melphalan and Sarcoma

Soft tissue sarcomas constitute 1% of adult malignant tumors. They are a heterogeneous group of more than 50 different histologic types. Isolated limb perfusion is an established treatment strategy for locally advanced sarcomas. Since its adoption for sarcomas in 1992, after the addition of TNFα, few modifications have been done and although indications for the procedure are essentially the same across centers, technical details vary widely. The procedures mainly involves a 60 min perfusion with melphalan and TNFα under mild hyperthermia, achieving a limb preservation rate of 72-96%; with an overall response rates from 72 to 82.5% and an acceptable toxicity according to the Wieberdink scale. The local failure rate is 27% after a median follow up of 14-31 months compared to 40% of distant recurrences after a follow up of 12-22 months. Currently there is no consensus regarding the benefit of ILP per histotype, and the value of addition of radiotherapy or systemic treatment. Further developments towards individualized treatments will provide a better understanding of the population that can derive maximum benefit of ILP with the least morbidity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials, Phase II as Topic; Extremities; Humans; Hyperthermia, Induced; Melphalan; Randomized Controlled Trials as Topic; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

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

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

The management of locally advanced extremity soft tissue sarcoma of the limbs is challenging, particularly for recurrent tumors and those adjacent to neurovascular bundles and joints. Typically, the tumors are large, below the fascia, and high-grade (T2b or stage III according to the American Joint Committee on Cancer) and thus require multimodal therapy. Treatment options must be tailored to patient and tumor characteristics. Isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan (TNF-ILP) adds a therapeutic option to radiation therapy (RT) and systemic chemotherapy. Although the procedure is somewhat sophisticated to learn, it is a safe method and has been used now for almost 2 decades at more than 50 centers worldwide. TNF-ILP yields a high rate of complete or nearly complete pathologic tumor remission. In combination with surgical resection of the tumor remnant after isolated limb perfusion, the limb salvage rate is close to 90%. Often, patients can be spared adjuvant RT without long-term local tumor control rates being compromised. Nevertheless, TNF-ILP has never been compared with another treatment regimen in a randomized trial. This review summarizes the mode of action and standard application of TNF-ILP and focuses on a critical discussion of the role of TNF-ILP in the multimodal treatment of locally advanced primary and recurrent extremity sarcoma. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2624-2632. © 2016 American Cancer Society.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Drug Therapy, Combination; Extremities; Humans; Limb Salvage; Melphalan; Neoplasm Recurrence, Local; Sarcoma; Tumor Necrosis Factor-alpha

Sarcomas of the hand and wrist are rare malignancies, which should be referred to high-volume comprehensive cancer centres providing multidisciplinary treatment options. The tumour board should propose patient-oriented oncological pathways as well as sophisticated hand and plastic reconstructive procedures. In Addition, isolated limb perfusion with TNF-alpha and melphalan is likely to lead to preoperative tumour shrinkage allowing for R0 resection in sano. Our clinical results in long-term survivors demonstrate reduced amputation rates and salvage of basic hand function when a risk-adapted treatment rationale is applied.

Topics: Adolescent; Adult; Amputation, Surgical; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Cooperative Behavior; Female; Hand; Humans; Interdisciplinary Communication; Limb Salvage; Male; Melphalan; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Plastic Surgery Procedures; Prognosis; Radiotherapy, Adjuvant; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha; Wrist

Isolated limb perfusion (ILP) may provide a limb salvage option for locally advanced soft tissue sarcoma (STS) not amenable to local resection.. A systematic review was performed for studies reporting outcome of ILP for locally advanced STS performed after 1980 in patients aged ≥ 12 years old. The main endpoints were tumour response and limb salvage rates. Complication and recurrence rates were secondary endpoints.. Eighteen studies were included, providing outcomes for 1030 patients. Tumour necrosis factor-alpha with melphalan was the commonest chemotherapy regime. When reported, 22% of cases achieved a complete tumour response (216/964, 15 studies) with an overall response rate of 72% (660/911, 15 studies). At median follow-up times ranging between 11 and 125 months, the limb salvage rate was 81% in patients who otherwise would have been subjected to amputation. However, 27% of patients suffered local recurrence and 40% suffered distant failure. ILP was associated with severe locoregional reactions in 4% (22/603) of patients. Amputation due to complications within 30 days was necessary in 1.2% of cases (7/586, nine studies). There was insufficient evidence to determine the effect of ILP on survival.. ILP induces a high tumour response rate, leads to a high limb salvage rate but is associated with a high recurrence rate. It provides a limb salvage alternative to amputation when local control is necessary.

Topics: Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Humans; Limb Salvage; Melphalan; Neoplasm Recurrence, Local; Recurrence; Sarcoma; Soft Tissue Neoplasms; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha

Tumor necrosis factor (TNF) is an extraordinarily pleiotropic cytokine with a central role in immune homeostasis, inflammation, and host defense. Dependent on the cellular context, it can induce such diverse effects as apoptosis, necrosis, angiogenesis, immune cell activation, differentiation, and cell migration. These processes are of great relevance in tumor immune surveillance, and also play crucial roles in tumor development and tumor progression. It is therefore no surprise that TNF in a context-dependent manner displays pro- and antitumoral effects. Modulation of the activity of the TNF-TNF receptor system thus offers manifold possibilities for cancer therapy. In fact, TNF in combination with melphalan is already an established treatment option in the therapy of advanced soft tissue sarcoma of the extremities and many preclinical data suggest that TNF neutralization could also be exploited to fight cancer or cancer-associated complications.

Topics: Animals; Apoptosis; Cell Differentiation; Cell Movement; Humans; Immunologic Surveillance; Melphalan; Neovascularization, Pathologic; Receptors, Tumor Necrosis Factor; Sarcoma; Tumor Necrosis Factor-alpha

Limb-sparing surgery has become all the more important in soft tissue sarcoma (STS) of the extremities since we learned that amputation does not improve survival of these patients. In bulky tumours, however, preoperative strategies to reduce tumour size are then required. Isolated limb perfusion (ILP) with tumour necrosis factor (TNF) has been developed as a biochemotherapeutic therapy to act both on the tumour-associated vasculature and on the tumour itself. It has shown to be a very potent treatment modality, as in early reports response rates were around 80%. Limb salvage could then be achieved in a quite similar percentage. Many confirmatory studies have been performed since, with consistent results even in patients with multiple tumours, after extensive radiotherapy or with metastatic disease, all at the cost of very limited toxicity. This chapter gives an overview of the ILP studies performed in patients with soft tissue limb sarcoma, discusses the mechanism of TNF-mediated vasculotoxic effects on tumour vasculature, and places TNF-based ILP in the multimodality treatment of these patients with extensive STS of the extremities.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melphalan; Sarcoma; Tumor Necrosis Factor-alpha

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

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

Hyperthermic isolated limb perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan was repeatedly reported to achieve extraordinarily high clinical remission rates in advanced and non-resectable soft tissue sarcoma of the limbs, thus avoiding imminent mutilation or amputation for most of those patients. With the limb being isolated throughout the extracorporal perfusion, high doses of recombinant TNF-alpha as well as melphalan can be applied. Basically, TNF-alpha directly affects the vasculature of the tumour and induces a severe inflammation with consecutive deterioration of the tumour capillaries. Furthermore, TNF-alpha increases the tumour-selective uptake of melphalan into the tumour cells thus leading to synergy of antivascular targeted treatment and antineoplastic effects of highest dose chemotherapy supplemented by hyperthermia. Meanwhile, a lot of sarcoma centres in Europe adopted this technique and established referral programmes for patients with non-resectable soft tissue sarcomas of the limbs. Despite these programmes many patients still do not get offered hyperthermic ILP with TNF-alpha and melphalan as a treatment option and modality. This article summarizes multimodality in treatment of soft tissue sarcoma of the limbs and reviews the current status of melphalan-based ILP with TNF-alpha (TM-ILP) and its results, to enable comparison and critical consideration of other treatment options.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Humans; Hyperthermia, Induced; Limb Salvage; Melphalan; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

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

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

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

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

Isolated limb perfusion (ILP) with chemotherapy alone has uniformly failed in the treatment of irresectable extremity soft tissue sarcomas. The addition of tumor necrosis factor-alpha (TNF-alpha) to this treatment approach contributed to a major step forward in the treatment of locally advanced extremity soft tissue sarcoma (STS). High response rates and limb salvage rates have been reported in multicenter trials, which combined ILP with TNF-alpha plus melphalan, which resulted in the approval of TNF-alpha for this indication in Europe in 1998. Subsequently a series of confirmatory single institution reports on the efficacy of the procedure have now been published. TNF-alpha has an early and a late effect; it enhances tumor-selective drug uptake during the perfusion and plays an essential role in the subsequent selective destruction of the tumor vasculature. These effects result in a high response rate in high-grade soft tissue sarcomas. This induction therapy thus allows for resection of tumor remnants some 3 months after ILP and thus avoidance of limb amputation. TNF-alpha-based ILP is a well-established treatment to avoid amputations. It represents an important example of tumor vascularity-modulating combination therapy and should be offered in large volume tertiary referral centers.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Drug Therapy, Combination; Extremities; Female; Humans; Limb Salvage; Melphalan; Sarcoma; Tumor Necrosis Factor-alpha

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

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

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

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

Pulmonary metastasectomy is a widely accepted treatment for many patients with pulmonary metastases from various solid tumors. Nevertheless, 5-year survival is disappointing, with rates of 25-40%, and many patients develop recurrences. Isolated lung perfusion (ILuP) is a promising new technique to deliver high-dose chemotherapy to the lungs, while minimising systemic toxicities. This procedure is technically safe and feasible; however, clinical value and efficacy remain unclear. The aim of this paper is to give a review of literature on ILuP in humans, and to describe the development of the perfusion procedure in our institute.

Topics: Animals; Antineoplastic Agents; Blood Transfusion, Autologous; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Clinical Trials, Phase I as Topic; Combined Modality Therapy; Drug Screening Assays, Antitumor; Embolism, Air; Equipment Design; Extracorporeal Membrane Oxygenation; Feasibility Studies; Humans; Hydroxyethyl Starch Derivatives; Hyperthermia, Induced; Intraoperative Complications; Isotonic Solutions; Lung Neoplasms; Melphalan; Pilot Projects; Rheology; Ringer's Lactate; Sarcoma; Solutions; Temperature; Treatment Outcome

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melphalan; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

In high-grade musculoskeletal sarcomas, adjuvant chemotherapy is often performed to prevent distant metastases. The efficacy of chemotherapy varies according to the histological type of sarcoma. Prognoses are poor in patients with osteosarcoma, Ewing's sarcoma, or rhabdomyosarcoma, when surgery alone is performed. However, because these sarcomas are chemosensitive, their prognoses are improved with adjuvant chemotherapy. On the other hand, the efficacy of chemotherapy is not statistically demonstrated in non-round cell sarcomas, e. g., malignant fibrous histiocytoma. Nowadays, several kinds of antitumor agents are usually used for adjuvant chemotherapy, and many authors have reported various kinds of regimens and their clinical results. Commonly used drugs include adriamycin, ifosfamide, cisplatin, methotrexate, cyclophosphamide, dacarbazine, vincristine, and actinomycin-D. Recently, high-dose chemotherapy combined with autologous peripheral blood or bone marrow stem cell transplantation has been begun in patients who do not respond to standard chemotherapy, and a better prognosis is expected.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Combined Modality Therapy; Cyclophosphamide; Dacarbazine; Dactinomycin; Doxorubicin; Drug Administration Schedule; Humans; Ifosfamide; Melphalan; Mesna; Methotrexate; Osteosarcoma; Rhabdomyosarcoma; Sarcoma; Sarcoma, Ewing; Soft Tissue Neoplasms; Vincristine

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

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

High local drug concentrations can be achieved in a limb with minimal systemic toxicity with the technique of hyperthermic isolated limb perfusion (HILP). The currently most successful drugs are still Tumor Necrosis Factor alpha (TNFalpha) and melphalan. With HILP, as an induction chemotherapy treatment of locally advanced primarily irresectable soft tissue sarcomas of a limb, a limb salvage rate of 71% can be achieved, with a minimal treatment related morbidity. For the HILP is no upper age limit. Systemic inflammatory response syndrome is currently seldom seen. The exact working mechanisms of TNFalpha are still unknown. Experimental work is now directed to the development of drugs sensitizing the tumor vasculature to the effects of TNFalpha. In the clinical HILP setting are currently lower doses of TNFalpha in combination with melphalan investigated. Although multidrug resistance (MDR) is a major issue in effectiveness of chemotherapy in human cancer treatment, HILPs with TNFalpha and melphalan did not induce MDR in sarcomas. The future research in HILP with TNFalpha is directed in increasing tumor sensitivity for TNF with lowering the dosage without decreasing tumor response.

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

Isolated limb perfusion (ILP) with melphalan is effective against melanoma in-transit metastases but has failed in the treatment of limb-threatening extremity sarcomas. Tumor necrosis factor-alpha (TNF) has changed this situation completely. Now, ILP with TNF + melphalan is a very successful treatment to prevent amputation. In a multicenter European trial, ILP with TNF + melphalan resulted in a 76% response rate and a 71% limb salvage rate in patients with limb-threatening soft-tissue sarcomas, deemed unresectable by independent review committees, leading to approval of TNF in Europe. We have also reported on the success of this regimen against bulky melanomas, multifocal skin cancers, and drug-resistant bony sarcomas. High-dose TNF destructs tumor vasculature, and, most importantly, it enhances tumor-selective drug uptake (ie, melphalan and doxorubicin) by threefold to sixfold. Similar synergy is observed in well-vascularized liver metastases after isolated hepatic perfusion with TNF and melphalan. New (vasoactive) drugs and mechanisms of action and interaction with chemotherapy are in development. ILP is also a promising treatment modality for adenoviral vector-mediated gene therapy. Many clinical phase I/II evaluations in ILP are now underway.

Topics: Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Forecasting; Humans; Melphalan; Neoplasm Metastasis; Rats; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

To review the importance of prognostic factors in developing new protocols for children with rhabdomyosarcoma (RMS).. Four studies conducted by the Intergroup Rhabdomyosarcoma Study (IRS) Group from 1972 through 1991.. Favorable prognostic factors are: (1) undetectable distant metastases at diagnosis; (2) primary sites in the orbit and nonparameningeal head/neck and genitourinary nonbladder/prostate regions; (3) grossly complete surgical removal of localized tumor at the time of diagnosis; (4) embryonal/botryoid histology; (5) tumor size < or = 5 cm; and (6) age younger than 10 years at diagnosis. The IRS-V protocols are risk-based and refine therapy by reducing exposure to cyclophosphamide and radiation therapy (XRT) in patients at low risk while adding new, active agents such as topotecan or irinotecan to the standard therapy of vincristine, actinomycin D, and cyclophosphamide (VAC) plus XRT for patients with unfavorable histology or advanced disease. Collection of biologic specimens from patients with newly diagnosed disease continues to identify other factors that may distinguish patients with favorable features from those who need more intensive therapy. A new protocol that takes into account their previous treatment is needed for patients with recurrent disease. This program (being planned) does not include bone marrow/stem cell reconstitution because this strategy has thus far failed to improve survival rates of patients with metastases at diagnosis.. Better understanding of biologic differences and new, active agents are needed to improve outcome of patients with unfavorable features at presentation.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Disease-Free Survival; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Infant; Male; Melphalan; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Neoplasm Staging; Pilot Projects; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Rhabdomyosarcoma; Salvage Therapy; Sarcoma; Soft Tissue Neoplasms; Survival Rate; Topotecan; Treatment Outcome; Vincristine

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

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

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

Hyperthermic isolated limb perfusion (HILP) with various chemotherapeutic agents has been used for the local treatment of high-grade soft tissue sarcomas (STS) of the extremities, but in most cases with a disappointing result. Most regimens should certainly not be considered superior to surgery plus radiotherapy. Although the majority of extremity STS can be resected locally, some have a very large size and are in close proximity to bones, nerves or blood vessels. In these cases, amputation is the only means of resecting the tumour. A new combination of drugs used in the set-up of HILP with tumour necrosis factor-alpha and melphalan has emerged as a very promising option for the limb-saving management of locally advanced STS. In recent studies, complete response rates of approximately 30% and partial remission rates of 50% have been achieved, while the overall limb-salvage rate is more than 80%.

