on follow-up for up to 36 months are comparable to those reported in the literature, with survival rates of about 90% for stage II and III patients and nearly 50% for stage IV patients. Thus, our technique appears to be beneficial, especially in respect of the very low rate of side effects.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Leg; Lymph Node Excision; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Skin Neoplasms

Since 1979, our treatment protocol for extremity melanoma includes wide local excision, regional lymph node dissection and hyperthermic limb perfusion. We report on the results of a follow-up of the patients treated in the first decade (n = 451). According to the UICC Classification of 1987, 4% of our patients were in stage I, 36% in stage II, 50% in stage III and 9% in stage IV. The respective 5-year survival rates were 93%, 91%, 49%, and 20%. We conclude that regional chemotherapy appears to be beneficial even for stage II patients, as 5-year survival rates of more than 90% can be achieved.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arm; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Combined Modality Therapy; Female; Humans; Leg; Lymph Node Excision; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Skin Neoplasms

From 1978 to 1990, 32 patients with Clark V melanoma were treated by wide excision of the primary and adjuvant regional isolated perfusion with melphalan. M.D. Anderson stage of disease was stage I in 22 and stage IIIb in 10 patients. Five-year survival rates were 58% and 27%, respectively. Seven patients developed a recurrence in the perfused limb [stage I, 2, stage IIIb, 5 patients (P = 0.03)], and 4 of 17 patients developed regional lymph node metastases. Of the well-known prognostic variables, only ulceration of the primary tumor significantly influenced survival (P = 0.03). We did not see any improvement in survival rates compared with literature data on nonperfused patients. In the absence of data on locoregional recurrence rates in nonperfused Clark V melanoma patients, we cannot say whether adjuvant perfusion diminished this risk. Therefore, the results of the prospective randomized EORTC/WHO trial in primary high-risk extremity melanoma have to be awaited.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Evaluation Studies as Topic; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prognosis; Skin Neoplasms; Treatment Outcome

Forty-two patients with measurable recurrent melanoma of the lower limb were treated according to a double-perfusion schedule.. To assess the advantage of this schedule compared with that of a single-perfusion treatment, a retrospective study was done comparing the 42 patients with 45 patients who had undergone a single-perfusion procedure. Both groups were well balanced with respect to patient and tumor characteristics. For patients treated with a double schedule, the dose of melphalan given in the first perfusion was low (6 mg/l; 1 hour; normothermic conditions) to make it possible to perform a second perfusion (9 mg/l; 1 hour; normothermic conditions) with a planned short interval of 3-4 weeks. In the single-perfusion group, a normothermic perfusion with 10 mg melphalan/l was performed.. The toxicity did not differ between the two treatment modalities. The response rate was significantly higher in the double-perfusion group (90% versus 68%; P = 0.007) because of a higher complete remission rate (76% versus 48%; P = 0.006). In both groups, approximately half of the patients with complete remission experienced disease recurrence in the perfused area (50% versus 52%). No significant differences were seen in the two groups in the regional node recurrence rate (33% in the double-perfusion group versus 20% in the single-perfusion group), distant recurrence rate (50% in the double-perfusion group versus 58% in the single-perfusion group), and their corresponding recurrence-free intervals. The overall 3-year survival rate was 46% in both groups.. In the patient groups studied, the double-perfusion schedule shows a better complete remission benefit than does the single-perfusion procedure. No differences are seen in limb, regional node, and distant recurrence rates in the two groups. Thus, additional improvement of the perfusion methodology is warranted.

Topics: Adult; Aged; Drug Administration Schedule; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Perfusion; Retrospective Studies

Resistance to alkylating agents has been correlated with cellular levels of reduced glutathione (GSH) and glutathione-S-transferase (GST). GSH is also involved in regulation of melanin synthesis. Therefore, we examined sensitivity to melphalan as a function of differentiation and GSH/GST levels in three human melanoma cell lines. The Me8 cell line, classified as undifferentiated on the basis of cell shape, absence of pigment, insignificant dopa oxidase activity and presence of inhibitors of dopa-melanin formation, showed the lowest GST activity among the cell lines investigated. GLL19 cells exhibited normal differentiation as indicated by the presence of dendrites, typical eumelanosomes, melanin granules and dopa oxidase activity. These cells showed the highest GSH content and the highest GST activity. The JUSO cell line showed incomplete differentiation, and its dopa oxidase and GST activities were intermediate between the Me8 and GLL19 cell lines. The sensitivity of melanoma cell lines to melphalan increased with their degree of differentiation; it was lowest for Me8, intermediate for JUSO and highest for GLL19. Dibutyryl cyclic AMP (dbcAMP) enhanced melphalan toxicity against Me8 cells. Depletion of intracellular GSH with buthionine sulphoximine (BSO) resulted in a three-fold increase in melphalan sensitivity in all three cell lines. Our results indicate that melphalan toxicity is related to cell differentiation and GSH status of melanoma cells. Based on the observed relationship between dopa oxidase, GSH/GST levels and drug toxicity, it is proposed that competition for the GSH pool between quinonoid melanin intermediates and melphalan could diminish drug conjugation and increase cytotoxicity.

Topics: Bucladesine; Buthionine Sulfoximine; Cell Differentiation; Cell Division; Cell Survival; Dose-Response Relationship, Drug; Eye Neoplasms; Glutathione; Glutathione Transferase; Humans; Kinetics; Melanins; Melanoma; Melphalan; Methionine Sulfoximine; Microscopy, Electron; Monophenol Monooxygenase; Neoplasm Staging; Skin Neoplasms; Tumor Cells, Cultured

Levels of melphalan (L-phenylalanine mustard) were measured in the tissues of tumour-bearing limbs treated by isolated limb perfusion (ILP). 41 samples of melanoma tissue, normal fat and skin were excised from 15 patients during ILP. A high performance liquid chromatography assay was used to measure melphalan concentrations. Levels of melphalan were higher in tumour than in fat (P < 0.01, Wilcoxon signed-ranks test), and not significantly different from levels in adjacent skin. In 2 cases there was significant regional toxicity in the treated limb, but this was not related to the levels of melphalan measured in the tissues of the limb. It is encouraging that the concentrations of melphalan which were achieved in large necrotic nodules by ILP were similar to those in well-perfused normal skin.

Topics: Adipose Tissue; Chemotherapy, Cancer, Regional Perfusion; Humans; Melanoma; Melphalan; Skin; Tissue Distribution

The existence of a distinct pool of glutathione in the nucleus of cultured human melanoma cells was demonstrated. Melanoma cell nuclei contained 13-35 pmol of glutathione/10(6) nuclei, or approximately 0.4-1.3% of the total cellular glutathione. This nuclear glutathione pool resisted depletion by buthionine sulfoximine, an agent that inhibits glutathione synthesis, but was rapidly and reversibly depleted by subtoxic concentrations of Adriamycin plus carmustine, two agents that promote oxidation of glutathione without permitting its regeneration through enzymatic reduction of glutathione disulfide. The ability of Adriamycin plus carmustine to deplete this small but significant pool of glutathione in the cell nucleus may explain why these agents potentiate the cytotoxic effects of the DNA-alkylating agent melphalan to a much higher degree than does buthionine sulfoximine at concentrations that are equipotent in depleting cytosolic glutathione.

Topics: Buthionine Sulfoximine; Carmustine; Cell Division; Cell Nucleus; Cytosol; Doxorubicin; Drug Synergism; Glutathione; Glutathione Disulfide; Humans; Melanoma; Melphalan; Methionine Sulfoximine; Oxidation-Reduction; Tumor Cells, Cultured

Buthionine sulfoximine (BSO), a specific inhibitor of glutathione synthesis, showed variable growth-inhibitory activity in different tumor cell lines with a high degree of inhibitory activity against melanoma-derived cell lines. A correlation between BSO growth-inhibitory effects and cellular glutathione peroxidase activity was observed. In contrast, no correlation was demonstrated between the response to BSO and cellular tyrosinase, gamma-glutamylcysteine synthetase, glutathione transferase, gamma-glutamyl transpeptidase, or glutathione reductase activities. BSO enhanced 3,4-dihydroxybenzylamine (3,4-DHBA) (fourfold) and melphalan (threefold) in vitro cytotoxic activity as determined by inhibition of DNA synthesis in human melanoma cells and this enhancement was dependent on the duration of exposure to drug. BSO demonstrated in vivo antitumor activity in B16 melanoma-bearing mice prolonging survival by 29% and in combination with 3,4-DHBA resulted in a slight (48% versus 38%) increase in life span as compared to 3,4-DHBA alone. The combination of BSO and melphalan, however, increased the life span of B16 melanoma-bearing mice by 170%, as compared to melphalan alone (80%). These studies demonstrate a unique in vivo antimelanoma activity of BSO.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Buthionine Sulfoximine; Dopamine; Glutathione Peroxidase; Humans; Hydrogen Peroxide; Melanoma; Melanoma, Experimental; Melphalan; Methionine Sulfoximine; Mice; Tumor Cells, Cultured

We report on a patient with simultaneous manifestation of two different side-effects of a cytostatic therapy, which have to be ascribed to cytotoxic influences of different intensity. In this 37-year-old woman, "Mees-like" transverse white bands appeared on all the nails on the left hand after isolated cytostatic perfusion of the left arm. The nails on the right hand and the feet remained free of visible changes. However, the low doses of cytostatic drugs shunted into the systematic circulation induced diffuse toxic hair loss.

Topics: Adult; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Dose-Response Relationship, Drug; Drug Eruptions; Female; Forearm; Humans; Melanoma; Melphalan; Nail Diseases; Skin Neoplasms

The rate of formation of the major glutathione conjugate of the antitumor alkylating agent melphalan can be directly measured by high pressure liquid chromatography. Rates of melphalan-glutathione conjugate formation were determined in the presence and in the absence of human melanoma cell homogenates, or cell fractions from various tissue sources, and the relative contributions of enzyme-catalyzed and nonenzymatic conjugate formation to the overall rates of conjugation were determined. Significant rates of conjugation were observed in the absence of any enzyme-containing cell fractions. These rates were not increased by the addition of melanoma cell homogenates, animal liver microsomes or human liver cytosol or microsomes, even though these preparations all enhanced the rate of conjugation of 1-chloro-2,4-dinitrobenzene. Animal liver cytosol contains enzymes that provided a significant contribution to the overall rate of melphalan conjugate formation. We conclude that although liver cytosol contains enzymes that significantly enhance the rate of glutathione conjugation with melphalan, in the case of the tumor cells studied, cellular glutathione S-transferase-catalyzed activity appears to be, at best, a very minor determinant of the overall rate of melphalan-glutathione conjugate formation.

Topics: Animals; Dinitrochlorobenzene; Glutathione; Guinea Pigs; In Vitro Techniques; Liver; Male; Melanoma; Melphalan; Mice; Mice, Inbred C57BL; Rabbits; Rats; Rats, Inbred Strains; Tumor Cells, Cultured

We describe melphalan pharmacokinetics in 26 patients treated by isolated limb perfusion (ILP). Group A (n = 11) were treated with a bolus of melphalan (1.5 mg kg-1), and in a phase I study the dose was increased to 1.75 mg kg-1. The higher dose was given as a bolus to Group B (n = 9), and by divided dose to Group C (n = 6). Using high performance liquid chromatography (HPLC) the concentrations of melphalan in the arterial and venous perfusate (during ILP) and in the systemic circulation (during and after ILP) were measured. Areas under the concentration time curves for perfusate (AUCa, AUCv) and systemic (AUCs) data were calculated. In all three groups the peak concentrations of melphalan were much higher in the perfusate than in the systemic circulation. The pharmacokinetic advantages of ILP can be quantified by the ratio of AUCa/AUCs, median value 37.8 (2.1-131). AUCa and AUCv were both significantly greater in Group B than in Group A (P values less than 0.01, Mann-Whitney). In Groups B and C acceptable 'toxic' reactions occurred but were not simply related to melphalan levels. Our phase I study has allowed us to increase the dose of melphalan to 1.75 mg kg-1, but we found no pharmacokinetic advantage from divided dose administration.

Topics: Arteries; Chromatography, High Pressure Liquid; Half-Life; Humans; Leg; Melanoma; Melphalan; Perfusion; Time Factors; Veins

The cytotoxic effects of the bifunctional DNA-reactive drugs cisplatin, mustine and melphalan were studied in two human melanoma cell lines, RPMI 8322 and A 375. A 375 cells were 3.0 times more sensitive to cisplatin and 1.5 times more sensitive to mustine than RPMI 8322 cells. In contrast, A 375 cells were less sensitive to melphalan than RPMI 8322 cells. The increased sensitivity of A 375 cells was parallelled by an increased induction of DNA interstrand crosslinks following exposure to cisplatin and mustine. After cisplatin exposure A 375 cells also showed higher levels of platinum-DNA intrastrand adducts than RPMI 8322 cells. The increased effect of cisplatin in A 375 cells was not due to an increased drug accumulation in these cells. The higher sensitivity of A 375 cells to cisplatin may be related to lower intranuclear levels of glutathione, compared to RPMI 8322 cell nuclei, while the sensitivity to mustine may depend on lower overall levels of glutathione than in RPMI 8322 cells.

Topics: Cell Line; Cell Survival; Cisplatin; DNA, Neoplasm; Glutathione; Humans; Mechlorethamine; Melanoma; Melphalan; Platinum; Tumor Cells, Cultured

Glutathione transferases are enzymes implied in the resistance of tumor cells to bifunctional alkylating cytostatic drugs. We have investigated the effect of the glutathione transferase inhibitor by ethacrynic acid on the cytotoxicity of melphalan to a human melanoma cell line (RPMI 8322) with a high level of glutathione transferase activity. Using 1-chloro-2,4-dinitrobenzene as substrate, ethacrynic acid was shown to inhibit the activity of purified human glutathione transferases, with 50% inhibition values of 1, 10, and 15 microM for transferase mu (class mu), transferase epsilon (class alpha) and transferase pi (class pi), respectively, all of which occur in RPMI 8322 cells. Ethacrynic acid at a concentration of 20 microM, which by itself was noncytotoxic, increased the cytotoxicity of melphalan to RPMI 8322 human melanoma cells approximately 2-fold. The induction of DNA interstrand cross-links by 40 microM melphalan was increased 1.4-fold by 30 microM ethacrynic acid. These results indicate that a potentiation of the cytotoxic effect of bifunctional alkylating agents can be achieved by inhibition of glutathione transferase and that the enhanced cytotoxicity may be caused at least in part by increased formation of drug-DNA adducts.

Topics: Cell Survival; Cross-Linking Reagents; Dose-Response Relationship, Drug; Drug Synergism; Ethacrynic Acid; Glutathione Transferase; Humans; In Vitro Techniques; Isoenzymes; Melanoma; Melphalan; Tumor Cells, Cultured

The kinetics of melphalan leakage into the peripheral blood were studied in 21 patients undergoing hyperthermic isolation perfusion of the upper or lower limb as an adjuvant treatment in high-risk melanoma; in 5 patients cisplatin was added. The melphalan concentrations in the peripheral blood rose predominantly during the first 20 min of perfusion and levelled out to an apparent steady state of about 0.28 micrograms/ml in upper extremity perfusions, and 0.34 (without cisplatin) and 0.37 micrograms/ml (with cisplatin) in lower extremity perfusion. Erythrocytes labelled with technetium Tc 99m, which were added concomitantly with melphalan to the perfusion medium, appeared in the systemic circulation of the patients at an almost constant rate of 0.32% (lower and upper limb perfusions without cisplatin and 0.37% (with cisplatin) of total tracer/min. This perfusate flow rate indicated by labelled erythrocytes completely explained the leakage of melphalan from the perfusion circuit into the peripheral blood. Peak concentrations of melphalan in the peripheral blood were observed immediately after reconstitution of normal hemodynamic conditions once isolation perfusion had been terminated. This fraction of melphalan might originate from tissue-binding sites, but also from vascular compartments; therefore, a thorough washing-out procedure might minimize this effect.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arm; Blood Flow Velocity; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Erythrocytes; Female; Humans; Hyperthermia, Induced; Leg; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Technetium

Exposure of cultured human melanoma cells from three different cell lines to Adriamycin and carmustine at non-cytotoxic (micromolar) concentrations results in a rapid, reversible depletion of cellular glutathione; maximal depletion is achieved within 1 h, and glutathione levels recover within 2-3 h. Glutathione depletion is accompanied by an enhancement of the cytotoxic effects of the alkylating agent melphalan, which ranges from 15- to 55-fold. These results suggest that the combination of Adriamycin and carmustine may provide a rational drug combination for the rapid depletion of glutathione from malignant melanoma, thereby sensitizing these tumor cells to alkylating agent cytotoxicity.

Topics: Carmustine; Cell Cycle; Doxorubicin; Drug Interactions; Glutathione; Humans; Melanoma; Melphalan; Tumor Cells, Cultured

In a consecutive series of studies, 164 patients with symptomatic and/or visceral metastatic malignant melanoma were treated with single agent vindesine, high dose melphalan with autologous bone marrow transplantation (AMBT), high dose BCNU with ABMT or the BOLD (bleomycin, vincristine, CCNU and DTIC) combination. The high dose treatments and the combination chemotherapy resulted in significantly higher response rates but no prolongation of survival. Factors associated with longer survival included the absence of visceral metastases, the absence of bulky disease and good performance status. For all treatments, life table estimates of survival at 1 and 2 years were only 10% and 4% respectively.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Transplantation; Dacarbazine; Female; Humans; Lomustine; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Vincristine; Vindesine

Topics: Drug Synergism; Drug Therapy, Combination; Humans; Interferons; Melanoma; Melphalan; Skin Neoplasms; Tumor Necrosis Factor-alpha

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Dactinomycin; Extracorporeal Circulation; Extremities; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Neoplasm Recurrence, Local; Osteosarcoma; Sarcoma; Soft Tissue Neoplasms; Survival Rate

The use of isolated regional perfusion with melphalan as an adjuvant treatment for stage I melanoma of the extremity continues to be controversial. The present retrospective study evaluates the past 25 years' experience by comparing 227 perfused patients from Groningen with 238 matched controls from five hospitals in The Netherlands and Westphalia (West Germany). All patients underwent wide local excision for a primary extremity melanoma of 1.5 mm or greater in thickness. A proportional hazards regression analysis for recurrence of disease and survival identified the significant prognostic factors, of which, besides level of infiltration, ulceration, age and sex, tumour thickness was found to be the most important. Corrected for these factors, it was not possible to demonstrate a statistically significant effect for perfusion in terms of time to limb recurrence (p = 0.61), time to regional lymph node metastasis (p = 0.11), time to distant metastasis (p = 0.73), disease-free interval (p = 0.42), and survival (p = 0.90). No statistically significant differences were seen for adjuvant perfusion in any of the subgroups.

Topics: Adult; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Regression Analysis; Retrospective Studies; Skin Neoplasms

The pharmacokinetics and systemic availability of melphalan after high-dose oral administration with and without 1,3-bis(2-Chloroethyl)-1-nitrosourea (BCNU) or etoposide were examined in three patients undergoing autologous bone marrow transplantation. Patient 1 (advanced melanoma) received melphalan at 80 mg/m2/day p.o. on days -6, -5, and -4, followed by BCNU at 300 mg/m2/day i.v. on days -3, -2, and -1 prior to bone marrow transplantation. Patient 2 (advanced colon carcinoma) received melphalan at 75 mg/m2/day p.o. on days -3, -2, and -1. Patient 3 (advanced refractory lymphoma) received etoposide at 800 mg/m2/day i.v. on days -7, -5, and -3, followed by melphalan at 157 mg/m2/day p.o. on days -2 and -1. Melphalan was administered as a bolus oral dose, using 2-mg tablets. Blood samples were collected at 0, 5, 10, 15, 30, and 45 min and 1, 2, 3, 4, 6, 8, 12, and 24 h after each dose of melphalan. Peak plasma melphalan concentrations in the three patients ranged from 0.354 (patient 2) to 1.768 micrograms/ml (patient 1). Plasma melphalan concentration X time products (C x Ts) showed extreme variability in one patient (patient 2), ranging from 0.76 to 4.48 micrograms.h/ml. To determine the relative systemic availability of orally administered melphalan, i.v. C X Ts proportional to the p.o. doses were extrapolated from previously reported i.v. bolus pharmacokinetic data. The p.o.:i.v. plasma C X T ratios for high-dose melphalan ranged between 0.09 (patient 3) and 0.58 (patient 2). Although these C X T data suggest a dose-response for orally administered melphalan, the systemic availability of these high p.o. melphalan doses was extremely variable, both within and between study patients. Thus, we cannot recommend the use of high-dose p.o. melphalan regimens in patients undergoing autologous bone marrow transplantation.

