melphalan and Skin-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

Hyperthermic isolated limb perfusion (HILP) has an established role in the management of melanoma, but its role for Merkel cell carcinoma (MCC) is less well defined.. Retrospective review of our institutional experience with HILP for MCC was conducted (2009-2015). Literature search was performed through 04/2015 and 10 studies met inclusion criteria.. Four patients underwent HILP for MCC at our institution. There were no major complications and complete response was achieved in all patients. Early metastatic recurrence developed in two patients. The remaining two had no evidence of disease at last follow-up (36 months) or death (39 months). Systematic review identified an additional 12 pts that underwent HILP for MCC, for a total of 16 cases. Median age was 73 [IQR 69-78] years and 56% were men. Of the patients with reported follow-up, 12 (86%) had complete response, 1 had stable disease, and 1 partial response. Four patients developed local-regional recurrence and six distant metastases, all within 6 months. Overall median follow-up time was 15 [7-36] months.. Among a highly selective group of patients, regional perfusion for MCC is safe and has a high complete response rate. HILP is an acceptable therapeutic modality for obtaining durable loco-regional control but early distant metastatic disease remains a significant cause of mortality. J. Surg. Oncol. 2016;114:187-192. © 2016 Wiley Periodicals, Inc.

Topics: Aged; Aged, 80 and over; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Humans; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies; Skin Neoplasms

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

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 metastases of Merkel cell carcinoma (MCC) are an unusual and therapeutically challenging manifestation of the disease. Given the similarity to melanoma, in-transit MCC may be amenable to isolated regional therapy.. To present a case series of 12 patients who underwent isolated limb perfusion (ILP) or isolated limb infusion (ILI) for in-transit MCC.. A literature search was conducted using Medline and Pubmed databases for MCC, ILP, and ILI as key words. Ten cases were identified and reviewed; two cases from our hospital were also included in the series.. Nine patients underwent ILP, and three were treated with ILI. Eleven patients had a complete clinical response, and one had a partial response. All patients avoided limb amputation. Mean follow-up was 25.3 months. Mean duration of response was 21.8 months. Four patients relapsed regionally. Two patients developed distant metastases and died of their disease.. This is the largest case series of in-transit MCC treated with ILP or ILI. Both techniques appear to be a low-morbidity alternative to amputation for the treatment of isolated extremity in-transit MCC. ILI is less invasive than ILP and may be a more practical first-line treatment option. The authors have indicated no significant interest with commercial supporters.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Female; Follow-Up Studies; Humans; Infusions, Intra-Arterial; Limb Salvage; Lymphatic Metastasis; Male; Melphalan; Middle Aged; Skin Neoplasms; Treatment Outcome

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 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

Merkel cell carcinoma (MCC) is a very rare and aggressive neoplasm. Due to its rarity, therapeutic guidelines are not well established, especially for regionally advanced disease. Hyperthermic isolated limb perfusion (HILP) with Melphalan and either with or without tumor necrosis factor-alpha (TNF-alpha) is becoming more common in clinical practice, yet the long-term response is not clear. Previous reports have established indications for treatment of unresectable MCC as well as the outcome of MCC patients receiving perfusion treatment in combination with other therapies (e.g., radiation).. A review was performed of the most important articles in MEDLINE from the last 20 years related to HILP and MCC. It was possible to collect all cases of HILP from the literature. Details of one case of MCC where HILP was administered was included in the literature review.. A total of nine cases of MCC receiving ILP were identified in the literature; of these, seven achieved a complete response, one a partial response and one no response. All five patients treated without TNF-alpha had a complete response. Of the four patients treated with TNF-alpha, two had complete, one partial and one no response.. Based on the cases described, isolated limb perfusion is an acceptable option to treat regional advanced cases of MCC, and the use of TNF-alpha does not impact the overall response.

Topics: Aged, 80 and over; Antineoplastic Agents; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Extremities; Fatal Outcome; Female; Groin; Humans; Hyperthermia, Induced; Lymph Node Excision; Lymphatic Metastasis; Melphalan; Skin Neoplasms; Tumor Necrosis Factor-alpha

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

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

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 (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

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

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

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

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: 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: Acne Vulgaris; Adult; Aged; Child, Preschool; Female; Gonorrhea; Hirsutism; Humans; Ichthyosis; Infant; Male; Melphalan; Middle Aged; Psoriasis; Sarcoidosis; Skin Diseases; Skin Neoplasms; Syphilis; Tetracycline; United States

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

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

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

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

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

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

Among non-Hodgkin's lymphoma subtypes, T-cell phenotype confers a poor clinical prognosis. For more aggressive histologies, patients frequently present with advanced disease that is inherently chemoresistant. For cutaneous histologies, disease progresses less rapidly, but is debilitating and often incurable in the long term. Here we report the retrospective analysis of data from 27 patients with mature T-cell lymphoma treated with salvage allogeneic haematopoietic cell transplantation at the City of Hope, Duarte, CA, USA, using a reduced-intensity fludarabine/melphalan conditioning regimen between the years 2001 and 2008. Eleven of the twenty-seven patients had cutaneous T-cell lymphoma (CTCL). The majority of patients had advanced disease at the time of transplant (17/27 or 63%). Median follow-up was 36 months. We observed a 2-year OS of 55%, a PFS of 47% and a cumulative incidence of relapse/progression and non-relapse mortality (NRM) of 30 and 22%, respectively. For CTCL, patients had a 2-year PFS of 45% and NRM of 27% compared with patients with other histologies, who had a PFS of 62% and NRM of 19%. Overall, our results suggest that meaningful long-term survival rates and disease control can be achieved with acceptable non-relapse mortality in patients with mature T-cell lymphomas, including CTCL using reduced-intensity conditioning with melphalan and fludarabine.