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

Topics: Amputation, Surgical; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Humans; Melphalan; Sarcoma; Tumor Necrosis Factor-alpha

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

Topics: Animals; 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

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: 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

Up to 66% of patients show local pulmonary disease progression after pulmonary metastasectomy. Regional treatment with isolated lung perfusion (ILuP) may improve local control with minimal systemic adverse effects. The aims of this study were to evaluate local and distant control after ILuP, determine the effect on overall survival compared with historical controls, and confirm the safety and feasibility of ILuP.. A total of 107 patients with resectable pulmonary metastases of colorectal carcinoma, osteosarcoma, and soft-tissue sarcoma were included in a prospective phase II study of pulmonary metastasectomy combined with ILuP with 45 mg melphalan at 37°C. Local and distant control, overall survival, lung function, and 90-day mortality and morbidity were monitored.. We report 0% mortality, low morbidity, and no long-term pulmonary toxicity. For colorectal carcinoma, median time to local pulmonary progression, median time to progression, and median survival time were 31, 14, and 78 months, respectively. Median time to local progression was not reached for sarcoma, whereas median time to progression and median survival time were 13 and 39 months, respectively. The 5-year disease-free rate and pulmonary progression-free rate were 26% and 44% for colorectal carcinoma and 29% and 63% for sarcoma, respectively.. ILuP with melphalan combined with metastasectomy is feasible and safe. Compared with historical controls, favorable results were obtained in this phase II study for local control. Further evaluation of locoregional lung perfusion techniques with other chemotherapeutic drugs is warranted.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Bone Neoplasms; Colorectal Neoplasms; Combined Modality Therapy; Disease Progression; Female; Historically Controlled Study; Humans; Lung Neoplasms; Male; Melphalan; Metastasectomy; Middle Aged; Perfusion; Prospective Studies; Sarcoma; Survival Analysis

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

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

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 objective of this study was to determine whether (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can adequately assess the risk of systemic disease progression in patients with primary, localized, high-grade soft tissue sarcomas of the extremities undergoing neoadjuvant isolated limb perfusion (ILP) with tumour necrosis factor and melphalan.. This was a retrospective analysis of the files of 35 patients who underwent a PET or PET/CT scan prior to and after ILP followed by surgical resection with curative intent between 2006 and 2012. SUVmax₁ was defined as the maximum standardized uptake value (SUV) at diagnosis, SUVmax₂ as the maximum SUV after ILP and ΔSUVmax as the percentage difference between SUVmax1 and SUVmax₂.. The median follow-up was 40 months for all patients. The median SUVmax1 amounted to 7.6, while the median SUVmax₂ was 4.7. The median ΔSUVmax was -44%. Overall survival (OS) probability at 2 and 5 years amounted to 78 and 70%, respectively, while metastasis-free survival (MFS) probability at 2 and 5 years was 67 and 64%, respectively. Receiver-operating characteristic (ROC) curve analysis showed that both SUVmax2 and ΔSUVmax could predict systemic disease progression, while SUVmax1 could not adequately identify patients who went on to develop metastatic disease. The optimal cut-off value was 6.9 for SUVmax2 and -31 % for ΔSUVmax. Patients with an SUVmax2 <6.9 had a 2-year MFS of 80%, compared to 31 % for patients with an SUVmax2 ≥ 6.9 (p < 0.001). Patients with a ΔSUVmax < -31 %, i.e. patients with a higher metabolic response, had an MFS of 76% at 2 years, compared to 42% for patients with a ΔSUVmax ≥ -31% (p = 0.050).. SUVmax after ILP for primary, locally advanced, non-metastatic high-grade soft tissue sarcomas of the extremities appears to be significantly correlated with prognosis. Whether patients with a high SUVmax after ILP will benefit from standard or experimental adjuvant systemic treatment options should be evaluated in future studies.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Neoadjuvant Therapy; Positron-Emission Tomography; Predictive Value of Tests; Radiopharmaceuticals; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

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

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

Hyperthermic isolated limb perfusion (ILP) with recombinant tumour necrosis factor alpha (TNF) and melphalan contributes to limb-saving treatment in patients with locally advanced extremity soft tissue sarcoma (STS). This study was conducted to evaluate the dynamic changes of tumour oxygenation and temperature during ILP and their effects on treatment response.. Tumour oxygenation (pO(2)) and tumour temperature were measured by intratumourally placed O(2)-sensitive catheter electrodes in 34 patients who underwent ILP for locally advanced or recurrent STS. Tumour response to ILP was assessed by the fraction of tumour necrosis in the resection specimen.. Mean tumour pO(2) prior to application of TNF and melphalan was 36 mm Hg (range: 2-116 mm Hg) and dropped significantly to 13 mm Hg (range: 0-67 mm Hg, p = 0.03) during ILP. Mean tumour tissue temperature increased from 34.4°C (range 32.4-36.4) to 38.5°C (range 34.1-40.4, p = 0.0001). The mean fraction of necrosis in the resection specimen was 65% (range 5-99). Only the tumour tissue temperature at the onset of ILP correlated with the extent of tumour necrosis (p = 0.01).. ILP with TNF and melphalan induces severe oxygen deprivation in soft tissue sarcoma. However, changes in tumour oxygenation did not correlate with treatment response.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Body Temperature; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Lower Extremity; Male; Melphalan; Middle Aged; Oxygen; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha; Upper Extremity; Young Adult

Controversy has surrounded the role of isolated limb perfusion (ILP) for unresectable extremity sarcomas. However, there remains a group of sarcoma patients for whom amputation is the only potential treatment. Because systemic therapies are limited, the authors evaluated ILP in an effort to provide a limb-salvage option.. Since 1995, patients with unresectable extremity sarcomas were entered in 2 prospective trials using ILP. Study 1 used tumor necrosis factor (TNF) and melphalan in the perfusion circuit at hyperthermic temperatures (39-41°C). Study 2 used doxorubicin at normothermic temperatures. All ILPs were performed using the standard, previously described technique.. Seventeen patients were entered into study 1; there were 10 (58%) partial responses, 1 (6%) near complete response (CR), 1 (6%) CR, and 5 (30%) no response/minor response. Fourteen patients died of their disease, with a median follow-up of 17 months. Seven (41%) patients maintained their limb intact until the time of death. Twelve patients were entered into study 2; there were no partial or CRs and 2 (20%) minor responses. With a median follow-up of 35 months, there are 3 patients alive (2 with their extremity intact and 1 with an amputation). Six patients developed myonecrosis with creatine phosphokinase levels up to 54,000 U/dL.. Although doxorubicin is active systemically, TNF and melphalan appear to have greater activity and less toxicity during ILP. Future clinical trials are needed to clearly identify the role for ILP in patients with unresectable extremity sarcomas. Cancer 2011. © 2011 American Cancer Society.

Topics: Chemotherapy, Cancer, Regional Perfusion; Doxorubicin; Extremities; Female; Humans; Hyperthermia, Induced; Limb Salvage; Male; Melphalan; Middle Aged; Sarcoma; Tumor Necrosis Factor-alpha

Isolated limb perfusion (TM-ILP) achieves high response rates in soft tissue sarcomas (STS). Some tumors show an insufficient association between radiological and pathological response. We investigated STS after TM-ILP with a primary emphasis on histologic regression patterns.. In 53 patients with STS, TM-ILP with subsequent tumor resection was performed. Regression was assessed by the Salzer-Kuntschik regression scale. Microvessel density (MVD) of primary biopsies of 37 patients was determined by immunohistochemistry. Tumor regression was correlated with MVD of primary biopsies and other clinico-pathological parameters.. Regression presented mainly as necrosis or fibrosis/sclerosis upon histopathology. MFH, leiomyosarcoma, or clear cell sarcoma (CCS) responded well; whereas liposarcomas, synovial sarcomas, or MPNST were poor responders. MFH often had abundant necrosis; while other STS mainly presented with fibrosis/sclerosis. MVD had no influence on regression grade but modulated histologic regression patterns. Excellent regression demonstrated a trend toward an association with improved survival and local control.. TM-ILP yielded high response rates in STS. Regression after TM-ILP exhibits MVD-dependent histopathologic patterns and variable efficacy in different sarcoma types. Complete regression seems to be a favorable prognostic factor. A concerted consideration of histopathology and clinical findings may contribute to a better clinical assessment of regression after TM-ILP.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Immunoenzyme Techniques; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Neovascularization, Pathologic; Sarcoma; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult

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

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

Patients with locally advanced or metastatic/recurrent soft tissue and Ewing's sarcoma (EWS) have few treatment options. The purpose of our phase II study was to assess the feasibility, safety and efficacy of tandem high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) in such patients.. Thirteen patients were enrolled onto this study. The first cycle of HDCT consisted of doxorubicin (150 mg/m(2)) and ifosfamide (14 g/m(2)) mixed with mesna (14 g/m(2)), while the second cycle consisted of melphalan (150 mg/m(2)) and cisplatin (200 mg/m(2)).. Eleven out of 13 patients were able to complete both cycles of HDCT. No treatment-related mortality occurred and grade 3 or 4 toxicity was clinically tolerable. The 5-year progression-free survival (PFS) and overall survival (OS) for all patients was 23% (confidence interval, CI: 0-46%) and 31% (CI: 14-70%), respectively. Out of the four patients still alive, two had EWS and measurable disease at the time of ASCT and achieved a complete remission, remaining progression free 126 and 155 months after ASCT.. Our study demonstrates the feasibility and safety of tandem HDCT in patients with high-risk or metastatic/recurrent sarcoma, with some patients achieving long-term PFS and OS.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Combined Modality Therapy; Disease Progression; Doxorubicin; Feasibility Studies; Female; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Immunoenzyme Techniques; Male; Melphalan; Mesna; Neoplasm Recurrence, Local; Neoplasm Staging; Neuroectodermal Tumors, Primitive, Peripheral; Osteosarcoma; Prognosis; Prospective Studies; Protective Agents; Remission Induction; Rhabdomyosarcoma; Safety; Sarcoma; Sarcoma, Ewing; Survival Rate; Transplantation, Autologous; Treatment Outcome; Young Adult

We prospectively studied the efficacy of high dose therapy (HDT) versus an oral maintenance treatment (OMT) in patients with stage IV soft tissue sarcoma (STS).. Both groups were pretreated with the CEVAIE combination consisting of carboplatin, etoposide, vincristine, actinomycin D, ifosfamide, and epirubicin. HDT consisted of a tandem cycle of thiotepa (600 mg/m(2)) plus cyclophosphamide (4,500 mg/m(2)) and melphalan (120 mg/m(2)) plus etoposide (1,800 mg/m(2)). This treatment was compared with OMT, consisting of four cycles trofosfamide (10 days 2 x 75 mg/m(2)/day) plus etoposide (10 days 2 x 25 mg/m(2)/day), and 4 cycles trofosfamide (10 days 2 x 75 mg/m(2)/day) plus idarubicin (10 days 4 x 5 mg/m(2)). Eligibility criteria were: diagnosis confirmed by reference pathology, primary stage IV, below 22 years of age, and having completed the study therapy.. From 96 patients 45 were treated with HDT and 51 with OMT. The main risk parameters were equally distributed in both arms. After a median follow-up of 57.4 months, 11/45 (24.4%) patients in the HDT-arm and 26/51 (57.8%) patients in OMT-arm were alive. Kaplan-Meier analysis demonstrated an overall survival for the whole group of 0.27 (OMT group: 0.52, HDT group 0.27, log rank P = 0.03). The proportional hazard analysis for patients with rhabdomyosarcoma (RMS) or "RMS-like" tumors (77.1% of all patients) demonstrated an independent benefit of OMT on outcome.. Oral maintenance therapy seems to be a promising option for patients with RMS-like stage IV tumors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Cyclophosphamide; Dactinomycin; Epirubicin; Etoposide; Female; Humans; Idarubicin; Ifosfamide; Infant; Kaplan-Meier Estimate; Male; Melphalan; Sarcoma; Soft Tissue Neoplasms; Thiotepa; Treatment Outcome; Vincristine

Limited information is available regarding the use of amifostine in pediatric hematopoietic stem cell transplant (HSCT) patients. Melphalan, carboplatin, etoposide +/- cyclophosphamide is a commonly used preparatory regimen in pediatric solid tumor HSCT. Therefore, we decided to determine the feasibility of the addition of amifostine (750 mg/m b.i.d. x 4 d) to melphalan (200 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) (level 1) and escalating doses of cyclophosphamide (3000 mg/m and 3800 mg/m, levels 2 and 3, respectively) followed by autologous HSCT. Thirty-two patients with a variety of pediatric solid tumors were studied. Seventeen patients were accrued at level 1, 9 at level 2, and 6 at level 3. Major toxicities during the administration of the preparatory regimen were hypocalcemia, emesis, and hypotension. Hypocalcemia required aggressive calcium supplementation during the conditioning phase. No dose limiting toxicities were encountered at level 3. Amifostine at 750 mg/m b.i.d. for 4 days can be administered with a double alkylator regimen consisting of melphalan (200 mg/m), cyclophosphamide (up to 3800 mg/m), carboplatin (1200 mg/m), and etoposide (800 mg/m) with manageable toxicities.

Topics: Adolescent; Adult; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Bone Neoplasms; Carboplatin; Central Nervous System Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Etoposide; Feasibility Studies; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Hypocalcemia; Kidney Neoplasms; Melphalan; Neoplasms; Neuroblastoma; Pilot Projects; Recurrence; Risk Factors; Sarcoma; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Wilms Tumor

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

Current 5-year survival after complete resection of pulmonary metastases is 20% to 40%, and many patients develop intrathoracic recurrences. Isolated lung perfusion is an experimental technique to deliver high-dose chemotherapy to the lung without systemic exposure. A phase I trial of isolated lung perfusion with melphalan (MN) combined with pulmonary metastasectomy for resectable lung metastases was conducted to define the dose-limiting toxicity and maximum tolerated dose.. From May 2001 to August 2003, 16 patients underwent isolated lung perfusion with MN, followed by surgical resection of lung metastases. Patients were treated with increasing MN doses (15, 30, 45, and 60 mg). For each dose level, normothermia (37 degrees C) and hyperthermia (42 degrees C) were evaluated (n = 3 per level). Serum samples were obtained during the procedure. Pulmonary, hematologic, and nonhematologic toxicities were recorded. The primary tumor was colorectal in 7 patients, renal in 5, sarcoma in 3, and salivary gland in 1. Isolated lung perfusion was performed unilaterally in 11 patients, and staged bilaterally in 5.. In total, 21 procedures of isolated lung perfusion with complete metastasectomy were performed without technical difficulties. Operative mortality was 0%, and no systemic toxicity was encountered. Grade 3 pulmonary toxicity developed at a dose of 60 mg of MN at 37 degrees C in 2 of 3 patients at this dose, terminating the trial.. Isolated lung perfusion with MN combined with pulmonary metastasectomy is feasible. Dose-limiting toxicity occurred at a dose of 60 mg of MN at 37 degrees C, and the maximum tolerated dose was set at 45 mg of MN at 42 degrees C.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Female; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Melphalan; Middle Aged; Pulmonary Surgical Procedures; Salivary Gland Neoplasms; Sarcoma

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 MMT4 study was designed to explore an intensive chemotherapy regimen (MMT4-89) and the role of high-dose melphalan (MMT4-91) in children with metastatic soft tissue sarcoma, including extraosseous peripheral neuroectodermal tumor (PNET). Thirty-one patients with PNET were treated between 1989 and 1995 (11 according to MMT4-89 and 20 according to MMT4-91). Chemotherapy consisted of four CEVAIE cycles, each including three 3-week courses: CEV (carboplatin 500 mg/m(2), epirubicin 150 mg/m(2), vincristine 1.5 mg/m(2)), IVA ifosfamide 9 g/m(2), actinomycin 1.5 mg/m(2), vincristine 1.5 mg/m(2)), IVE (ifosfamide 9 g/m(2), etoposide 600 mg/m(2), vincristine 1.5 mg/m(2)). In MMT4-91 the fourth CEVAIE was replaced with melphalan 200 mg/m(2) with stem cell rescue. The CEV combination was evaluated as a window study. Surgery followed the second cycle. Radiotherapy was administered to post-surgical residual disease. The response rate was 55% after CEV, rising to 80% after the first CEVAIE. Twenty-five patients achieved complete remission (CR). Overall, the 5-year EFS was 22.6%: 36.4% and 15% for patients treated according to MMT4-89 and MMT4-91, respectively (P = 0.3). Local control was achieved in 77% of irradiated patients vs 45% of non-irradiated. Age >10 years was associated with significantly poorer outcome (P = 0.04). In conclusion, despite the high CR rate, intensive chemotherapy with or without high-dose melphalan appeared to have little impact on the survival of patients with metastatic extraosseus PNET.