Topics: Adenocarcinoma; Administration, Oral; Adult; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Bone Marrow Transplantation; Carmustine; Etoposide; Female; Humans; Injections, Intravenous; Lymphoma; Male; Melanoma; Melphalan; Middle Aged; Time Factors

The therapeutic efficacy of isolated limb perfusion in patients with localized melanoma of the extremity remains controversial. We compared patients treated at the University of Texas M.D. Anderson Cancer Center, Houston, with wide local excision and isolated limb perfusion using either melphalan or imidazole carboxamide with a group matched for prognostic factors from the University of Alabama at Birmingham and the University of Sydney (Australia) who were treated with wide local excision alone. No significant difference in disease-free or overall survival rates was found between patients treated with wide local excision with adjuvant isolated limb perfusion or wide local excision alone. However, a subset of patients with thicker lesions (greater than 2.0 mm) treated with wide local excision and isolated limb perfusion using melphalan had a significant improvement in both disease-free and overall survival rates. These data suggest that isolated limb perfusion using melphalan may improve survival rates in selected patients with localized melanoma of the extremity who are at increased risk for local and regional micrometastases, and justifies the continued study of this treatment approach in prospective clinical trials.

Topics: Aminoimidazole Carboxamide; Antineoplastic Agents; Arm; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Humans; Leg; Lymphatic Metastasis; Melanoma; Melphalan; Middle Aged; Prognosis; Skin Neoplasms; Survival Rate

Patients receiving high-dose chemotherapy (HDC) and autologous bone marrow transplantation (ABMT) may experience life-threatening hemorrhagic myocarditis. The authors investigated whether HDC was associated with an acquired platelet defect. Platelet aggregation and release were evaluated after HDC in ten patients with either metastatic breast carcinoma or melanoma. Platelets underwent shape change and a primary wave of aggregation. High-dose chemotherapy was associated with the inhibition of secondary aggregation of platelets induced by adenosine diphosphate (ADP), arachidonic acid, prostaglandin H2 (PGH2) analog (U44619), and collagen. Although electron microscopic study of the platelets revealed normal morphologic features with an adequate number of dense bodies and alpha-granules, release of adenosine triphosphate (ATP) from dense granules was less than 20% of normal. The acquired platelet defect occurred before development of thrombocytopenia. Aggregation of platelets from normal volunteers was not inhibited by either the addition of the chemotherapeutic agents, chemotherapy metabolites, or the patients' sera. In conclusion, HDC induces an acquired abnormality in platelet secretion and aggregation which may contribute to the development of hemorrhagic complications after ABMT.

Topics: Adenosine Triphosphate; Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Platelet Disorders; Blood Platelets; Bone Marrow Transplantation; Breast Neoplasms; Carmustine; Cisplatin; Cyclophosphamide; Female; Hemorrhage; Humans; Male; Melanoma; Melphalan; Middle Aged; Myocarditis; Platelet Aggregation

Ninety five patients who developed in transit melanoma either as their initial site of recurrent melanoma or following regional node metastases were retrospectively reviewed. In transit melanoma occurred most frequently on the lower extremity and appeared to be associated with deeply invasive primary tumors. The median time to development of in transit melanoma was 16 months. Eighty-two (86%) of these patients have progressed to systemic disease from 2 to 244 months (median 16 months) following the development of in transit melanoma, and 72 (79%) died (median survival 19 months). Survival appears to correlate with the extent of in transit melanoma and with the disease-free interval. These findings suggest that in transit melanoma represents an early manifestation of systemic disease, warranting careful clinical follow-up and perhaps systemic treatment, when effective therapy becomes available. However, some patients will respond to local immunotherapy, surgical excision, and isolated limb perfusion and will enjoy significant length and quality of life. This sequential approach remains the treatment of choice for this manifestation of metastatic melanoma.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Combined Modality Therapy; Female; Humans; Immunotherapy; Lymph Node Excision; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Retrospective Studies; Skin Neoplasms; Survival Rate

From 1982-1989, 113 hyperthermic limb perfusions were carried out in 102 patients. Ninety-three patients were treated for malignant melanoma and nine for soft tissue sarcoma. 47/93 patients had high-risk stage I melanoma with a 5-year survival rate of 89%. For the 46 patients treated for recurrent and metastatic melanoma the projected 5-year survival rate was 40%. The nine patients with soft tissue sarcoma were perfused for local recurrences or because of anatomically difficult tumor locations. 3/9 patients subsequently developed recurrent disease of the extremity; two of these patients had to be treated by amputation. The rate of major complications was low: no patient died in the postoperative course, an amputation due to toxic reaction was never required. Erythema and oedema (57%), severe skin reaction (6%) and transient nerve palsy (15%) were common side effects of therapy. Only two cases of leucopenia were observed (2%). The favourable results after hyperthermic limb perfusion show the efficacy of this method in the treatment of malignant melanoma and selected cases of soft tissue sarcoma.

Topics: Adolescent; Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Lung Neoplasms; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Postoperative Complications; Sarcoma; Soft Tissue Neoplasms; Survival Rate

A retrospective study of 91 patients with malignant melanoma treated by lower limb isolated hyperthermic regional perfusion was performed. Objective response in patients with evaluable disease was 78 per cent. The role of perfusion as primary treatment of large melanomas of the foot is confirmed and recommended. Control of locoregional disease and limb salvage remains a valuable and attainable therapeutic goal using this technique.

Topics: Chemotherapy, Cancer, Regional Perfusion; Humans; Hyperthermia, Induced; Leg; Lymphatic Metastasis; Melanoma; Melphalan; Neoplasm Recurrence, Local; Neoplasm Staging; Retrospective Studies

The success of extremity perfusion and the protection from systemic side effects largely depend upon the prevention of systemic drug leakage from the extremity circulation. The use of autologous 111-Indium labelled erythrocytes for leakage control allows a continuous exact surveillance and timely correction of the tourniquet position in case a major leak should occur. A total of 97 patients were studied. In 6 patients (= 6%) the perfusion had to be discontinued within the first 30 min due to an uncorrectable leak of greater than 20%. In 31 patients (= 32%), a major leak could be reduced by manipulation of the tourniquet. No systemic side-effects could be observed in any of our patients. Applying leakage control by means of 111-Indium labelled erythrocytes extremity perfusion has proved to be a safe procedure in patients with high risk or recurrent malignant melanoma and soft tissue sarcoma.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arm; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Combined Modality Therapy; Erythrocytes; Extravasation of Diagnostic and Therapeutic Materials; Female; Humans; Hyperthermia, Induced; Indium Radioisotopes; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Radionuclide Imaging; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Energy Metabolism; Female; Humans; Magnetic Resonance Spectroscopy; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Phosphates; Phosphocreatine; Skin Neoplasms

Since systemic application of a high-dose chemotherapy is limited by the extent of intolerable toxicity and overall response rates so far are rather poor, the systemic mode of chemotherapy for metastatic melanoma appears to be of only limited benefit. On the other hand, results from isolated limb perfusion for satellitosis and in-transit metastasis suggest distinct dose-response correlations with tumoricidal properties of appropriate antineoplastic agents. This experience prompted the idea to pilot the anti-tumor action of a high-dose regimen confined to one hemibody compartment for targeted tumor therapy. After having standardized the surgical procedure this goal appeared to be achievable by expanding the perfused area and by simultaneously detoxifying toxic drug levels within the non-perfused compartment by venous filtration. Two initial causal experiences revealed impressive tumor regressions and are therefore reported on preceding subsequent evaluation within a controlled clinical trial being designed at different solid tumors.

Topics: Adult; Antineoplastic Agents; Catheters, Indwelling; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Dose-Response Relationship, Drug; Extremities; Female; Heart-Lung Machine; Hemofiltration; Humans; Infusions, Intra-Arterial; Male; Melanoma; Melphalan; Mitomycin; Mitomycins; Neoplasm Metastasis; Pilot Projects; Skin Neoplasms

In experiments with dogs (n = 68), the influence of temperature, flow rate, perfusate, and perfusion duration on the hind leg subjected to an isolation perfusion was studied. The perfusion pressure, the blood gases, and the metabolic status in specimens of skeletal muscle obtained at the end of the perfusion period served as parameters. A perfusion of 1 and 2 h with whole blood, a flow rate of 10 mL/10 g/min, and temperatures of up to 42 degrees C did not result in alterations of the energy metabolism. When the flow rate was lowered to 5 mL/100 g/min, when other perfusates were used, or when the in temperature was raised to 43.5 degrees C, then tissue damage occurred. Knowledge gained in these experiments was utilized in the treatment of 371 patients with malignancies of the extremities, and an extremely low complication rate was observed.

Topics: Animals; Arm; Blood Flow Velocity; Carbon Dioxide; Chemotherapy, Cancer, Regional Perfusion; Dogs; Doxorubicin; Energy Metabolism; Evaluation Studies as Topic; Hindlimb; Humans; Leg; Melanoma; Melphalan; Muscles; Oxygen; Sarcoma; Soft Tissue Neoplasms; Temperature

Between 1976 and 1988, 182 patients--135 females (74.3%) and 47 males (25.7%)--were submitted to 206 isolation perfusions, using melphalan and mild hyperthermia for 34 upper and 172 lower limbs. Stage I melanoma represented 37.4% including 75.4% greater than 1.5 mm Breslow thickness or with regression, ulceration or incisional biopsy. Stage II melanoma included 62.6% of the cases. Peri-operative mortality occurred in 2/182 patients. Amputation was performed within 1 month for toxic reasons in three patients and delayed in six for progressive disease. Regional toxicity consisted in oedema (76%), pain (61%), nerve palsy (24%), thrombosis (7%), septicemia (3%), thrombocyto-granulopenia (1.5%), minor miscellaneous (52%). Mean peripheral leakage was 1.0, 7.8 and 12.4% at respectively 5, 10 and 60 minutes. Projected 5-year disease-free survival was 79% for Stage I and 27% for Stage II. Survival at 5 years was 92% in Stage I and 53.5% in Stage II. Twenty-five patients were perfused twice for recurrence or incomplete response. Although the median disease-free interval was only about 8 months, the 5-year survival was 67%. This may indicate that isolation perfusion renders melanoma metastases less aggressive despite the fact they may recur at a high rate.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arm; Axilla; Chemotherapy, Cancer, Regional Perfusion; Child; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Leg; Lymph Node Excision; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Postoperative Complications

236 patients with various advanced malignant solid tumors treated by combined chemotherapy with routine doses of cisplatin (DDP) from 1980 to 1986 are presented. According to different doses of cisplatin everyday, the patients were divided into 4 groups: 1. 20 mg/day x4-5, 80 cases; 2. 30 mg/day x3-5, 91 cases; 3. 40 mg/day x3-4, 37 cases; 4. 50 mg/day x2-3, 28 cases. Each group was repeated for 3 weeks. The effect and toxicity were analysed and compared with 22 cases treated by single DDP in 1975. The response (CR + PR) rate was 39.2% in 194 evaluated patients. The response rate was similar in group 20 mg and single DDP (29.2% and 27.3%). The response rate was lower than that of group 30 mg, 40 mg, and 50 mg (43.4%, 42.4%, and 50%) (P less than 0.05). The remissions in various groups were not significantly different. The toxicity of combined chemotherapy was not severe. 91.1% of patients had nausea and vomiting. There was no statistical difference in the various groups. Bone marrow suppression was less in single DDP group than that of combined chemotherapy group, (P less than 0.05). DDP 30 mg-50 mg 1/d x5-3 was better than HD-DDP in some patients.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Humans; Lomustine; Lung Neoplasms; Male; Melanoma; Melphalan; Methotrexate; Middle Aged; Neoplasms; Procarbazine; Testicular Neoplasms; Vincristine

Thirty-seven patients with widely metastatic malignant melanoma were treated with one of three chemotherapy regimens, incorporating high-dose dacarbazine (DTIC). The chemotherapy was followed by autologous bone marrow rescue which was harvested under local anesthesia in 25 of the patients. The three regimens comprised a 24-hour infusion of DTIC (Regimen A for patients less than 45 years of age, 4.3 to 10.5 g/m2; B, if greater than 45 years of age 2.7 to 4.0 g/m2; and later C, if greater than 45 years of age 7.0 to 8.0 g/m2). The second alkylating agent was given at +8 and +16 hours from the start of DTIC. The total doses of the melphalan ranged from 60 to 130 mg/m2 for Regimen A and 30 to 40 mg/m2 for Regimen B. Ifosfamide 5.0 to 8.0 g/m2 was given instead of melphalan in Regimen C. The response rates for the regimens were 81% (25% CR) for A, 27% (11% CR) for B, and 20% (with no complete responders) for Regimen C. There was no statistically significant difference between the three regimens for survival with a median value of 6 months. One of the 16 patients treated with the very high dose Regimen A died of septicemia and three of ten patients in Regimen C died within the first 2 weeks of treatment. There was statistically significant greater myelosuppression, stomatitis, and diarrhea in the very high dosage DTIC and melphalan (Regimen A) compared with the other two regimens. No significant difference in response rate or toxicity was observed for the different dosages escalated within each of the three regimens. Although hematologic and gastrointestinal toxicity were very severe, no unusual side effects were noted except for one episode of severe acute renal failure in the high-dose DTIC and melphalan, Regimen A. Responses occurred mainly in nonvisceral, nodal, and cutaneous sites and occasionally in pulmonary metastases. The Karnofsky performance improved 4 to 6 months after treatment notably with the high-dose DTIC and melphalan therapy. No survival benefit for the combination chemotherapy despite the high dosages was detected and such an approach currently cannot be recommended.

Topics: Adult; Aged; Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Dacarbazine; Humans; Ifosfamide; Lung Neoplasms; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Skin Neoplasms

A total of 23 patients were treated at five dose escalations with high-dose combination cyclophosphamide, cisplatin, and melphalan with autologous bone marrow support. The maximum tolerated doses of cyclophosphamide, cisplatin, and melphalan were 5,625, 180, and 80 mg/m2, respectively. The dose-limiting toxicity was cardiac toxicity. Objective tumor regression occurred in 14 of 18 evaluable cases, with a median duration of 3.5 months. Pharmacokinetic evaluation of melphalan in 20 patients revealed a dose-related increase in maximum plasma concentration (Cmax) and area under the curve (AUC). Perturbation of the melphalan plasma half-life and AUC, associated with severe toxicity, resulted when renal insufficiency occurred. The results suggest that high-dose combination cyclophosphamide, cisplatin, and melphalan produces frequent, rapid responses in breast cancer, melanoma, and sarcoma, although with significant extramedullary toxicity. The pharmacokinetics suggest that modification of the treatment schedule may result in a reduction of treatment-related toxicity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasms; Sarcoma; Transplantation, Autologous

Eight patients with advanced malignant melanoma were treated with high-dose melphalan (80-90 mg/m2) and BCNU (600-800 mg/m2). In all patients autologous bone marrow preservation was performed prior to therapy. Bone marrow was stored for 48 h in a refrigerator at 10 degrees C and reinfused 48 h post-therapy. Three patients had a complete response (CR), 1 a partial response and 4 patients no response. Two patients with CR died 4 and 5 months after therapy. One had an interstitial pneumonitis and 1 patient died from unknown cause. The third patient had a relapse 12 months after therapy. Major side effects were severe nausea/vomiting and a mild mucositis. Two patients suffered from BCNU-related encephalopathy. All patients had a full hematologic reconstitution after 6 weeks. High-dose chemotherapy with autologous bone marrow support achieves a high response rate. Long-term disease-free survival, however, was not seen with this approach.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Skin Neoplasms

Since 1957, 961 patients with invasive malignant melanoma of the limbs were treated by regional perfusion. Forty-eight patients were black, representing 5 per cent of all patients with regional melanoma treated during this period. Thirty-one of the 48 patients were men, and 17 were women. Only 21 of the 48 patients had stage I lesions (M.D. Anderson classification), of whom 63 per cent had level IV or greater invasion. The average depth of invasion was 3.70 mm. Of 21 patients with stage III disease, 15 came to diagnosis with an intact primary lesion in addition to regional disease, and the majority of lesions arose on a plantar site with level V invasion. Eighty per cent of the patients had acral lentiginous melanoma. All melanoma patients were treated by isolated regional perfusion with wide excision of the primary plus regional lymph node dissection for biopsy-proven regional disease. At 10 years, survival rates were 71 per cent for stage I patients and 12.5 per cent for those with stage III disease. When black patients having had acral melanoma on a plantar or palmar site were compared with white patients of a similar stage of disease, however, it was found that black patients had equivalent long-term survival rates.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Black People; Chemotherapy, Cancer, Regional Perfusion; Female; Foot Diseases; Hand; Humans; Male; Melanoma; Melphalan; Middle Aged; Prognosis

Between October 1969 and December 1986, 136 patients with recurrent limb melanoma were treated with hyperthermic antiblastic perfusion (HAP). This retrospective analysis is aimed at identifying tumor-related and treatment-related variables likely to influence tumor response, locoregional control, disease-free survival, and overall survival. Independent factors predicting a complete response (CR) were the number of lesions (P less than 0.0001) and the minimum tumor temperature (minT) (P = 0.03). Only a positive trend was observed for the drug dose (P = 0.08). However, the proportion of CR was significantly higher (57.7%; P = 0.02) in patients who had a minT of 41.5 degrees C or greater and who were given a dose equal to or greater than the standard dose than in patients treated with lower temperatures and/or lower drug doses. The occurrence of a CR significantly increased the rates of locoregional control (77%; P = 0.007), disease-free survival (55.6%; P = 0.006), and overall survival (68.6%; P = 0.03). Treatment optimization may provide further therapeutic improvements by increasing the incidence of CR. However, the overall survival rates also were influenced by the number of lesions (P = 0.0014), sex (P = 0.04), and the number of previous relapses (P = 0.01). Therefore, tumor aggressiveness also is crucial in determining the outcome of the disease, and only early treatment with HAP can reduce the risk of distant metastases.

Topics: Adult; Aged; Aged, 80 and over; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Prospective Studies; Remission Induction; Retrospective Studies; Skin Neoplasms

Isolated limb perfusion (ILP) for melanoma of the extremity was first used clinically more than 30 years ago. Although ILP with chemotherapeutic agents has become routine practice in many oncologic centers, few studies have evaluated the therapeutic efficacy of particular agents. Two consecutive groups of 100 patients with stage I extremity melanoma of 1.5 mm thickness or greater were treated by ILP with either melphalan (L-PAM) or dacarbazine (DTIC). Demographics, clinical and pathologic stage, disease site, and complications were similar in both groups. No significant difference in the overall incidence of recurrent disease at two years was found between patients treated with either DTIC or L-PAM (22% vs 16%, respectively; P = .28). Patients who had perfusion with L-PAM, however, had a lower incidence of in-transit metastasis and recurrence at the scar than those having DTIC therapy (4% vs 12%, P = .06) at two years of follow-up. This preliminary report suggests that L-PAM may be more effective than DTIC in controlling scar recurrences and in-transit metastasis. Continued follow-up of this series of patients, with further analysis of patterns of recurrence and disease-free and overall survival at five years, will be necessary to better define the relative efficacy of L-PAM and DTIC in isolated limb perfusion.

Topics: Adult; Chemotherapy, Cancer, Regional Perfusion; Cicatrix; Dacarbazine; Extremities; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Retrospective Studies

A panel of four cell sublines, each selected for resistance to a different antineoplastic agent, has been developed from a human malignant melanoma cell line G3361. Following repeated exposure to escalating doses of the drug of interest, cloned sublines were developed that are 9-fold resistant to cisplatin (G3361/CP), 11-fold resistant to 4-hydroxyperoxy-cyclophosphamide (4-HC) (G3361/HC), 4-fold resistant to carmustine (BCNU) (G3361/BCNU), and 4-fold resistant to melphalan (G3361/PAM). The cross-resistance of each resistant cell line was determined for cisplatin, BCNU, 4-HC, melphalan, carboplatin, nitrogen mustard, and Adriamycin. In general, the alkylating agent-resistant cell lines were specifically resistant to the drug used for selection with the exception of the G3361/CP line, which was greater than 10-fold resistant to the cisplatin analogue carboplatin, 4-fold resistant to 4-HC, and slightly (1.5-fold) resistant to melphalan, and the G3361/BCNU line, which was slightly (1.8-fold) resistant to melphalan. Collateral sensitivity of the G3361/CP, G3361/PAM, and G3361/4HC lines to killing by BCNU was also observed. Glutathione-S-transferase activity was elevated in each of the alkylating agent-resistant cell lines by 3- to 5-fold with chlorodinitrobenzene substrate. On Western blotting, the glutathione-S-transferase-pi (GST-pi) isoenzyme protein was elevated in the resistant cells by 3- to 5-fold. A complementary DNA (pTS4-10) coding for GST-pi has been cloned from a lambda gt11 library, sequenced, and used as a probe to determine the relative levels of GST-pi mRNA in the alkylating agent-resistant cell lines. GST-pi mRNA levels were elevated (8- to 15-fold) in the resistant cell lines, indicating that the GST-pi increases were mediated through an increase in mRNA levels. GST-pi elevations are a frequent event in cells selected for alkylating agent resistance, and in some cases, of multiple drug resistance. However, the lack of cross-resistance among cell lines selected for resistance to different alkylating agents, all of which have elevated GST-pi levels, indicates that increased levels of GST-pi cannot be the predominate mechanism for resistance to the tested drugs in these cell lines.