Topics: Adult; Aged; Antineoplastic Agents; Disease-Free Survival; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, T-Cell, Cutaneous; Male; Melphalan; Middle Aged; Myeloablative Agonists; Retrospective Studies; Skin Neoplasms; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

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 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

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

Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor alpha (TNF-alpha), interferon gamma, and melphalan has proved to be useful in the treatment of recurrent malignant melanoma and of locally advanced soft tissue sarcomas of the extremities.. To determine whether this modality is also effective in the treatment of locally advanced nonmelanoma skin tumors of the extremities.. Fifteen patients with locally advanced primary, recurrent, or metastatic skin tumors of the extremities (12 with squamous cell carcinoma and 3 with Merkel cell carcinoma) underwent HILP with TNF-alpha, interferon gamma, and melphalan. Six tumors were localized in the upper extremity (40%), and 9 in the lower extremity (60%). Treatment-related complications, limb salvage rate, local recurrence, and regional and distant metastases were scored during a median follow-up of 20 months.. After HILP, 9 patients (60%) showed a complete response (with histopathological confirmation). Four patients (27%) showed a partial response (with histopathological confirmation in 1 patient), and 2 patients (13%) showed no change (with histopathological confirmation in 1 patient and with clinical evidence in 1 patient). Two patients (13%) showed treatment-related complications. The limb salvage was achieved in 12 patients (80%), and the local recurrences developed in 4 patients (27%). During follow-up, regional lymph node metastases were observed in 2 patients (13%) and distant metastases in 2 patients (13%).. Based on our results, HILP with TNF-alpha, interferon gamma, and melphalan should be considered as a limb-saving treatment modality in patients with locally advanced nonmelanoma skin tumors of the extremities who would otherwise be candidates for ablative surgery.

Topics: Adult; Aged; Antineoplastic Agents; Arm; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Female; Follow-Up Studies; Hot Temperature; Humans; Interferon-gamma; Leg; Male; Melphalan; Middle Aged; Skin Neoplasms; 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

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

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

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

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

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

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

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

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

A randomized trial of Adriamycin (A) in combination with melphalan (M), (MA therapy), and in combination with M plus cyclophosphamide (C) (MAC therapy), was initiated in 40 evaluable patients with metastatic breast cancer. Twenty-two patients demonstrated an objective response to therapy: 9/20 to the MA regimen, and 13/20 to the MAC regimen. For the 22 responders, median duration of response is not yet achieved for either complete or partial responders, at 10 and 9 months, respectively. The addition of the two alkylating agents to Adriamycin was superior to the single alkylating agent addition, both in total response rate and in completeness of response. Maintenance therapy, after achieving the maximum cumulative dose of Adriamycin, was provided by cyclophosphamide plus methotrexate and 5-fluorouracil (CMF). In 19 patients completing induction and entering maintenance therapy, only one relapse has developed with maximun follow-up at 15 months.

Topics: Adult; Aged; Bone Neoplasms; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Melphalan; Middle Aged; Neoplasm Metastasis; Remission, Spontaneous; Skin Neoplasms; Time Factors

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

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 induction of adaptive cellular immunity in patients with in-transit melanoma metastasis treated with hyperthermic isolated limb perfusion (ILP) with melphalan has been shown to contribute to the effectiveness of the therapy. Activated CD8. A murine vaccination model that utilized melphalan-exposed melanoma cells was used to mimic certain immunological features of melphalan-based ILP. The effects of the vaccine on tumour growth and PD-1 expression on CD8. Treatment with melphalan-based therapy significantly induced the expression of PD-1 on CD8. This study thus suggests that the addition of PD-1 blockade to melphalan-based therapies, such as ILP, may be therapeutically beneficial.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; CD8-Positive T-Lymphocytes; Female; Immune Checkpoint Inhibitors; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Melanoma, Experimental; Melphalan; Mice; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor; Skin 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