Topics: Adolescent; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Female; Humans; Male; Melphalan; Neuroectodermal Tumors; Peripheral Blood Stem Cell Transplantation; Remission Induction; Sarcoma; Survival Analysis; Treatment Outcome

In patients with unresectable soft tissue sarcoma of the extremities, isolated limb perfusion (ILP) has been reported to result in significant tumor regression enabling limb-sparing resection in the majority of patients. However, clinical tumor response as evaluated by imaging and histopathology (extent of tumor necrosis) often differ significantly. The current study was initiated to evaluate prospectively the role of 31phosphorus-magnetic resonance spectroscopy (31P-MRS) in the noninvasive assessment of histologic response in patients treated with ILP.. Thirty-two patients with locally advanced and unresectable soft tissue tumors (sarcoma in 28 patients and bulky melanoma in 4 patients) were treated by ILP with recombinant human tumor necrosis factor-alpha and melphalan or with cytostatics. 31P-MRS was performed prior to treatment and at regular intervals after ILP until definite tumor resection. Clinical response parameters according to the World Health Organization as well as the histopathologic necrosis rate of the resection specimen were correlated with changes in the energy-rich phosphorous metabolites phosphocreatine (PCR); alpha-, beta-, gamma-adenosine triphosphate (ATP); phosphomonoesters (PME); and inorganic phosphate (Pi).. Clinically, 15 of 32 patients (response rate [RR] of 47%) demonstrated a partial response (PR). The ratios of PME/PCR and PME/beta-ATP decreased significantly after ILP in comparison with preoperative values (P < 0.001). The changes in the PME/beta-ATP ratio were significantly different between clinical responders and nonresponders (P < 0.02) in contrast with the PME/PCR ratios (P < 0.09). Histologic necrosis of > 90% (pathologic (p) PR) was present in 17 resection specimens, 7 of which demonstrated no clinical response. Seven tumors demonstrated a pathologic complete response (pCR). When combining PR, pPR, and pCR (RR of 68%), 31P-MRS was able to predict response with a specificity of 94% and a sensitivity of 68% (P < 0.006, by the chi-square test).. The considerable difference between clinical and pathologic RR after ILP underlines the shortcomings of established response criteria. Utilizing changes in PME/beta-ATP ratios, 31P-MRS is a highly specific tool with which to predict histologic response in this setting. This finding may be of major value in those patients in whom the decision to perform a major resection or amputation must be made for local tumor control.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Magnetic Resonance Spectroscopy; Male; Melphalan; Middle Aged; Phosphorus Isotopes; Predictive Value of Tests; Prospective Studies; Radionuclide Imaging; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

Patients with non-resectable soft tissue sarcomas of the extremities do not live longer if they are treated by amputation or disarticulation. In order to avoid major amputations, we tested isolated limb perfusion (ILP) with tumour necrosis factor alpha (TNF)+melphalan+/-interferon-gamma (IFN) as a pre-operative, neoadjuvant limb salvage treatment.. Twenty-two patients were included (six men and 16 women; three upper limb and 19 lower limb tumours). The AJCC stage was IIA in four patients, III in seven and IV in 11. Thirteen cases were recurrent or progressive after previous therapy; five tumours had a diameter >/=20 cm, and four were multiple or regionally metastatic. There were six malignant fibrous histiocytomas, five liposarcomas, four malignant peripheral nerve sheath tumours, three rhabdomyosarcomas, two leiomyosarcomas, one recurrent extraskeletal osteosarcoma and one angiosarcoma.. Twenty-four ILPs were performed in the 22 patients, and 18 (82%) experienced an objective response: this was complete in four (18%) and partial in 14 (64%). Three patients had a minimal or no response and the tumour progressed in one case. All patients had fever for 24 hours but only one developed a reversible grade 3 distributive shock syndrome with no sequelae. There was no grade 4 toxicity. Seventeen patients (77%) underwent limb-sparing resection of the tumour remnants after a median time of 3.4 months: 10 resections were intracompartmental and seven extracompartmental. Surgery included flaps or skin grafts in five patients, arterial replacement in two and knee arthrodesis in one. Adjuvant chemotherapy was given to eight patients and radiotherapy to six. In one patient amputation was necessary after a second ILP. Secondary amputations were performed for recurrence in two patients, resulting in an overall limb salvage rate of 19/22 (86%). After a median follow-up of 18.7 months, 10 recurrences were recorded: seven were both local and systemic and three were only local. The median disease free and overall survival times have been >12.5 and 18.7 months respectively: this is similar to the outcome after primary amputations for similar cases.. ILP with TNF and chemotherapy is an efficient limb sparing neoadjuvant therapy for a priori non-resectable limb soft tissue sarcomas.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Doxorubicin; Female; Humans; Ifosfamide; Interferon-gamma; Leg; Male; Melphalan; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Radiotherapy, Adjuvant; Salvage Therapy; Sarcoma; Soft Tissue Neoplasms; Survival Analysis; Tumor Necrosis Factor-alpha

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

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

The prognosis for recurrent multifocal limb soft tissue sarcoma (STS) is dismal due to systemic spread. However, many of these patients undergo amputation due to ineffective local control. The purpose of the present study was to determine whether isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan permits limb salvage and palliation for such patients.. Of 53 STS patients treated with hyperthermic ILP with TNF (3-4 mg) and melphalan (1-1.5 mg/kg), 13 (25%) had multifocal STS and were candidates for amputation.. The overall response rate was 92% (12/13) with 38% complete response and 54% partial response. Two patients died during the early postoperative period. Limb salvage was achieved in 85% of patients. One patient (8%) had only stable disease and underwent amputation. Local recurrence occurred in 38% but did not result in amputation.. Although the number of patients in this study is too small to allow definitive conclusions, it seems that ILP/TNF offer limb salvage and palliation for recurrent multifocal STS patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Drug Therapy, Combination; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

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

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

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

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

The unique property of high dose recombinant tumor necrosis factor alpha (rTNF alpha) is to activate and selectively destroy the tumor-associated microvasculature. For the systemic application of rTNF alpha it has been shown that the maximum tolerated dose (MTD) is 10 times less than the effective dose in animals. The main toxicity corresponds to systemic inflammatory response syndrome with a decrease in vascular resistance and hypotension. We found that it is possible to administer rTNF alpha at 10 times the MTD in an isolated limb perfusion (ILP) system with heart-lung machine, for locally advanced extremity soft tissue sarcomas. One hundred forty patients received an ILP with high-dose TNF alpha. In 55 patients treated with the combination of high-dose rTNF alpha + interferon-gamma + melphalan an overall objective response rate of 87% with 36% complete responses was observed; it was 81% and 28%, respectively, in a group treated with TNF alpha and melphalan (n = 85). Angiographic and immunohistological studies showed the selective and early damage of the sarcoma-associated microvasculature preceded by the upregulation of adhesion molecules and intratumoral leak of von Willebrand factor. Tumor invasion by platelets and, in some cases, by polymorphonuclear cells, appeared within hours after the application of rTNFa long before the lysis of the tumor. Thus, ILP with high-dose TNF alpha and chemotherapy seems to act through a dual targeting: TNF hits the tumor associated vasculature, and chemotherapy attacks the tumor cells. Therefore, ILP with TNF is a new option in the management of locally advanced soft tissue sarcoma of the extremities.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Drug Administration Schedule; Extremities; Female; Heart-Lung Machine; Humans; Hyperthermia, Induced; Interferon-gamma; Male; Melphalan; Middle Aged; Recombinant Proteins; Sarcoma; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha

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 objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible.. To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation.. In 8 cancer centers, 186 patients were treated over a period of almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interferon-tau. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP.. A major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow-up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths.. In the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Histiocytoma, Benign Fibrous; Humans; Liposarcoma; Male; Melphalan; Middle Aged; Sarcoma; Sarcoma, Synovial; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

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

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

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

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

Irresectable extremity sarcomas are large (grade II/III) tumors requiring amputation of the limb for local control. Limb salvage can be achieved by isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF-alpha), interferon-gamma and melphalan. To obtain insight into the effects of single dose ILP on extremity tumors, phosphate metabolism was monitored by 31P magnetic resonance spectroscopy (MRS) using the chemical shift imaging (CSI) technique. 2D CSI was used in combination with a slice select gradient in the third dimension to obtain true 3D localization. Spectral maps obtained prior to ILP revealed reductions in phosphocreatine (PCr) level and increases in phosphomonoester (PME) and phosphodiester (PDE) in tumor compared with muscle tissue. ILP treated tumors showed highly divergent changes in Pi while PME decreased in all cases (n = 11). Tumor volume, unchanged on day 8 after ILP, was decreased by 58 +/- 29% (mean +/- SD) at 2 months. Linear regression analysis revealed correlation between the changes in tumor metabolites measured on day 8, with percent volume decrease (Pi: r = -0.88, p < 0.001) and percent necrosis at resection (PME: r = -0.79, p -0.01). Correlation between pretreatment spectra and effectiveness of ILP treatment was not found. It is concluded that a single ILP with TNF-alpha + melphalan induced changes in tumor metabolite levels (measured on day 8) that reflect treatment efficacy. 31P MRS can thus provide information facilitating the decision as to when to remove tumor (residue) and, in the case where tumor remains inoperable, whether or not to apply additional therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Magnetic Resonance Spectroscopy; Male; Melphalan; Middle Aged; Phosphates; Phosphorus; Predictive Value of Tests; Sarcoma; Tumor Necrosis Factor-alpha

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

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

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

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

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

A total of 144 patients with advanced sarcomas were entered into a randomized prospective protocol with four treatment arms utilizing different combinations of chemotherapeutic agents. Of these, 120 patients (83%) were judged acceptable. Treatment 1: actinomycin-D (Act-D), 0.01 mg/kg IV, days 1--5; phenylalanine mustard (L-PAM), 4 mg PO, days 1--10 every six weeks. Treatment 2: Act-D, 0.01 mg/kg IV, days 1--5; L-PAM, 4 mg PO, days 1--10; vincristine, 1 mg IV, days 1, 8, 15, 22, 29, 36, repeat every six weeks. Treatment 3: Act-D, 0.01 mg/kg IV, days 1--5; L-PAM, 4 mg PO, DAYS 1--10; NSC-1026, 200 mg/kg IV, days 1--6. Treatment 4: Adriamycin, 0.4 mg/kg IV, days 1, 2, 3, 8, 9, 10, then 2XWK starting day 15 (max. 1,200 mg). There was a provision that upon progression of the disease in the first three treatment regimens, patients would be crossed over to Treatment 4. Responses were as follows: 1 - Partial Response (PR) 1/25; No Change (NC) 9/25 (36%). gF2 - NC 17/26 (65%). 3 - NC 13/25 (52%). 4 - Complete Response (CR) 1/41; PR 6/41; (15%); NC 27/41 (66%). Clearly Treatment 4 was the best arm, with a 17% response rate and an initial progression rate of 17%. The only other response was a partial in 1. The difference is statistically significant (H = 17.247, P = 0.0006). If the responders to Adriamycin were analyzed without crossovers, the response rate would be 22% (6/27). (H = 14.079, P = 0.003). Median times to progression were 12.5, 8.7 weeks for 1 and 2, and 5 weeks for 3 and 4. There was no significant difference in the median survival times among the four treatment arms. It appears that Adriamycin as a single drug is superior to the drug combinations and would probably be even more effective used in combination with known active agents.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Cycloleucine; Dactinomycin; Doxorubicin; Drug Evaluation; Drug Therapy, Combination; Humans; Melphalan; Remission, Spontaneous; Sarcoma; Soft Tissue Neoplasms; Time Factors; Vincristine

Considerable progress is being made in the chemotherapy of some gynecologic cancers. A random study comparing postoperative irradiation therapy with chemotherapy shows the two to be equally effective. Chemotherapy has the advantages of added safety and of being much less expensive for the patient. Postoperative chemotherapeutic treatment with VAC of patients with embryonal carcinoma of the ovary can prevent recurrence of this frequently fatal tumor. In some patients with advanced embryonal carcinoma of the ovary, chemotherapy with VAC may produce permanent remissions. Combined irradiation and chemotherapy and vincristine and actinomycin-D may be curative for some patients with advanced sarcomas in the pelvis or abdomen. This treatment combination is associated with severe complications; however, some are preventable.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Chlorambucil; Cyclophosphamide; Dactinomycin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Melphalan; Middle Aged; Ovarian Neoplasms; Pelvic Neoplasms; Sarcoma; Teratoma; Vincristine

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

Patients with locally extensive high-grade extremity soft tissue sarcomas (eSTS) are often presented in multidisciplinary teams to decide between ablative surgery (amputation) or limb-salvage surgery supplemented with either neo-adjuvant radiotherapy (RT) or induction isolated limb perfusion (ILP). In The Netherlands, ILP typically aims to reduce the size of tumors that would otherwise be considered irresectable, whereas neo-adjuvant RT aims mainly at improving local control and reducing morbidity of required marginal margins. This study presents a 15-year nationwide cohort to describe the oncological outcomes of both pre-operative treatment strategies.. All consecutive patients with locally extensive primary high-grade eSTS surgically treated between 2000 and 2015 at five tertiary sarcoma centers that received neo-adjuvant ILP or RT were included. 169 patients met the inclusion criteria (89 ILP, 80 RT). Median follow-up was 7.3 years.. Limb salvage was achieved in 84% of cases in the ILP group (80% for patients with amputation indication) and 96% of cases in the RT group. 5-Year overall survival was 47% in the ILP group, 69% in the RT group. 5-Year local recurrence rate was 14% in the ILP group, 10% in the RT group. Distant metastasis rate was 55% in the ILP group, 36% in the RT group.. We find oncological outcomes and limb salvage rates in line with existing literature for both treatment modalities. Whether the tumor was locally advanced with an indication for induction therapy to prevent amputation or morbid surgery appeared to be the main determinant in choosing between neo-adjuvant ILP or RT.

Topics: Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Limb Salvage; Melphalan; Neoplasm Recurrence, Local; Perfusion; Radiotherapy, Adjuvant; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the response rates of different extremity soft-tissue sarcoma subtypes (eSTS) after isolated limb perfusion (ILP), based on an international multi-centre study.. The retrospective cohort comprised eSTS patients from 17 specialised ILP centres that underwent melphalan-based ILP, with or without recombinant human tumour necrosis factor (rhTNFα) (TM-ILP and M-ILP, respectively). Response was measured on imaging (magnetic resonance imaging) and/or clinical response, for which M-ILPs were excluded.. A total of 1109 eSTS patients were included. The three most common histological subtypes were undifferentiated pleomorphic sarcoma (17%, n = 184), synovial sarcoma (16%, n = 175) and myxofibrosarcoma (8%, n = 87). rhTNFα was used in 93% (TM-ILP) and resulted in a significantly better overall response rate (ORR, p = 0.031) and complete responses (CR, p < 0.001) in comparison to M-ILP, without significant differences among histological subgroups. The ORR of TM-ILP was 68%, including 17% CR. Also, 80% showed progressive disease. Significantly higher response rates were shown for Kaposi sarcoma (KS) with 42% CR and 96% ORR (both p < 0.001), and significantly higher CR rates for angiosarcoma (AS, 45%, p < 0.001) and clear cell sarcoma (CCS, 31%, p = 0.049). ILP was followed by resection ≤ 6 months in 80% of the patients. The overall limb salvage rate was 88%, without significant differences among histological subgroups, but was significantly higher for ILP responders compared to non-responders (93% versus 76%, p < 0.001).. ILP resulted in high response and LRS among all eSTS subtypes, however, with significant differences between subtypes with most promising results for KS, AS and CCS.

Topics: Adult; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Melphalan; Perfusion; Retrospective Studies; Sarcoma; Sarcoma, Kaposi; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

This novel study compared the use of tumor necrosis factor (TNF)-alpha and melphalan-based isolated limb perfusion (TM-ILP) to the standard treatment of locally recurrent soft tissue extremity sarcoma. The aim was to assess whether TM-ILP positively influences the recurrence-free survival of locally recurrent high-grade soft tissue sarcoma (STS) of the extremities.. We retrospectively analyzed our clinical database for patients with STS. Variables were analyzed using chi-square test or Mann-Whitney rank-sum test. Furthermore, Kaplan-Meier survival plots were calculated and a proportional hazard regression model was developed.. Out of 448 patients with extraabdominal STS treated between August 2012 and December 2015, 52 cases involving 47 patients had locally recurrent STS. Twenty-eight of these patients were treated with TM-ILP prior to surgical resection (TM-ILP-group), and 24 were treated with standard therapy (without TM-ILP). The 3-year recurrence-free survival for the TM-ILP-group was estimated at 75% (95% confidence interval (CI), 71.5-78.5). Local recurrence-free survival in the standard group was significantly lower (LRFS: 43.4%, 95% CI 38.7-48.1, p = 0.026). Multivariable analysis revealed resection with negative margins, lower number of previous recurrences, and TM-ILP as positive predictors for recurrence-free survival.. TM-ILP and consecutive resection of residual tumor with negative resection margins significantly improves local recurrence-free survival for patients with a first local recurrence of high-grade STS in the extremities.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Hyperthermia, Induced; Melphalan; Neoplasm Recurrence, Local; Perfusion; Prognosis; Retrospective Studies; Sarcoma; Tumor Necrosis Factor-alpha

Hyperthermic isolated limb perfusion uses therapeutic effect of hyperthermia in the bounded compartment of the limb together with increased concentration of chemotherapy effect than what would be achieved in systemic application. Gold standard was melphalan (Alkeran) in combination with tasonermin (Beromun, tumor necrosis factor alpha). The efficacy of this combination has been demonstrated in limb soft tissue sarcomas and in patients with limb isolated bulky disease of malignant melanoma.. We describe a case of a 65-year-old female patient with undifferentiated spindle-cell sarcoma treated by a multidisciplinary team at the 2nd Surgical Clinic of Cardiovascular Surgery and Clinic of Oncology General University Hospital in Prague and at the Department of Orthopaedics Na Bulovce Hospital with the aim of preserving the limb despite the advanced disease. The patient underwent hyperthermic isolated limb perfusion with tasonermin and melphalan with partial response on magnetic resonance imaging. Subsequent wide resection was done with complete pathological remission according to histological examination maintaining a fully functional limb. The patient is followed without signs of recurrence.. Hyperthermic isolated limb perfusion with tasonermin and melphalan is an important part of a multimodal approach in the treatment of extremity sarcomas with a high percentage of responses that increase the percentage of limbs retaining resections. Multidisciplinary team should consider this option in patients with localized limb sarcomas and should be performed in specialized centers with experience in this procedure. This work was supported by project Progres Q28-LF1. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Topics: Aged; Chemotherapy, Cancer, Regional Perfusion; Humans; Hyperthermia, Induced; Lower Extremity; Magnetic Resonance Imaging; Melphalan; Neoadjuvant Therapy; Sarcoma; Tumor Necrosis Factor-alpha

This feasibility study presents the results of a new intensive treatment regimen for locally advanced extremity soft tissue sarcomas (ESTS), consisting of hyperthermic isolated limb perfusion (HILP), preoperative external beam radiotherapy (EBRT), and surgical resection.. From 2011 to 2016, 11 high grade locally advanced ESTS patients underwent this treatment regimen. Preoperative EBRT (12 × 3 Gy) started <4 weeks following the HILP (TNF-α and melphalan) and the surgical resection was planned to take place <2 weeks following the end of the EBRT.. All patients completed the treatment. After a median follow-up of 32 (23-50) months, the limb was saved in 10 patients (91%), 1 patient (9%) developed a local recurrence, 5 patients (45%) developed distant metastases, and 3 patients (27%) died of their disease. During follow-up two patients (18%) developed a pathologic fracture of the treated limb and three patients (27%) developed a major wound complication requiring surgical intervention. The median overall treatment time (OTT) was 56 (49-69) days.. This intensive treatment regimen is feasible and safe in locally advanced ESTS, and it achieves oncological results that are comparable with conventional HILP treatment. In addition, the major wound complication risk is comparable and the OTT is reduced.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Cytoreduction Surgical Procedures; Extremities; Feasibility Studies; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Preoperative Care; Prognosis; Radiotherapy; Salvage Therapy; Sarcoma; Survival Rate