Topics: Alkylating Agents; Antineoplastic Agents; Blotting, Northern; Carmustine; Cell Line; Cell Survival; Clone Cells; Cyclophosphamide; Drug Resistance; Glutathione Transferase; Humans; Melanoma; Melphalan; RNA, Neoplasm; Tumor Cells, Cultured

The effects of heat and the interaction between hyperthermia and alkylating agents, such as cisplatin (CDDP) and melphalan (L-PAM) in human malignant melanoma biopsies have been investigated by a short-term assay based upon the inhibition of 3H-thymidine incorporation. Cell suspensions from 50 cutaneous and lymph nodal metastases were heated at 40.5 degrees C or at 42 degrees C for 1 h. There were significant antiproliferative effects due to heat in 10% of the tumors exposed to 40.5 degrees C and 34% to 42 degrees C. Thermal resistance was evident in 73% (at 40.5 degrees C) and 54% (at 43 degrees C) of tumors, and there was significant enhancement of cell growth in 17% and 12% of tumors. The combined effects of hyperthermia and drugs were studied on 36 tumors. Cell suspensions were exposed to different concentrations of CDDP or L-PAM for 1 h at 40.5 degrees C and 42 degrees C. Synergy between heat and CDDP was observed in 7% of cases treated with the lowest drug dose and 38% of cases treated with the highest (40.5 degrees C), with only a slight increase in the frequency of synergy at 42 degrees C. Synergy between heat and L-PAM was also observed in 12% to 44% of tumors at 42 degrees C as a function of drug concentration.

Topics: Antineoplastic Agents; Cisplatin; Combined Modality Therapy; Hot Temperature; Humans; Melanoma; Melphalan; Tumor Cells, Cultured

One hundred forty patients affected by high risk or locally advanced melanoma of the extremities were submitted to hyperthermic perfusion in extracorporeal circulation at the National Cancer Institute of Milan, Italy. Using adequate temperature and drug dosage, we increased survival of stage IIIA patients from 8-15% to 51% and stage IIIAB patients from 7-8% to 35%, and good local control was achieved in stage IV patients. A comparison was made with 297 patients with similar disease treated in a previous period in this institute with conventional therapies such as surgery with or without chemotherapy. In stage IIIA patients we obtained 51% overall survival at 5 years in perfused cases, whereas survival in the series with conventional treatment reached 16%. Similarly, in stage IIIAB patients we observed 34% (perfused) versus 16% (conventional treatment) survival. There are still no data available for high-risk stage I, in which perfusion is employed as an adjuvant treatment.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Dacarbazine; Extracorporeal Circulation; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Neoplasm Staging; Risk Factors; Time Factors

In spite of the better results observed during the last decades and particularly due to earlier diagnosis and earlier surgical excision, malignant melanoma remains a tumour with a disconcerting course. This relative therapeutic impotence explains the variety of treatments used, including chemotherapy, radiotherapy, immunotherapy, etc. Surgical excision after chemotherapy under hyperthermic regional perfusion with extracorporeal circulation is an original method which has been applied for more than 3 decades with conflicting results but which may prove useful in several circumstances. The principle of regional perfusion using cytostatic drugs injected into the regional arterial blood flow resulted from a study by Klopp et al. in 1950. This technique was developed in practice by Creech et al. in 1957, and it was improved about 10 years later by additional hyperthermia, an idea suggested by Cavaliere et al. and by Stehlin. In Strasbourg, we have been using this method since January, 1982. Indications for perfusion are melanoma of the limbs with Breslow thickness greater than or equal to 0.85 mm, but from 1984 onwards these indications have been limited to patients with high-risk tumours such as melanoma with a Breslow thickness greater than or equal to 1.5 mm. Such melanomas are situated on the upper limb below the brachial insertion of the deltoid muscle, and on the lower limb below the upper third portion of the thigh. The technique consists of regional chemotherapy of the limb using extracorporeal circulation with hyperthermic perfusion. Melphalan is the drug used, and its dosage is based on body-weight: 1.4 mg/kg for the lower limb, and 0.9 mg/kg for the lower limb. Melphalan is introduced in the perfusion when the subcutaneous temperature near the tumour reaches 38 degrees C. The temperature of the limb is maintained at 40-42 degrees C for 45 minutes. At completion of the perfusion a wash-out is performed, and the tumour is excised with a 3 cm margin. From January, 1982 to January, 1987, 68 patients with malignant melanoma were treated by this method. Perfusion could not be performed in 5 patients because the small caliber of the vessel did not allow sufficient perfusion flow rate. No lethal complication occurred, and morbidity was very low.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adult; Aged; Combined Modality Therapy; Extracorporeal Circulation; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Injections, Intra-Arterial; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local

Nineteen patients with metastatic malignant melanoma were treated with 20 courses of high-dose combination alkylating agent chemotherapy and autologous bone marrow support. All 20 treatment courses were evaluable for toxic reactions and 17 of 20 courses were assessable for response. Twelve of the 20 courses were given at the phase 2 dose per square meter of cyclophosphamide (5.625 g), cisplatin (165 mg), and carmustine (600 mg). Marrow reconstitution occurred with a median time to recovery of 21 and 24 days for more than 500 neutrophils and more than 20,000 platelets, respectively. The overall response rate was 65%, with one patient achieving a complete response with chemotherapy alone. Ten additional patients achieved partial responses following chemotherapy, of which three were subsequently rendered disease free by surgical resection of single areas of residual tumor. Two of these patients are alive and disease free more than 22 months following chemotherapy and one remains relapse free. The median survival for responding patients was 15.2 months and 8.6 months for the entire group.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Liver Neoplasms; Lung Neoplasms; Male; Melanoma; Melphalan; Middle Aged; Pelvic Neoplasms; Remission Induction

The effects of D,L-buthionine-S,R-sulfoximine (BSO) on cytotoxicity and DNA cross-linking induced by bifunctional DNA-reactive cytostatic agents in a human melanoma cell line (RPMI 8322) were investigated. RPMI 8322 cells were exposed to 0.01 mM BSO for 24 h, which resulted in a decrease in cellular glutathione to 14% without any reduction of cell proliferation or plating efficiency. BSO pretreatment significantly enhanced cytotoxicity of melphalan with a dose modification factor (DMF) of 3.4 and nitrogen mustard (HN2) (DMF 3.3). The increased cytotoxicity was paralleled by similar increases in DNA cross-linking (melphalan: DMF 2.2, HN2: DNF 2.5). A small but significant potentiation by BSO of cis-diamminedichloroplatinum(II) toxicity was seen (DMF 1.5), with a corresponding minor but significant increase in DNA cross-linking (DMF 1.1). Similarly, the potentiation of bis-chloroethylnitrosurea toxicity was small but significant (DMF 1.1), with no significant increase in DNA cross-linking (DMF 1.0). No effect of BSO pretreatment on the rate of removal of HN2-induced DNA cross-links was observed. Thus, the observed sensitization of RPMI 8322 cells to melphalan, HN2, cis-diamminedichloroplatinum(II), and bis-chloroethylnitrosourea was correlated to similar changes in drug-induced DNA cross-linking. Despite the increased cytotoxicity and DNA cross-linking BSO did not significantly increase the intracellular concentration of intact melphalan. These findings support the hypothesis that the potentiation of the cytotoxicity of bifunctional alkylating agents by BSO is due to an increased DNA cross-linking caused by a reduced intracellular conjugation of drug with glutathione, which results in an increased binding of drug to DNA targets.

Topics: Antineoplastic Agents; Buthionine Sulfoximine; Cell Division; Cell Survival; Cross-Linking Reagents; DNA; Drug Synergism; Glutathione; Humans; Melanoma; Melphalan; Methionine Sulfoximine; Tumor Cells, Cultured

The use of isolated regional perfusion in an adjuvant setting for stage I melanoma of the extremity continues to be controversial. The present retrospective study evaluates the past 20 years' experience by comparing 227 perfused patients from Groningen with 238 matched controls from five hospitals in The Netherlands and Westphalia (a region of West Germany bordering the Netherlands). All patients underwent wide local excision for a primary extremity melanoma of 1.5 mm or greater in thickness. A proportional hazards regression analysis for recurrence of disease and survival identified the significant prognostic factors, of which tumor thickness was the most important. Corrected for these factors, it was not possible to demonstrate a statistically significant effect for perfusion in terms of time to limb recurrence (P = .61), time to regional lymph node metastasis (P = .11), time to distant metastasis (P = .73), disease-free interval (P = .42), and survival (P = .90). No statistically significant differences were seen for adjuvant perfusion in any of the subgroups.

Topics: Adult; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Perfusion; Retrospective Studies; Skin Neoplasms

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melanoma; Melphalan; Neoplasm Recurrence, Local

The time course of tissue levels of melphalan during normothermic isolated limb perfusion, and the overall tissue levels per 60 min of perfusion, were estimated from the known pharmacokinetic parameters for a fixed dose of drug per liter of tissue (Benckhuijsen et al., J. Pharmacol Exp Ther 1986; 237: 583-8). The application of differing total doses of drug resulted in varying concentrations in the perfusate plasma. Above a certain plasma level, uptake into the bulk of the tissues did not increase with the area under the plasma concentration vs time curve or its beta-phase. Similar tissue levels were found after perfusion of regions of less than three and a half liter with 13 mg/l as in regions of 5 to 16 liter after perfusion with 10 mg of melphalan per liter. It cannot be predicted from the available data whether the extent of uptake of melphalan into the tumour tissue is equal to or greater than that into the bulk of the tissues. The estimated uptake of drug into the tissues confirms the validity of the dose calculation per liter of tissue. On the basis of the present results, a refined dosimetric formula will be obtainable that includes the desired area under the plasma concentration vs time curve as a determinant for an optimal dose.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged

The relationship between DNA crosslinks and cell death as a result of exposure to melphalan (MLN) was studied in the F1 variant of B16 melanoma cells. The formation of DNA crosslinks is believed to represent the lethal lesion following exposure of cells to bifunctional alkylating agents. The production of DNA crosslinks by MLN was determined by the recently described ethidium bromide fluorescence assay [De Jong et al., Int. J. Cancer 37, 557 (1986)]. A direct correlation between the percentage of DNA crosslinks (Ct) and cytotoxicity of melphalan has not been previously reported utilizing the fluorescence assay. The cytotoxicity of MLN and the production of DNA crosslinks by this drug were determined following a 1-hr incubation at 37 degrees. The concentrations of MLN necessary to reduce colony growth to 37% of control and 10% of control were 6.7 microM (EC37) and 26 microM (EC10) respectively. Utilizing the ethidium bromide fluorescence assay (EFA), the relationship between MLN concentration (x axis) and DNA crosslinks expressed as Ct (y axis) was best described by a power curve (y = 0.28 x 0.81; r = 0.985). The respective Ct values at the EC37 and EC10 of MLN were 1.3 and 3.8%. It appears that the sensitivity of the EFA is similar to the alkaline elution assay and, in addition, that the EFA is less technically difficult to employ with tumor cells obtained from patients.

Topics: Cell Line; Cell Survival; DNA Damage; DNA, Neoplasm; Ethidium; Fluorescence; Humans; Melanoma; Melphalan; Tumor Cells, Cultured; Tumor Stem Cell Assay

The administration of chemotherapy by isolated regional perfusion was developed in 1957 at Tulane University and was found to be of greatest benefit for patient with melanoma of the limbs. From 1957 to 1984, 897 patients were treated by this method. The 10-year survival rate for 831 patients with primary melanoma was 77 per cent. Women survived longer than men, with 10-year rates of 81 per cent and 65 per cent, respectively. Prophylactic lymph node dissection was of benefit for males with poor prognosis distal lower limb lesions, but other groups did not benefit. Primary lesions on the arm and thigh did better than lesions of the hand or foot, with plantar and subungual lesions having the least favorable results. Thickness, level, and histologic type were also significant prognostic indicators. Thirty-three patients with locally recurrent melanoma (stage II) treated by perfusion and excision had a 10-year survival rate of 59 per cent. For 129 patients with metastases to the regional lymph nodes (IIIB), perfusion plus RLND produced a 10-year rate of 51 per cent; survival rates for those with a single positive node was 64 per cent. Seventy patients with satellitosis or intransit metastases (IIIA) had a 10-year survival rate of 23 per cent. Thirty-eight patients with metastases to limbs from unknown primaries had a 10-year survival rate of 52 per cent. The overall 10-year rate for all stage III patients was 41 per cent. Perfusion produced useful palliation in 144 patients with limb melanoma in the presence of systemic metastases.

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Male; Melanoma; Melphalan; Nitrogen Mustard Compounds; Thiotepa

Fifty-nine patients received 61 courses of cyclophosphamide, cisplatin, and carmustine combined. The phase I study consisted of seven dose escalations. Dose levels 5 and 6 also included the attempted addition of melphalan at 40 and 80 mg/m2. The maximum tolerated dose for the three-drug combination was 5620 mg/m2 of cyclophosphamide, 165 mg/m2 of cisplatin, and 600 mg/m2 of carmustine. The dose-limiting toxic effect was fatal veno-occlusive disease of the liver in two of five patients treated at the highest dose level. Veno-occlusive disease of the liver was fatal in two of 40 patients treated at Dose level 4, the maximum tolerated dose. The median time to recovery of polymorphonuclear leukocyte counts to greater than 500/microliters and platelet counts to transfusion independence greater than 20,000/microliters was 19 and 22 days, respectively, after marrow reinfusion. Other toxic effects observed included postdischarge pulmonary toxicity, which appeared to respond to prednisone therapy. Thus, this combination of alkylating agents can be combined at close to the transplant dose of each individual agent. The response rate was high despite considerable prior treatment in most patients. Of 16 evaluable patients with breast cancer, 15 responded (six complete responses). Of six evaluable patients with sarcoma, six responded (one complete response). While patients with melanoma had had no prior treatment, 11 of 17 patients responded (65%). There are currently three patients who are disease-free. Two patients with melanoma were rendered disease-free by excisional biopsy of the only remaining nodule after good partial response, and a patient with metastatic breast cancer remains disease-free after a complete response at 36+ months.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Drug Evaluation; Female; Hematologic Diseases; Humans; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasms; Statistics as Topic

Regional hyperthermic chemotherapeutic perfusion (RHCP) has been used to treat over 1000 patients with advanced melanoma and soft tissue sarcoma. This study analyzes the impact of RHCP on the peripheral vasculature. Forty-one patients (23 women, 18 men) with an average age of 51.3 years were treated by RHCP of an upper or lower extremity using phenyalanine mustard for 60 minutes at a mean extremity temperature of 40 C. Patients were examined preoperatively and postoperatively at 36 hours, 7 days, 1 month, and 6 months by noninvasive arterial (Doppler-resting analog velocity waveform, response to stress) and venous (Doppler, impedance plethysmography [IPG], phleborrheography [PRG]) measurements. Upper-extremity evaluation of 14 patients (9 women, 5 men) indicated no abnormal studies. Response to stress showed an increase of the brachial:distal vessel ratio of 0.1 +/- 0.05; tendency of the analog velocity waveform toward triphasic; and response to stress augmented by 0.18 +/- .03 at 36 hours. Lower-extremity evaluation of 27 patients (15 women, 12 men) indicated two with thrombophlebitis. Response to stress showed an increase of the ankle: brachial ratio of .016 +/- 0.04; change in the analog velocity waveform toward triphasic; and response to stress augmented by 0.08 +/- 0.08 at 36 hours. All measurements returned to preoperative values at 7 days. Results of this study indicate RHCP has no long-term adverse effect on the vasculature of the extremity, as monitored by the noninvasive blood flow studies.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Ultrasonography

The formation and removal of nitrogen mustard (HN2)- and melphalan-induced DNA cross-links (DNA interstrand and DNA-protein cross-links) in a human melanoma cell line (RPMI 8322), as determined by alkaline elution of DNA, was compared and related to the cytotoxic effect of each drug. HN2 was considerably more cytotoxic than melphalan as determined by inhibition of colony formation. Immediately following exposure to HN2 maximum levels of DNA cross-links were found. Melphalan, in contrast, caused a protracted induction of DNA cross-links with maximum levels obtained 6-12 h following drug exposure. HN2 induced approximately 13 times higher peak levels of DNA cross-links compared to equal concentrations of melphalan. Removal of DNA cross-links following exposure to both drugs followed an exponential time course. The rate of removal of HN2-induced DNA cross-links was, however, 1.5-2.4 times more rapid than that of melphalan-induced cross-links. A strong correlation was obtained between the cytotoxicity of both drugs and the total area under the curve for DNA interstrand cross-links, indicating that both the initial induction of as well as the rate of removal of DNA interstrand cross-links are important for the cytotoxic effects of bifunctional alkylating agents.

Topics: Cell Line; Cell Survival; DNA; Humans; Mathematics; Mechlorethamine; Melanoma; Melphalan; Neoplastic Stem Cells

Previous studies with cultured human normal fibroblasts indicated that pretreatment of the cells with zinc for 12 h prior to exposure to the alkylating agent melphalan increased survival by seven- to ninefold over survival values obtained in cultures treated with drug only. Comparable pretreatment of cells derived from a variety of human tumors resulted in an increase in survival of 1.7-fold or less. To determine whether the limited responsiveness to zinc represented a general property of tumor cells (which would be characterized by a lack of highly zinc-responsive subpopulations contained within the parental tumor populations), a series of clones was prepared from the A101D human melanoma line and the A549 human alveolar cell carcinoma line. Cells from each clone were then challenged with melphalan with and without zinc pretreatment. Twenty-five percent of the tumor clones exhibited increased resistance to melphalan following pretreatment with zinc (range of 2.1- to 5.2-fold increase in survival), indicating that the parental tumor lines were highly heterogenous in regard to inducibility to a state of reduced sensitivity to melphalan. There was no evidence of a relationship between zinc-induced reductions in toxicity and induced elevations in total intracellular glutathione content, indicating that the primary effect of zinc is not directed toward elevating intracellular levels of glutathione.

Topics: Cell Survival; Clone Cells; Glutathione; Humans; Lung Neoplasms; Melanoma; Melphalan; Pulmonary Alveoli; Zinc

Three human melanoma cell lines of known content of specific glucocorticoid-binding sites were studied for colony formation after a microM dose of glucocorticoid combined with melphalan. In one of the three cell lines, M-5A, subcloned from M-5 (formerly designated RPMI 8322), the effect of combined treatment was markedly increased compared to that of melphalan even if the glucocorticoid was applied for 1 h only, 10 h before the melphalan. Semilogarithmic dose-effect plots for a reduction of final plating efficiency by glucocorticoid were curvilinear, according to a receptor-mediated process. The effects of glucocorticoid, melphalan, and their combination were linearized by bilogarithmic median-effect plotting which allowed the quantitation of a synergism which was more marked in case of glucocorticoid pretreatment, for 1 or 24 h, than on simultaneous exposure. According to sequential DNA per cell cytophotometry, melphalan abolished in M-5A a glucocorticoid-induced arrest in the G1 phase of the cell cycle. The cytotoxic synergism correlated with an apparent stimulation by glucocorticoid of the rate of acid-insoluble incorporation of [3H]uridine and [14C]leucine and an increase in cell size and protein content in M-5A cells but not in the other two cell lines. The way in which glucocorticoids induce an enhanced susceptibility to melphalan is not clear. Our results appear compatible with a hypothesis that chromatin in a transcriptionally activated state is more vulnerable to cytotoxic attack by an alkylating agent than under average conditions.

Topics: Cell Cycle; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Glucocorticoids; Humans; Leucine; Melanins; Melanoma; Melphalan; Proteins; Tritium; Uridine

Topics: Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Humans; Leg; Melanoma; Melphalan; Skin Neoplasms

Between 1964 and 1983, 65 patients with Stage II extremity melanoma were treated in a nonrandomized fashion with wide local excision, lymph node dissection, and hyperthermic perfusion with 1-phenylalanine mustard at 1.0-1.5 mg/kg. Southwest Oncology Group Stage II criteria were used, including IIA (node positive), IIB/C (recurrent local/regional), or both. During the study interval, literature reports of 5-year survival for Stage II melanoma ranged from 6% to 50% and averaged approximately 26% to 30%. In this study group, 40% of patients had recurrent disease confined to regional lymph nodes, 33% had recurrent cutaneous disease, and 26% had recurrent disease in both locations. Survival for all Stage II patients at 5 years was 56.6%, and 40% at 10 years. When recurrent disease was confined to regional nodes only (IIA), survival at 5 years was 70.5%, and 40% at 10 years. Survival for patients with Stage IIB/C disease at 5 and 10 years was 58% and 43.7%. When recurrent melanoma was present in both skin and nodes, 5-year survival was 29%. The present study indicates that aggressive treatment of Stage II extremity melanoma, which includes hyperthermic isolation perfusion, can prolong survival in these high-risk patients.