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

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

Intravascular large B-cell lymphoma (IVLBCL) is a rare subset of extranodal non-Hodgkin lymphoma characterized by neoplastic lymphocytes within the lumina of small to medium-sized blood vessels. IVLBCLs are B-cell tumors that can present in essentially any organ system, including the skin. Cutaneous manifestations vary greatly and can mimic other skin disease which may delay diagnosis; in the absence of skin lesions, blind skin biopsies can be utilized for diagnosis. Early studies suggested that IVLBCL is a very aggressive lymphoma with high overall mortality rate and short survival times. However, earlier diagnosis and use of new treatment modalities have shown promise in recent studies. This case series illustrates the heterogeneity of clinical and pathologic presentations of this uncommon lymphoma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Blood Vessels; Carmustine; Cyclophosphamide; Cytarabine; Delayed Diagnosis; Diagnosis, Differential; Doxorubicin; Early Detection of Cancer; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Podophyllotoxin; Prednisone; Rituximab; Skin; Skin Neoplasms; Treatment Outcome; Vincristine

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

Topics: Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Humans; Melphalan; Skin Neoplasms

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

Topics: Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Humans; Melphalan; Skin Neoplasms

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

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

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

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

A small minority of patients present with locally advanced cutaneous Squamous Cell Carcinoma (cSCC). The aim of this study was to evaluate the effectiveness of Tumour necrosis factor α (TNF) and melphalan based isolated limb perfusion (TM-ILP) as a limb saving strategy for locally advanced extremity cSCC.. A retrospective search from prospectively maintained databases, at two tertiary referral centers, was performed to identify patients treated with TM-ILP for locally advanced cSSC of an extremity between 2000 and 2015.. A total of 30 patients treated with TM-ILP for cSCC were identified, with a median age of 71 years (36-92) and 50% female. Response could not be evaluated in 3 patients. After a median follow up of 25 months, the overall response rate was 81% (n = 22), with 16 patients having a complete response (CR, 59%). A total of 7 patients developed local recurrence, with a median time to recurrence of 9 months (Interquartile Range 7-10). Progressive disease was observed in 5 patients (19%). Limb salvage rate was 80%. The overall 2-year survival was 67%.. TM-ILP should be considered as an option in patients with locally advanced cSCC in specialised centers, resulting in a high limb salvage rate.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Female; Humans; Limb Salvage; Lower Extremity; Male; Melphalan; Middle Aged; Perfusion; Retrospective Studies; Skin Neoplasms; Survival Analysis; Tertiary Care Centers; Treatment Outcome; Tumor Necrosis Factor-alpha

Cutaneous plasmacytosis (CP) is a syndrome of multiple cutaneous plasma cell tumors, in the absence of multiple myeloma. Although rare in both humans and dogs, treatment recommendations are usually extrapolated from multiple myeloma protocols. To date, no case series of CP have been described in the veterinary literature.. To describe clinical presentation, determine treatment response rates and duration, and report overall survival of dogs with CP.. Twenty-one client-owned dogs with CP.. Medical records of 21 dogs with CP were reviewed. Diagnosis was based on histopathologic evaluation of at least 1 representative cutaneous or subcutaneous lesion in dogs with ≥3 lesions. Dogs with suspicion of multiple myeloma were excluded.. The most commonly affected breeds were the golden (5/21) and Labrador retriever (3/21). Fourteen of 21 dogs had >10 lesions, with some having >100. Lesions commonly were described as round, raised, pink-to-red, and variably alopecic or ulcerated. The most commonly used drug protocol was combined melphalan and prednisone, with an overall response rate (ORR) of 73.7% (14/19 dogs). Single-agent lomustine was associated with a similar ORR of 71.4% (5/7 dogs). For all treatments combined, the median progression-free interval after the first treatment was 153 days. The median survival time from the first treatment was 542 days.. Alkylating agents were effective in inducing remission of CP; corticosteroids, melphalan, and lomustine were the most commonly used drugs. Survival times were similar to those reported in dogs with multiple myeloma treated with alkylating agents.

Topics: Animals; Antineoplastic Agents, Alkylating; Dog Diseases; Dogs; Drug Therapy, Combination; Female; Lomustine; Male; Melphalan; Plasmacytoma; Prednisone; Skin; Skin Neoplasms

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

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

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

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

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

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

Topics: Adult; Breast Neoplasms; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Crizotinib; Drug Resistance, Neoplasm; Female; Gene Rearrangement; Humans; Immunoglobulin G; Lung Neoplasms; Melphalan; Oncogene Proteins, Fusion; Pyrazoles; Pyridines; Skin Neoplasms

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

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

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

A 3-year-old girl with a history of bilateral retinoblastoma presented with a new right lower periorbital mass that showed calcifications on ultrasound. She had previously undergone systemic and intra-arterial chemotherapy for retinoblastoma but had no evidence of active disease for at least 6 months previously. Her family and oncologists feared that this mass was an extraocular metastasis of her retinoblastoma. On excision, it was diagnosed as a pilomatrixoma, an uncommon benign neoplasm that originates from the matrix of the hair root. This is the first reported case of pilomatrixoma in a patient with retinoblastoma.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Eyelids; Female; Hair Diseases; Humans; Melphalan; Pilomatrixoma; Retinal Neoplasms; Retinoblastoma; Skin Neoplasms; Ultrasonography