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

Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) in combination with complete tumor resection is an effective treatment option for non-resectable soft-tissue sarcoma of the extremities, with limb salvage rates greater than 80%. The aim of this study was to assess quality of life (QoL) after TM-ILP, also with regard to long-term survival.. We retrospectively examined 27 patients who had primarily non-resectable soft-tissue sarcoma of the leg and who had undergone TM-ILP and complete tumor resection (with limb-sparing intent) during their follow-up examinations using the Quality of Life Questionnaire (QLQ-C30) and the German Short Musculoskeletal Function Assessment (SMFA-D). The results from the QLQ-C30 were compared to the reference values for the general population, to the "all cancer patients" reference values (both reference values published by the European Organization for Research and Treatment of Cancer (EORTC)), and to the reference values of a historical amputation group from the literature. The results of the SMFA were compared with those from a reference group of healthy individuals.. Surprisingly, we found that the global health status/QoL in the TM-ILP group was not significantly different from the general population or from patients with amputation, but it was higher than that of patients with cancer in general. Concerning the SMFA, we did find functional impairments in patients after TM-ILP compared to the reference group. With regard to long-term survival, we found no time-dependent deterioration in QoL for longer time intervals after treatment.. These results support the use of TM-ILP in limb-sparing multimodal therapy settings from a quality-of-life perspective, but they also encourage further research on this matter.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Child; Female; Follow-Up Studies; Humans; Lower Extremity; Male; Melphalan; Middle Aged; Neoplasm Staging; Prognosis; Quality of Life; Retrospective Studies; Sarcoma; Tumor Necrosis Factor-alpha; Young Adult

Treatment-resistant, locally advanced soft tissue sarcomas often require amputation for complete tumor extirpation. Isolated limb infusion (ILI) selectively delivers high-dose chemotherapy to the extremity in an attempt to achieve limb salvage. The aim of this study was to report perioperative and oncologic outcomes after ILI in patients with extremity soft tissue sarcomas.. From 1994 to 2016, 77 patients underwent 84 ILIs at a total of 5 institutions. Melphalan and actinomycin D were circulated for 30 minutes after complete tourniquet occlusion of the limb, then actively washed out to prevent systemic exposure.. The procedure was performed in an upper extremity on 19 patients (21 infusions) and in a lower extremity on 58 patients (63 infusions). The 3-month overall response rate (ORR) for the entire cohort was 58%, and there was a statistically significant difference (p = 0.03) between upper (37%) and lower extremity (66%) ORR. With median follow-up of 20.6 months (range 0.6 to 146.1 months), the overall limb salvage rate was 77.9%. For those who underwent amputation due to progression of disease, the median time to amputation was 4.5 months. With a median follow-up of 20.6 months, the median overall survival for the entire cohort was 44.3 months. The distant metastatic-free survival was longer for responders than nonresponders (p = 0.01), though the disease-specific survival was not different for the same groups (p = 0.2).. Isolated limb infusion for extremity soft tissue sarcoma results in an objective response for half of the patients who are otherwise facing amputation, and offers prolonged limb salvage for the vast majority of patients. The procedure is well tolerated without serious complications.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Follow-Up Studies; Humans; Limb Salvage; Male; Melphalan; Middle Aged; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Young Adult

Hyperthermic isolated limb perfusion (HILP) is a locoregional treatment aimed at avoiding amputation in patients with advanced extremity soft tissue sarcomas (STS). Over the last 25 years, HILP procedure has been implemented to maximise its therapeutic ratio.. A retrospective analysis including 117 patients who underwent HILP from 1989 to 2013 was performed. Three different drug schedules were applied: 1) doxorubicin (n = 47), 2) high dose (3-4 mg) tumour necrosis factor-alpha (TNF-α) plus doxorubicin (n = 30), 3) low dose (1 mg) TNF-α plus melphalan (L-PAM) (n = 40). Tumour response was evaluated by MRI or CT and surgical specimens. Toxicity and local progression-free survival (LPFS) were also evaluated.. In total 92 (78.6%) patients had primary, 25 (21.4%) had recurrent and 17 (14.5%) had metastatic disease. The subjects in the three groups were homogeneous for clinical-pathological features. Pathological response was complete in 55 patients (47%), partial in 35 (29.9%), regardless of drug schedule (p = 0.501) and tumour presentation (p = 0.094). Wieberdink III-V toxicity was registered in 19.1%, 20% and 2.5% of patients, respectively (p < 0.051). Twenty-eight patients (23.9%) received adjuvant radiotherapy with no relevant toxicity. Five-year LPFS was 81.6% and 74.2% in patients with primary or recurrent disease, respectively (p = 0.652). After a median follow-up of 36.5 months, the limb sparing rate was 77.8%.. HILP performed with different drugs was equally active, either in primary, recurrent or metastatic STS, providing effective limb sparing and durable local control. Low dose TNF-α plus L-PAM had the most favourable toxicity profile. Adjuvant radiotherapy was not associated with relevant toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Doxorubicin; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Tumor Burden; Tumor Necrosis Factor-alpha; Young Adult

Histological response assessment following neoadjuvant treatment can help identify patients at a higher risk for systemic disease progression. Our goal was to evaluate whether mitotic count and the amount of viable tumour following neoadjuvant isolated limb perfusion (ILP) for primary, locally advanced, non-metastatic, high-grade extremity soft tissue sarcoma correlate with prognosis.. This study is a retrospective analysis of 61 patients who underwent neoadjuvant ILP followed by surgical resection with curative intent between 2001 and 2011. Non-parametric analyses were carried out with the Mann-Whitney U and the Wilcoxon signed-rank test. Survival curves were calculated with the Kaplan-Meier method and compared with the log-rank test.. The median follow-up was 44 months for all patients and 55 months for survivors. The amount of viable tumour after ILP had no correlation with overall (OS) (P = 0.227) or event-free (EFS) (P = 0.238) survival probability. Patients with a low mitotic count after ILP had a significantly higher OS (P < 0.001), EFS (P = 0.002) and post-relapse survival probability (P = 0.030) compared to patients with an intermediate or high mitotic count.. The mitotic count following ILP for primary, high-grade, locally advanced, non-metastatic soft tissue sarcoma appears to significantly correlate with prognosis. If these results are validated in a prospective setting, they could provide a rationale for the design of adjuvant systemic chemotherapy trials with the goal of improving the prognosis of patients with an intermediate or high mitotic count after ILP.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Neoadjuvant Therapy; Prognosis; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha; Young Adult

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

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

The management of locally advanced or recurrent extremity sarcoma often necessitates multimodal therapy to preserve a limb, of which isolated limb perfusion (ILP) is a key component. However, with standard chemotherapeutic agents used in ILP, the duration of response is limited. Novel agents or treatment combinations are urgently needed to improve outcomes. Previous work in an animal model has demonstrated the efficacy of oncolytic virotherapy when delivered by ILP and, in this study, we report further improvements from combining ILP-delivered oncolytic virotherapy with radiation and surgical resection. In vitro, the combination of radiation with an oncolytic vaccinia virus (GLV-1h68) and melphalan demonstrated increased cytotoxicity in a panel of sarcoma cell lines. The effects were mediated through activation of the intrinsic apoptotic pathway. In vivo, combinations of radiation, oncolytic virotherapy and standard ILP resulted in delayed tumour growth and prolonged survival when compared with standard ILP alone. However, local disease control could only be secured when such treatment was combined with surgical resection, the timing of which was crucial in determining outcome. Combinations of oncolytic virotherapy with surgical resection and radiation have direct clinical relevance in extremity sarcoma and represent an exciting prospect for improving outcomes in this pathology.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Disease Models, Animal; Extremities; Genetic Vectors; Humans; Male; Melphalan; Oncolytic Virotherapy; Oncolytic Viruses; Proton Therapy; Radiotherapy; Rats; Recurrence; Sarcoma; Transduction, Genetic; Tumor Burden

An increasing number of children with advanced malignancies have recently received high-dose chemotherapy (HDC) with hematopoietic stem cell transplantation (HSCT), followed by surgery. In this study, we reviewed our experience with surgery after HDC and autologous (auto) or allogeneic (allo) HSCT to elucidate the problems associated with this treatment and establish the optimum surgical management strategy.. We retrospectively reviewed the cases of 24 children with advanced malignancy treated with HDC and HSCT before tumor resection at our institution. The tumors included 18 neuroblastomas, 5 soft tissue sarcomas, 2 hepatoblastomas, and 1 Wilms tumor. The source of hematopoietic stem cells was auto-HSCT in 19 patients and allo-HSCT in 5 patients. To be able to undergo surgery, it was necessary that the patient's general condition, including hemostasis, should be fairly good and that the results of hematological examinations should include a white blood cell (WBC) count of>1,000/µL, hemoglobin level of>10 g/dL and platelet count of>5 × 10(4)/µL.. The mean duration before WBC recovery after HSCT was 14.5 ± 1.4 days after auto-HSCT and 23.8 ± 1.2 days after allo-HSCT, respectively (p<0.01). The mean duration before platelet recovery after HSCT was 46.5 ± 5.2 days for auto-HSCT and 48.6 ± 5.5 days for allo-HSCT (not significant [n.s.]). The mean interval between allo-HSCT and surgery was significantly longer (92.8 ± 6.2 days) than that between auto-HSCT and surgery (57.0 ± 3.9 days) (p<0.01), likely because of the use of steroids and immunosuppressants after HSCT. The tumors were completely resected in all cases without severe complications. All the patients treated with allo-HSCT had an acute graft versus host (aGVH) reaction at 2 to 3 weeks after HSCT, and specifically required the administration of steroids and immunosuppressants to prevent aGVH. The postoperative complications included paralytic ileus in two cases and a tacrolimus-associated encephalopathy in one case involving allo-HSCT. In half of the patients, the WBC count was not elevated after surgery, whereas the postoperative serum C-reactive protein (CRP) level was elevated in all cases.. Our data indicate that surgical treatment can be safely performed even after HDC with HSCT if attention is paid to myelosuppression and the adverse effects of both chemotherapeutic agents and immunosuppressants.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Child; Child, Preschool; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Hepatoblastoma; Humans; Infant; Kidney Neoplasms; Liver Neoplasms; Male; Melphalan; Neoadjuvant Therapy; Neoplasms, Complex and Mixed; Neuroblastoma; Perioperative Care; Retrospective Studies; Sarcoma; Thiotepa; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Wilms Tumor

Tumour necrosis factor-α (TNF) and melphalan based isolated limb perfusion (TM-ILP) is an attractive treatment option for advanced extremity soft tissue sarcomas (STS). This study reports on a 20-year single centre experience and discusses the evolution and changes in methodology since the introduction of TNF in ILP.. We performed 306 TM-ILPs in 275 patients with extremity STS. All patients were candidates for amputation or mutilating surgery in order to achieve local control. Clinical response evaluation consisted of clinical examination and magnetic resonance imaging. To evaluate the importance of TNF-dose, treatment results of two periods (1991-2003 high dose (3-4 mg) TNF; 2003-2012 reduced dose (1-2mg) TNF) were compared.. During the study period, more femoral perfusions were done instead of iliac perfusions. Reduction of TNF dose and reduction of total ILP time did not lead to different clinical response rates (70% and 69% for periods 1 and 2 respectively) or different local recurrence rates, but was associated with less local toxicity (23% and 14% for periods 1 and 2 respectively). Hospital stay was significantly reduced during the study period. There was an improved pathological response in the high dose TNF group without consequences for clinical outcome.. TM-ILP remains a very effective treatment modality for limb threatening extremity STS. Moreover, reduction of dose and the growing experience in ILP led to less local toxicity and shorter hospital stay.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Dose-Response Relationship, Drug; Extremities; Female; Humans; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Perfusion; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha

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

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

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

Isolated limb perfusion (ILP) is an effective limb salvage strategy in patients with advanced soft tissue sarcoma (STS) where surgery alone would result in significant functional morbidity or mandate an amputation. Most previous reports of patients undergoing ILP focus on limb salvage rates rather than local and distant relapse rates. Here, we report the oncological outcome of sarcoma patients treated by ILP and surgery.. Data were retrieved from prospective ILP databases from two ILP centers following similar ILP techniques and surgical approaches. Only patients with primary, intermediate, or high grade non-metastatic STS were included.. The cohort comprised 90 patients. Median follow-up was 39 months (range 3-165 months). Median tumor size was 11 cm (range 5-34). Twenty of 90 (22%) patients underwent prior debulking surgery outside the centers. Twenty-nine of 90 (32%) had postoperative irradiation. Four of 90 underwent amputation either related to local recurrence or irresectability, 4 of 90 underwent amputation for treatment-related complications. Fifteen of 83 (18%) patients had local recurrences after ILP and limb sparing surgery, 39 of 90 (43%) developed metastatic disease. Twenty-two of 90 (24%) died of disease.. Preoperative ILP and tumor resection resulted in good local control in a cohort of high-risk STS patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Limb Salvage; Male; Melphalan; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Prognosis; Prospective Studies; Retrospective Studies; Sarcoma; Survival Rate; Tumor Necrosis Factor-alpha; Young Adult

To evaluate the long-term results of 20 years of experience with isolated limb perfusion (ILP) with tumour necrosis factor α (TNF-α) and melphalan, followed by surgical resection and adjuvant radiotherapy, for the treatment of advanced soft tissue sarcomas of the extremities.. Retrospective cohort study.. From 1991 to 2011, 113 patients with primary irresectable soft tissue sarcomas underwent 117 ILPs at the University Medical Centre Groningen. 96 ILPs (82%) were performed in the lower limb, and 21 (18%) in the upper limb. The dosages used were 1-4 mg TNF-α and 10-13 mg/l melphalan.. After a median follow up of 8 (range 2-15) weeks after ILP, 107 tumours were resected: 81 (76%) of the resection margins were tumor-free. After the resection, 69 patients (61%) received adjuvant radiotherapy. In total, 85 ILPs resulted in a tumoural response; 16 patients (14%) developed a local recurrence and after 46 treatments (39%), distant metastases had developed. After a median follow-up of 51 months, the limb had been spared in 88 patients (78%). The 10- year disease-specific survival was 53.8%. There was a median follow-up period of 76 months (range: 7-234); still alive at the end of this period were 56 patients (50%). A total of 83 perfusion- or resection-related complications occurred from 58 ILPs (50%): 55 (66%) early and 28 (34%) late treatment-related complications. None of the patients died as a result of the treatment.. ILP is a safe and effective procedure in the treatment of advanced primary irresectable soft tissue sarcoma that can prevent amputation in many cases. It is however associated with significant morbidity and is burdensome for the patient.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Cohort Studies; Extremities; Female; Humans; Limb Salvage; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Radiotherapy, Adjuvant; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

Hyperthermic isolated limb perfusion with tumor necrosis factor-α and melphalan (TM-HILP) has been successfully used to treat limb soft tissue sarcomas (STSs) with high response rates. The data on the effectiveness of HILP-TM for the treatment of STSs are mainly based on various STS types. The aim of this study was to investigate the responses of synovial sarcomas (SS) to TM-HILP.. A total of 125 TM-HILP-treated tumors (STS all), including 14 SSs, were included in the study. The tumors were subdivided into proximal and distal limb localizations. Tumor typing (using the WHO classification), resection status (using the UICC classification), and response to therapy were assessed using light microscopy. The SSs were tested for the SYT-SSX translocation using RT-PCR. The following tests were applied: a chi-squared test, a t test, and the Mann-Whitney U test.. The SSs were localized distally more often than were the STS cohort (STS(-SS)) (85.7% vs. 32.4%) and were smaller (5.8 cm vs. 10.7 cm). There were no differences in the responder/nonresponder ratios or the mean percentages of pathological regression between the SS and STS(-SS) cohorts (74.0% vs. 76.0%). A general localization-dependent difference in the tumor responses to TM-HILP could not be detected in the STS all cohort (distal, 72.0% vs. proximal, 78.0%); however, a UICC R0 status was more often observed in proximal tumors (distal, 50.0% vs. proximal, 71.4%). There was no association between the SYT-SSX type and SS responses to TM-HILP.. Because of the high response rates, TM-HILP is recommended for the treatment of SSs. The distal limb localization of TM-HILP-treated STSs was generally (STS all cohort) associated with fewer R0 resections.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Child; Cohort Studies; Combined Modality Therapy; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Neoplasm Staging; Perfusion; Prognosis; Sarcoma; Sarcoma, Synovial; Tumor Necrosis Factor-alpha; Young Adult

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

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

This paper reports a single-institution experience with the use of isolated limb infusion for limb salvage in locally advanced, unresectable, recurrent limb threatening soft tissue sarcomas.. Locally advanced, limb threatening soft tissue sarcomas (STS) pose a significant treatment challenge. We report our experience using isolated limb infusion (ILI) in patients with unresectable extremity STS.. A total of 22 patients with extremity STS underwent 26 ILIs with melphalan and dactinomycin. Patient characteristics, intra-operative parameters and toxicity were recorded. Outcome measures included limb-salvage and in-field response rates.. Of the 19 lower and 7 upper extremity ILIs, Wieberdink grade III toxicity or less was observed in all. Median followup was 11 months. A total of 17 patients were evaluable at 3 months post-ILI with an overall response rate of 42%. Four (24%) had complete response (CR), three (18%) partial response (PR), three (18%) stable disease (SD) and seven (41%) progressive disease (PD). Twelve of 17 (71%) underwent successful limb preservation at a median of 9 months post-ILI. Two (12%) were downstaged to resectable disease and remain showing no evidence of disease (NED) after surgery at 30 and 22 months post-ILI.. ILI is an attractive modality that provides regional disease control and limb preservation in patients with limb threatening sarcoma. Although short-term results appear encouraging, long-term follow-up is needed to fully assess the role of ILI in unresectable extremity STS.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Humans; Male; Melphalan; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Young Adult