Topics: Arm; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Leg; Lymphatic Metastasis; Male; Melanoma; Melphalan; Neoplasm Recurrence, Local; Neoplasm Staging; Skin Neoplasms

Current methods for cytostatic dosimetry in isolation perfusion of the limbs are based on either limb tissue volume (LTV) or body weight. None of them take into account the actual blood volume intra- and extracorporal, including even the blood leakage if any, in which the pharmacokinetics take place. The present study describes a method which allows the assessment of the actual exchangeable blood volume. The latter is calculated by a formula based on three hematocrit measurements. Thirty-one cases entered the study. Exchangeable limb blood volume representing the limb vascular bed was found to average 340 +/- 148 (SD) ml for upper limb perfusion and 768 +/- 279 and 621 +/- 454 ml for iliac and femoropopliteal perfusion, respectively. There was a good correlation between exchangeable limb blood volume and limb tissue volume (LTV, r = 0.7), a poor one with body weight (r = 0.3), and no correlation at all with body surface. Melphalan dosage was calculated per ml of blood and applied at 20 to 40 micrograms/ml. Comparison between calculated dose and concentration measured by high performance liquid chromatography showed a high correlation (r = 0.963). Since there was a correlation between exchangeable limb blood volume and LTV, it was possible to derive a conversion for melphalan dosage where 13 mg/liter corresponds to 20 micrograms/ml in upper limb perfusion and 10 mg/liter corresponds to 40 micrograms/ml in lower limb perfusion. Comparison between calculated melphalan dosage based on our method and the LTV method showed a large dispersion of values in the latter (12 to 18% coefficient of variation) while the dispersion given by the body weight-based method increased 2-fold (16 to 31% coefficient of variation). It is concluded that the present dosimetry method is the most suitable up to the present for accurate prediction of cytostatic concentration in isolation perfusion.

Topics: Blood Volume; Body Weight; Extracorporeal Circulation; Extremities; Humans; Melanoma; Melphalan; Metabolic Clearance Rate; Perfusion

Patients with regional metastases of malignant melanoma (75 with Stage IIIA soft tissue metastases, 124 with Stage IIIB nodal metastases and 75 with Stage IIIAB soft tissue and nodal metastases) treated by regional perfusion between 1957 and 1982 were retrospectively studied to identify prognostic factors relating to survival. In patients with Stage IIIB disease, the melanoma specific cumulative survival rates at five years was 72 per cent for one, 33 per cent for two to three and 20 per cent for four or more positive lymph nodes. In patients with Stage IIIAB disease, those with one node had a better survival rate at five years than those with multiple nodes (45 versus 25 per cent). In patients with Stage IIIA melanoma, two groups were identified based upon the results of prior treatment--those with and without prophylactic lymph node dissection (PLND) at the time of primary therapy. The factors associated with decreased survival rates in patients with PLND were: 1, increasing age; 2, presence of subcutaneous or both subcutaneous and dermal metastases, and 3, treatment at normothermic temperatures or earlier date of treatment. No significant factors were found in the group without PLND; however, the survival time was similar to that for patients with Stage IIIAB and one positive node (45 per cent at five years). Knowledge of these factors is important in assessing the prognosis and establishing randomization criteria for prospective studies evaluating various forms of therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Soft Tissue Neoplasms

A review of the development of regional chemotherapy by perfusion is presented. Techniques have been developed for most regions of the body. Early response rates ranged from 48% for glioblastoma and 55% with carcinoma to 67% with soft tissue sarcoma and 84% with melanoma. By 1984, 1325 patients had been perfused 1509 times. The best responses have occurred with melanoma and soft tissue sarcoma of the limbs. Thus, at 10 years, the cumulative overall survival for Stage I melanoma of the limbs, combining regional perfusion and conservative excisional surgery, was 77%. The best results occurred in female patients with upper-limb disease (83%), and the poorest results were in male patients with lower-limb disease (53%). The overall 10-year survival for regional melanoma was 41%, ranging from 23% for in-transit metastases to 51% for patients with positive regional nodes treated by perfusion and regional lymph node dissection. The 10-year survival for perfusion and limb-sparing excision for soft tissue sarcoma was 65%. Advantages and complications are presented and discussed. Questions and plans for the future are reviewed.

Topics: Animals; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Costs and Cost Analysis; Extremities; Female; Humans; Lymph Node Excision; Male; Melanoma; Melphalan; Neoplasms; Sarcoma; Thiotepa

Sixteen patients with advanced (stage III) malignant melanoma were treated with escalating doses of intravenous BCNU and melphalan starting at 400 and 35 mg/m2, respectively, and escalating to 1,000 and 110 mg/m2, respectively, combined with autologous marrow transplantation. The duration of granulocytopenia and time to granulocyte recovery was similar in all groups regardless of chemotherapy dose. Platelet recovery was delayed in patients receiving the highest doses of chemotherapy. This study showed that bone marrow colony-forming units in culture took as long as 6 months to recover. This was adequate to bring peripheral blood counts to normal but not to pretreatment levels. These studies indicate that autologous bone marrow transplantation is beneficial in enhancing short-term recovery, but may not be beneficial in the long-term hematopoietic recovery.

Topics: Agranulocytosis; Bone Marrow Transplantation; Carmustine; Colony-Forming Units Assay; Hematopoietic Stem Cells; Humans; Melanoma; Melphalan; Platelet Count; Time Factors

High-dose chemotherapy with BCNU, melphalan, or both, followed by autologous bone marrow transplantation (ABMT) has been reported to produce response rates in excess of 60% in patients with advanced melanoma. We tested doses of BCNU associated with reversible bone marrow toxicity and acceptable extramedullary toxicity without the use of ABMT in 19 patients with a diagnosis of advanced malignant melanoma. All patients were evaluable for toxicity and 18 were evaluable for response; one patient had a new primary tumor. The patient population had a median age of 44 years (range, 16 to 71) and a median Karnofsky performance status of 80 (range, 50 to 100). Ten were women and nine were men, all had visceral dominant disease, and none had received previous chemotherapy. Our purpose was to test the feasibility of treatment without ABMT, its toxicity and efficacy, and the possibility of administering sequential repeated courses of therapy. Vincristine was added to the regimen to potentially increase efficacy. Treatment consisted of BCNU (750 mg/m2) and vincristine (2 mg days 1 and 8). Six patients who recovered bone marrow function received melphalan (60 mg/m2) and vincristine (2 mg days 1 and 8). Twenty-two percent (95% confidence limits, 3% to 39%) of patients had remissions (all partial) and these were of short duration. Toxicity was substantial with 16% early lethality and 29% incidence of lethal drug-related complications. Two patients (11%) died toxic after a second course of BCNU. Our results suggest that there is no practical role for high-dose BCNU in the treatment of melanoma.

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bone Marrow Transplantation; Carmustine; Central Nervous System Diseases; Drug Administration Schedule; Female; Humans; Lung Diseases; Male; Melanoma; Melphalan; Middle Aged; Thrombocytopenia; Vincristine

Topics: Chemotherapy, Cancer, Regional Perfusion; Humans; Infusions, Intra-Arterial; Leg; Melanoma; Melphalan; Skin Neoplasms

Cytogenetic studies were carried out on peripheral lymphocytes from cancer patients at different times after therapy with melphalan. The frequency of sister chromatid exchange (SCE) was increased markedly shortly after treatment, and then declined to near pretreatment levels over a four-week period. In-vitro studies showed that the SCE frequency induced by melphalan is reduced slowly in resting G0 lymphocytes and considerably faster in mitogen-stimulated G1 cells. The results demonstrate that measurement of SCE is useful for the study of newly-induced chromosome damage in melphalan-treated cells, but is less suitable for the detection of persistent, cytogenetic alterations long after therapy. The frequency of chromosomal aberrations in a cohort of 50 patients with ovarian carcinoma was increased for up to ten years after melphalan therapy. The predominant aberrations were chromosomal translocations, marker chromosomes and cells with multiple, complex rearrangements. The frequency distribution of chromosomes involved in aberrations was studied in cells from some of the patients. An overrepresentation of chromosomes 8 and 9 was found in these cells, whereas the X chromosome was overrepresented in cells from control subjects. An increased frequency of chromosomal rearrangements was found in long-term cultures of T-lymphocytes from three of the patients, indicating that these aberrations are compatible with cell survival and proliferation. Seven patients in the cohort developed a second, primary tumour during the observation time. The frequencies and types of aberrations in these patients were similar to those of the other patients in the cohort.

Topics: Carcinoma; Cell Division; Cell Survival; Chromosome Aberrations; Chromosomes; DNA Damage; Female; Humans; In Vitro Techniques; Karyotyping; Lymphocytes; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Sister Chromatid Exchange; Thrombocytopenia; Time Factors

Verapamil had previously been shown to increase cellular melphalan uptake and cytotoxicity in fibrosarcomas, and increased the area under the blood concentration versus time curve (AUC) for melphalan in CBA mice. Verapamil (10 mg kg-1 i.p.) had no effect on the fractional distribution of cardiac output (FDCO), measured with 86Rb-rubidium chloride, to subcutaneous fibrosarcomas. 14C-Melphalan uptake by FS13 fibrosarcomas was increased 60 min after verapamil (10 mg kg-1 i.p.), but not after lower doses which did not affect the AUC. Flunarizine (5 mg kg-1 i.p.) also had no effect on FDCO to FS13 fibrosarcomas, and tended to increase 14C-melphalan content of blood and the fibrosarcomas and to promote growth delay by melphalan. Alcohol increased FDCO to FS13 fibrosarcomas, maximally at a 1:20 dilution in saline, but had no effect on 14C-melphalan uptake or growth delay. Thus, melphalan cytotoxicity correlated with tumour melphalan uptake, and both followed changes in the AUC for melphalan but not changes in FDCO. In these murine fibrosarcomas melphalan uptake and cytotoxicity were not limited by blood flow. In subcutaneous human melanoma HX46 xenografts, verapamil had no effect on the FDCO, nor on 14C-melphalan uptake, and did not affect blood 14C-melphalan levels, suggesting absence of effects on the AUC and on cellular uptake. Alcohol did not increase the FDCO to HX46 xenografts, providing evidence for a different vascular supply.

Topics: Animals; Cinnarizine; Drug Synergism; Ethanol; Female; Fibrosarcoma; Flunarizine; Humans; Male; Melanoma; Melphalan; Mice; Mice, Inbred CBA; Regional Blood Flow; Verapamil

BRO human melanoma cells, which are exceptionally tumorigenic and lethal for nude mice, were inoculated intraperitoneally or intracerebrally in varying numbers. An inverse linear correlation was observed between the logarithm of the number of cells inoculated and host survival. In mice bearing 10(7) cells intraperitoneally, 2.4-2.8 log10 units of cell kill were obtained after a single intraperitoneal injection of vincristine, and some mice inoculated with 10(5) cells were cured by this treatment. Fewer cells were killed by L-phenylalanine mustard. Vincristine did not prolong survival of nude mice with intracerebral BRO tumors. Cell kill after administration of anticancer agents can be quantitated for BRO cells inoculated intraperitoneally or intracerebrally.

Topics: Animals; Cell Line; Drug Evaluation, Preclinical; Humans; Injections, Intraperitoneal; Injections, Intravenous; Injections, Intraventricular; Melanoma; Melphalan; Mice; Mice, Nude; Neoplasm Transplantation; Transplantation, Heterologous; Vincristine

6-[Bis-(2-chloroethyl)-amino]-6-deoxy-D-glucose (C-6) is a new glucose-containing nitrogen mustard that has significant activity for murine P388 leukemia with relative sparing of bone marrow in mice. The in vitro myelotoxicity of C-6 compared with that of melphalan, a clinically active, myelosuppressive nitrogen mustard, was determined in the CFU-C assay in human bone marrow samples obtained from normal volunteers. There was no significant difference between the myelosuppressive actions of C-6 and melphalan at any of the concentrations used except for 4.0 microM, at which C-6 was significantly (P less than 0.05) more toxic than melphalan. Both agents decreased the number of bone marrow cell colonies to approximately 12% of control at 6.6 microM (1 h incubation), which is a good approximation of melphalan's CxT (concentration by time) in man. We used the human tumor stem cell assay (HTSCA) to investigate in vitro antitumor activity. We obtained two specimens of malignant melanoma and two of malignant ovarian carcinoma from patients not previously treated with chemotherapy. The antitumor activity of melphalan was either similar to or greater than that of C-6 at all concentrations utilized against any of the four tumor specimens, except at 1.3 microM for tumor I. In particular, there was no significant difference in the antitumor activities of the two agents at 6.6 microM. These results suggest that C-6 will not be less myelosuppressive than melphalan at doses that produce equivalent antitumor activity in man. In addition, C-6 did not demonstrate increased myelotoxicity for normal human bone marrow cells incubated in glucose-deficient medium as against medium containing 300 mg% glucose at any of the concentrations used. This suggests that C-6 is not transported into normal human bone marrow cells via the glucose transport system, despite the presence of a glucose moiety within the molecule.

Topics: Analysis of Variance; Bone Marrow; Colony-Forming Units Assay; Female; Humans; In Vitro Techniques; Melanoma; Melphalan; Nitrogen Mustard Compounds; Ovarian Neoplasms; Structure-Activity Relationship; Tumor Stem Cell Assay

Menogarol is a new anthracycline undergoing phase I clinical trial. We report here the lethality after 2 hr exposure to 2 drug combinations of menogarol and several antitumor agents. A new statistical procedure was used to identify synergistic combinations. Most of these combinations were additive, except for menogarol plus melphalan, which was synergistic. Adriamycin plus melphalan was also synergistic. The menogarol-melphalan combination wa studied in detail with regard to the effect of dose and drug-schedule, lethality for exponential and plateau phase cells and effect on cell cycle progression. Although the combination was synergistic for exponential cells it was additive for plateau phase cells. The combination exerted a synergistic effect in inhibiting progression of cells through the cell cycle. After 2 hr menogarol exposure cells were blocked in G2 for about 12 hr following which the block was reversed. This reversal was inhibited when menogarol was combined with melphalan. The uptake of menogarol or melphalan was not changed in the presence of the other drug.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Cell Survival; Cells, Cultured; Daunorubicin; Doxorubicin; Drug Synergism; Melanoma; Melphalan; Menogaril; Mice; Nogalamycin

Present-day therapy for disseminated malignant melanoma is unsatisfactory; chemotherapy offers a small fraction of patients a short-lived palliative effect. Evidence exists to suggest more responses to chemotherapy could occur if dosages of chemotherapeutic agents were increased. The dosages of many chemotherapeutic agents used for melanoma are limited by myelotoxicity of the drugs. Autologous bone marrow transplantation offers a means to escalate chemotherapeutic dosages by shortening the period of life-threatening marrow toxicity to a survivable length of time. A review of 103 cases of melanoma treated with high-dose chemotherapy and autologous marrow rescue plus two cases reported here revealed that 48% of patients responded to therapy and 34% of those were complete responses. The exact role this technic will play in management of disseminated malignant melanoma requires further study.

Topics: Adult; Alkylating Agents; Antineoplastic Agents; Bone Marrow Transplantation; Combined Modality Therapy; Humans; Male; Melanoma; Melphalan; Skin Neoplasms; Transplantation, Autologous

Twenty patients with metastatic malignant melanoma were treated with melphalan (180-225 mg/m2 iv over 3 days) followed by re-infusion of previously harvested and cryopreserved autologous bone marrow. Granulocyte (greater than 500/microliter) and platelet (greater than 20,000/microliter) count recovery occurred a median of 14 days (range, 12-22) and 19.0 days (range, 12-28) after bone marrow transplantation, respectively. Three patients died due to hemorrhage or infection. One of these patients and another (who ultimately achieved a complete response), both with brain metastases, developed intralesional hemorrhage when the platelet count was only moderately reduced. Complete responses occurred in six patients and ranged from 4 to 14 months, with a median of 5 months. Six patients achieved a partial remission lasting 2-5 months. High-dose melphalan and autologous bone marrow transplantation are a promising therapy for patients with metastatic malignant melanoma.

Topics: Adult; Bone Marrow Transplantation; Female; Humans; Male; Melanoma; Melphalan; Middle Aged

During the period from February to October 1983, 21 patients with malignant melanoma of the extremities were treated by hyperthermic regional isolated perfusion with L-phenylalanine mustard (melphalan). The melphalan dose for each patient was determined by the tissue volume of the perfused region, using a dose of 10 mg/l perfused tissue. Despite an average increase of melphalan dosage of 18% above the maximum for iliac perfusions recommended in the literature, no increase in toxic tissue reactions was observed after hyperthermic iliac perfusions. The same dose of 10 mg/l perfused tissue was used in hyperthermic axillary perfusions, resulting in an average decrease of melphalan dosage of 14% below the minimum recommended in the literature. By applying a constant dose per unit tissue volume, a standardization of treatment is achieved. This excludes variations like body weight, age, type of complexion, and hair color, which so far have determined dosimetry.

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Hot Temperature; Humans; Male; Melanoma; Melphalan; Skin Neoplasms

The pharmacokinetics of melphalan in clinical hyperthermic isolation perfusion was studied in 16 patients with malignant melanoma. Analysis by computer-generated lines of best fit showed that the loss of melphalan from perfusate conforms best to a biexponential equation. The initial loss with a half-life (t1/2) of approximately 5 to 10 min is interpreted as rapid uptake of melphalan by the tissue of the perfused extremity. The terminal portion of the curve with a half-life of approximately 35 to 50 min is interpreted as due predominantly to the hydrolysis of melphalan, with a lesser component of loss due to absorption of melphalan to the filters and tubing of the perfusion apparatus. Determination of the area under the curve suggests that there is no appreciable uptake of melphalan by the tissue of the perfused extremity after 30 min.

Topics: Chemotherapy, Cancer, Regional Perfusion; Computers; Extremities; Half-Life; Humans; Kinetics; Melanoma; Melphalan

The pharmacokinetics of isolated limb perfusion were studied to see what melphalan concentrations were achieved and how effective the isolation was. Twenty-eight patients received 32 limb perfusions with heat and melphalan for locally recurrent or level V melanoma. Melphalan was given 0.75 mg/kg for axillary/popliteal or 1.2 mg/kg for femoral perfusions with heat (perfusate 42 degrees C, limb 40 degrees C) for 1 hour. Melphalan concentratives were measured by high-performance liquid chromatography in seven patients. Peak perfusate melphalan concentrations were 6.1 to 115 mg/ml, which was one to two logs higher than peak systemic concentratives of melphalan. Isolation of the perfusate circuit from the systemic circulation was better for axillary and popliteal perfusions than for femoral perfusions (P less than 0.05). Complete responses were seen in 81% of evaluable patients; long-term local control was achieved in most patients, although many developed hematogenous metastases. Toxicity included erythema and edema in all, mild leukopenia in two, neuropathy in two, and amputation was required in one patient. Improvements in surgical technique include regional anesthesia to reduce vasospasms and transcutaneous measurement of fluorescein to measure leak. Perfusion with heat and melphalan remains the treatment of choice for in-transit metastases from melanoma.

Topics: Chemotherapy, Cancer, Regional Perfusion; Extravasation of Diagnostic and Therapeutic Materials; Extremities; Female; Hot Temperature; Humans; Kinetics; Male; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms

One hundred and thirty three specimens from mammary and ovarian adenocarcinoma and from melanoma were cultured according to an agar/agar clonogenic assay. Melanoma and ovarian cancers exhibited a 70 per cent rate of success for culture; 50 per cent of the mammary adenocarcinomas were successfully cultured. Fifty-nine ovarian cancers were cultured in order to test the in vitro effectiveness of Cisplatinum and Adriamycin. Thirty percent of cultured tumors gave rise to relevant chemograms. The chemoresistance measured in vitro was correlated to the ineffectiveness of the patient's treatment. In contrast, we were unable to predict chemosensitivity. Taking into account the technical difficulties encountered in these assays, human tumor clonogenic assays cannot at present be proposed as a routine procedure in the prediction of the effectiveness of chemotherapeutic treatments. Nevertheless, they must be developed in order to determine the spectrum of activity of new antineoplastic agents on various human tumors.