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

A 7-year-old, male, mixed breed dog was referred to the Veterinary Teaching Hospital at Kitasato University because of anorexia, lameness and multiple cutaneous lesions. Observation of bone marrow plasmacytosis, osteolytic bone lesions, serum myeloma protein and cutaneous infiltration of myeloma cells led us to a diagnosis of multiple myeloma (MM) with cutaneous involvement. Polymerase chain reaction and sequence analysis for the rearranged genes of immunoglobulin and T-cell receptor demonstrated that the neoplastic cells found in skin lesions or bone marrow are of B-lymphocyte lineage and share a common original precursor cell. The dog was treated with UW-Madison protocol or melphalan/prednisone protocol and survived 175 days. This is rare case of anaplastic MM with cutaneous involvement in dog.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Dog Diseases; Dogs; Fatal Outcome; Lomustine; Male; Melphalan; Multiple Myeloma; Prednisolone; Skin Neoplasms

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

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

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

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

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

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

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

To demonstrate the efficacy of isolated limb infusion (ILI) in limb preservation for patients with locally advanced soft-tissue sarcomas and nonmelanoma cutaneous malignant neoplasms.. Locally advanced nonmelanoma cutaneous and soft-tissue malignant neoplasms, including soft-tissue sarcomas of the extremities, can pose significant treatment challenges. We report our experience, including responses and limb preservation rates, using ILI in cutaneous and soft-tissue malignant neoplasms.. We identified 22 patients with cutaneous and soft-tissue malignant neoplasms who underwent 26 ILIs with melphalan and dactinomycin from January 1, 2004, through December 31, 2009, from 5 institutions. Outcome measures included limb preservation and in-field response rates. Regional toxic effects were measured using the Wieberdink scale and serum creatinine phosphokinase levels.. The median age was 70 years (range, 19-92 years), and 12 patients (55%) were women. Fourteen patients (64%) had sarcomas, 7 (32%) had Merkel cell carcinoma, and 1 (5%) had squamous cell carcinoma. The median length of stay was 5.5 days (interquartile range, 4-8 days). Twenty-five of the 26 ILIs (96%) resulted in Wieberdink grade III or less toxicity, and 1 patient (4%) developed grade IV toxicity. The median serum creatinine phosphokinase level was 127 U/L for upper extremity ILIs and 93 U/L for lower extremity ILIs. Nineteen of 22 patients (86%) underwent successful limb preservation. The 3-month in-field response rate was 79% (21% complete and 58% partial), and the median follow-up was 8.6 months (range, 1-63 months). Five patients underwent resection of disease after an ILI, of whom 80% are disease free at a median of 8.6 months.. Isolated limb infusion provides an attractive alternative therapy for regional disease control and limb preservation in patients with limb-threatening cutaneous and soft-tissue malignant neoplasms. Short-term response rates appear encouraging, yet durability of response is unknown.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Creatine Kinase; Dactinomycin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Length of Stay; Limb Salvage; Male; Melphalan; Middle Aged; Retrospective Studies; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Treatment Outcome; Young Adult

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

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

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

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Lymphoma, Large B-Cell, Diffuse; Melphalan; Middle Aged; Recurrence; Remission Induction; Skin Neoplasms

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

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

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

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

Isolated limb perfusion (ILP) is a surgical technique that enables the administration of high-dose chemotherapy while minimizing serious systemic side effects. The clinical value and indications are well established for skin and soft tissue tumors on limbs. For skin tumors, this technique is mainly indicated for melanoma with in-transit metastasis. For soft tissue tumors--sarcoma and osteosarcoma--it is useful as a palliative technique to reduce the tumoral mass. Limb perfusion can also be an option in other tumors, such as advanced stage squamous cell carcinoma or Merkel cell carcinoma. We present a case report of a 68-year-old man with Merkel cell carcinoma on the right tibiotarsical region, with in-transit metastasis throughout the whole lower limb. Regional chemotherapy involving ILP with melphalan and tumor necrosis factor-alpha (TNFalpha) was performed in order to avoid amputation; the primary tumor was not excised. A steady regression of the disease was observed, with complete resolution of all visible in-transit metastases at the 45th day post-perfusion. However, systemic metastasis leading to fatal outcome occurred 4 months later. Although there was no change in the patient's prognosis, ILP was able to avoid limb amputation as it controlled local-regional disease and produced complete regional remission. The addition of TNFalpha to melphalan in ILP appears to produce greater efficacy in the treatment of patients with bulky tumors or a large number of in-transit metastases.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Fatal Outcome; Follow-Up Studies; Humans; Immunohistochemistry; Limb Salvage; Lower Extremity; Male; Melphalan; Neoplasm Metastasis; Neoplasm Staging; Palliative Care; Risk Assessment; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

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

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

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

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

We described a 57-yr-old male diagnosed with cutaneous T-cell lymphoma that had failed multiple treatment options, as his disease was mainly confined to one limb. We attempted a novel approach in this condition using a technique of intra-arterial limb infusion with cytotoxic agent Melphalan (ILI) which has been proven beneficial in management of localised malignant melanoma. This treatment approach was well tolerated with mild myelosuppression and moderate limb toxicity. However, a significant improvement has been noted in the affected limb. This case demonstrated the successful use of isolated limb infusion with Melphalan in the management of localised cutaneous T-cell lymphoma. However, this result needs to be confirmed and further study is recommended. We are unaware there have been similar cases reported in the literature.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Humans; Lymphoma, T-Cell, Cutaneous; Male; Melphalan; Middle Aged; Skin Neoplasms