Approximately 10% of soft tissue sarcomas (STS) occur in the most distal parts of the extremities. The standard therapy is local excision with adjuvant radiotherapy, but achieving wide resection margins might be difficult in the distal parts of the limb. Tumor necrosis factor-alpha (TNF) and melphalan-based isolated limb perfusion (TM-ILP) is effective in locally advanced STS of the extremities. We report the results of TM-ILP for STS in the most distal parts of the limb.. Between 1991 and 2009, 34 ILPs were performed in patients with irresectable STS of the wrist, hand, ankle, or foot. Disease was unifocal in 21 (62%) patients.. Overall response rate was 71% (n = 24). After a median follow-up of 34 (range 1-143) months the local recurrence rate was 32%. Amputation was unavoidable in four patients (13%), four other patients (13%) underwent a partial amputation of the hand or foot.. With a limb salvage rate of 87%, TM-ILP is an effective treatment modality in patients with distal STS. In all patients with an indication for amputation surgery due to an STS in the distal part of the limb, TM-ILP should be considered.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Extremities; Humans; Limb Salvage; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha; Young Adult

Isolated limb perfusion with tumor necrosis factor alpha and melphalan (TM-ILP) has proven to be a successful option in treating advanced soft tissue sarcomas (STS), where amputation otherwise is needed to achieve safe surgical margins.. From 2000 to 2009, 54 patients with locally advanced STS, who all were candidates for amputation, were treated with totally 57 TM-ILP procedures and then followed prospectively. The median follow-up time was 30 months. Median tumor size was 10 cm, and 94% of the patients had high-grade tumors.. The clinical overall response after TM-ILP was 71% (including 21% CR), and 60% of the patients underwent resection of the tumor remnant after a median of 2 months. The histopathologic response rate in the resected specimens was 76%. Local recurrence/progress occurred in 37% of the patients after a median of 7 months. Thirteen patients finally underwent amputation after a median of 11 months, giving a long-term limb salvage of 76%.. TM-ILP of advanced soft tissue sarcoma of the extremities makes limb-sparing surgery possible in a high proportion of patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extracorporeal Circulation; Extremities; Female; Follow-Up Studies; Humans; Limb Salvage; Male; Melphalan; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Prospective Studies; Sarcoma; Survival Rate; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult

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

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

The clinical assessment of the response of sarcomas to preoperative treatment is usually defined using size-based evaluation standards. For nonresectable sarcomas, hyperthermic isolated limb perfusion with TNF-α and melphalan (TM-ILP) yields high response rates. Based on our experience, we assume that anatomic radiological response criteria are insufficient to assess the degree of regression after TM-ILP.. The clinical response of 35 sarcomas to TM-ILP was assessed by unidimensional, bidimensional, and tridimensional size-based anatomical criteria, and responders were identified according to the established thresholds. The same tumors were investigated for pathological response according to the Salzer-Kuntschik regression scale (>90% devitalization) and reviewed for cystic degeneration, hemorrhage, and predominant necrotic or fibrosclerotic regression phenotype.. None of the clinical response criteria were able to reliably identify the pathologic responders. The extent of size changes showed no association with the pathological degree of regression. The number of clinical responders was low compared with the number of pathological responders (RECIST N = 1, WHO N = 3, volumetry N = 3, pathology N = 19). The occurrence of hemorrhage and/or cystic degeneration was more frequently observed in predominant necrotic sarcomas and was associated with an increase in tumor size after TM-ILP. Furthermore, we identified the fibrosclerotic phenotype of regression to be more significantly strongly associated with posttherapeutic shrinkage than necrosis.. Size-based clinical response evaluation is insufficient to assess clinical response in TM-ILP-treated sarcomas. The size changes of tumors after therapy reflect the type of regression rather than the extent of destruction.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Chi-Square Distribution; Female; Humans; Hyperthermia, Induced; Lower Extremity; Magnetic Resonance Imaging; Male; Melphalan; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Remission Induction; ROC Curve; Sarcoma; Statistics, Nonparametric; Tomography, X-Ray Computed; Treatment Outcome; Tumor Burden; Tumor Necrosis Factor-alpha; Upper Extremity; Young Adult

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

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

Standard treatment for localized soft tissue sarcoma (STS) is resection plus adjuvant radiotherapy (RTx). In approximately 10% of cases, resection would cause severe loss of function or even require amputation because of the extent of disease. Isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF-α) and melphalan can achieve regression of the tumor, facilitating limb-saving resection. RTx improves local control but may lead to increased morbidity.. In our database of over 500 ILPs, 122 patients with unifocal STS were treated by ILP followed by limb-sparing surgery. All included patients were candidates for amputation.. Surgery resulted in 69 R0 resections (57%), and in 53 specimens (43%) resection margins contained microscopic evidence of tumor (R1). Histopathological examination revealed >50% ILP-induced tumor necrosis in 59 cases (48%). RTx was administered in 73 patients (60%). Local recurrence rate was 21% after median follow-up of 31 months (2-182 months). Recurrence was significantly less in patients with >50% ILP-induced necrosis versus ≤50% necrosis (7% vs. 33%, P = 0.001). A similar significant correlation was observed for R0 versus R1 resections (15% vs. 28%, P = 0.04). In 36 patients with R0 resection and >50% necrosis, of whom 21 were spared RTx, no recurrences were observed during follow-up.. In patients with locally advanced primary STS, treated with ILP followed by R0 resection, and with >50% ILP-induced necrosis in the resected specimen, RTx is of no further benefit.

Topics: Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Humans; Lymphatic Metastasis; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Radiotherapy Dosage; Retrospective Studies; Sarcoma; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha

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

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

Dose reduction and shortening of duration of perfusion in isolated limb perfusion with TNF-α and Melphalan (TM-ILP) are associated with less systemic toxicity and seem to be safe and effective on short-term. However, data on long-term patient outcome are scarce.. From 1991 to 2008, 102 TM-ILPs were performed in 98 patients for a locally advanced soft tissue sarcoma of the extremity. Perfusions were categorized in three groups: (A) high dose and long duration (n = 59), (B) high dose and short duration (n = 16), and (C) low dose and short duration (n = 27). Long-term local control rates and (limb)-survival were evaluated.. Limb salvage rates were in group A 76.3%, B 62.5%, and C 85.2% (P = 0.2). With a median follow up of 76 (range 4-203) months, 50 patients were still alive (51%). Disease-specific 5-year survival was not different between the three groups: A 55.4%, B 52.5%, and C 57.3% (P = 0.9). There was no difference in local recurrence-free 5-year survival (adjusted P = 0.1) and distant metastases-free survival (P = 0.9).. Dose reduction and shorter duration of TM-ILP seem to be safe and effective regarding long-term patient outcome, as 5-year local control rates and (limb)-survival are not compromised.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Therapy, Combination; Extremities; Female; Humans; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Salvage Therapy; Sarcoma; Soft Tissue Neoplasms; Survival Rate; Tumor Necrosis Factor-alpha; Young Adult

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

Because there is no survival benefit of amputation for extremity soft tissue sarcomas (STSs), limb-sparing surgery has become the gold standard. Tumor size reduction by induction therapy to render nonresectable tumors resectable or facilitate function-preserving surgery can be achieved by tumor necrosis factor α (TNF) -based and melphalan-based isolated limb perfusion (TM-ILP). This study reports the long-term results of 231 TM-ILPs for locally advanced extremity STS.. We analyzed 231 TM-ILPs in 208 consecutive patients (1991 to 2005), who were all candidates for functional or anatomic amputation for locally advanced extremity STS. All patients had a potential follow-up of up to 5 years. TM-ILP was performed under mild hyperthermic conditions with 1 to 4 mg of TNF and 10 to 13 mg/L of limb-volume melphalan. Almost all patients (85%) had intermediate- or high-grade tumors.. The overall response rate (ORR) was 71% (complete response, 18%; partial response, 53%). Multifocal sarcomas had a significantly better ORR of 83% (P = .008). The local recurrence rate was 30% (n = 70); local recurrence rates were highest for multifocal tumors (54%; P = .001) and after previous radiotherapy (54%; P < .001). Five-year overall survival rate was 42%. Survival was poorest in patients with large tumors (P = .01) and with leiomyosarcomas (P < .001). Limb salvage rate was 81%.. We demonstrated that TM-ILP results in a limb salvage rate of 81% in patients with locally advanced extremity STS who would otherwise have undergone amputation. Whenever an amputation is deemed necessary to obtain local control of an extremity STS, TM-ILP should be considered.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Child; Combined Modality Therapy; Disease-Free Survival; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Recombinant Proteins; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha; Young Adult

Topics: Adult; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Equipment Design; Female; Humans; Lower Extremity; Lung Neoplasms; Lymphatic Metastasis; Male; Melphalan; Middle Aged; Retrospective Studies; Sarcoma; Treatment Outcome

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

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

Hyperthermic isolated limb perfusion with TNF-alpha and melphalan (HILP-TM) achieves high response rates in sarcomas. Melphalan resistance was previously reported to be associated with overexpression of metallothioneins (MTs). Objective of this study was to investigate the influence of MT expression on tumor responses in HILP-TM-treated soft tissue (STSs) and bone sarcomas (BS).. In primary biopsies of 41 HILP-TM-treated sarcomas (37 STSs and 4 BS), MT expression was assessed by an immunoreactive score. The pathologic response to HILP-TM was quantified in the corresponding tumor resection specimens. We studied the association of MT-IRS between histological regression (responder >90%, or non-responder

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Drug Resistance, Neoplasm; Female; Humans; Immunohistochemistry; Male; Melphalan; Metallothionein; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

Isolated limb perfusion (TM-ILP) is an effective limb-sparing treatment for primarily nonresectable soft tissue sarcomas (STS). Surgical margins of STS after ILP were yet not systematically studied.. In 47 patients with nonresectable STS, TM-ILP with subsequent tumor resection was performed. Surgical margins were systematically analyzed by light microscopy using the TNM and the Enneking classification. Furthermore, margins were analyzed for tumor regression in terms of improved resectability. Results were correlated with clinical and pathological parameters.. Of 47 STS, 44 were classified as high-grade (93.6%) with a median tumor size of 10.0 cm. Primary limb-salvage rate was 85.1%. According to TNM resection margins were complete in 70.2% (R0) and incomplete in 29.8% (R1=21.3%, R2=8.5%). According to Enneking, 27.7% intralesional, 42.6% marginal, 21.3% wide, 2.1% radical, and 6.4% unclassifiable margins were found. Prior surgery and/or radiotherapy significantly decreased margin quality. Ten patients with incomplete resection (three intralesional, seven marginal) had no viable tumor at the plane of dissection, which was designated as "improved margins." Whereas those patients remained relapse free, five patients with viable tumor (not improved margins) at the resection margin had local recurrences. Poor margins were associated with local and distant recurrences and limited disease-specific survival.. TM-ILP is effective for achieving limb salvage. Histopathology of surgical margins demonstrates cases with so-called "improved margins" after TM-ILP, which are related to a better outcome even in intralesionally resected tumors. Improvement of margins should be further evaluated as a potential relevant prognostic parameter.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Drug Therapy, Combination; Female; Humans; Limb Salvage; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Sarcoma; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult

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

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

In a prior randomized phase II trial comparing hyperthermic isolated limb perfusion (HILP) with four different doses of tumor necrosis factor alpha (TNF-alpha), no dose effect was detected for response, but systemic toxicity was far lower with low-dose TNF-alpha. The objective of the present study was to confirm these data on a larger sample size of locally advanced or recurrent extremity soft tissue sarcomas with low-dose TNF-alpha.. We assessed a prospective database comprising 100 HILP (38-40 degrees C) with melphalan (10 mg/L) and TNF-alpha (1 mg). The remnant tumor was resected 2 months later.. Among 52 recurrences, 18 were in a previously irradiated field. Stages according to the American Joint Committee on Cancer classification were II (19 patients), III (78 patients), and IV (3 patients). The site/size were: 30 patients/57 mm and 70 patients/86 mm for the upper and lower limbs, respectively. Tumor grades (FNCLCC) were 1 (23 patients), 2 (34 patients), and 3 (43 patients). Fifty-one patients had received systemic chemotherapy before HILP. Responses on magnetic resonance imaging were 30% complete, 49% partial, 9% no change, and 12% progression. No mortality or systemic toxicity occurred. Local toxicity (Wieberdink) attained grade 2 (16 patients), 3 (5 patients), and 4 (1 patient). Limbs were able to be saved in 87% patients. Three-year overall survival and the local recurrence rate were 89% and 18%, respectively. Age, sex, tumor size, recurrence, uni- or multifocality, grade, preoperative chemotherapy, and a previously irradiated field were not predictive of response or local toxicity.. We confirm that 1 mg of TNF-alpha is as effective as the standard dose and results in no systemic toxicity.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Drug Therapy, Combination; Extremities; Female; Fibromatosis, Aggressive; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Neoplasm Staging; Prognosis; Prospective Studies; Sarcoma; Survival Rate; Tumor Necrosis Factor-alpha; Young Adult

Isolated limb infusion (ILI) is a minimally invasive technique for delivering high-dose regional chemotherapy. We report our experience with ILI for the treatment of soft tissue sarcoma (STS).. From our prospective database, 21 patients with STS of the limb treated with ILI between 1994 and 2007 were identified. In all patients, a high-dose cytotoxic drug combination was used.. There were 14 men, and the median age was 60 years (range, 18-85 years). Eighteen patients (86%) had lower limb tumors. All patients had advanced local disease. The procedure was well tolerated. Fourteen patients (67%) received ILI before definitive surgery. The overall response rate was 90% (complete response [CR] rate 57%, partial response rate 33%). The disease-specific overall survival was 61.9% (median follow-up, 28 months). Only American Joint Committee on Cancer stage was associated with overall survival. The local recurrence rate was 42%. CR and malignant fibrous histiocytoma tumor subtype were associated with a lower local recurrence rate. A lower initial skin temperature (median 35.8 degrees C) was associated with a CR (P = .033). Patients who had a steep increase in intramuscular temperature during the procedure were more likely to have a CR (P = .055). Classification tree analysis identified patients with an initial PaO(2) of >/=194 mmHg as being more likely to have a CR. Ultimately, the overall limb salvage rate was 76%.. The outcomes after ILI are comparable to those achieved by conventional isolated limb perfusion. ILI is a minimally invasive alternative to isolated limb perfusion for patients with advanced STS of the extremity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cohort Studies; Dactinomycin; Extremities; Female; Humans; Male; Melphalan; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Prospective Studies; Sarcoma; Survival Rate

Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) is a limb salvage therapy for non-resectable soft tissue sarcomas (STS) of the extremities. It is indicated for patients for whom amputation or debilitating surgery is the only alternative. It can be used either as an exclusive therapy (in palliation) or as a neo-adjuvant treatment, followed by marginal resection of tumor remnants with minimal functional impairment.. Between February 1992 and March 2006, 57 TM-ILPs were performed on 51 patients with 88% high grade and 84% advanced stage tumors.. Mean follow-up is 38.9 months (4-159, median 22 months). Twenty-one percent patients had significant early complications, with 3 major re-operations, and 23% suffered long-lasting complications. Complete response was observed in 25%, partial response in 42%, stable disease in 14% and progressive disease in 14%. Resection of the tumor remnants was possible in 65%. A complementary treatment was necessary in 31%, mostly radiation therapy. A local recurrence was observed in 35%, after a mean of 20.3 months (2-78), and distant relapse was seen in 45%, after a mean of 13.4 months (5-196). Mean Disease-free survival was 14.9 months, and overall 5-year-survival 43.5%. Amputation rate at 5 years was 24%.. TM-ILP is a conservative treatment with a high complications rate, but it can be successful even for the most severe STS of extremities. As a consequence the limb can be spared from amputation or debilitating surgery on the long term in about 75% of patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Limb Salvage; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Remission Induction; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

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

Recombinant tumor necrosis factor-alpha (TNF-alpha) combined to melphalan is clinically administered through isolated limb perfusion (ILP) for regionally advanced soft tissue sarcomas of the limbs. In preclinical studies, wild-type p53 gene is involved in the regulation of cytotoxic action of TNF-alpha and loss of p53 function contributes to the resistance of tumour cells to TNF-alpha. The relationship between p53 status and response to TNF-alpha and melphalan in patients undergoing ILP is unknown.. We studied 110 cases of unresectable limbs sarcomas treated by ILP. Immunohistochemistry was carried out using DO7mAb, which reacts with an antigenic determinant from the N-terminal region of both the wild-type and mutant forms of the p53 protein, and PAb1620mAb, which reacts with the 1620 epitope characteristic of the wild-type native conformation of the p53 protein. The immunohistochemistry data were then correlated with various clinical parameters.. P53DO7 was found expressed at high levels in 28 patients, whereas PAb1620 was negative in 20. The tumours with poor histological response to ILP with TNF-alpha and melphalan showed significantly higher levels of p53-mutated protein.. Our results might be a clue to a role of p53 protein status in TNF-alpha and melphalan response in clinical use.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Cancer, Regional Perfusion; Child; Disease-Free Survival; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Melphalan; Middle Aged; Mutation, Missense; Sarcoma; Treatment Outcome; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53

Isolated hepatic perfusion with high-dose chemotherapy is a treatment option for patients with irresectable metastases confined to the liver. Prolonged local control and impact on survival have been claimed. Major drawbacks are magnitude and costs of the procedure. We developed an isolated hypoxic hepatic perfusion (IHHP) with retrograde outflow without the need for a heart-lung machine.. Twenty-four consecutive patients with irresectable metastases of various origins were treated. IHHP inflow was via the hepatic artery, outflow via the portal vein with occlusion of the retrohepatic caval vein. Radiolabeled albumine was used for leakage monitoring. Melphalan was used at 1-2 mg/kg. A 25-minute perfusion period was followed by a complete washout. Local and systemic melphalan concentrations were determined.. Compared with oxygenated classical IHP, the IHPP procedure reduced operation time from >8 h to 4 hours, blood loss from >4000 to 900 cc and saved material and personnel costs. Leakage was 0% with negligible systemic toxicity and 0% perioperative mortality. Tumor response: complete response (CR) in 4%, partial response (PR) in 58%, and stable disease (SD) in 13%. Median time to progression was 9 months (2-24 months); pharmacokinetics demonstrated intrahepatic melphalan concentrations more than 9 fold higher than postperfusion systemic concentrations.. IHPP is a relatively simple procedure with reduced costs, reduced blood loss, no mortality, limited toxicity, and response rates comparable to classic IHP. The median duration of 9 months of tumor control should be improved. Hereto, vasoactive drugs, will be explored in further studies.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Disease Progression; Eye Neoplasms; Female; Follow-Up Studies; Gas Chromatography-Mass Spectrometry; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Melphalan; Middle Aged; Neoplasms, Unknown Primary; Portal Vein; Sarcoma; Survival Rate; Treatment Outcome