Topics: Adenocarcinoma; Agar; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cisplatin; Colony-Forming Units Assay; Cyclophosphamide; Doxorubicin; Drug Resistance; Female; Humans; Melanoma; Melphalan; Ovarian Neoplasms; Tumor Stem Cell Assay

Topics: Antineoplastic Combined Chemotherapy Protocols; Arm; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Doxorubicin; Female; Hot Temperature; Humans; Leg; Male; Melanoma; Melphalan; Neoplasm Metastasis; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms

Topics: Agar; Animals; Biopsy; Breast Neoplasms; Cell Survival; Colonic Neoplasms; Colony-Forming Units Assay; Culture Techniques; Female; Humans; Male; Melanoma; Melphalan; Mice; Neoplasms; Ovarian Neoplasms; Rectal Neoplasms; Tumor Stem Cell Assay

Isolated regional perfusion for the treatment of malignant melanoma is an accepted method of treatment. No standard of anaesthetic practice has been established for those individuals. Perioperative records of patients undergoing isolated limb perfusion were studied to determine adequate blood replacement. Records were examined and compared for (1) age, (2) ASA physical status, (3) presence of associated disease, (4) anaesthetic technique, (5) the amount of blood and fluid replacement, (6) preoperative haemoglobin (hgb) and haematocrit (hct) and postoperative serial complete blood counts. Fifteen patients were studied (mean age 53 +/- 16 yrs). Mean blood and fluid replacement was: packed red blood cells; 2.28 +/- 0.82 units, 722 +/- 17 ml of 5 per cent albumin, 1747 +/- 21 ml crystalloid. There were twelve Physical Status Class I or II and three Class III patients. All patients received general anaesthesia. There was a statistically significant difference in the preoperative and postoperative values for haemoglobin and haematocrit (p less than 0.01) with no difference between the postoperative and discharge values. Adequate blood replacement was determined by the equation: (Formula: see text) Extensive invasive monitoring is not routinely required for adequate blood replacement or the detection of leaks between the systemic and isolated circulation.

Topics: Adult; Anesthesia, General; Chemotherapy, Cancer, Regional Perfusion; Hemodynamics; Humans; Melanoma; Melphalan; Middle Aged; Skin Neoplasms

One hundred and fifty-six patients with extremity melanomas of known level or thickness who were perfused prophylactically with l-phenylalanine mustard (1-PAM) between January 1974 and December 1978 were studied retrospectively to determine the effect of variation of drug dosage and temperature on regional toxicity and disease control. The median drug dosage of 1-PAM for 57 patients undergoing axillary perfusion was 0.85 mg/kg (range 0.48-1.0 mg/kg) and the median dosage was 1.2 mg/kg (range 0.59-1.69 mg/kg) for 99 patients undergoing iliac perfusions. Sixty-five percent of patients achieved a maximum skin temperature of between 101 degrees and 102 degrees F during perfusion. Determinate survival in the entire group was 93% at 5 years; 10% of patients developed positive regional nodes; and 2.5% developed local or intransit metastases. Based on analysis of other series of patients with extremity melanoma with equivalent Clark's level 5-year determinate survival might be expected to be between 65 and 80%. The expected incidence of nodal metastases should be 19.1%-24.0% and the incidence of local and intransit metastases should be 3-6%. While this series suggests a survival advantage for a series of extremity melanomas treated by regional chemotherapy when compared to other series treated by wide excision +/- regional node dissection, the results obtained were independent of dosage of drug administered or maximal temperature attained over the range studied. This suggests consideration be given to exploring other dose ranges of drugs and heat in an effort to achieve equivalent control with lower regional toxicity.

Topics: Adolescent; Adult; Aged; Arm; Chemotherapy, Cancer, Regional Perfusion; Child; Dose-Response Relationship, Drug; Female; Humans; Hyperthermia, Induced; Leg; Lymphatic Diseases; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms

Alkylating agents and their functional analogues belong to the most useful antineoplastic drugs in the treatment of disseminated malignant melanoma. In conjunction with an open clinical phase II trial evaluating the combination of cisplatin and ifosfamide, 17 melanoma xenograft lines were established from patients often refractory to dacarbazine (DTIC). These xenograft lines were exposed to cisplatin, dacarbazine, dibromodulcitol, ifosfamide, methyl-CCNU, mitomycin C, and malonato-diaminocyclohexane-platinum II (PHM) at the respective LD 10/30 doses. Growth delay values less than 2 corresponded in 26/27 instances with progressive disease, whereas values greater than 2 corresponded in only 10/13 instances with achievement of a no-change status or a partial remission of the donor patient's disease. Among the panel of DNA-damaging agents tested, cross-resistance was incomplete. Some xenograft lines revealed unique chemosensitivity patterns in contrast to a uniform pattern of drug resistance in others (pleiotropic or multidrug resistance). The data confirm independently of results obtained in the phase II study that the combination of cisplatin and ifosfamide is effective against malignant melanoma refractory to dacarbazine. Suboptimal drug exposure, repeated up to 21 transplant generations, was employed to induce secondary resistance to either dacarbazine, melphalan or methyl-CCNU in a melanoma xenograft line originally quite sensitive to drug treatment. When the resistant sublines were exposed to the other agents, only partial cross-resistance was observed. Tumour volume responses to treatment with dacarbazine correlated with persisting DNA damage assayed 24 h after in vivo drug exposure in a sensitive line and the absence of such lesions in a resistant line.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dacarbazine; Disease Models, Animal; DNA; Drug Resistance; Humans; Ifosfamide; Kinetics; Melanoma; Melphalan; Mice; Mice, Nude; Neoplasm Transplantation; Semustine; Transplantation, Heterologous

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms

We report on a patient with primary cutaneous malignant melanoma, with numerous intransit metastases involving the left lower extremity. The clinical presentation was striking in that the intransit metastatic lesions of the skin had morphologic characteristics of Kaposi's sarcoma. Her disease was complicated by marked lower limb edema. Cutaneous ulceration did not develop despite the extensive tumor burden. Treatment with regional limb perfusion resulted in marked reduction of the edema and shrinkage of the tumor mass. In addition to presenting this case report and response to therapy, we would like to suggest the term "chronic melanoma of the extremity" (CME) as a descriptive term for this unusual variant of malignant melanoma.

Topics: Aged; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Melanoma; Melphalan; Sarcoma, Kaposi; Skin Neoplasms

Topics: Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dactinomycin; Extremities; Humans; Hyperthermia, Induced; Injections, Intravenous; Melanoma; Melphalan; Perfusion; Sarcoma; Soft Tissue Neoplasms

Lonidamine alone or in combination with hyperthermic perfusion, with or without melphalan, was investigated in 12 patients with stage II, III, and IV malignant melanoma. The authors evaluated the most effective methods and sequence of Lonidamine administration. Preliminary results suggest that the highest effectiveness is obtained with the simultaneous administration of Lonidamine and hyperthermia.

Topics: Administration, Oral; Antineoplastic Agents; Humans; Hyperthermia, Induced; Indazoles; Injections, Intra-Arterial; Melanoma; Melphalan; Pyrazoles

In the human melanoma cell line MM127 , the melphalan survival curve was linear and exhibited reciprocity with respect to concentration and treatment time. The survival curve of an allogeneic line, MM253c1 , exhibited a shoulder and, on a concentration X time basis, was resistant to 1-hr compared with 4-hr treatment. This type of resistance, which was not found using chlorambucil, nitrogen mustard, or methyl methanesulfonate, could be overcome by simultaneous hyperthermia (42 degrees) but not by treatment with thymidine or caffeine. Both lines had similar levels of DNA interstrand cross-linking (perchlorate renaturation method) after 1-hr treatment, but MM253c1 cells were able to repair most of this damage during the next 23 hr. The cross-links formed in MM253c1 cells after 1 hr were predominantly heat sensitive and photoresistant , whereas those formed in MM127 cells were heat resistant and photosensitive. These results suggest that melphalan formed repairable (possibly diadeninyl or adeninyl - guaninyl ) cross-links in MM253c1 cells during the first hr of treatment and nonrepairable , possibly diguaninyl cross-links in MM127 cells at all stages of treatment. It appears therefore that the mode of action of melphalan and the effect of synergistic agents may not be identical in all cells.

Topics: Caffeine; Cell Line; Cell Survival; Chlorambucil; DNA, Neoplasm; Drug Resistance; Drug Synergism; Hot Temperature; Humans; Kinetics; Mechlorethamine; Melanoma; Melphalan; Methyl Methanesulfonate; Thymidine

Topics: Adult; Combined Modality Therapy; Hot Temperature; Humans; Lymph Node Excision; Melanoma; Melphalan; Middle Aged; Perfusion; Poly A-U; Prognosis

In regional hyperthermic perfusion with melphalan for patients with malignant melanoma of the leg, plasma leakage between the perfusion circuit and the systemic circulation was 4-7 ml X min-1. The melphalan concentration in the perfusate was biphasic, with half-lives of 8-12 mins for the initial phase and 19-28 mins for the second phase, after the first dose. After a second dose, the corresponding values were 11-13 and 26-34 mins. The highest concentration in general circulation was 0.38 micrograms X ml-1.

Topics: Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Half-Life; Humans; Hyperthermia, Induced; Iodine Radioisotopes; Leg; Melanoma; Melphalan

Twenty-eight patients with advanced life-threatening metastatic malignant melanoma were treated with high dose (140-260 mgm-2) intravenous melphalan and autologous bone marrow. Cyclophosphamide "priming" 300 mgm-2 i.v. was given to 19 patients one week previously and this resulted in clinical but not histological evidence of amelioration of gastrointestinal toxicity. In 11 patients (43%) there was evidence of tumour response to treatment and in 2 patients complete remissions were observed. However in most patients, responses were short-lived and no patient lived longer than 17 months from start of treatment or 24 months from first recorded evidence of distant metastatic disease.

Topics: Adult; Blood Cell Count; Bone Marrow Transplantation; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Time Factors

Topics: Agar; Animals; Cell Count; Cell Division; Cell Line; Clone Cells; Cytological Techniques; Dactinomycin; Female; Humans; Melanoma; Melphalan; Mice; Stimulation, Chemical

Thirty-three adult and pediatric patients with refractory malignancies were treated with escalating doses of melphalan (120-225 mg/m2 IV over 3 days) followed by reinfusion of previously harvested and cryopreserved autologous marrow. The hematological and nonhematological toxicities and the therapeutic effects of this regimen were evaluated. Increasing doses of melphalan did not alter the rate of decline nor the recovery of peripheral blood counts. Granulocyte (greater than 500/microL) and platelet count (greater than 20,000/microL) recovery occurred in a median of 19 (range 12-54) and 24 (range: 12-54) days after bone marrow transplantation, respectively. Five patients experienced severe infection, three of which were fatal, and one patient died due to thrombocytopenic hemorrhage. Toxicity to the gastrointestinal system was dose limiting. The maximum tolerated dose of melphalan was 180 mg/m2; only three of 24 patients experienced severe stomatitis, esophagitis, and diarrhea at this level or less, while eight of nine patients at 225 mg/m2 were affected (p less than 0.005). Administration of cyclophosphamide (300 mg/m2 IV) 1 week before melphalan therapy did not reduce the incidence of severe gastrointestinal toxicity. Plasma melphalan concentration peaked 30-60 min after infusion (4.8-11.5 micrograms/mL) but declined rapidly. Cerebrospinal fluid concentration was 10% of the corresponding plasma concentration and was undetectable at 3 hours. Antitumor responses occurred in nine of 13 patients with malignant melanoma (five complete and four partial remissions), and ranged 2-12+ months with a median of 5 months. Four of six neuroblastomas demonstrated responses (three complete and one partial remission( lasting a median of 7.5 (range: 5-10) months. Other tumors in which this regimen had activity included breast cancer and Ewing's sarcoma. The overall response rate for the 33 patients was 30% complete remissions (10 patients) and 21% partial remissions (seven patients). High dose melphalan and autologous bone marrow transplantation is a promising therapy for patients with malignancies for which no effective treatment is known or for patients whose cancer is refractory to conventional therapeutic agents.

Topics: Adolescent; Adult; Aged; Bone Marrow Transplantation; Breast Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Evaluation Studies as Topic; Female; Gastrointestinal Diseases; Humans; Male; Melanoma; Melphalan; Middle Aged; Neuroblastoma; Neutropenia; Sarcoma, Ewing; Thrombocytopenia; Time Factors

Local recurrence after conventional surgical treatment of malignant melanomas of the extremities has frequently been observed in our department in the past. As at other centers, this sometimes necessitated amputation, and on a few occasions amputations were performed exclusively for palliative reasons. In an effort to improve this situation, regional perfusion as local regional treatment was added to conventional therapy in 1965. We have since observed no further instances of massive local tumor growth, and since that time no amputations have had to be performed for this reason. Of course this complicated therapy caused new problems, particularly in the early years, but we have learned to reduce these to what we believe to be an acceptable minimum. In the last 2 years we have done nearly 100 perfusions and have had no major complications. A comparison of the results of regional perfusion plus local excision in the treatment of stage-I melanoma with those of other reported series (Cascinelli et al. 1978; Elder et al. 1979; Fortner et al. 1977; Goldsmith et al. 1970; Lee 1979; McCarthy et al. 1974; Veronesi et al. 1977; Wanebo et al. 1975) treated only by local excision is difficult, owing to the complexity of the known variables relating to survival and local recurrence. The 5-16 year determinate survival rate for our perfusion patients was 74%. The local recurrence rate in the perfused extremities was 9%, 14 patients, and nine of these 14 had distant metastases as well. The other five patients still show no evidence of disease after retreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amputation, Surgical; Arm; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Follow-Up Studies; Humans; Hyperthermia, Induced; Leg; Melanoma; Melphalan; Neoplasm Staging; Skin Neoplasms

Between December 1975 and December 1980 a total of 154 patients with potentially curable malignant melanoma were treated by adjuvant hyperthermic perfusion. The basic therapy consisted in local excision of the primary tumor with elective dissection of the regional lymph nodes. The 4- and 5-year survival rates for our 103 patients with stage-I disease who were perfused are 90% +/- 9% and 80% +/- 17%. The 4- and 5-year survival rates for 51 patients with stage-II disease are 50% +/- 16% and 37% +/- 28%. Compared with historic control groups of patients who were treated at our hospital with the same surgical methods but without perfusion, essentially better results were achieved with adjuvant hyperthermic perfusion. It is concluded from our results that hyperthermic perfusion can further improve the prognosis for patients with malignant melanomas of the limbs.

Topics: Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Skin Neoplasms

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Skin Neoplasms

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Skin Neoplasms

The results obtained with isolation perfusions in stage IIIA-IIIAB melanoma patients, performed at 42.5-43 degrees C for 2.5 h, are reported. These temperatures and perfusion times were chosen on the basis of experimental data in animal models and in vitro. The clinical results were impressive, but the high percentage of complications and the high cost from a social and human point of view make this experience negative with regard to its clinical applicability, at least with such a high temperature and long perfusion time.

Topics: Adult; Aged; Anesthesia; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Hyperthermia, Induced; Leg; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Skin Neoplasms; Temperature; Time Factors

In 171 cases of isolated perfusion of the extremities for treatment of melanomas and soft tissue sarcomas, standardized operation techniques were perfected. The arterial double cannulation makes an iliac cannulation feasible also in cases of second and third perfusion. Cytostatics are dosed per liter of perfused extremity. Cis-Platinum and dacarbacine were recently introduced in isolation perfusion treatment. So-called preheating of the extremity before adding the drugs allows administration of cytostatics besides tumortoxic hyperthermia.

Topics: Arm; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Dacarbazine; Drug Therapy, Combination; Extracorporeal Circulation; Humans; Hyperthermia, Induced; Leg; Mechlorethamine; Melanoma; Melphalan; Postoperative Care; Soft Tissue Neoplasms

In undisturbed cells one can detect a discrete population of 10 kb DNA replication intermediates, which indicates the existence of gaps spaced about 10 kb away from each other in the newly synthesized DNA. In melphalan-treated cells one can detect both 10 kb and 20 kb DNA intermediates, indicating that in such cells the gaps present in a replicon are not filled at the same time which allows the detection of a molecule which is formed by the joining of two 10 kb DNA intermediates. In contrast in undisturbed cells it is likely that the filling of the gaps present in a replicon occurs at the same time which prevents the detection of a 20 kb DNA intermediate.

Topics: Cell Line; Cross-Linking Reagents; DNA Replication; DNA, Neoplasm; Humans; Melanoma; Melphalan; Neoplasms, Experimental

The toxicity of melphalan in mice was reduced by the injection of S-2-(3-aminopropylamino)-ethylphosphorothioic acid (WR2721). This was seen in terms of reduced toxicity to the stem cells of the bone marrow and intestinal epithelium as well as improved animal survival. Using human melanoma xenografts and growth delay as an end-point, it was demonstrated that WR2721 did not protect this tumor from melphalan. With radio-labelled WR2721, it was shown that WR2721 was rapidly cleared from the blood and actively accumulated by all normal tissues except the CNS. Intact human tumor xenografts and Lewis lung tumors were less able to accumulate WR2721 than normal tissues, but in vitro studies showed that tissue fragments or single cell suspensions of tumors were as efficient as liver fragments or bone marrow cells in accumulating the drug. The rapid clearance of WR2721 and poor vascularity of the intact tumors were thought to be responsible for the differential uptake and protection of normal tissues by WR2721.

Topics: Amifostine; Animals; Colony-Forming Units Assay; Female; Hematopoietic Stem Cells; Male; Melanoma; Melphalan; Mice; Mice, Inbred CBA; Neoplasms, Experimental; Organothiophosphorus Compounds; Spleen

Thirteen patients with advanced (Stage III) malignant melanoma have been treated with high-dose chemotherapy (nitrogen mustard or a combination of BCNU and melphalan) combined with autologous, nonfrozen, bone marrow transplantation. Three patients (24%) achieved a complete remission and are currently alive and free of disease without further therapy at 26, 60, and 73 weeks. Five patients (38%) achieved partial remissions and five patients (38%) had no response. There was no difference in the response rate to nitrogen mustard and the BCNU-melphalan combination. Severe side effects to nitrogen mustard, however, precluded its further use in this study. The major cause of death in patients was intracerebral metastases, raising the question of prophylactic brain irradiation in future studies. Studies of the recovery rate of peripheral blood neutrophil, platelet, and peripheral blood and bone marrow CFU-C suggest that autologous bone marrow infusion may be of benefit in shortening hematopoietic recovery following intensive chemotherapy.

Topics: Adolescent; Adult; Antineoplastic Agents; Bone Marrow Transplantation; Brain Neoplasms; Carmustine; Cell Survival; Colony-Forming Units Assay; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Lymphatic Metastasis; Male; Mechlorethamine; Melanoma; Melphalan; Middle Aged; Transplantation, Autologous

Hyperthermic isolated extremity perfusion has been undertaken in 117 patients with advanced melanoma of the extremities from october 1979 to may 1981. Perfusion is indicated in cases above level III and tumor thickness above 1,5 mm. Among the cytostatic agents used were melphalane, melphalane and dactinomycin, nitrogen mustard/dactinomycin, as well as DTIC, cis-platinum and the combination of cis-platinum and dactinomycin. All cytostatics lead to tumor regression, as observed on tumors left in situ. Longterm results have yet to be awaited. While melphalane may be perfused at 42 degrees C, the cisplatinum perfused extremity should not be heated to above 40 degrees C because permanent neurological damage may be induced. For this reason maximal hyperthermia is reached before the cytostatic agent is introduced and has to be lowered when the drug is added.

Topics: Antineoplastic Agents; Arm; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Dacarbazine; Dactinomycin; Drug Therapy, Combination; Hot Temperature; Humans; Leg; Mechlorethamine; Melanoma; Melphalan; Skin Neoplasms

The optimal single dosage of melphalan in isolation perfusion of the limbs for malignant melanoma was assessed. For this purpose a method to determine the volume of the isolated region in the individual patient and a grading system for the reaction of the normal tissues were introduced. A strictly standardized pharmacosurgical routine was developed that permitted an analysis of the correlation between dosage and the grade of toxic reaction in 90 perfusions. The optimal dosage of a cytostatic drug was considered to be the highest amount tolerated at an acceptable risk. Melphalan at 10 mg/l perfused tissue was determined as the likely optimum. This dose provoked remarkably little variation in toxicity, all reactions falling within a safe range. No exception to the applicability of this dosage was encountered.

Topics: Arm; Body Weight; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Drug Administration Schedule; Extremities; Humans; Leg; Melanoma; Melphalan

Topics: Adult; Female; Humans; Male; Melanoma; Melphalan; Nurse-Patient Relations; Professional-Family Relations; Terminal Care

Unscheduled DNA synthesis (UDS) indicated by melphalan was studied in freshly collected tumor cells from human melanoma metastases. Comparative studies were done on human bone marrow blast cells. Significant levels of UDS comparable with those in myeloblasts were found in only two of eight melanoma cell populations. This difference between melanoma and blast cells was not related to different cellular uptake of melphalan. When UDS was induced by ultraviolet irradiation, significant levels of UDS were found in all melanoma and blast cell populations studied. Also, in a human melanoma cell line, high levels of UDS were found after exposure to ultraviolet irradiation, while treatment with melphalan did not result in detectable levels of UDS. Possible explanations for the divergent results of UDS in melphalan-exposed melanoma cells are discussed.