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

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Carcinoma, Squamous Cell; Clarithromycin; Dexamethasone; Diphosphonates; Glomerulonephritis; Humans; Idarubicin; Imidazoles; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Multiple Myeloma; Nephrotic Syndrome; Pamidronate; Protein Synthesis Inhibitors; Pyrazines; Skin Neoplasms; Thalidomide; Zoledronic Acid

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

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

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

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

Topics: Aged; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Humans; Immunoglobulin A; Immunoglobulin kappa-Chains; Male; Melphalan; Multiple Myeloma; Plasmacytoma; Prednisolone; Skin Neoplasms

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 patient is a 74-year-old woman first diagnosed with a peripheral cutaneous T-cell lymphoma (PCTCL) in April of 1994. Initially she presented with subcutaneous indurated areas in the right forearm, scapula, and submadibular region. After chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), she went into remission for 2 years before relapse of her PCTCL localized to the right lower extremity. Persistent isolated disease in the extremity since then led to numerous chemotherapy regimens and localized radiation therapy. Due to dramatic limb threatening progression of the disease in 2001, she underwent isolated hyperthermic limb perfusion with melphalan (1-phenylalanine mustard). Although limb preservation could not be achieved, this treatment resulted in complete clinical and pathological regression of the lesions of the perfused extremity.

Topics: Aged; Amputation, Surgical; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Lower Extremity; Lymphoma, T-Cell, Cutaneous; Melphalan; Neoplasm Metastasis; Neoplasm Recurrence, Local; Skin Neoplasms

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

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

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

Cutaneous Stewart-Treves lymphangiosarcomas represent a rare group of tumors characterized by a high grade of vascularization and by localization in an extremity with lymphedema. The multifocality and the localization makes these tumors eligible for treatment with isolated limb perfusion (ILP). ILP with tumor necrosis factor (TNF) and melphalan is a safe and highly effective procedure that can achieve limb salvage in >or=80% of all patients with nonresectable extremity soft tissue sarcoma or melanoma.. In 10 patients with multifocal Stewart-Treves lymphangiosarcoma of the extremities, 16 ILPs with TNF plus melphalan were performed. All patients would have been candidates for exarticulation of the extremity.. We observed an 87% overall response rate (complete and partial responses); one patient had a mixed response, and one patient did not respond to the therapy. In nine perfusions (56%), a complete response was achieved, and five perfusions (31%) resulted in a partial response. Limb salvage was achieved in eight patients (80%), with a mean follow-up duration of 34.8 months (range, 3 to >or=115 months). Regional toxicity was limited and systemic toxicity minimal to moderate, with no toxic deaths.. Multifocal Stewart-Treves lymphangiosarcomas in extremities with chronic lymphedema can be successfully treated by ILP with TNF and melphalan.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Limb Salvage; Lymphangiosarcoma; Melphalan; Middle Aged; 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

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

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

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

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

Topics: Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Leiomyosarcoma; Melphalan; Skin Neoplasms; Tumor Necrosis Factor-alpha

Merkel's cell carcinoma is an uncommon neuroendocrine cutaneous neoplasm. An unusual mode of dissemination of this tumor is the phenomenon of in-transit metastases. We report complete resolution of in-transit metastases from a Merkel's cell carcinoma in response to treatment with isolated hyperthermic limb perfusion with melphalan. Limb perfusion appears to be a promising modality for such lesions.

Topics: Aged; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Humans; Hyperthermia, Induced; Lymphatic Metastasis; Male; Melphalan; Skin Neoplasms

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

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

An 87-yr-old woman diagnosed with recurrent Merkel's cell carcinoma was treated with therapeutic limb perfusion and underwent PET scanning with 18F-fluorodeoxyglucose (FDG). PET studies were obtained before and after treatment to determine the response to the intervention. A baseline whole-body study was obtained to assess the extent and degree of disease activity. This was followed by a repeat PET scan 2 mo. later after treatment with isolated limb chemotherapy with high-dose melphalan and tumor necrosis factor-alpha. The initial scan demonstrated multiple foci of high FDG uptake in the left calf, a left supraclavicular lesion and also detected concurrent keratinizing squamous cell metastasis in the right axilla. A repeat PET study showed complete metabolic resolution of the lesions in the left calf after treatment. FDG PET may be a useful technique for staging Merkel cell carcinoma and for assessing the tumor response after therapy of this rare tumor.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Female; Fluorodeoxyglucose F18; Humans; Leg; Melphalan; Radiopharmaceuticals; Recurrence; Skin Neoplasms; Tomography, Emission-Computed; 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