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

Nonresectable primary and metastatic liver tumors remain an important clinical problem. Melphalan-based isolated hepatic perfusion (M-IHP) leads to more than 70% objective responses in selective groups of patients with nonresectable metastases confined to the liver. Complete responses are rare and progression-free survival is limited. Tumor necrosis factor (TNF), a very active agent in isolated limb perfusion, is linked to serious hepatotoxicity, restricting its use in IHP. Because of its vasoactive properties, histamine (Hi) is an alternative to TNF. In this article we evaluate its potential synergistic effect in M-IHP, improving response rates.. Our experimental rat IHP model is used for the treatment of soft tissue sarcoma liver metastases. Blood samples are collected for monitoring liver enzymes. Livers are excised 72 h and 7 days after treatment for histologic evaluation.. After sham-IHP and Hi-IHP, tumor progression was observed in 100% of treated animals, while after M-IHP this number fell to 62% and after Hi + M-IHP it fell to only 22% (P = 0.006). Overall response rates were of 55% for Hi + M-IHP vs. 25% for M-IHP, and, more importantly, complete responses (CR) were observed only after Hi + M-IHP (22%) (P = 0.009). Hepatotoxicity peaked within 24 h after IHP, independent of the treatment administered, recovered in 48 h, and was related mainly to the elevation of transaminases (grade 3 ASAT and grade 1 ALAT for control group and grades 3 and 4, respectively, for all other treatments). No serious systemic toxicity was observed. Histology of the liver showed no serious damage.. Hi + M-IHP has synergistic antitumor effects without any increase in regional or systemic toxicity.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease Models, Animal; Drug Synergism; Histamine; Liver Neoplasms, Experimental; Male; Melphalan; Neoplasm Transplantation; Rats; Sarcoma

To explore the prognostic impact of isolated limb perfusion (ILP) in locally advanced extremity soft tissue sarcomas (ESTS).. From August 1982 to April 2005, 1,119 patients affected by ESTS (girdle excluded) were observed and treated at our institution. Eighty-eight (7.9%) were judged non-resectable or locally advanced and underwent ILP. Thirty-seven patients received antiblastic alone (non-TNF-ILP) while 51 had anti-blastic + recombinant-tumor necrosis factor alpha (TNF-ILP). Local disease-free survival (LDFS) was calculated by the Kaplan-Maier method and was reported separately in the two subgroups.. Limb salvage was achieved in 83% (73/88) of the patients. The observed overall (complete + partial) response rate was 59%. In the TNF-ILP group a complete response (CR) was achieved in 21 (41%) patients, while in the non-TNF ILP group a CR was obtained in seven (19%) cases (P < 0.05). Patients with in-transit metastases (epithelioid sarcomas and clear cell sarcomas) had a significantly worse long-term outcome (LDFS at 5 years was 40.9 vs 67.3%, P < 0.05). A trend towards a better LDFS at 5 years could be observed in the patients receiving TNF (63.6 vs 57.1%) and post-operative radiation therapy (RT) (79.3 vs 55.4%).. Isolated limb perfusion is an active treatment. By adding TNF a better local control seems to be obtained, possibly due to a higher rate of CR. It should therefore be considered as a valid option for patients affected by limb-threatening STS, save for in-transit metastases from epithelioid and clear cell sarcoma. Post-operative RT should always be considered.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Doxorubicin; Female; Humans; Male; Melphalan; Middle Aged; Neoplasm Staging; Neoplasm, Residual; Prognosis; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Survival Analysis

The aim of this study was to investigate the long-term limb salvage rate and overall survival after isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma (STS).. From 1991 to 2003, 73 patients (36 men, 37 women, median age 54 [range 14-80] years) with biopsy-proven STS underwent 77 perfusions followed by delayed surgical resection, with or without adjuvant radiation. Limb salvage and overall survival curves were calculated by the Kaplan-Meier method.. A total of 21 amputations (28%) were performed. Overall 1, 5, and 10 years' limb salvage was 80.1% +/- 4.8%, 68.2% +/- 6.5%, and 60.6% +/- 9.2%, respectively. We found that the risk of amputation was linked to three time periods. The first was within a year after perfusion, mainly as a result of massive necrosis of the tumor and overlying skin, resulting in soft tissue deficit or recurrent disease (n = 17). The second was within 5 years, with two amputations performed for late local recurrence. The third occurred 10 years after perfusion, with two amputations performed for critical leg ischemia. Another two patients developed a pathological fracture of the femur due to radiation osteonecrosis. These four patients received adjuvant radiotherapy. Overall, 1, 5, and 10 years' survival was 82.9% +/- 9.2%, 58.7% +/- 13.1%, and 42.5% +/- 18.2%, respectively.. ILP treatment with tumor necrosis factor alpha and melphalan followed by delayed surgical resection and adjuvant radiation treatment is an effective limb salvage treatment regimen for locally advanced STS. However, we observed late morbidity, with two amputations performed for critical leg ischemia and two pathological fractures of the femur in patients receiving adjuvant radiotherapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Radiotherapy, Adjuvant; Risk Factors; Sarcoma; Soft Tissue Neoplasms; Survival Rate; Tumor Necrosis Factor-alpha

Isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF-alpha) and melphalan, followed by delayed surgical resection and adjuvant external-beam radiotherapy is a limb salvage treatment strategy for locally advanced soft tissue sarcomas. The long-term vascular side effects of this combined procedure were evaluated.. Thirty-two patients were treated for a locally advanced sarcoma of the upper (n = 5) or lower limb (n = 27). All patients underwent a noninvasive vascular work-up.. Five patients underwent a leg amputation, in two cases due to critical leg ischemia 10 years after ILP. With a median follow-up of 88 (range, 17-159) months, none of the patients with a salvaged lower leg (n = 22) experienced peripheral arterial occlusive disease. Ankle-brachial index (ABI) measurements in the involved leg (median, 1.02; range, .50-1.20) showed a significant decrease compared with the contralateral leg (median, 1.09; range, .91-1.36, P = .001). Pulsatility index (PI) was decreased in the treated leg in 17 of 22 patients at the femoral level (median, 6.30; range, 2.1-23.9 vs. median, 7.35; range, 4.8-21.9; P = .011) and in 19 of 20 patients at popliteal level (median, 8.35; range, 0-21.4 vs. median, 10.95; range, 8.0-32.6; P < .0005). In patients with follow-up of >5 years, there was more often a decrease in ABI (P = .024) and PI at femoral level (P = .011).. ILP followed by resection and external-beam radiotherapy can lead to major late vascular morbidity that requires amputation. Objective measurements show a time-related decrease of ABI and femoral PI in the treated extremity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Ischemia; Limb Salvage; Male; Melphalan; Middle Aged; Radiotherapy, Adjuvant; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha; Vascular Diseases

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

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

The aim was to investigate the value of adjuvant radiotherapy for locally advanced soft tissue sarcoma after hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan followed by limb-saving surgery.. From 1991 to 2003, 73 patients (median age, 54 years; range, 14-80 years) underwent 77 ILPs, followed by resection in 68 patients (93%). Radiotherapy was administered in case of marginally or microscopically positive resection margins. Local recurrences were scored and calculated according to the Kaplan-Meier method and log-rank test.. After residual tumor mass resection, 58% received radiotherapy (external beam radiotherapy [EBRT]+ group), and 42% did not (EBRT- group). The median follow-up was 28 months (range, 2-159 months). A significantly better local control rate was observed in the EBRT+ compared with the EBRT- group (P<.0001). When only R0 resections in patients without metastasis were considered, the significance remained between groups (P=.0003). In the EBRT- group, an R1 or R2 resection resulted in earlier relapse of local disease compared with R0 resections (P=.0475).. Adjuvant EBRT reduces the risk for local recurrence after delayed resection in soft tissue sarcoma patients treated with ILP and tumor necrosis factor and is indicated when resection margins are close or microscopically positive. It also seems beneficial after an R0 resection.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Limb Salvage; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Radiotherapy, Adjuvant; Sarcoma; Soft Tissue Neoplasms; Survival Analysis; Tumor Necrosis Factor-alpha

Extensive and mutilating surgery is often required for locally advanced soft tissue sarcoma (STS) of the limb. As it has become apparent that amputation for STS does not improve survival rates, the interest in limb-preserving approaches has increased. Isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF) and melphalan is successful in providing local tumor control and enables limb-preserving surgery in a majority of cases. A mature, large, single-institution experience with 217 consecutive ILPs for STS of the extremity is reported.. At a prospectively maintained database at a tertiary referral center, 217 ILPs were performed from July 1991 to July 2003 in 197 patients with locally advanced STS of the extremity. ILPs were performed at mild hyperthermic conditions with 1-4 mg of TNF and 10-13 mg/L limb-volume melphalan (M) for leg and arm perfusions, respectively.. The overall response rate was 75%. Limb salvage was achieved in 87% of the perfused limbs. Median survival post-ILP was 57 months and prognostic factors for survival were Trojani grade of the tumor and ILP for single versus multiple STS. The procedure could be performed safely, with a perioperative mortality of 0.5% in all patients with no age limit (median age, 54 yrs; range, 12-91). Systemic and locoregional toxicity were modest and easily manageable.. TNF+M-based ILP can provide limb salvage in a significant percentage of patients with locally advanced STS and has therefore gained a permanent place in the multimodality treatment of STS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Child; Extremities; Female; Humans; Limb Salvage; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Recombinant Proteins; Sarcoma; Survival Rate; Tumor Necrosis Factor-alpha

Quality of life (QoL) and posttraumatic stress symptoms (PTSS) were studied in patients with soft tissue sarcoma (STS) of the extremities treated with isolated limb perfusion and delayed resection, with or without adjuvant irradiation.. Forty-one patients received a questionnaire that included the RAND-36 and Impact of Event Scale.. Thirty-nine STS survivors (16 [41%] male and 23 [59%] female; median age, 59 years; range, 15-78 years) participated in the questionnaire survey (response rate, 95%). The median age at perfusion was 49 years (range, 14-72 years). No significant differences were found in mean scores between STS survivors and the reference group with the exception of a worse physical functioning. Patients with amputations showed significantly worse physical and social functioning and more role limitations than patients whose limbs were saved. Eleven patients (28%) had a PTSS score of 0, and eight patients (20.5%) had a score>or=26, which suggested the need for psychological counseling. None of these eight patients had lost a limb. Patients who indicated that the choice of treatment was made by the surgeon rather than collaboratively showed significantly decreased social functioning, more role limitations, and intrusion. Greater treatment satisfaction was significantly related to better social functioning, more vitality, better general health perception, less intrusion, avoidance, and total Impact of Event Scale scores.. Even though STS survivors' QoL was different from that of a reference group only in physical functioning, one fifth of the patients had PTSS. An amputation, the physician's decision rather than the patient's decision for the perfusion treatment and a low satisfaction with the performed treatment negatively influenced QoL.

Topics: Adolescent; Adult; Aged; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Interferon-gamma; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Quality of Life; Radiotherapy, Adjuvant; Sarcoma; Soft Tissue Neoplasms; Stress Disorders, Post-Traumatic; Surveys and Questionnaires; Treatment Outcome; Tumor Necrosis Factor-alpha

The cytokine interleukin 2 (IL-2) is a mediator of immune cell activation with some antitumor activity, mainly in renal cell cancer and melanoma. We have previously shown that tumor necrosis factor (TNF)-alpha has strong synergistic antitumor activity in combination with chemotherapeutics in the isolated limb perfusion (ILP) setting based on a TNF-mediated enhanced tumor-selective uptake of the chemotherapeutic drug followed by a selective destruction of the tumor vasculature. IL-2 can cause vascular leakage and edema and for this reason we examined the antitumor activity of a combined treatment with IL-2 and melphalan in our well-established ILP in soft tissue sarcoma-bearing rats (BN175). ILP with either IL-2 or melphalan alone has no antitumor effect, but the combination of IL-2 and melphalan resulted in a strong synergistic tumor response, without any local or systemic toxicity. IL-2 enhanced significantly melphalan uptake in tumor tissue. No signs of significant vascular damage were detected to account for this observation, although the tumor sections of the IL-2- and IL-2 plus melphalan-treated animals revealed scattered extravasation of erythrocytes compared with the untreated animals. Clear differences were seen in the localization of ED-1 cells, with an even distribution in the sham, IL-2 and melphalan treatments, whereas in the IL-2 plus melphalan-treated tumors clustered ED-1 cells were found. Additionally, increased levels of TNF mRNA were found in tumors treated with IL-2 and IL-2 plus melphalan. These observations indicate a potentially important role for macrophages in the IL-2-based perfusion. The results in our study indicate that the novel combination of IL-2 and melphalan in ILP has synergistic antitumor activity and may be an alternative for ILP with TNF and melphalan.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Capillary Permeability; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Drug Synergism; Endothelial Cells; Hindlimb; Hydrogen-Ion Concentration; Interleukin-2; Leukocytes; Macrophages; Male; Melphalan; Rats; Rats, Inbred BN; Sarcoma; Soft Tissue Neoplasms

Recurrent extremity soft tissue sarcoma (STS) in a previously operated and irradiated area can usually be managed only by amputation. Tumor necrosis factor (TNF)-alpha-based isolated limb perfusion (ILP) is an established alternative to achieve limb salvage but is assumed to require sufficient vasculature. Because radiotherapy is known to destroy vasculature, we wanted to evaluate retrospectively whether the outcome of ILP in patients with radiotherapy for their primary tumor nonetheless showed a benefit from TNF treatment.. We consulted a prospective database of TNF-based ILPs at the Erasmus MC-Daniel den Hoed Cancer Center in Rotterdam. Out of 342 TNF-based ILPs between 1991 and 2003, 30 ILPs were performed in 26 patients with recurrent STS in the irradiated field after prior surgery and radiotherapy. Eleven patients (42%) had multiple tumors (n = 2-20). All patients were candidates for amputation.. We observed 6 complete responses (20%), 15 partial responses (50%), no change in 8 patients (27%), and progressive disease in 1 patient (3%). The median duration of response was 16 months (range, 3-56 months) at a median follow-up of 22 months (range, 3-67 months). The local recurrence rate was 45% in patients with multiple tumors and 27% in patients with single tumors. Ten patients (35%) died of systemic metastases. Limb salvage was achieved in 17 patients (65%). Regional toxicity was limited and systemic toxicity minimal.. TNF-based ILP can avoid amputations in most patients with recurrent extremity STS in a prior operated and irradiated field.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Arm; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Humans; Leg; Limb Salvage; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Sarcoma; 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

To prospectively evaluate the use of MRI with dynamic sequences during isolated limb perfusion (ILP) for soft tissue sarcomas, an aggressive local treatment using very high-dose chemotherapy and tumor necrosis factor aimed at avoiding limb amputation.. Twenty-six patients were referred for ILP over one and a half years; eight were excluded as the lesions were either too proximal or suspicious inflammatory changes without tumor were found on the initial MRI, or the vascular status was poor. The indications for ILP were: vessel nerve involvement (13), multiple lesions (8), tumor size (4) or the presence of pulmonary metastases (2). MRI was performed 1 and 2 months after ILP, immediately prior to surgery and histological analysis. The MR examinations included T1-weighted SE and fast SE T2-weighted fat-saturated sequences, as well as dynamic sequences (T1-weighted SE repeated six times every 40 s), displaying the maximum intensity slope in each pixel.. The tumor had disappeared in three patients. One patient still had histologically proven isolated widespread tumor cells without a mass. The tumor size had increased in two patients. In six patients, the size of the tumor had not changed but it had become completely necrotic, with a thin wall. In three patients, after an initially good result MRI demonstrated that the tumor wall had become thickened from 1 to 2 months after ILP. Dynamic MRI was mainly useful during the initial examination, demonstrating two patients with inflammatory changes without tumor. Three amputations and a second ILP were proposed based on poor results. Conservative limb-sparing surgery was successful in the other cases.. MRI proved valuable in demonstrating the variable responses to ILP.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Magnetic Resonance Imaging; Male; Melphalan; Middle Aged; Prospective Studies; Salvage Therapy; Sarcoma; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Connective Tissue; Extremities; Heart-Lung Machine; Humans; Hyperthermia, Induced; Melphalan; Necrosis; Neoplasm Staging; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Follow-Up Studies; Humans; Melphalan; Sarcoma; Treatment Outcome; Tumor Necrosis Factor-alpha