Topics: Bone Marrow; Cell Line; DNA Repair; DNA Replication; DNA, Neoplasm; Female; Humans; Hydroxyurea; Male; Melanoma; Melphalan; Neoplasm Metastasis; Ultraviolet Rays

The in vivo response of B16 melanoma and Lewis lung carcinoma to combinations of hyperthermia and graded doses of CCNU or Melphalan was studied. To obtain dose-response curves and quantitative comparisons of different treatments, an agar-colony assay was used to measure survival of cells from excised tumours. For heating experiments, the use of 2 tumours per animal, one heated and one not, allowed all other factors to be kept constant. When tumours were immersed in a water-bath at 43 degrees C for 1 h, Thermal Enhancement Ratios (TER) measured from the slopes of the dose-response curves were up to 1.6 for CCNU and 2.4 for Melphalan. Direct heat killing of about 1 decade was seen for 1 h at 43 degrees C. The anaesthetic Saffan also enhanced drug cell kill; the largest Dose Modifying Factor (2.7) was measured for Melphalan in the Lewis lung tumour. The duration of heating, and waterbath temperature, both influenced the enhancement of cell killing by CCNU, as did the time of excision of tumours between 0 and 3 1/2 h after treatment. There was no difference in effect between 3 1/2 and 24 h. The interaction between heat and CCNU varied if the interval between them was altered. The maximum effect was found if the heat and drug were given in close sequence.

Topics: Animals; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Hot Temperature; Lomustine; Lung Neoplasms; Male; Melanoma; Melphalan; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Nitrosourea Compounds; Temperature; Time Factors

The tourniquet infusion method was compared with hyperthermic perfusion in canine limbs by using Adriamycin, actinomycin-D, and melphalan. Tourniquet infusion provided comparable tissue levels with Adriamycin and significantly higher levels with actinomycin-D and melphalan in the treated extremity than hyperthermic perfusion with the same drugs and dosages. Higher systemic leak was observed, more so with melphalan, with the tourniquet infusion method. Tourniquet infusion has caused complete regression of four malignant tumors involving extremities (one malignant melanoma, two Kaposi's sarcomas, one squamous cell carcinoma) and partial greater than 50% regression of nine tumors (three malignant melanomas, three squamous cell carcinomas, one malignant schwannoma, one malignant fibrohistiocytoma, one liposarcoma) followed by excision of residual tumor. Five patients with extremity sarcomas precluding adequate surgical margins were treated preoperatively with the this method. Longer follow-up is needed, as is a larger number of patients for a valid comparison of tourniquet infusion with hyperthermic perfusion.

Topics: Aged; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Dogs; Doxorubicin; Extremities; Female; Hindlimb; Humans; Infusions, Intra-Arterial; Male; Melanoma; Melphalan; Middle Aged; Sarcoma; Skin Neoplasms; Tissue Distribution; Tourniquets

From September 1969 through 1979, 68 patients with already locally metastasized malignant melanomas of the extremities were treated by hyperthermic regional perfusion and local excision(s). Of these, 53 patients could be evaluated after a follow-up of at least 2 years: 31 had been perfused with melphalan and 22 with melphalan in combination with actinomycin D. Local recurrence rates were about the same in both groups: 32 versus 33%. The same applied to the symptom-free interval between perfusion and local recurrence: about 12 versus about 13 months. Virtually all recurrences in both groups (90 versus 85%) were seen within 2 years. The interval between perfusion and systemic metastization was also roughly the same: about 25 versus about 23 months. These results indicate the need for better chemotherapeutics in order to achieve further improvement. The results of these perfusions were otherwise by no means disappointing, and hyperthermic regional perfusion is indicated in the treatment of patients with locally metastasized malignant melanomas.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Drug Therapy, Combination; Extremities; Female; Hot Temperature; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local

We investigated the effects of combinations of BCNU and misonidazole, and melphalan and misonidazole on growth delay in two human malignant melanoma xenograft lines grown in immune-deprived mice. Misonidazole on its own had no effect on the growth of these tumors, but combinations of BCNU-misonidazole and melphalan-misonidazole produced greater tumor growth delays than those produced by the cytotoxic drugs alone. This was accompanied by increased weight loss. Misonidazole in combination with melphalan also increases hemopoietic stem cell toxicity, but in the case of BCNU there was no enhancement of bone marrow toxicity at the dose chosen for tumor experiments.

Topics: Animals; Antineoplastic Agents; Bone Marrow; Carmustine; Cell Line; Drug Synergism; Drug Therapy, Combination; Female; Humans; Male; Melanoma; Melphalan; Mice; Mice, Inbred CBA; Misonidazole; Neoplasm Transplantation; Neoplasms, Experimental; Nitroimidazoles; Transplantation, Heterologous

Topics: Aged; Anesthesia; Chemotherapy, Cancer, Regional Perfusion; Female; Hot Temperature; Humans; Leg; Melanoma; Melphalan; Middle Aged; Monitoring, Physiologic

One hundred twenty-two clinically Stage I malignant melanoma patients were treated prospectively in a nonrandomized trial by hyperthermic isolation perfusion with l-phenylalanine mustard (l-Pam), regional lymphadenectomy (RL), and wide local excision (WLE) between April 1965 and July 1980. There were 31 males and 91 females. All primary lesions were retrospectively microstaged by Clark's levels and Breslow's thickness criteria by one of the senior authors. Morphologically, 71% were superficial spreading melanomas (SSM), 16.5% were nodular melanomas (NM), and 11.9% were acral lentiginous melanomas. Survival by microstaging and morphology are reported in Table 1. Eighty-one per cent of all patients were disease-free at five years. Twenty-three patients (18.8%) recurred and of these, 15 died of their disease. This included six of the seven patients with histologically positive lymph nodes. Complications were not only acceptable but preventable and will be discussed. Microstaging provides a valid basis by which to compare treatment regimens and, more importantly, a valid criteria by which to select treatment for a given patient. These data compare favorably with other reported series. At the time these studies were initiated, five-year survivals for clinically Stage I and II melanoma were roughly 55% and 15%, respectively. Existing data clearly indicate that hyperthermic isolation perfusion with RL is superior to WLE and warrants further study in selected patients.

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Hot Temperature; Humans; Male; Melanoma; Melphalan; Neoplasm Recurrence, Local; Prospective Studies

Human melanoma xenografts in immune-deprived mice have been used to assess the value of the agar diffusion chamber for chemosensitivity testing. Tumor cells were treated with melphalan, Adriamycin, or methyl trans-1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea either as solid tumors growing in mice or as suspensions in agar in i.p. diffusion chambers. Survival of clonogenic human tumor cells was measured by the agar diffusion chamber assay in both cases. Cell survival curves were log-linear for treatment of tumor cells in vivo or in the chambers. For melphalan the slopes of survival curves were significantly greater for treatment in the chambers than as solid tumors in vivo, but for methyl trans-1-(2-chloroethyl(-3-(4-methylcyclohexyl)-1-nitrosourea or Adriamycin, they were indistinguishable. Experiments with [14C]melphalan showed that the levels of drug achieved were less inside the diffusion chambers than in the tumors in vivo so that the sensitivity of tumor cells to melphalan was much greater when they were treated in chambers. The differences in drug exposure and in cellular chemosensitivity between chambers and tumors suggest caution in the interpretation of drug testing using this system, but the log-linear nature of the dose-response curves is an important feature which may be useful in the eventual development of optimal chemosensitivity testing systems.

Topics: Agar; Animals; Antineoplastic Agents; Cell Survival; Diffusion; Doxorubicin; Drug Evaluation, Preclinical; Humans; Melanoma; Melphalan; Mice; Neoplasm Transplantation; Semustine; Transplantation, Heterologous

Topics: Arm; Chemotherapy, Cancer, Regional Perfusion; Female; Hot Temperature; Humans; Leg; Male; Melanoma; Melphalan

Melphalan resistance developed previously in a human melanoma cell line (MM253) could not be further increased. Cross-resistance was found to nitrogen mustard but not to ultraviolet light radiation. A clone of MM253 had the same drug sensitivity and heterogeneous chromosome complements as did the parent culture. The melphalan-resistant cells (MM253-12M) had 2.6-fold the D0, 1.5-fold the size, 1.3-fold the RNA content, 1.4-fold the protein content, and 2.6-fold the DNA content of the sensitive parent line. There was no evidence for activation or detoxification of melphalan by intact melanoma cells or by mouse liver microsomes competent for the activation of other drugs. Melphalan transport was similar in both cell lines, reaching a steady-state level 3 times the concentration in the medium after 2.5 min. Both lines covalently bound the same total amount of [3H]melphalan per cell, but in MM253-12M a 50% decrease in binding to DNA was almost sufficient to account for the increase in resistance. The level of melphalan-induced DNA interstrand cross-links, which were heat labile but not alkali labile, reached a maximum during the 4-hr treatment period and then declined slowly. The degree of cross-linking in MM253-12M was 50% less than that in MM253. Unlike ultraviolet light, methyl methanesulfonate, and nitrogen mustard, melphalan at equitoxic doses did not damage the DNA sufficiently to immediately inhibit DNA synthesis. Although both lines were proficient for repair of ultraviolet light and methyl methane sulfonate damage, melphalan did not induce significant levels of DNA repair synthesis and had little effect on the rate of DNA chain elongation. In MM253 cells, strand breaks were detected only at high melphalan doses; MM253-12M formed breaks more readily. This evidence suggests that the cross-linking events and that developed resistance arises from decreased susceptibility to DNA to this damage.

Topics: Biological Transport; Cell Line; Cross-Linking Reagents; DNA; DNA Repair; Drug Resistance; Humans; Melanoma; Melphalan; Mutation; Neoplasm Proteins; Neoplasms, Experimental; RNA; Time Factors

Topics: Aminoacridines; Amsacrine; Animals; Antineoplastic Agents; Carmustine; Dacarbazine; Drug Therapy, Combination; Leukemia L1210; Male; Melanoma; Melphalan; Mice; Mice, Inbred Strains; Neoplasms, Experimental

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melanoma; Melphalan; Skin Neoplasms

From December 1978 through December 1980 a total of 81 patients with malignant melanoma of the extremities were treated by local excision, isolated regional hyperthermic perfusion and regional lymphadenectomy. The extracorporeal circuit was primed with 650 ml whole blood. Flow rates for the lower extremity were 494 +/- 38 ml/min. and 273 +/- 66 ml/min. For the upper extremity. The systemic pressure was 80 +/- 15 mm Hg. Limb temperatures were elevated to 42 degrees C. Intraoperatively there was one case of intima dissection, but no other serious complications. Post operatively one patient died one the 19th day due to congestive heart failure and in one patient a temporary loss of peroneal nerve function was noted. Delay in wound-healing was seen in five patients and 70 patients developed transitory erythema of the extremities. 75 patients are alive and free of disease. Of the 33 patients who underwent more than one operation prior to perfusion, six developed local recurrences or in-transit lesions.

Topics: Adult; Aged; Body Temperature; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Skin Neoplasms

The effect of prednisolone upon the therapeutic index of melphalan has been studied in a variety of laboratory systems. The anti-tumour action of melphalan was assessed for a human melanoma xenograft growing in immune-deprived mice, clonogenic cell survival and tumour growth delay being used as end-points. Normal tissue toxicity was assessed for human bone marrow colony-forming units, murine bone marrow colony-forming units, murine gastrointestinal crypt microcolony-forming cells, and mouse survival. Prednisolone had no anti-tumour effect when given alone, but increased the anti-tumour effect of melphalan significantly. No increase in the toxicity of melphalan to marrow or gut colony-forming cells could be demonstrated. However, mouse survival was significantly lower after treatment with the combination than with melphalan alone. This study supports the view that steroids may enhance the anti-tumour effect of some alkylating agents, but this may be at the expense of increased normal tissue toxicity in some circumstances.

Topics: Animals; Antineoplastic Agents; Cell Survival; Drug Interactions; Drug Therapy, Combination; Humans; Melanoma; Melphalan; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Neoplasms, Experimental; Prednisolone

From December 1978 to February 1981 91 regional hyperthermic perfusions with melphalan (1.0 or 1.5 mg/kg body weight) were performed in 87 patients with malignant melanoma of the extremities. During a one-hour perfusion with whole blood at an intramuscular temperature of 42 degrees C the flow rate was 264 +/- 62 ml/min in the upper and 495 +/- 42 ml/min in the lower limb. Apart from one intima dissection there were no serious intraoperative complications. Postoperatively one female patient died on the 19th day from acute right heart failure with severe bone marrow suppression. In six patients intransigent metastases appeared after an average of six months. One patient developed lung metastases 7 months postoperatively from which he died. Seventy-nine patients remained free of tumour during the observation period.

Topics: Adult; Aged; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Hot Temperature; Humans; Intraoperative Complications; Male; Melanoma; Melphalan; Middle Aged; Postoperative Complications; Skin Neoplasms

When human melanoma cells are lysed in a neutral buffer they release from the chromosomes double-stranded DNA replication intermediates. We have now examined the effect of a bifunctional alkylator (melphalan) on the formation of these intermediates. After treatment for 25 min there is little or no release of double-stranded DNA intermediates from the chromosomes. When the cells are washed free of the drug and cultivated further there is a resumed formation of the DNA intermediates. This is paralleled by the finding that the cells, when the drug is removed, after a time-lag, regain the capacity to proliferate.

Topics: Cell Division; Cells, Cultured; DNA Replication; Humans; Kinetics; Melanoma; Melphalan; Thymidine; Tritium

Topics: Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Follow-Up Studies; Hot Temperature; Humans; Male; Melanoma; Melphalan; Neoplasm Recurrence, Local; Neoplasm Staging; Sex Factors

In a total of 1,828 determinations, urinary excretion of 5-S-Cysteinyldopa was studied over a period of three years in 384 patients treated for melanoma or with metastases of malignant melanoma. By serial investigations the excretion of 5-S-Cysteinyldopa was compared to the course of the disease. In the case of small and circumscribed metastases which could be eliminated by surgical treatment, the excretion of 5-S-Cysteinyldopa remained normal. When the disease became generalized, an increase of the urinary excretion of 5-S-Cysteinyldopa prior to the clinical manifestation of the metastases was observed in only four out of 26 cases. In the remaining cases, the increase of 5-S-Cysteinyldopa coincided with the manifestation of metastases, or the excretion of the substance became pathological when the metastases were already conspicuous. In five patients, the urinary excretion of 5-S-Cysteinyldopa remained normal inspite of widespread disease. Therefore, its diagnostic value seems to be similar to that of the "common" laboratory investigations the results of which are only pathological when the disease has already become generalized. Our investigations demonstrate that serial investigations of the urinary excretion of 5-S-Cysteinyldopa only rarely indicate melanoma metastases prior to their clinical manifestation. In cases of early metastasing melanoma, all common laboratory investigations are of limited value. BSR and GGT levels which become pathological very early in the course of the disease are so sensitive that slightly pathological levels may be ambiguous. In these cases, however, pathological levels of 5-S-Cysteinyldopa most probably will indicate a widespread disease.

Topics: BCG Vaccine; Cysteinyldopa; Dihydroxyphenylalanine; Female; Humans; Male; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms

Topics: Chemotherapy, Cancer, Regional Perfusion; Hot Temperature; Humans; Leg; Melanoma; Melphalan; Skin Neoplasms

An in vitro chemosensitivity test has been applied to malignant melanoma cells from 5 patients. The tumour cells were first grown as xenografts in immune-suppressed mice, so that the results of the in vitro test could be compared with precise measurements of the sensitivity of the melanoma cells when exposed to chemotherapeutic drugs in vivo in the mouse. The in vitro assay involved exposing the tumour cells to each of 8 drugs, after which cell survival was determined by colony assay in soft agar. Dose-response curves were obtained and the surviving fraction at drug levels estimated to be achieved in man was used as a measure of in vitro drug sensitivity. Significant differences among the 8 drugs were detected, and these accorded with clinical experience. The correlation of in vivo (in the mouse) and in vitro sensitivities to Melphalan and MeCCNU was also significant.

Topics: Animals; Antineoplastic Agents; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Male; Melanoma; Melphalan; Mice; Neoplasm Transplantation; Semustine; Transplantation, Heterologous

The experimental synergism of melphalan with DTIC and the ability of transfer factor to improve immunocompetence were the basis of an attempt to improve therapeutic results in disseminated malignant melanoma. Sixty-four evaluable patients with disseminated malignant melanoma were treated in a 21-day cycle as follows: DTIC 250 mg/M2 intravenously days 1 to 5, Connaught BCG 6 X 10(8) organisms on days 7, 12, and 17 by scarification, and transfer factor 1 unit (10(9) lymphocytes equivalent, from immunocompetent relatives of patients) subcutaneously on day 12, with or without L-PAM 30 mg/M2 on day 1. Twenty-nine patients received L-PAM and 35 did not. Remission rates of 17% and 23%, respectively, occurred in these groups. An additional 15 patients received DTIC-BCG and three doses of transfer factor on days 7, 12, and 17 and had a remission rate of 20%. Remission duration and survival were compared to historical controls of 111 patients treated with DTIC and 89 treated with DTIC-BCG. Median survival on DTIC-BCG-Transfer Factor was seven months compared to four months for DTIC (P = .003) but did not differ from DTIC-BCG. Addition of L-PAM did not improve remission duration or survival compared to DTIC-BCG but enhanced myelosuppression and immunosuppression. A 60% increase in delayed type hypersensitivity to recall antigens occurred in this study compared to 34% with DTIC-BCG (P = .005). Prognosis and immunocompetence were not directly related. In summary, in this study, (1) transfer factor therapy did not enhance the clinical effects of DTIC-BCG, although it augmented delayed type hypersensitivity to recall antigens; and (2) L-PAM was not additive to DTIC in the treatment of disseminated malignant melanoma and may have abrogated the effect of immunotherapy.

Topics: Adult; Aged; BCG Vaccine; Blood Cell Count; Dacarbazine; Drug Therapy, Combination; Female; Humans; Immunocompetence; Immunotherapy; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Prognosis; Skin Tests; Time Factors; Transfer Factor

Seventy patients with invasive malignant melanoma confined to one limb were treated by isolated perfusion with 1-phenylalanine-dihydrochloride (melphalan) and regional lymphadenectomy between 1959 and 1979. Five patients were perfused twice. This treatment did not modify the results of appropriate local excision in early melanoma. Twenty-one patients with stage I disease have had 76 per cent 5-year survival. Forty-eight per cent of 29 patients with extensive local recurrent tumour showed marked tumour regression. Nine of these had subsequent local recurrence with a mean remission of 7 months. Survival in those who responded was 2 years longer than in those who did not. In 6 patients with slight local recurrence, and 19 patients with regional node metastases, response could not be assessed directly. Their 5-year survival was 52 per cent. There have been no deaths as a result of the procedure and no amputations. Mean postoperative hospital stay was 25 days. We conclude that this technique has a useful place in the palliation of extensive local recurrent melanoma.

Topics: Adolescent; Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Retrospective Studies; Skin Neoplasms

Twenty-one patients with recurrent malignant melanoma on the extremities were treated by regional hyperthermic perfusion with melphalan (Alkeran). Four patients had a second perfusion. The recurrence site was on the foot in one patient, on the lower part of the leg in 13 patients, below the mid-thigh in 6 patients and on the elbow in one patient. The temperature of the extremities was registered continuously during the perfusion. Perfusion was performed under hyperthermic conditions with a temperature of 40-41.0 degrees C i.m. The perfusion time was 2 hours. Alkeran was given in a dose of 0.9 mg/kg bodyweight for lower extremity perfusion and 0.45 mg/kg for upper extremity perfusion. Complete tumour regression or more than 50% tumour regression was registered in 8 out of the 10 patients with manifest tumour. As the first sign of recurrence after perfusion, 4 patients had local recurrence and 10 had systemic recurrence. Altogether one-third of the patients had local recurrences and half of the patients systemic recurrences. Local recurrences occurred after a median time of 8 months and systemic recurrences after a median time of 7 months. Nine patients are still alive after an observation time of 5.5 months to 44 months. Three patients are without any signs of recurrent disease.

Topics: Aged; Arm; Chemotherapy, Cancer, Regional Perfusion; Female; Hot Temperature; Humans; Leg; Lymph Node Excision; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Skin Neoplasms

There is now considerable evidence that heat can be used to destroy tumours. The metabolism of many types of cancer cell is selectively damaged at temperatures of 42-43 degrees C, and deficient tumour blood-flow at raised temperature represents a further exploitable Achilles heel. A striking feature of tumour heating is that metastases may regress with cure of the host; this has occurred with recurrent melanoma and sarcomas of the limbs. Heat acts synergistically with X-rays and some cytotoxic drugs to increase the therapeutic ratio for local tumour control. Guidelines for tumour heating are now being formulated against a strong experimental background in animal systems. The association of a wide variety of disciplines from oncology to electronics has already resulted in techniques for selectively treating human tumours at 50 degrees C and in internal heat applicators for insertion via natural passages. It is predicted that heat will achieve a place, most likely as an adjuvant, in cancer therapy. Work on animals and in vitro is of limited value in helping to define this place. The complexity of the tumour/host response to heat and the deficiencies in our knowledge of the biophysics of heating militate against early routine application of hyperthermia in the clinic.