Malignant melanoma are chemoresistent tumors with poor prognosis. The aim of this study was to determine whether multimodality therapy of murine melanoma involving a combination of radiation with thermosensitive-liposome-encapsulated melphalan and local hyperthermia would result in enhancement of therapeutic efficacy for a more effective management of melanoma. Melphalan was entrapped in thermosensitive liposomes prepared from natural lipids: egg phosphatidyl choline, cholesterol and ethanol to show phase transition at 42 +/- 0.5 degrees C and used in combination with localized heating of B16F10 murine melanoma transplanted into the legs of C57B1/6 mice for selective drug targeting at the tumors and/or radiation for treatment of melanoma. Murine melanoma transplanted into C57B1/6 mice were subjected to bimodality treatments involving a combination of radiation, hyperthermia or melphalan. Partial tumor regression was observed in mice receiving a combination of hyperthermia and radiation (median tumor volume 427.3 mm3) or a combination of free melphalan and radiation (512.1 mm3) as compared to untreated controls (630.9 mm3). Each group consisted of 18 animals, and the results are expressed as median tumor volume +/- SD. Animals receiving multimodality therapy comprising irradiation followed by injection of thermosensitive liposomal melphalan and hyperthermic treatment of the tumor-bearing leg at 42 +/- 0.5 degrees C for 1 h showed marked tumor regression in comparison with untreated controls or animals treated with a combination of radiation and hyperthermia or radiation and free-drug melphalan. Animals receiving thermoradiochemotherapy also showed prolonged survival; 70% of animals survived for more than 3 months. The study shows greater tumor cell killing, tumor growth delay and prolonged survival produced by a combination of radiation, thermosensitive-liposome-entrapped melphalan and hyperthermia compared with animals receiving single-modality or bimodality treatments. It is concluded that this multimodality approach will be potentially useful for more effective management of melanoma.

Topics: Animals; Cell Survival; Combined Modality Therapy; Disease-Free Survival; Drug Carriers; Hyperthermia, Induced; Liposomes; Male; Melanoma, Experimental; Melphalan; Mice; Mice, Inbred C57BL; Skin Neoplasms; Survival Rate; Tumor Cells, Cultured

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

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

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

We report a case of Kaposi's sarcoma in a patient who underwent autologous bone marrow transplantation (ABMT) for multiple myeloma. Four months after ABMT he presented with numerous asymptomatic, dark blue and purplish macules and nodules on the trunk and lower extremities. Biopsy revealed the typical histologic pattern of Kaposi's sarcoma. The patient died due to disseminated Kaposi's sarcoma while in complete remission of his hematologic malignancy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Etoposide; Fatal Outcome; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Immunocompromised Host; Immunologic Factors; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Sarcoma, Kaposi; Skin Neoplasms; Transplantation, Autologous

Merkel cell carcinoma of the skin is a rare malignant tumour first described in 1972 by Toker. The optimal management of this disease has not been clearly defined, especially that of advanced locoregional disease. Surgery, radiotherapy and chemotherapy have been advocated separately or in combination, with less-than-optimal results. Localized high-dose chemotherapy has never been tried, although it would seem to be the logical step forward.

Topics: Aged; Antineoplastic Agents, Alkylating; Carcinoma, Merkel Cell; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dissection; Humans; Hyperthermia, Induced; Leg; Male; Melphalan; Skin Neoplasms

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

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

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

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

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

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

Multiple skin lesions developed in a 70 year-old-man. Pathological examination revealed plasmacytomas. Because of the presence of a IgD paraprotein and 15% abnormal plasma cells in the bone marrow Kahler's disease of the IgD type was diagnosed. In accordance with literature the course of the disease was rapidly progressive. After an initial favourable response to chemotherapy and radiotherapy, the patient died one year after diagnosis. Extraosseous tissue involvement and hepatosplenomegaly are well-known phenomenon of IgD-Kahler's disease. Skin plasmacytomas as the first symptom of the disease are very rare.

Topics: Aged; Combined Modality Therapy; Drug Therapy, Combination; Humans; Male; Melphalan; Multiple Myeloma; Prednisone; Skin Neoplasms

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

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 examine in detail the sensitivity to chemotherapy of tumour cells at various organ sites and at various stages of metastasis, we have used a series of cell lines, all selected from sister subpopulations derived from a single mouse mammary tumour, which can be distinguished and quantitated from normal cells and from each other through growth in selective medium. For the studies described here, we used two lines, 4T07 and 66FAR, which will form colonies in vitro in medium containing 60 microM 6-thioguanine or 330 microM 2,6-diaminopurine, respectively. Both cell lines have similar sensitivity to the test chemotherapeutic agent, melphalan, in vitro. These two tumour cell lines were treated with melphalan in vivo, when growing either in lungs as experimental metastases at various times after cell injection or as palpable tumours growing subcutaneously. Responses to various doses of melphalan were measured by removing lungs or subcutaneous tumours and performing colony-forming assays in selective medium. The data indicate marked shifts in sensitivity as a function of metastatic stage. Analyses of dose-response curves show that both cell lines were similarly sensitive to melphalan at early times (45 min) after cell injection i.v. but became less sensitive at an intermediate time after injection (3 days). Differences between the two lines became apparent at later times after i.v. injection (by day 8 or 9) and in subcutaneous tumours, where a marked reduction in the shoulder of the dose response curve was seen in line 4T07, resulting in sensitivity equal to or greater than the of early times, whereas the dose response parameters of 66FAR remained at those of the intermediate time point. These results show that, in heterogeneous tumours, individual subpopulations of tumour cells may respond differently to chemotherapeutic agents at various disease stages. In vitro measures of tumour sensitivity do not predict these changes in in vivo sensitivity. Model systems similar to the one described here may yield information which will eventually be useful in maximising the efficacy of clinically relevant adjuvant chemotherapy regimens.