Isolated hepatic perfusion (IHP) with melphalan with or without tumour necrosis factor alpha (TNF-alpha) is currently performed in clinical trials in patients with hepatic metastases. Previous studies led to the hypothesis that the use of TNF-alpha in isolated limb perfusion causes specific destruction of tumour endothelial cells and thereby induces an increased permeability of tumour vasculature. However, whether TNF-alpha contributes to the therapeutic efficacy in IHP still remains unclear. In an in vivo rat liver metastases model we studied three different tumours: colon carcinoma CC531, ROS-1 osteosarcoma and BN-175 soft-tissue sarcoma which exhibit different degrees of vascularisation. IHP was performed with melphalan with or without the addition of TNF-alpha. IHP with melphalan alone resulted, in all tumour types, in a decreased growth rate. However in the BN-175 tumour addition of TNF-alpha resulted in a strong synergistic effect. In the majority of the BN-175 tumour-bearing rats, a complete response was achieved. In vitro cytoxicity studies showed no sensitivity (CC531 and BN-175) or only minor sensitivity (ROS-1) to TNF-alpha, ruling out a direct interaction of TNF-alpha with tumour cells. The response rate in BN-175 tumour-bearing rats when TNF-alpha was coadministrated with melphalan was strongly correlated with drug accumulation in tumour tissue, as only in these rats a five-fold increased melphalan concentration was observed. Secondly, immunohistochemical analysis of microvascular density (MVD) of the tumour showed a significantly higher MVD for BN-175 tumour compared to CC531 and ROS-1. These results indicate a direct relation between vascularity of the tumour and TNF-alpha mediated effects. Assessment of the tumour vasculature of liver metastases would be a way of establishing an indication for the utility of TNF-alpha in this setting.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Cell Division; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Disease Models, Animal; Immunoenzyme Techniques; In Vitro Techniques; Liver Neoplasms, Experimental; Male; Melphalan; Microcirculation; Osteosarcoma; Rats; Rats, Inbred BN; Sarcoma; Tissue Distribution; Tumor Necrosis Factor-alpha

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

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

The objective of this study was to evaluate whether dynamic contrast-enhanced MR imaging can determine tumor response and localize residual viable tumor after isolated limb perfusion (ILP) chemotherapy in soft tissue tumors. Twelve consecutive patients, with histologically proven high-grade soft tissue sarcoma, prospectively underwent non-enhanced MR and dynamic contrast-enhanced MR imaging before and after ILP. Tumor volume was measured on non-enhanced MR images. The temporal change of signal intensity in a region of interest on dynamic contrast-enhanced MR images was plotted against time. Start, pattern, and progression of enhancement were recorded. Histopathologic response was defined as complete response if no residual viable tumor was present, partial remission if <50% viable tumor was present, and no change if > or =50% viable tumor was present in the resection specimen. Resected specimens for correlation with histopathology were available for 10 patients; 5 patients had partial remission and 5 had no change. Volume measurements correctly predicted tumor response in 6 of 10 patients. Dynamic contrast-enhanced MR correctly predicted tumor response in 8 of 10 patients. Early rapidly progressive enhancement correlated histologically with residual viable tumor. Late and gradual, or absence of enhancement, was associated with necrosis, predominantly centrally located, or granulation tissue. These preliminary results show that dynamic contrast-enhanced MR imaging offers potential for non-invasive monitoring of response to isolated limb perfusion in soft tissue sarcomas due to identification of residual areas of viable tumor and subsequently may provide clinically useful information with regards to timing and planning of additional surgery. Further prospective studies in a larger patient population is warranted.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Contrast Media; Extremities; Female; Gadolinium DTPA; Humans; Magnetic Resonance Imaging; Male; Melphalan; Middle Aged; Sarcoma; Tumor Necrosis Factor-alpha

Since 1992, isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNFalpha) and melphalan has been used for the treatment of patients with unresectable soft tissue sarcomas of the extremities. The authors retrospectively studied the results of limb salvage surgery using TNFalpha-ILP at their institution.. From 1992 to 2001, 49 patients (mean age, 51 years; range, 14-85 years) underwent ILP for unresectable soft tissue sarcomas of the extremities. All patients received melphalan and TNFalpha (four patients also received interferon-gamma). The median follow-up was 26 months (range, from 2 days to 103 months).. In 1 patient (2%) who died 2 days after undergoing ILP, response and acute limb toxicity could not be assessed. One patient (2%) attained a clinical complete response (2%), 23 patients (47%) attained a clinical partial response, 17 patients (35%) demonstrated no change, and 7 patients (14%) had tumor progression. Thirty-one patients (63%) underwent tumor resection. Histologic material also was available from eight amputations and three punctures/biopsies. Pathologic response was complete in 4 patients (8%), partial in 14 patients (29%), and no change was observed in 24 patients (49%). Final response, based on both clinical and pathologic assessment in which pathology was decisive, was complete in 4 patients (8%) and partial in 27 patients (55%), resulting in a final overall response rate of 63%. Local control with preservation of the limb was attained in 28 patients (57%). Four of 32 patients (13%) who had been rendered tumor free by ILP with or without undergoing resection and radiation therapy, developed a local recurrence. The 5-year disease specific survival rate was 48% for the 49 patients. Acute limb toxicity after ILP was a mild Grade 1-2 reaction in 35 patients (71%) patients, a Grade 3 reaction in 12 patients (25%), and a Grade 4 reaction in 1 patient (2%). Three major ILP-related complications were encountered, including arterial thrombosis in two patients and a fulminant Clostridial infection leading to death in one patient. There were no severe cardiovascular reactions after ILP.. In patients with unresectable soft tissue sarcomas of the limbs who underwent ILP with TNFalpha and melphalan followed by resection of the tumor remnant when possible, a 63% overall tumor response rate and a 57% local control rate with limb preservation was achieved.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chemotherapy, Cancer, Regional Perfusion; Cohort Studies; Drug Therapy, Combination; Extremities; Female; Follow-Up Studies; Humans; Limb Salvage; Male; Melphalan; Middle Aged; Neoplasm Staging; Palliative Care; Retrospective Studies; Risk Assessment; Sarcoma; Soft Tissue Neoplasms; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha

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

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

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

Cytokine gene transfer using (multiple) intratumoral injections can induce tumor regression in several animal models, but this administration technique limits the use for human gene therapy. In the present studies we describe tumor growth inhibition of established limb sarcomas after a single isolated limb perfusion (ILP) with recombinant adenoviral vectors harboring the rat IL-3 beta gene (IG.Ad.CMV.rIL-3 beta). In contrast, a single intratumoral injection or intravenous administration did not affect tumor growth. Dose-finding studies demonstrated a dose-dependent response with a loss of antitumor effect below 1 x 10(9) IU of IG.Ad.CMV.rIL-3 beta. Perfusions with adenoviral vectors bearing a weaker promoter (MLP promoter) driving the rIL-3 beta gene did not result in antitumor responses, suggesting that the rIL-3 beta-mediated antitumor effect depends on the amount of rIL-3 beta protein expressed by the infected cells. Furthermore, it was shown by direct comparison that ILP with IG.Ad.CMV.rIL-3 beta in the ROS-1 osteosarcoma model is at least as efficient as the established therapy with the combination of TNF-alpha and melphalan. Treatment with IG.Ad.CMV.rIL-3 beta induced a transient dose-dependent leukocytosis accompanied by an increase in peripheral blood levels of histamine. Leukocyte infiltrations were also histopathologically demonstrated in tumors after perfusion. These results demonstrate that ILP with recombinant adenoviral vectors carrying the IL-3 beta transgene inhibits tumor growth in rats and suggest that cytokine gene therapy using this administration technique might be beneficial for clinical cancer treatment.

Topics: Adenoviridae; Animals; Carrier Proteins; Dose-Response Relationship, Drug; Extremities; Gene Transfer Techniques; Histamine; Leukocytes; Male; Melphalan; Neoplasm Transplantation; Osteosarcoma; Perfusion; Promoter Regions, Genetic; Rats; Receptors, Interleukin-3; Sarcoma; Time Factors; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Multidrug resistance (MDR) is associated with expression of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and lung resistance-related protein (LRP). Tumor necrosis factor (TNF-alpha) is able to modify the expression of these three proteins in different cell types. The effect of TNF-alpha in the clinical situation on patients with soft tissue sarcomas (STS) is indeterminate.. Thirty-seven patients with a locally advanced extremity STS underwent hyperthermic isolated limb perfusion (HILP) with TNF-alpha and melphalan; 15 patients received additional interferon gamma. Clinical and histologic responses were documented and used to define the overall response. Samples before and after HILP were analyzed immunohistochemically for P-gp, MRP1, and LRP. Samples were scored as negative or positive (< or = 5% or > 5% positive tumor cells).. Six patients had an overall complete response, 25 patients had a partial response, and 4 patients with STS revealed no change; in 2 patients, the response remained unclear. The percentage STS samples that were positive for all three proteins dropped from 92% before HILP to 85% after HILP. P-gp positive samples were encountered more often than MRP1 positive samples (P < 0.05). The percentage of samples that were negative for all three MDR proteins increased after HILP from 6% to 16%. MDR status had no significant correlation with tumor response.. HILP with TNF-alpha and melphalan results in excellent overall tumor response in patients with locally advanced STS. STS more often are positive for P-gp than for MRP1. MDR status in patients with STS is not predictive for tumor response after HILP. Data from the current study suggest that the combination of TNF-alpha and melphalan does not induce MDR positive STS: a result with clinical importance when consecutive, adjuvant, doxorubicin-containing chemotherapy is considered.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Chemotherapy, Cancer, Regional Perfusion; Drug Resistance, Multiple; Female; Humans; Hyperthermia, Induced; Immunoenzyme Techniques; Interferon-gamma; Male; Melphalan; Middle Aged; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Prognosis; Sarcoma; Soft Tissue Neoplasms; Survival Rate; Tumor Necrosis Factor-alpha; Vault Ribonucleoprotein Particles

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

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

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

Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan was used as induction treatment in locally advanced extremity soft-tissue sarcomas for limb sparing surgery. The typical histopathological changes that occur in these tumoral masses are described in a series of 30 patients.. Fresh tumor specimens of 27 high grade extensive soft-tissue sarcomas and 3 recurrent desmoid tumors of the extremities were collected 6 to 8 weeks after hyperthermic isolated limb perfusion with tumor necrosis factor-alpha plus melphalan. The specimens were studied for surgical margins, extent and type of tumor necrosis, lymph node involvement, perineural and vascular invasion, and the effects on adjacent normal tissues such as nerves, muscles, and blood vessels.. The typical histological changes were central cystic hemorrhagic necrosis with pericystic extensive fibrosis. Some nonspecific changes were noted in the soft tissues around the mass. In eight cases, more than 90% necrosis was found. In 17 cases, the extent of necrosis ranged between 60% and 90% (80%-90% in 4 of 17 cases). In five cases, less than 60% necrosis was noted. The best responses (>90% necrosis) were observed in distally located tumors. The responsive types were malignant fibrous histiocytoma, followed by myxoid liposarcoma and synovial sarcoma. Desmoid tumors showed less necrosis than high grade sarcomas. Vascular invasion was observed in two cases and intralesional venous thrombosis in one case. No perineural invasion or lymph nodes involvement were observed. The soft tissues adjacent to the tumor bed did not show major morphological changes. No correlation was found between the histological changes and each of the following: the anatomical (upper vs. lower limb) or compartmental location of the tumor; whether the tumor was primary or recurrent; and the types of previous treatment (systemic chemotherapy or radiotherapy) and tumor size.. This is the first serial histological description of the effects of tumor necrosis factor-alpha and melphalan administered via hyperthermic isolated limb perfusion on the tumoral masses of limb soft-tissue sarcomas. The small number of specimens and, especially, the variability of tumors preclude definite conclusions. Larger numbers and more homogeneity are needed in future studies.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Fibrosis; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Necrosis; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

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

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

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

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

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

Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan (HILP-TM) with or without IFN-gamma is a promising local treatment in patients with locally advanced extremity soft tissue sarcomas (STSs), with response rates of up to 84%. The mechanisms of the treatment response are poorly understood. Here, we determined the HILP-TM-induced changes in mitotic activity, proliferation, and apoptosis in 37 STSs; the additional effect of IFN-gamma; and the association of HILP-TM with treatment response and clinical outcome. On archival material, obtained before and 6-8 weeks after HILP-TM with (n = 15) or without (n = 22) IFN-gamma, the number of mitoses was counted, and the proliferation fraction was determined by immunohistological staining for the proliferation associated Ki-67 antigen (MIB1). Apoptosis was visualized by enzymatic detection of DNA fragmentation (terminal deoxynucleotidyl transferase-mediated nick end labeling method). Clinical and histological response, follow-up status, and survival were recorded. The number of mitoses dropped 57% and proliferation rate decreased with 40% after HILP-TM, whereas the amount of apoptosis after HILP-TM more than doubled as before HILP-TM. The addition of IFN-gamma to HILP-TM did not influence the changes in tumor parameters and did not affect treatment response. A better clinical response to HILP-TM was correlated with high mitotic activity and low amount of apoptosis in tumor samples before HILP-TM. Patients with highly proliferative STS before and after HILP-TM had a relatively poor prognosis. Furthermore, patients who developed distant metastases after HILP-TM had a relatively high number of dividing cells in the tumor remnants after treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Division; Chemotherapy, Cancer, Regional Perfusion; Female; Follow-Up Studies; Foot Diseases; Humans; Hyperthermia, Induced; Interferon-gamma; Male; Melphalan; Middle Aged; Sarcoma; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha

High-dose chemotherapy with autologous peripheral blood stem cell transplantation was administered to 10 patients with refractory bone and soft tissue sarcoma (2 patients with primitive neuroectodermal tumor, 4 patients with Ewing's sarcoma, 3 patients with synovial sarcoma and one patient with osteosarcoma). Busulfan 4 mg/kg x 4, melphalan 140 mg/m2 and thiotepa 200 mg/m2 x 3 were used in the high-dose chemotherapy. Complications related to the treatment were limited to one patient who developed hepatic veno-occlusive disease, no serious complications were seen in the other patients. Four patients died of their disease, one patient was alive with the disease and 5 patients were alive with no evidence of disease. The prognosis for non-resectable primitive neuroectodermal tumor and Ewing's sarcoma is said to be very poor. However, there are some patients in whom the disease is kept in remission by high-dose chemotherapy with autologous peripheral blood stem cell transplantation, so this therapy may be a possible substitute for radical operation. With spindle cell sarcomas, the efficacy of this treatment was temporary, so it will be necessary to investigate frequent high-dose chemotherapy and to change the high-dose chemotherapy regimen.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Busulfan; Child; Combined Modality Therapy; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Sarcoma; Sarcoma, Ewing; Sarcoma, Synovial; Soft Tissue Neoplasms; Thiotepa; Transplantation, Autologous

Isolated limb perfusion (ILP) with recombinant tumour necrosis factor-alpha (rTNF-alpha) and melphalan has recently been reported to induce major tumour responses and permit limb salvage in over 80% of patients with unresectable soft-tissue sarcomas of the extremities. We investigated whether TNF-based ILP could allow limb-sparing surgery in patients with primary, recurrent or metastatic bone sarcoma to the lower extremity who met the criteria for an amputation and had failed or refused chemotherapy.. From August 1992 to December 1997, we employed ILP with rTNF-alpha and melphalan in 13 patients with unresectable bone sarcoma of the lower extremity, all of whom were candidates for amputation. The aim was to reduce tumour size and allow the performance of a limb-sparing surgery (LSS).. Following ILP, none of the patients had severe local toxicity and only one patient experienced significant systemic side-effects. LSS was subsequently performed in nine of the 13 patients. LSS was feasible in an additional three patients but was not performed because of the emergence of diffused metastatic disease.. ILP with rTNF-alpha and melphalan can allow limb salvage in patients wih locally advanced bone sarcomas who had failed standard treatment options. Its potential role in the treatment of unresectable bone sarcomas of the extremities merits further evaluation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Leg; Male; Melphalan; Middle Aged; Recombinant Proteins; Sarcoma; Treatment Outcome; Tumor Necrosis Factor-alpha

Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and melphalan is associated with a dramatic antitumor effect in locally advanced extremity soft-tissue sarcomas (STS). The aim of this study was to demonstrate the feasibility and efficacy of adjuvant radiotherapy after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed surgical resection.. Between 1991 and 1995, 34 patients--16 males and 18 females, median age 50 (range 18-80) years--underwent HILP for locally advanced extremity STS. Resection of the residual tumor mass was performed in most patients after 6-8 weeks. Fifteen patients with histopathological viable tumor after resection received adjuvant 60-70 Gy external beam radiotherapy (EBRT) (44%, HILP + EBRT group). Nineteen patients received HILP without adjuvant EBRT (56%, HILP-only group). Five patients in the HILP-only group had also distant metastases (15%) and received HILP as a palliative treatment. Treatment morbidity, local recurrences, and regional and distant metastases were scored.. During a median follow-up of 34 months (range 8-54), limb salvage was achieved in 29 patients (85%): 14 patients after HILP + EBRT and 15 patients after HILP only. None of the patients from the HILP + EBRT group developed local recurrences; however, five patients from the HILP-only did (26%) (p < 0.05). Regional metastases were observed in one patient from the HILP + EBRT group (7%) and in two patients from the HILP-only group who were treated with curative intent (14%). Distant metastases occurred in four patients after HILP + EBRT (27%) and in four patients after HILP only with curative intent (29%). The mean morbidity (subjective, objective, medical management, and analytical evaluation) score in both groups was, respectively, 0.33 for skin and subcutaneous tissue and for muscle and soft tissue, 0.34 (HILP + EBRT group) and 0.33 (HILP-only group).. Adjuvant EBRT after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed tumor resection of locally advanced extremity STS is feasible and may increase local tumor control without increasing treatment morbidity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Feasibility Studies; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Interferon-gamma; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Radiotherapy, Adjuvant; Sarcoma; Tumor Necrosis Factor-alpha