Topics: Bacillus; Bacterial Toxins; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Diathermy; Evaluation Studies as Topic; Hot Temperature; Humans; Hyperthermia, Induced; Immunotherapy; Melanoma; Melphalan; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Streptococcus; X-Ray Therapy

The clinical picture and long-term results of the treatment of 123 patients with melanoblastoma of the limbs have been studied. 39 patients were subjected only to the surgical treatment, 84 patients with a developed tumor process were subjected to the combined treatment -- surgery with perfusional chemotherapy. 3 years survival has proved to be similar in both groups; (70.0% and 72.9%); 5 years survival has been 10% higher in the group subjected to the combined treatment (54.5% and 64.0%).

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Thiotepa

Topics: Adult; Antineoplastic Agents; Bone Marrow; Burns; Creatine Kinase; Electroencephalography; Etoposide; Female; Humans; Hyperthermia, Induced; L-Lactate Dehydrogenase; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasms; Peripheral Nervous System Diseases; Remission, Spontaneous; Tachycardia

In a Phase I study, melphalan 140 mg/m2 was administered to 8 patients with disseminated malignant melanoma. Marrow was removed from the patients immediately before melphalan administration and returned i.v. 8 h later. Studies on marrow culture and melphalan pharmacokinetics predicted that this was a safe time to administer non-cryopreserved marrow. Four patients received lower doses of i.v. melphalan without autologous marrow. In the group receiving autologous marrow the time for recovery of peripheral-blood granulocytes to 800/mm2 or greater was significantly less (P = 0.01) than in those not receiving marrow. In 7 patients the tumour showed evidence of response to the drug and there was 1 complete remission. This treatment deserves investigation in patients with tumours more sensitive to drugs than melanoma.

Topics: Adult; Bone Marrow Transplantation; Colony-Forming Units Assay; Female; Granulocytes; Humans; Leukocyte Count; Male; Melanoma; Melphalan; Middle Aged; Time Factors; Transplantation, Autologous

Autologous non-cryopreserved bone marrow infused 8 hours after an intravenous injection of melphalan, 140 mg/m2, accelerates bone marrow recovery. This effect is most noticeable in the recovery of peripheral blood granulocytes. Twenty patients with disseminated malignant melanoma were treated with this regimen: there were 12 responses, two of them complete but the toxicity of the treatment was not sufficient to justify using this method of treatment routinely since survival was little influenced by treatment (4-11 months). In 8 patients with disseminated neuroblastoma, high dose melphalan/autograft was used in a program of combined modality treatment. Three of the patients are disease free at 16, 11 and 6 months and in one the disease is 'static', not having grown for 13 months. The treatment for this tumour deserves further exploration, and perhaps similar treatment ought to be explored for other tumours.

Topics: Bone Marrow Transplantation; Humans; Leukocyte Count; Melanoma; Melphalan; Neuroblastoma; Neutrophils

The best combination and schedule for dacarbazine and melphalan with the Harding-Passey melanoma in C3D2F1 mice is achieved when dacarbazine is administered first, followed by melphalan, given on either the day of dacarbazine therapy or the first three days after dacarbazine is given. When dacarbazine is given first, followed by melphalan on day 0, 1, 2, or 3, the effect of the two drugs is considerably more than additive. Other schedules reduce the outcome to a simple additive effect, or to an outcome that is less than additive, in which the combination is less effective than melphalan used alone. The effect of variations in the order and schedule of drug administration should be investigated in future trials of cancer chemotherapeutic agents, since profound effects may occur with these variations.

Topics: Animals; Dacarbazine; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Female; Melanoma; Melphalan; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Neoplasms, Experimental; Skin Neoplasms; Triazenes

The effects of 5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC), 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU), and L-phenylalanine mustard (L-PAM) have been compared by using three i.p. transplanted mouse melanomas: the B16 melanoma in C57BL/6 mice; the Harding-Passey (HP) malanoma in BALB/c X DBA/2F1 (hereafter called CD2F1) mice; and the Cloudman S91 melanoma in DBA/2 mice. HP melanoma responds well to all three drugs. S91 responds only to L-PAM and MeCCNU. DTIC may accelerate death in mice bearing this tumor. B16 responds well to L-PAM and moderately well to MeCCNU and to multiple injections of DTIC. The best response to DTIC and MeCCNU is given by HP, while the best response to L-PAM is given by S91. Tumor cell-doubling times were found to be 1.5 days for B16, 2 DAYS FOR HP, and 3 days for S91. HP would seem to be the most responsive malanmoma with respect to the 3 agents studied. This may be due to an interaction between the chemotherapeutic agents and the host immune response, since the HP tumor arose in a noninbred mouse and is thus nonsyngeneic with the CD2F1 host. All three tumors appear to be interesting biological models for studying drug combinations and combined therapeutic modalities against melanoma.

Topics: Animals; Cell Count; Dacarbazine; Female; Melanoma; Melphalan; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Nitrosourea Compounds; Semustine; Time Factors; Transplantation, Isogeneic; Triazenes

Chemotherapy was administered in the immediate postoperative period to seventy patients (52 with melanomas and 18 with sarcomas) after a total of eighty-seven major operations, with no morbidity or mortality traceable to the chemotherapy. There was no apparent interference with wound healing or what would be considered a normal postoperative course. Fourteen of these patients (5 with melanomas and 9 with sarcomas) received a combination of radiation anc chemotherapy initiated in the postoperative period, and it was tolerated well. This combination appears to be safe, provided the field of radiation is not so large that is may add significantly to the myelosuppressive effect of chemotherapy and the dosage of concomitantly administered radiopotentiating agent(s) is reduced. Sixteen patients had Bacillus Calmette-Gúerin (BCG) immunotherapy in the immediate postoperative period without complications. This policy of a tight interweaving of modalities is safe, has the theoretic advantage of an earlier concerted attack on microscopic residual tumor, and appears particularly promising in sarcomas.

Topics: BCG Vaccine; Dacarbazine; Estramustine; Humans; Melanoma; Melphalan; Radiotherapy Dosage; Sarcoma; Skin Neoplasms

Eleven years have elapsed since we first added heat to regional perfusion for treatment of melanoma of the extremities. This report describes briefly our laboratory findings and our technique of hyperthermic perfusion and brings up to date the survival figures for the 165 patients (185 perfusions) which were originally reported in 1975 (Stehlin et al., Surg. Gynecol. Obstet., 122: 3--14, 1966). A dramatic increase in the survival rate is documented for those patients with recurrent melanoma confined to the extremities.

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Hot Temperature; Humans; Immunity; Melanoma; Melphalan; Neoplasm Metastasis; Recurrence; Skin Neoplasms

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Hot Temperature; Humans; Melanoma; Melphalan; Skin Neoplasms

Report on the application of a dinitrochlorobenzene ointment of 61 postoperative melanoma patients exhibiting clinical stages I and II. After contact sensitization the erythemogenic threshold concentrations of DNCB were mostly found in the range of 0,05% and 0,1%. Patients with reactions at low concentrations of 0,01% and 0,05% DNCB were in the mean 8 years younger than those with reactions at 0,1% and 0,5%, but no connection to different stages of malignant melanoma could be evaluated. 3 melanoma patients suffering from skin metastases were treated by epifocal DNCB-application. One of them became clinically tumor free since more than 1 year, whereas the two other exhibiting multicentric and/or profound tumor growth did not respond. In a 82-year-old wife a superficial lentigo maligna melanoma disappeared by DNCB-application. In none of the 61 cases we observed a "tumor enhancement" after immunoprophylaxis or adjuvant immunotherapy with DNCB. The DNCB-method in malignant melanoma is yet in the experimental stage and is not recommended for general use in practice.

Topics: Adult; Aged; Dinitrochlorobenzene; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Nitrobenzenes; Postoperative Care; Skin Neoplasms

In seven human melanoma cell lines and one human fibroblast strain some correlation of resistance to cell killing was found with two bifunctional alkylating agents (melphalan, chlorambucil) and three monofunctional agents (4(5)-(3,3-dimethyl-l-triazeno)imidazole-5(4)-carboxamide (DTIC), methylmethane sulphonate (MMS) and N-methyl-N1-nitro-N-nitrosoguanidine (MNNG), but little cross-resistance was found between these two groups of agents or with cytosine arabinoside (ara-C). In contrast to previous studies with rodent tumours, potentially synergistic (chloroquine, arginine) or antagonistic (ascorbic acid, leucine) compounds did not affect the toxicity of melphalan in a human melanoma cell line. In two melanoma lines DTIC induced patterns of DNA damage (inhibition of semi-conservative synthesis) and repair (strand breaks and repair synthesis) similar to, but not identical with, those induced by the methylating agent MMNG. These results suggest that a methylating species is derived from DTIC but has a different reactivity toward DNA compared with MNNG.

Topics: Animals; Cell Survival; Cells, Cultured; Cytarabine; Dacarbazine; DNA; DNA Repair; DNA, Neoplasm; Fibroblasts; Humans; Melanoma; Melphalan

Topics: Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Drug Therapy, Combination; Extremities; Female; Hot Temperature; Humans; Male; Melanoma; Melphalan; Paralysis; Remission, Spontaneous; Sarcoma; Soft Tissue Neoplasms

7 patients with advanced malignant melanoma who were given cyclophosphamide (500 mg intravenously) 7 days before a high dose of melphalan (140 mg/m2) had a more rapid recovery of the peripheral white-cell count than did 4 patients who received melphalan alone. "Priming" by cyclophosphamide might be a practicable means of offsetting the bone-marrow toxicity of some chemotherapy regimens and it may permit higher doses of drugs to be given safely.

Topics: Blood-Brain Barrier; Bone Marrow; Bone Neoplasms; Cyclophosphamide; Drug Evaluation; Drug Therapy, Combination; Humans; Injections, Intravenous; Leukocyte Count; Leukocytes; Melanoma; Melphalan; Neoplasm Metastasis; Premedication; Skin Neoplasms

Twelve consecutive treatments of a human melanoma cell line (MM253) with melphalan gave a subline (MM253-12M) which was five times more resistant to melphalan with respect to survival. In contrast to mustard-resistant rodent cells, the MM253-12M line had a higher stemline number than the parent line while growth rate and cell and colony morphology were unchanged. A further melphalan treatment following attempted mutagenesis with UV did not increase resistance. In a comparison of these two lines with two melanoma lines derived from other patients and the rat XC line, resistance was correlated with lower frequency of melphalan-induced chromosome aberrations, determined 48 h after a 4-h exposure to melphalan (3 microgram/ml). In the two cell lines studied, aberration-free metaphase cells from treated culture had fewer chromosomes than untreated cells. DNA synthesis studied in the 4- to 72-h period after treatment was inhibited to the same extent in MM253 and MM253-12M cells at 4 microgram/ml but to a greater extent in the sensitive line at 0.1-1.5 microgram/ml. During the first hour of treatment at 0.1-1.5 microgram/ml, DNA synthesis in MM253 appeared to be enhanced.

Topics: Cell Line; Cell Survival; Chromosome Aberrations; Chromosomes; DNA, Neoplasm; Humans; Melanoma; Melphalan; Metaphase

Topics: Chemotherapy, Cancer, Regional Perfusion; Drug Evaluation; Humans; Melanoma; Melphalan; Skin Neoplasms

The influence of anaesthetics on the in vivo response of B16 melanoma to melphalan was studied using an in vitro cell-survival assay. Three anaesthetics were used, Saffan (Althesin) Sagatal (Nembutal) and Hypnorm. When Saffan was administered to tumour-bearing animals before melphalan there was a significant increase in tumour-cell kill. This effect was not observed with Sagatal or Hypnorm. Maximum increase in tumour-cell kill was achieved when Saffan was administered about 1 h before melphalan, and was dependent on Saffan dose. Clonogenic tumour-cell repopulation after melphalan was rapid (TD - 1 day) and the rate was similar from 2 levels of cell kill. When Saffan was combined with melphalan the repopulation rate was the same as with melphalan alone, and the increased cell kill was reflected in increased growth delay. The in vitro response of B16 melanoma cells to melphalan was unaltered by pretreatment with, or simultaneous exposure to Saffan. The results suggest that the mechanism of the enhanced cell kill in vivo is probably due to an indirect systemic effect, rather than a direct effect on the tumour cells.

Topics: Alfaxalone Alfadolone Mixture; Anesthetics; Animals; Butyrophenones; Cell Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Female; Fentanyl; Melanoma; Melphalan; Mice; Neoplasms, Experimental; Pentobarbital

Uracil and thymine alpha-methylene-gamma-lactones and related derivatives have been synthesized as novel potential alkylating antitumor agents. The synthesis of these compounds involved the convenient Reformatsky-type reaction between ethyl-alpha-(bromomethyl)acrylate and the proper pyrimidinyl ketones. Preliminary in vivo tumor assay indicated that these compounds were active against the Walker 256 carcinosarcoma in rats and the P-388 lymphocytic leukemia as well as the B-16 melanotic melanoma in mice at 2.5-25 mg/kg.

Topics: Animals; Antineoplastic Agents; Carcinoma 256, Walker; Lactones; Leukemia, Experimental; Male; Melanoma; Mice; Neoplasms, Experimental; Rats; Thymine; Uracil

Topics: Animals; Antineoplastic Agents; Chlorambucil; Drug Synergism; Goats; Humans; Immunoglobulins; Immunotherapy; Melanoma; Melphalan; Neoplasm Metastasis; Nitrogen Mustard Compounds; Skin Neoplasms; Vincristine

The survival of four human fibroblast strains and seven malignant melanoma cell lines was determined by the colony formation method following 4-hr treatment with various concentrations of melphalan, with or without simultaneous exposure to hyperthermia (42 degrees). The two amelanotic melanoma lines (MM127 and MM253) were 10 times more sensitive to melphalan at 36 degrees than were the four fibroblast strains, the five pigmented melanoma lines being of intermediate sensitivity. Sensitivity to melphalan was usually accompanied by sensitivity to heat, while combined treatment was not only synergistic in most lines but increased the differential between fibroblasts and melanoma cells. Survival studies carried out at 36 degrees, 40 degrees, 42 degrees, and 44 degrees, using human fetal lung fibroblasts and MM253 cells, showed that 42 degrees gave the greatest differential effect and allowed reasonable survival of the normal cells. Time-survival comparison of the same two lines demonstrated that there was no advantage in prolonging hyperthermia unless melphalan was used. A more convenient method for determination of survival was developed based on thymidine uptake of colonies grown in Linbro wells.

Topics: Cell Line; Cell Survival; Cells, Cultured; DNA; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Fibroblasts; Hot Temperature; Humans; Melanoma; Melphalan; Temperature; Time Factors

This paper reviews the changing concepts in the treatment of patients with malignant melanoma localized on the arm or leg. In addition to conventional surgical treatment, isolated regional perfusion of the extremities is discussed. An evaluation is presented of clinical and histological criteria applied to determine indications for conventional surgical treatment and for perfusion. It is maintained that isolated regional perfusion of arm or leg should be performed when the primary tumor meets one of the following criteria: (1) depth of tumor invasion beyond the papillary layer (Clark levels III, IV and V); (2) vascular invasion; (3) tumor diameter exceeding 1 cm; (4) ulceration. If none of these four criteria applies, conventional surgical treatment alone has proved to give very good results.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Evaluation Studies as Topic; Extremities; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Invasiveness; Recurrence; Skin Neoplasms; Skin Ulcer

16 patients with cutaneous or subcutaneous melanoma recurrence on an extremity were treated with regional perfusion with Melphalan. 18 perfusions were performed on 15 patients with stage II disease, that is with tumor growth restricted to an extremity including possible regional node metastases. All patients except two had new recurrences within the observation time. However, many of the patients had been treated surgically for recurrences once or several times previously. By comparing the length of the recurrence-free period following surgery alone with that following surgery plus perfusion in the same patients it was shown that perfusion treatment gave a significant extension of the recurrence-free time. Four perfusions were performed on patients in stage III, that is those with distant metastases. These perfusions gave a moderate or good temporary palliation as regards to tumor growths on the extremity. The traditional treatment for melanoma recurrences on an extremity has been surgical excision or less often amputation. An analysis of the literature shows that perfusion, usually combined with excision, seems to give definitely better results than surgical excision alone. There is evidence to suggest that perfusion treatment is even superior to amputation as regards survival; if so an immunological mechanism might be responsible for this effect.

Topics: Amputation, Surgical; Chemotherapy, Cancer, Regional Perfusion; Drug Evaluation; Evaluation Studies as Topic; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Skin Neoplasms

Topics: Adult; Aged; Female; Hot Temperature; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Perfusion

Asaley is an L-leucine derivative of sarcolysin which is more active against some rodent tumors. Studies in the USSR demonstrated activity in patients with ovarian and breast carcinoma, Hodgkin's disease, and multiple myeloma. This study in 73 evaluable patients indicated that an appropriate oral dose for patients with adequate bone marrow is 800 mg/M2/day X 4 days at 5-6 week intervals. The most common toxicities were myelosuppression, nausea, and vomiting. Antitumor activity was observed in 2 of 24 evaluable patients with melanoma, and stabilization of previously progressive disease was observed in patients with adenocarcinoma of the colon, multiple myeloma, lymphoma, breast carcinoma, and thyroid carcinoma. Responses were minimal and of short duration but most of the patients had received extensive prior therapy.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Animals; Bone Marrow; Colonic Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Multiple Myeloma; Nausea; Neoplasm Metastasis; Neoplasms; Rats; Remission, Spontaneous; Vomiting

Because of their initial appearance on extremities, malignant melanomas lend themselves to isolated chemotherapeutic perfusions. Perfusion is attractive because one can deliver effective cytotoxic drugs without systemic toxicity. We are reviewing 20 patients treated between 1960 and 1973 with isolated perfusion. Melphalan (L-phenylalanine mustard) was the drug of choice. Eleven of the 20 patients had previous surgical treatment. Three of the 11 patients are still alive from 27 to 72 months postperfusion. Eight died after an average survival time of 33 months. Of the seven patients who underwent perfusion as primary therapy, four patients are alive from 25 to 76 months postperfusion, and three died after an average survival time of 34 months. There is direct correlation between stages and levels of melanoma, and perfusion and prolonged survival time.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Lymph Node Excision; Lymphatic Metastasis; Male; Melanoma; Melphalan; Methotrexate; Middle Aged

Topics: Adult; Female; Humans; Leukemia, Myeloid, Acute; Melanoma; Melphalan; Neoplasms, Multiple Primary

Excision of the primary and isolation-perfusion with 1-phenylalanine mustard was the treatment in 199 patients with invasive Stage I melanoma of the extremities with the goal of improving regional disease control and long-term survival. The determinant survival in patients followed 5-15 years was 83%; Berkson-Gage survivals were 98% at 2 years, 88% at 5 years, and 84% at 10 years. The site of first recurrence was determined in all 49 (25%) patients who failed treatment: three (2%) developed local recurrence, six (3%) developed intransit recurrence, 24 (13%) developed positive regional lymph nodes, 15 (8%) developed systemic metastases, and one developed local recurrence plus positive regional nodes. Of these 49 patients failing treatment, 15 (31%) are currently surviving with no evidence of disease after retreatment of the recurrence. These data are compared to historical controls in the literature. It is concluded that regional control rates are improved by perfusion and that survival has probably been improved. In 14 patients treated by perfusion without local excision, regional control and survival was poor. Single drug (L-PAM) perfusion with the techniques employed is effective in controlling regional subclinical disease, but the primary should be widely excised.

Topics: Adolescent; Adult; Age Factors; Aged; Arm; Chemotherapy, Cancer, Regional Perfusion; Child; Female; Foot; Humans; Leg; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Retrospective Studies; Sex Factors; Skin Neoplasms

Regional perfusion has been utilized in the treatment of accessible melanomas for many years. This series of 245 patients, which encompasses over ten years of experience, is presented to reevaluate the results of regional perfusions in melanomas, and perhaps to redefine the indications for such a procedure. Fifty-nine patients died from three months to over five years following the procedure, and six of the deaths were from diseases other than melanoma. The overall survival in stage I disease was 93%; stage II, 68%; and stage III, 41%. There were no survivors in stage IV. Nearly all of the recurrences and deaths from disease were seen within two years of the perfusion. These results are similar to others, and 10% to 15% better than those of conventional methods. Indications are now more definite, and include most invasive melanomas in an area accessible to perfusion technique, except in very elderly and poor risk patients, those with severe arteriosclerosis in the area concerned, and those with widespread metastases.

Topics: Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Melanoma; Melphalan; Postoperative Complications; Recurrence; Retrospective Studies

Parenteral amygdalin was found to be ineffective in C57BL/6 mice with B16 melanoma and in AKR mice with BW5147 lymphatic leukemia, in doses ranging from 50 to 5000 mg/kg.