Topics: Animals; Cell Division; Dose-Response Relationship, Drug; Female; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Melphalan; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Skin Neoplasms; Tumor Cells, Cultured; Tumor Stem Cell Assay

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

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

Two patients with metastatic spread of unusual tumors responded to treatment with high-dose Melphalan and autologous bone marrow transplant. One patient had adenoid cystic carcinoma of a minor salivary gland and the other had Merkel cell tumor of the scalp. Both patients had undergone prior surgery and radiotherapy, but later relapsed with distant metastases. Both patients had progression of their disease despite conventional and salvage chemotherapy. Treatment with high-dose Melphalan and autologous bone marrow transplant resulted in partial responses for both patients. High-dose Melphalan should be considered for therapy earlier in the course of patients with these unusual cancers.

Topics: Adult; Bone Marrow Transplantation; Carcinoma, Adenoid Cystic; Carcinoma, Merkel Cell; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Male; Melphalan; Salivary Gland Neoplasms; Scalp; Skin Neoplasms

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

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

Topics: Dexamethasone; Drug Therapy, Combination; Humans; Lymphoma, T-Cell, Cutaneous; Male; Melphalan; Middle Aged; Prednisone; Skin Neoplasms

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

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

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 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

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

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

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

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

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

A 61-year-old man with an intractible and progressively disabling cutaneous non-Hodgkin's lymphoma (NHL) in the lower limb was treated with sequential regional isolated perfusion at 10-day intervals. The first perfusion was hyperthermic (40.2-43.1 degrees C tumor-temperature); the second was at controlled normothermia with high-dose 1-phenylalanine mustard (melphalan, L-Pam; 11 mg/l perfused tissue). This treatment resulted in a complete remission in the perfused area of significant duration and has prevented amputation.

Topics: Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Humans; Hyperthermia, Induced; Leg; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Skin Neoplasms

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: 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

The continuous human medulloblastoma cell line TE-671 was grown as s.c. and intracranial xenografts in athymic nude mice. Tumor-bearing animals were treated with chemotherapeutic agents at the 10% lethal dose; s.c. xenografts were sensitive to melphalan, 1-(2-chloroethyl)-3-(2,6-dioxo-1-piperidyl)-1-nitrosourea, and 5-azacytidine. No consistent response could be demonstrated to 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate, and no response to methylglyoxal bis(guanyl hydrazone), N-trifluoroacetyl adriamycin-14-valerate, or to 1-beta-D-arabinofuranosylcytosine was observed. Melphalan produced a significant (P = less than or equal to 0.007) increase in the median survival of mice bearing intracranial xenografts, whereas no response was seen to 1-(2-chloroethyl)-3-(2,6-dioxo-1-piperidyl)-1-nitrosourea or 5-azacytidine. This model will allow analysis of the chemotherapeutic profile of human medulloblastoma, and provides a means to differentiate cellular sensitivity and resistance from drug access to the intracranial site.

Topics: Animals; Azacitidine; Brain Neoplasms; Cell Line; Cytarabine; Doxorubicin; Humans; Medulloblastoma; Melphalan; Mice; Mice, Nude; Mitoguazone; Neoplasm Transplantation; Nitrosourea Compounds; Skin Neoplasms; Vidarabine Phosphate

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

Seven classical alkylators were tested for activity against the continuous human medulloblastoma cell line TE-671 grown in vitro and as s.c. and intracranial xenografts in athymic mice. Drugs tested included melphalan, cyclophosphamide (4-hydroperoxycyclophosphamide in vitro), iphosphamide (4-hydroperoxyiphosphamide in vitro), phenylketocyclo-phosphamide, phenylketoiphosphamide, Asta Z 7557, and thiotriethyl-enephosphoramide. All agents were active, with melphalan demonstrating the most activity in vitro and in vivo. Comparative studies of cyclophosphamide and phenylketocyclophosphamide revealed partition coefficients (log P) of 0.73 and greater than 1.69, respectively, and cyclophosphamide exhibited greater cytotoxic activity in post- (equitoxic) drug administration murine plasma. Hematological toxicity was limited to leukopenia/neutropenia for both of these agents. These studies suggest that the classical alkylators may have a role in the treatment of medulloblastoma and provide a means to further analyze their therapeutic potential.