Topics: Amygdalin; Animals; Female; Leukemia, Experimental; Melanoma; Melphalan; Mice; Mice, Inbred AKR; Mice, Inbred C57BL; Neoplasms, Experimental; Nitriles

Two forms of therapy employed for treatment of patients with recurrent melanoma limited to the extremity, and carried out during different intervals of time, are presented. Perfusion of the involved extremity with phenylalanine mustard has resulted in a 5-year survival rate of 28% of 43 patients. A second group of 25 patients has been treated by a four-stage immunotherapy program consisting of sensitization with intradermal BCG, followed in 6 weeks by intra tumor injection of BCG. A third stage involved the activation of the patients's lymphocytes, after removal by a blood cell separator, incubated in vitro with irradiated neuraminidase-treated melanoma cells and reintroduced into the patient either by subcutaneous or intratumor injection. The fourth stage of immunotherapy involves injection of an inoculum of irradiated neuraminidase-treated autochothonous tumor cells plus BCG injected intratumorally or subcutaneously. Sixteen of 24 patients receiving immunotherapy treatment program have experienced arrest of their disease lasting from 5 to 42 months.

Topics: Adult; Aged; Antigens, Neoplasm; BCG Vaccine; Extremities; Female; Humans; Immunotherapy; Lymphocyte Transfusion; Lymphocytes; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neuraminidase; Nitrogen Mustard Compounds; Perfusion; Skin Neoplasms; Transplantation, Autologous

Regional perfusion has been carried out in the limbs of a group of patients with recurrent melanoma, and has achieved disappearance of visible disease in the affected limb in 10 patients out of 28 (36%), prevention of local recurrence in five, and no effect on the disease in nine. This control of recurrent melanoma cost no mortality, but did carry a definite but acceptable morbidity.

Topics: Amputation, Surgical; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Neoplasm Recurrence, Local; Sex Factors; Skin Neoplasms; Thiotepa

Our studies show that the malignant melanoma cell in human beings is more sensitive to the lethal effect of heat than its normal counterpart, the melanocyte. Malignant melanoma of the extremities presents unique problems; at times, local control can be extremely difficult. The addition of heat to regional perfusion with melphalan has dramatically improved the objective response of melanoma. Complications rise as the tempreature and duration of perfusion increase. These risks must be weighed carefully against the volume and extent of tumor. One hundred and eighty-five hyperthermic perfusions have been perfomed on 165 patients. When done with meticulous attention to details, this procedure is accompanied by minimal morbidity and mortality. Hyperthermic perfusion is currently the best treatment for recurrent melanoma of the extremities and has almost eliminated the necessity for amputation. Perfusion is recommended as a prophylactic measure for the more deeply invasive primary lesions. It reduces the incidence of regional recurrence. A retrospective statistical analysis of survival rates of patients treated with nonheated and heated perfusion for recurrent melanoma, State IIIA, was conducted. If the experience of the heated group continues, which from a clinical standpoint appears likely, then a striking advantage of heated perfusion over nonheated perfusion will be demonstrated. This superiority in survival rates for the heated group is now three to one or 300 per cent. The most reasonable explanation for the improvement in survival time of patients in State IIIA is stimulation of the immune response. As a result of our experience with heated perfusion of limbs, we are investigating the possibility that systemic hyperthermia may enhance the antitumor effects of various chemotherapeutic agents on melanoma.

Topics: Acute Kidney Injury; Age Factors; Aged; Cell Line; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Hot Temperature; Humans; Hyperthermia, Induced; Male; Melanocytes; Melanoma; Melphalan; Neoplasm Metastasis; Pulmonary Embolism; Recurrence; Sex Factors

The survival of melanoma patients is directly related to the involvement of regional nodes and to the microscopic level of invasion of the tumor. During the past 10 years, with the increased use of aggressive surgical therapy (wide local excision or re-excision of the primary tumor and prophylactic dissection of predictably involved regional nodes) the 5-year survival rate has more than doubled. The 5-year survival has doubled in those patients with regional lymph node involvement who were infused for 5 days with L-phenylalanine mustard. Perfusion of the lower extremities with L-phenylalanine mustard has been abandoned at Vanderbilt. The potential aggressiveness of a specific melanoma can be predicted, and thus an appropriate treatment may be planned.

Topics: Adolescent; Adult; Aged; Arm; Child; Female; Head; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Neck; Neoplasm Metastasis; Retrospective Studies; Skin Neoplasms; Thorax

Nine patients with regionally inoperable malignant melanoma or soft tissue sarcoma were treated with combinations of intra-arterial chemotherapy, immunotherapy and operation or irradiation or both. Three of the heretofore untreatable patients with melanoma remain clinically free of detectable metastases at three years, three and one-half years and one and one-half years from their recurrence. One nodular melanoma remains well controlled two years after diagnosis, while an additional patient is free of disease several months after therapy. Two of the patients with melanoma died within a year of the onset of the recurrence but maintained the affected limb in useful condition until the time of their death. Two of the three patients with sarcoma remain free of disease at ten and four years. One patient who was known to have distant metastatic disease at the onset of the treatment currently is hospitalized for further therapy for tumor in the para-aortic lymph nodes.

Topics: Adult; Aged; BCG Vaccine; Chemotherapy, Cancer, Regional Perfusion; Dacarbazine; Dactinomycin; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Sarcoma

The most common causes of treatment failure in patients with malignant melanoma treated by surgical therapy alone are local or regional recurrences. These are presumed to be due to occult metastasis present at the time of the initial treatment. In an effort to control this occult regional disease, 202 patients with Stage I malignant melanoma underwent isolation-perfusion with 1-phenylalanine mustard between the years 1960 and 1970. The 2-5 and 10-year determinate survival rates were 98%, 86% and 83%, respectively. In these patients, 2% developed local recurrences, 3% developed intransit metastasis, 18% developed positive regional lymph nodes and 6% developed disseminated disease, as their first evidence of recurrence. Over 40% of these patients were benefitted by further therapy. When regional perfusion is used, the question of prophylactic lymph node dissection need not arise. There was one surgical death in this series and only a few patients had symptomatology referable to their limbs beyond 3 months.

Topics: Adolescent; Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Child; Extremities; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Postoperative Complications; Skin Neoplasms; Time Factors

Topics: Amputation, Surgical; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Lymph Node Excision; Lymphatic Metastasis; Male; Melanoma; Melphalan; Neoplasm Recurrence, Local; Postoperative Complications; Prognosis

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms

Topics: Chemotherapy, Cancer, Regional Perfusion; Clinical Enzyme Tests; Dactinomycin; Flavonoids; Histocytochemistry; Humans; Melanoma; Melphalan; NADH, NADPH Oxidoreductases; Oxidoreductases; Phosphoric Monoester Hydrolases; Radiotherapy Dosage; Skin Neoplasms; Time Factors

Topics: Cervical Vertebrae; Cobalt Radioisotopes; Cyclophosphamide; Female; Humans; Hyperbaric Oxygenation; Male; Melanoma; Melphalan; Methotrexate; Middle Aged; Neoplasm Metastasis; Radiography; Radioisotope Teletherapy; Radiotherapy Dosage; Vinblastine

Topics: Adenocarcinoma; Amides; Androstanols; Animals; Antineoplastic Agents; Cricetinae; Cyclohexanes; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Therapy, Combination; Estradiol; Female; Hydroxyurea; Imidazoles; Mammary Neoplasms, Experimental; Melanoma; Melphalan; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Osteosarcoma; Plasmacytoma; Progesterone; Rats; Sarcoma, Experimental; Triazenes

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Follow-Up Studies; Humans; Male; Melanoma; Melphalan; Neoplasm Recurrence, Local; Neuritis; Oxygenators; Postoperative Complications; Surgical Wound Dehiscence; Surgical Wound Infection; Thrombosis; Tourniquets

Topics: Antigens, Neoplasm; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Graft Rejection; Humans; Immunosuppression Therapy; Lectins; Lymphocyte Activation; Lymphocyte Depletion; Lymphocytes; Mechlorethamine; Melanoma; Melphalan; Prognosis; Streptolysins; Stress, Physiological

Topics: Adult; Aged; Arm; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Male; Mechlorethamine; Melanoma; Melphalan; Neoplasm Metastasis; Postoperative Complications; Skin Transplantation; Thiotepa

Topics: Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Humans; Melanoma; Melphalan; Neoplasm Recurrence, Local; Skin Neoplasms; Thiotepa

Topics: Adolescent; Amputation, Surgical; Female; Foot; Humans; Melanoma; Melphalan; Neoplasm Metastasis

Topics: Animals; Cyclophosphamide; Dihydroxyphenylalanine; Melanoma; Melphalan; Mice; Mice, Inbred BALB C; Neoplasms, Experimental; Radiation-Sensitizing Agents; Skin Neoplasms; Time Factors; Tritium

Topics: Humans; Lymph Nodes; Male; Melanoma; Melphalan; Middle Aged; Penile Neoplasms; Penis

Topics: Adult; Aged; Antineoplastic Agents; Chlorambucil; Colchicine; Cyclophosphamide; Cytarabine; Eye Neoplasms; Female; Floxuridine; Humans; Hydroxyurea; Idoxuridine; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Nitrogen Mustard Compounds; Nitrosourea Compounds; Skin Neoplasms; Vinblastine; Vincristine; Vulvar Neoplasms

Topics: Adolescent; Aged; Bone Neoplasms; Female; Hemangiosarcoma; Hodgkin Disease; Humans; Leukopenia; Lymphoma, Large B-Cell, Diffuse; Male; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Sarcoma, Ewing; Testicular Neoplasms; Thrombocytopenia; Tonsillar Neoplasms; Uterine Neoplasms

Topics: Animals; Anterior Chamber; Antibiotics, Antineoplastic; Choroid Neoplasms; Humans; Melanoma; Melphalan; Neoplasm Transplantation; Olivomycins; Rabbits; Thiotepa

Topics: Adult; Cervix Uteri; Female; Fluorouracil; Humans; Imidazoles; Melanoma; Melphalan; Neoplasm Metastasis; Prognosis; Uterine Cervical Neoplasms

Topics: Animals; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Creatinine; Female; Leukemia L1210; Male; Melanoma; Melphalan; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Neoplasms, Experimental; Rats; Sarcoma 180; Sarcoma, Experimental; Serotonin

Topics: Adult; Age Factors; Aged; Alabama; Biopsy; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Sex Factors; Skin Neoplasms

The presence of sex chromatin in a metastatic malignant melanoma from a male patient aged 26 who showed no evidence of any constitutional chromosome anomaly is described. A possible association between the apparently "female" origin of the tumour and the good response to therapy is considered.

Topics: Adult; Humans; Karyotyping; Male; Melanoma; Melphalan; Neoplasm Metastasis; Prognosis; Radioisotope Teletherapy; Sex Chromatin; Skin; Skin Neoplasms

Topics: Adult; Aged; Arm; Chemotherapy, Cancer, Regional Perfusion; Female; Hemangiosarcoma; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Oxygenators; Sarcoma; Sarcoma, Kaposi

Topics: Adult; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Lymph Node Excision; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms

Topics: Adolescent; Adult; Aged; Bone Neoplasms; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Child; Extremities; Female; Hemorrhage; Humans; Hypotension; Leukopenia; Lymph Node Excision; Lymphoma, Large B-Cell, Diffuse; Male; Melanoma; Melphalan; Methods; Middle Aged; Postoperative Complications; Sarcoma; Skin Neoplasms

Topics: Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melanoma; Melphalan; Neoplasms; Osteosarcoma; Skin Neoplasms; Thiotepa

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Lymph Node Excision; Male; Melanoma; Melphalan; Middle Aged; Skin Neoplasms; Thiotepa

Topics: Chemotherapy, Cancer, Regional Perfusion; Dioxoles; Humans; Hydrazines; Injections, Intra-Arterial; Melanoma; Melphalan; Vinblastine

Topics: Amputation, Surgical; Bone Marrow Diseases; Chemotherapy, Cancer, Regional Perfusion; Extracorporeal Circulation; Extremities; Fascia; Female; Hepatitis B; Humans; Lymph Node Excision; Lymphatic Metastasis; Male; Melanoma; Melphalan; Methods; Necrosis; Neoplasm Recurrence, Local; Neuritis; Prognosis; Thrombophlebitis

Topics: Adolescent; Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Child; Dactinomycin; Female; Humans; Leg; Male; Mechlorethamine; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Prognosis; Skin Neoplasms

Topics: Animals; Ascites; Cricetinae; Cyclophosphamide; Injections, Intraperitoneal; Injections, Subcutaneous; Lethal Dose 50; Melanoma; Melphalan; Neoplasm Transplantation; Neoplasms, Experimental

Topics: Biopsy; Chemotherapy, Cancer, Regional Perfusion; Female; Hot Temperature; Humans; Melanoma; Melphalan; Methods; Middle Aged; Neoplasm Metastasis; Skin Neoplasms; Thermography

Topics: Adult; Antineoplastic Agents; Catheterization; Chemotherapy, Cancer, Regional Perfusion; Female; Femoral Artery; Humans; Injections, Intra-Arterial; Iodine Radioisotopes; Melanoma; Melphalan; Methods; Radionuclide Imaging; Staining and Labeling

Topics: Humans; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis

Topics: Animals; Ascites; Cricetinae; Melanoma; Melphalan; Neoplasms, Experimental; Prognosis

Topics: Animals; Antineoplastic Agents; Melanoma; Melphalan; Mice; Sarcoma 37; Sarcoma, Experimental

Topics: Adult; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms

Topics: Arm; Burns; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Edema; Femoral Neoplasms; Foot Diseases; Hemangiosarcoma; Hemoglobinuria; Hemolysis; Hot Temperature; Humans; Leg; Melanoma; Melphalan; Neoplasm Metastasis; Sarcoma; Sarcoma, Ewing; Sarcoma, Kaposi; Time Factors

Topics: Adult; Animals; Cell- and Tissue-Based Therapy; Female; Humans; Immunosuppressive Agents; Lymph Nodes; Lymphocyte Transfusion; Lymphocytes; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasms; Skin Neoplasms; Spleen; Swine; Transplantation, Heterologous; Transplantation, Homologous

Topics: Carcinoma; Cecal Neoplasms; Cobalt Isotopes; Female; Fibrosarcoma; Humans; Kidney Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Maxillary Neoplasms; Melanoma; Melphalan; Multiple Myeloma; Myxosarcoma; Palliative Care; Radioisotope Teletherapy; Testicular Neoplasms

Topics: Adrenalectomy; Aged; Antineoplastic Agents; Breast Neoplasms; Bronchial Neoplasms; Cortisone; Cyclophosphamide; Drug Synergism; Ethinyl Estradiol; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Hydrazines; Hypophysectomy; Kidney Neoplasms; Lung Neoplasms; Male; Melanoma; Melphalan; Mesothelioma; Methotrexate; Middle Aged; Nandrolone; Neoplasm Metastasis; Ovarian Neoplasms; Podophyllin; Sarcoma; Thiotepa; Vinblastine

Topics: Antineoplastic Agents; Chlorambucil; Cyclophosphamide; Dactinomycin; Fluorouracil; Humans; Hydrazines; Hydroxyurea; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Melphalan; Methotrexate; Neoplasm Metastasis; Neoplasm Recurrence, Local; Perfusion; Vincristine

Topics: Adenocarcinoma; Ameloblastoma; Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Carcinoma; Carcinoma, Squamous Cell; Cyclophosphamide; Ethylenediamines; Facial Neoplasms; Fibrosarcoma; Glioma; Humans; Infusions, Parenteral; Mechlorethamine; Melanoma; Melphalan; Meningioma; Methotrexate; Osteosarcoma; Perfusion; Quinones; Retinoblastoma; Rhabdomyosarcoma; Sarcoma; Thiotepa

Topics: Bone Marrow Transplantation; Humans; Melanoma; Melphalan; Methotrexate; Transplantation, Autologous

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Skin; Skin Neoplasms

Topics: Antineoplastic Agents; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Fluorouracil; Head; Head and Neck Neoplasms; Humans; Leucovorin; Melanoma; Melphalan; Methotrexate; Mouth Neoplasms; Nasopharyngeal Neoplasms; Paranasal Sinus Neoplasms; Sarcoma; Thiotepa; Vinblastine

Topics: Adolescent; Adult; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Male; Melanoma; Melphalan; Middle Aged; Thiotepa

Topics: Amputation, Surgical; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Lymph Node Excision; Melanoma; Melphalan; Osteosarcoma; Sarcoma; Thiotepa

Topics: Adult; Arm; Axillary Artery; Chemotherapy, Cancer, Regional Perfusion; Female; Femoral Artery; Humans; Leg; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Prognosis; Skin Neoplasms

Topics: Humans; Melanoma; Melphalan; Skin Neoplasms

Topics: Blood; Cell Nucleus; Chemotherapy, Cancer, Regional Perfusion; Cytoplasm; Drug Therapy; Humans; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Thiotepa

Topics: Chemotherapy, Cancer, Regional Perfusion; Extracorporeal Circulation; Extremities; Humans; Melanoma; Melphalan; Thiotepa

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Mechlorethamine; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasms; Postoperative Complications; Surgical Procedures, Operative; Thiotepa; Toxicology; Wound Healing

Topics: Abdominal Neoplasms; Angiography; Breast Neoplasms; Geriatrics; Gold; Humans; Injections; Iodine Isotopes; Leukemia; Lymphatic Metastasis; Lymphatic System; Lymphography; Lymphoma; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Methotrexate; Neoplasms; Radioisotopes; Radionuclide Imaging; Retroperitoneal Neoplasms; Scandium; Thiotepa; Yttrium

Topics: Breast Neoplasms; Carcinoma, Bronchogenic; Dysgerminoma; Female; Gastrointestinal Neoplasms; Hodgkin Disease; Humans; Liver Neoplasms; Lymphoma; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Multiple Myeloma; Neoplasms; Ovarian Neoplasms; Sarcoma

Topics: Chemotherapy, Cancer, Regional Perfusion; Extracorporeal Circulation; Lymphatic Metastasis; Melanoma; Melphalan; Mice; Mustard Plant; Neoplasms; Neoplasms, Experimental; Pharmacology; Phenylalanine; Research

Topics: Adolescent; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Child; Chondrosarcoma; Dogs; Femur; Fibula; Hemangiosarcoma; Humans; Melanoma; Melphalan; Mesenchymoma; Neoplasms; Nitrogen Mustard Compounds; Osteosarcoma; Sarcoma; Sarcoma, Ewing; Ulna; Uracil

Topics: Abdomen; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Cyclophosphamide; Female; Geriatrics; Hodgkin Disease; Humans; Hypothermia; Hypothermia, Induced; Leiomyosarcoma; Mechlorethamine; Melanoma; Melphalan; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Pelvis; Rectal Neoplasms; Retroperitoneal Neoplasms; Uterine Cervical Neoplasms; Vaginal Neoplasms

Topics: Animals; Antineoplastic Agents; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Carcinoma, Krebs 2; Feeding and Eating Disorders; Leukopenia; Melanoma; Melphalan; Neoplasms; Neoplasms, Experimental; Pharmacology; Research; Sarcoma; Sarcoma, Experimental

Topics: Chemotherapy, Cancer, Regional Perfusion; Coccidioidomycosis; Dactinomycin; Drug Hypersensitivity; Drug Therapy; Hematologic Diseases; Humans; Melanoma; Melphalan; Mycetoma; Neoplasms; Sarcoma; Sepsis; Toxicology

Topics: Extremities; Humans; Melanoma; Melphalan; Perfusion

Topics: Crassulaceae; Humans; Melanoma; Melphalan; Surgical Procedures, Operative; Umbilicus

Topics: Antimitotic Agents; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Leg; Melanoma; Melphalan

Topics: Adolescent; Child; Geriatrics; Head and Neck Neoplasms; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mandibular Neoplasms; Maxillary Neoplasms; Melanoma; Melphalan; Multiple Myeloma; Neoplasms; Orbital Neoplasms; Plasmacytoma; Sarcoma; Sarcoma, Kaposi

Topics: Antimetabolites; Antineoplastic Agents; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Geriatrics; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Melanoma; Melphalan; Methotrexate; Mouth Neoplasms; Neoplasms; Neoplasms, Muscle Tissue; Nitrogen Mustard Compounds; Sarcoma; Toxicology; Triethylenemelamine

Topics: Aminopterin; Antineoplastic Agents; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Chlorambucil; Dactinomycin; Fibrosarcoma; Fluoresceins; Humans; Infusions, Parenteral; Injections, Intra-Arterial; Lymphoma; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Neoplasms; Pharmacology; Thiotepa; Toxicology

Topics: Bone Marrow; Bone Marrow Transplantation; Humans; Mechlorethamine; Melanoma; Melphalan; Nitrogen Mustard Compounds

Topics: Animals; Mechlorethamine; Melanoma; Melphalan; Neoplasms, Experimental; Nitrogen Mustard Compounds