Topics: Alkylating Agents; Animals; Blood Cells; Brain Neoplasms; Cell Line; Cyclophosphamide; Female; Humans; Male; Medulloblastoma; Melphalan; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Skin Neoplasms; Transplantation, Heterologous; Tumor Stem Cell Assay

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

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 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

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

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

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

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

A 62-year-old woman had multiple plasmacytomas of the skin with no roentgenographic or bone marrow evidence of multiple myeloma. Serum IgA-lambda level was increased to 1,000 mg/dL (normal range, 90 to 450 mg/dL). The skin lesions regressed completely when the patient was treated with melphalan. She had recurrence of a skin plasmacytoma and lytic bone lesions ten months later and died of bronchopneumonia 11 months after the was first seen. Solitary skin plasmacytomas are rare, and multiple skin plasmacytomas are even rarer. Occasionally, these lesions may precede roentgenographic and bone marrow evidence of multiple myeloma.

Topics: Female; Humans; Immunoglobulin A; Immunoglobulin lambda-Chains; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Skin Neoplasms

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 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

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

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

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

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 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

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

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

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

Topics: Animals; Antineoplastic Agents; Chlorambucil; Drug Synergism; Goats; Humans; Immunoglobulins; Immunotherapy; Melanoma; Melphalan; Neoplasm Metastasis; Nitrogen Mustard Compounds; Skin Neoplasms; Vincristine

A 49-year-old man with multiple myeloma, IgA type, contracted cutaneous plasmocytomas. No deposits of immunoglobulin were found in the cutaneous tumor by direct immunofluorescence. The case is an unusual manifestation occurring in multiple myeloma.

Topics: Fluorescent Antibody Technique; Humans; Immunoglobulin A; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Metastasis; Skin Neoplasms

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

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

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

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

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

Extramedullary plasmocytomas of the skin are rare, especially if a participation of the bone marrow is lacking. A 76-year-old patient developed multiple skin tumours within 2 months. In addition he showed an increase of serum immunoglobulin A. Histopathologically the tumours resembled reticulum cell sarcoma with few plasma cells, partly immature.

Topics: Aged; Blood Sedimentation; Humans; Hypergammaglobulinemia; Immunoglobulin A; Male; Melphalan; Multiple Myeloma; Prednisolone; Skin Neoplasms

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: Adult; Antineoplastic Agents; Bence Jones Protein; Hodgkin Disease; Humans; Immunoglobulin D; Male; Melphalan; Plasma Cells; Plasmacytoma; Radiotherapy; Skin Neoplasms; Testicular Neoplasms

Topics: Animals; Cell Division; Cell Nucleolus; Cell Nucleus; Chromosomes; Cytoplasm; Karyotyping; Male; Melphalan; Mice; Neoplasm Transplantation; Organ Size; Sarcoma 180; Skin Neoplasms; Spleen; Transplantation, Homologous

Topics: Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Humans; Melanoma; Melphalan; Neoplasm Recurrence, Local; Skin Neoplasms; Thiotepa

Topics: Animals; Cyclophosphamide; Dihydroxyphenylalanine; Melanoma; Melphalan; Mice; Mice, Inbred BALB C; Neoplasms, Experimental; Radiation-Sensitizing Agents; Skin Neoplasms; Time Factors; Tritium

Topics: Aged; Female; Humans; Melphalan; Multiple Myeloma; Prednisone; Skin Neoplasms

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: 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; 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: Adolescent; Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Child; Dactinomycin; Female; Humans; Leg; Male; Mechlorethamine; Melanoma; Melphalan; Middle Aged; Neoplasm Metastasis; Prognosis; Skin Neoplasms

Topics: Clofibrate; Humans; Lipid Metabolism; Liver Diseases; Male; Melphalan; Middle Aged; Multiple Myeloma; Skin Neoplasms; Xanthomatosis

Topics: Biopsy; Chemotherapy, Cancer, Regional Perfusion; Female; Hot Temperature; Humans; Melanoma; Melphalan; Methods; Middle Aged; Neoplasm Metastasis; Skin Neoplasms; Thermography

Topics: Adult; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Melanoma; Melphalan; Neoplasm Metastasis; Skin Neoplasms

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: Adult; Aged; Antitubercular Agents; Cyclophosphamide; Humans; Lung Neoplasms; Male; Melphalan; Multiple Myeloma; Neoplasms, Multiple Primary; Skin Neoplasms; Urethane

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

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: Antineoplastic Agents; Colchicine; Cyclophosphamide; Mannomustine; Melphalan; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Podophyllum; Research; Skin Neoplasms

Topics: Carcinogens; Carcinoma, Hepatocellular; Hepatectomy; Liver Neoplasms; Melphalan; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Research; Skin Neoplasms; Tissue Culture Techniques

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Carcinoma 256, Walker; Carcinoma, Hepatocellular; Chemistry, Pharmaceutical; Leukemia; Leukemia, Experimental; Liver Neoplasms; Lung Neoplasms; Melphalan; Neoplasms, Experimental; Nitrogen Mustard Compounds; Pharmacology; Phenylalanine; Research; Skin Neoplasms