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

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

The management of locally advanced soft-tissue sarcomas (STS) of the extremities in patients who present with regional and/or distant metastases at the time of diagnosis remains an unsolved problem. The recently introduced hyperthermic isolated limb perfusion (HILP) with tumour necrosis factor (TNF)-alpha and melphalan has been shown to be an effective limb-saving treatment modality, but is it feasible to use this approach with palliative intent? Nine patients, five men and four women, mean age 41 (range 21-75) years with locally advanced extremity STS and regional (n = 3) or distant (n = 6) metastases at the time of diagnosis, underwent a palliative HILP with TNF-alpha and melphalan. Resection of the residual tumour mass was performed, if possible, 6-8 weeks after HILP. Treatment-related morbidity, local recurrences and the limb salvage rate were scored during follow-up. The median follow-up period was 9 (range 3-39) months (seven deaths, but six were due to metastatic disease). Treatment-related morbidity was seen after 3 of the 10 perfusions performed (30%) and consisted of superficial wound infections (n = 2), blow out of the external iliac artery followed by an iliac thrombosis (n = 1). Two patients showed local recurrences after HILP followed by resection of the residual tumour mass, and one patient showed local progression after two perfusions without resection. Limb salvage was achieved in 8 patients (89%). Therefore, HILP with TNF-alpha and melphalan for locally advanced extremity STS in patients with disseminated disease is feasible. The local management of locally advanced extremity STS should be the same whether the intent is curative or palliative, as the local control improves the quality of life.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Arm; Chemotherapy, Cancer, Regional Perfusion; Feasibility Studies; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Leg; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Palliative Care; Salvage Therapy; Sarcoma; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

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

Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and melphalan is associated with a dramatic anti-tumor effect in which the neo-vascularization of the tumor is supposed to be the major target. The aim of the present study was to correlate the angiographic findings with the pathological response in patients undergoing HILP for locally advanced soft-tissue sarcoma.. Twenty-five patients, 14 male and 11 female, mean age 47 years (range 18-80) were studied. Angiographies were performed before and a median period of 7 weeks (range 4-14 weeks) after HILP. Eight weeks after perfusion, the residual tumor mass was resected and pathologically examined. The changes in tumor vascularization after treatment were scored and compared with the pathological response.. All baseline angiograms showed a hypervascular tumor. After HILP, a normal angiography result (NA) was observed in 18 patients (72%) and an abnormal angiography result (AA) was observed in seven patients (28%). All patients with an NA showed a pathologically complete response (pCR) or a pathological partial response with > 90% necrosis of the tumor. Of seven patients with an AA, pathological examination showed a pCR in one patient, 10-50% viable tumor volume in four patients, and no pathological response after perfusion in two patients. A good correlation was seen between angiographic and pathological classification (p < 0.001).. An angiography performed after hyperthermic isolated limb perfusion with TNF-alpha and melphalan provides a good indication, regardless of whether a good pathological response is expected.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiography; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Hyperthermia, Induced; Interferon-gamma; Male; Melphalan; Middle Aged; Prospective Studies; Sarcoma; Sensitivity and Specificity; Treatment Outcome; Tumor Necrosis Factor-alpha

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

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

Recombinant tumor necrosis factor-alpha (rTNF-alpha) is a highly potential antineoplastic agent. However, its systemic administration in humans has resulted in a life-threatening septic shock-like syndrome, and its use has been abandoned. The administration of high dose rTNF-alpha and melphalan via isolated limb perfusion (ILP) eliminated the systemic side effects and was shown to be very effective for metastatic melanoma confined to the limb. The purpose of the current study was to assess the role of rTNF-alpha and melphalan administered via ILP in patients with soft tissue sarcoma. Amputation is unavoidable in 10% of these patients despite aggressive conventional therapy. Limb preservation was the objective in this select group of candidates for amputation or mutilating surgery.. During a 36-month period, 35 patients with high grade soft tissue sarcoma underwent 41 ILPs with high dose rTNF-alpha (3-4 mg) and melphalan (1-1.5 mg/kg). There were 21 males and 14 females. The mean age was 48 years (range, 14-80 years). Histologic subtypes included malignant fibrous histiocytoma, synovial, liposarcoma, malignant schwannoma, desmoid, clear cell, epithelioid, rhabdomyosarcoma, leiomyosarcoma, and unclassifiable. Twenty-one patients presented with recurrent and 14 with very extensive primary tumors. The tumors were located in the upper extremity in 8 patients and in the lower extremity in 27 patients. Twenty-five patients were candidates for amputation and 10 for extensive mutilating surgery. ILP was performed via the corresponding vessels proximal to the tumor. Six patients with partial response (PR) insufficient to render them resectable underwent a second ILP. With the exception of 4 of 9 patients with multifocal lesions and 1 who refused surgery, resection of the residual tumor or tumor bed or limb was performed 6-8 weeks after ILP.. Marked tumor softening occurred within 48 hours, and in tumors protruding through the skin hemorrhagic necrosis was evident within 24 hours. The overall response rate was 91%. Thirteen patients (37%) had a complete response and 19 (54%) had a PR; in 5 of these patients > 90% necrosis of the tumor occurred. In 3 patients (8.5%), only minimal regression was observed (stabilization of disease). The rate of limb sparing was 85% (29 of 34 patients).. The combination of high dose rTNF-alpha and melphalan given via ILP appears to be effective in patients with advanced soft tissue sarcoma confined to the limb, achieving a high response rate and limb preservation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dose-Response Relationship, Drug; Female; Humans; Leg; Male; Melphalan; Middle Aged; Sarcoma; Tumor Necrosis Factor-alpha

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

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

Topics: Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Extremities; Humans; Interferon-gamma; Melphalan; Multicenter Studies as Topic; Sarcoma; Survival Analysis; 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

Isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF alpha) +/-interferon gamma (IFN gamma) and melphalan in patients with primarily irresectable soft tissue sarcoma is promising in terms of tumor regression and limb salvage. However, the feasibility of radiotherapy in combination with this treatment modality has not been established.. Fifteen patients with irresectable soft tissue tumors of the limb underwent ILP with TNF alpha, +/-IFN gamma, and melphalan. Three groups could be distinguished with respect to the role of radiotherapy. In nine patients, the residual tumor could be resected after ILP, and this was followed by radiotherapy with a total dose of 50-70 Gy (2 Gy/day). In one patient with aggressive fibromatosis, ILP was followed by radiotherapy without tumor resection (Group I). In two patients who underwent ILP for recurrent sarcoma, the primary tumor had been treated before by resection and radiotherapy (60 Gy) (Group II). In three patients whose tumors remained irresectable after ILP, radiotherapy was applied later in the course of disease for local palliation (Group III).. In Group I, healing of the resection wound was markedly delayed in four patients, with soft tissue necrosis and infection necessitating amputation in two of them. Following completion of radiotherapy, persistent lymphoceles were encountered in two patients. Radiotherapy-induced fibrosis was encountered in five patients, resulting in a mild limb malfunction in two. Three-patients developed mild edema during radiotherapy. Tumor-associated neuropathy was aggravated by ILP in three patients causing severely disabling motor deficits and limb contractures in two of them. In Group II, ILP did not cause any local problem in the heavily irradiated areas. In Group III, pre-existing limb edema was increased after a total palliative dose of 20 Gy in one patient. Another patient, who had been re-operated for arterial thrombosis immediately after ILP, developed occlusion of the brachial artery 4 months after completion of palliative radiotherapy (36 Gy in 6 Gy fractions).. In patients with irresectable soft tissue tumors, multimodality treatment using ILP with TNF alpha +/- IFN gamma and melphalan, tumor resection, and postoperative high-dose radiotherapy is associated with a considerable risk of tissue necrosis and impaired healing. This risk should be weighed against a possible benefit from radiotherapy in local tumor control.

Topics: Adult; Aged; Antineoplastic Agents; Arm; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Edema; Female; Humans; Interferon-gamma; Leg; Liposarcoma; Male; Melphalan; Middle Aged; Necrosis; Radiation Injuries; Radiotherapy Dosage; Retrospective Studies; Risk; Sarcoma; Skin; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

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

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

We investigated FDG-PET in patients undergoing hyperthermic isolated limb perfusion (HILP) with rTNF-alpha, rIFN-gamma and melphalan for locally advanced soft-tissue sarcoma of the extremities.. Twenty patients (11 women, 9 men; aged 18-80 yr, mean age 49 yr) were studied. FDG-PET studies were performed before, 2 and 8 wk after HILP. After the final PET study, the tumor was resected and pathologically graded. Patients with pathologically complete response (pCR) showed no viable tumor after treatment. Those with pathologically partial response (pPR) showed various amounts of viable tumor in the resected specimens.. Seven patients showed a pCR (35%) and 12 patients showed a pPR (60%). In one patient, pathological examination was not performed (5%). The pre-perfusion glucose consumption in the pCR group was significantly higher than in the pPR group (p<0.05). Visual analysis of the PET images after perfusion showed a rim of increased FDG uptake around the core of absent FDG uptake in 12 patients. The rim signal contained a fibrous pseudocapsule with inflammatory tissue in the pCR group, viable tumor was seen in the pPR group. The glucose consumption in the pCR group at 2 and 8 wk after perfusion had decreased significantly (p<0.05) in comparison to the glucose consumption in the pPR.. Based on the pretreatment glucose consumption in soft-tissue sarcomas, one could predict the probability of a patient achieving complete pathological response after HILP. FDG-PET indicated the pathological tumor response to HILP, although the lack of specificity of FDG, in terms of differentiation between an inflammatory response and viable tumor tissue, hampered the discrimination between pCR and pPR.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Deoxyglucose; Extremities; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Humans; Hyperthermia, Induced; Interferon-gamma; Male; Melphalan; Middle Aged; Sarcoma; Soft Tissue Neoplasms; Tomography, Emission-Computed; Tumor Necrosis Factor-alpha

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

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

To determine the efficacy of isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF) in combination with interferon-gamma (IFN) and melphalan as induction therapy to render tumors resectable and avoid amputation in patients with nonresectable extremity soft tissue sarcomas (STS).. Among 55 patients with 30 primary and 25 recurrent sarcomas, there were 48 high-grade and seven grade 1 sarcomas (very large, recurrent, or multiple). The composition of this series of patients is unusual: 13 patients (24%) had multifocal primary sarcomas or multiple recurrent tumors; tumors were very large (median, 18 cm); and nine patients (16%) had known systemic metastases. IFN was administered subcutaneously on the 2 days before ILP with TNF, IFN, and melphalan. A delayed marginal resection of the tumor remnant was usually performed 2 to 3 months after ILP.. A major tumor response was seen in 87% of patients and rendered the sarcomas resectable in most cases. Clinical response rates were as follows: 10 (18%) completes responses (CRs), 35 (64%) partial responses (PRs), and 10 (18%) no change (NC). Final outcome was defined as follows by clinical and pathologic response: 20 (36%) CRs, 28 (51%) PRs, and seven (13%) NC. Limb salvage was achieved in 84% (follow-up duration, 20+ to 50+ months). In 39 patients, resection of the tumor remnant (n = 31) or of two to eight tumors (n = 8) after ILP was performed; local recurrence developed in five (13%). When no resection was performed (multiple tumors or systemic metastases), local recurrences were frequent (five of 16), but limb salvage was often achieved as patients died of systemic disease. Regional toxicity was limited and systemic toxicity minimal to moderate with no toxic deaths. Histology showed hemorrhagic necrosis; angiographies showed selective destruction of tumor-associated vessels.. ILP with TNF, IFN, and melphalan is a safe and highly effective induction biochemotherapy procedure that can achieve limb salvage in patients with nonresectable extremity STS. TNF is an active anticancer drug in humans in the setting of ILP.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Hemodynamics; Humans; Interferon-gamma; Male; Melphalan; Middle Aged; Remission Induction; Salvage Therapy; Sarcoma; Treatment Outcome; Tumor Necrosis Factor-alpha

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

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

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

Soft-tissue sarcomas (STS) of the extremities are characterized by a high rate of local recurrences. Limb salvage approaches using multimodality therapy protocols have replaced amputation. In order to evaluate isolated hyperthermic limb perfusion (ILP) in a multimodality therapy concept, we reviewed our patients treated using this method. Between January 1982 and December 1995, 25 ILPs, using cisplatin, melphalan and adriamycin, were performed in 22 patients with STS. Forty percent were treated for local recurrences; histology was dominated by malignant fibrous histiocytoma (MFH) and synovial sarcoma. In all, 68% of the STS were classified as UICC stage IIb or IIIa/b. Most of the cases (14) underwent wide or radical resection, 4 patients received intraoperative radiotherapy, and 5 were treated with external beam radiation. Complications were recorded in 32% of the cases. With a median follow-up of 45 months (range 1-143), the 5-year overall survival rate was 81%. The median recurrence-free time was 19 months and the 5-year disease-free survival rate 34%. There were 13 local failures, and distant metastases developed in 36% of the patients. Concerning high-grade sarcomas (UICC stage IIb, IIIa/b), we found local recurrences in 75% of all cases. Five of 11 patients with local failures underwent perfusion after they refused amputation, and 7 incompletely resected STS received ILP without reoperation. All of these demonstrated local recurrence. This rate of local recurrence proved to be different from patients with tumor-free resection margins (p = 0.0001, log-rank test). The amputation rate after isolated limb perfusion was 27% (mean 11 months after treatment). Long-term results of ILP showed a considerable local recurrence rate and a low disease-free survival. Perfusion in patients without tumor-free resection margins does not prevent local recurrence. We conclude that ILP with cisplatin, melphalan and adriamycin should be considered carefully and is not an additional treatment strategy of fist choice.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Extremities; Female; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Sarcoma; Soft Tissue Neoplasms; Survival Rate

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

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

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

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

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

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

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

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

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

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

Twenty-two patients with locally advanced or metastatic soft tissue sarcomas received high dose chemotherapy with autologous bone marrow graft. Eleven patients receiving melphalan also received fractionated total body irradiation. Six patients (four in CR and two in PR) were intensified after first line therapy. Thirteen patients were grafted after chemosensitive relapse: seven in second CR, one in third CR, one in first PR, three in second PR and one in fourth PR. Three patients with primary refractory disease were intensified. The overall response rate in 66% in nine evaluable patients. The overall median survival and disease-free survival were 19 and 15 months, respectively. The actuarial survival rates at 2 and 5 years were 40% and 32% respectively. There was one treatment-related death due to infection. We conclude that high dose chemotherapy is feasible and provides reasonable response rates in patients with advanced soft tissue sarcomas.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Child, Preschool; Cisplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Etoposide; Female; Gastrointestinal Diseases; Humans; Ifosfamide; Male; Melphalan; Sarcoma; Soft Tissue Neoplasms; Survival Rate; Vincristine; Whole-Body Irradiation

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

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

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

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

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

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

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

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

High-grade soft tissue sarcomas of the extremities continue to pose problems of local disease control and deaths from distant metastases. Between 1969 and 1976, eight patients with primary and six with recurrent high-grade soft tissue sarcomas of the extremities were treated by isolated regional perfusion with cytostatics and local excision. None received systemic adjuvant chemotherapy or external-beam radiotherapy. During the follow-up (median, 13 years) five patients (36%) developed distant metastases. One was cured after resection of a pulmonary metastasis. In one other patient (7%) recurrent local disease was diagnosed after 48 months; he was cured after resection of the local lesion followed by postoperative external beam radiotherapy. The actuarial 5-year and 10-year survival was 69%. Treatment caused no cardiovascular complications and there was no postoperative mortality.

Topics: Adult; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Extremities; Female; Fibrosarcoma; Follow-Up Studies; Histiocytoma, Benign Fibrous; Humans; Male; Melphalan; Middle Aged; Sarcoma; Soft Tissue Neoplasms

A review of the development of regional chemotherapy by perfusion is presented. Techniques have been developed for most regions of the body. Early response rates ranged from 48% for glioblastoma and 55% with carcinoma to 67% with soft tissue sarcoma and 84% with melanoma. By 1984, 1325 patients had been perfused 1509 times. The best responses have occurred with melanoma and soft tissue sarcoma of the limbs. Thus, at 10 years, the cumulative overall survival for Stage I melanoma of the limbs, combining regional perfusion and conservative excisional surgery, was 77%. The best results occurred in female patients with upper-limb disease (83%), and the poorest results were in male patients with lower-limb disease (53%). The overall 10-year survival for regional melanoma was 41%, ranging from 23% for in-transit metastases to 51% for patients with positive regional nodes treated by perfusion and regional lymph node dissection. The 10-year survival for perfusion and limb-sparing excision for soft tissue sarcoma was 65%. Advantages and complications are presented and discussed. Questions and plans for the future are reviewed.

Topics: Animals; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Costs and Cost Analysis; Extremities; Female; Humans; Lymph Node Excision; Male; Melanoma; Melphalan; Neoplasms; Sarcoma; Thiotepa

Twenty-nine patients were treated with 31 courses of high-dose combination cyclophosphamide, cisplatin, and carmustine (BCNU) with and without melphalan with autologous bone marrow support. Toxicity was dose related. The maximum tolerated dose for cyclophosphamide, cisplatin, and BCNU in this combination in mg/m2 was 5,625, 165, and 600, respectively. Further dose escalation was precluded by the development of multiple organ toxicity, including venoocclusive disease, refractory thrombocytopenia, and hypertension. Melphalan added to the three-drug combination produced excessive renal and gastrointestinal toxicity. Objective tumor regression occurred in 21 of 25 evaluable cases. The results suggest that selected alkylating agents can be combined in full or nearly full doses before nonmyelosuppressive dose-limiting toxicity precludes further escalation.

Topics: Adult; Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carcinoma; Carmustine; Cisplatin; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Evaluation; Drug Tolerance; Female; Humans; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Sarcoma

A retrospective evaluation of 87 cases of uterine sarcoma treated during 1965-1980 at two Swedish hospitals has been made. Adjuvant postoperative radiotherapy has been compared with adjuvant chemotherapy. Various types of combination treatments were also evaluated. Both types of adjuvant therapy seem to reduce the failure rate, both locally in the pelvis and at distant sites, although survival, studied by the life table technique, was unaffected. Radiotherapy appears to reduce the number of pelvic failures when used as combination therapy and chemotherapy tends to prevent distant recurrences when used together with surgery. Further prospective and randomized studies are needed, however, to answer the question of the long-term value of adjuvant radiotherapy and/or chemotherapy in the treatment of uterine sarcomas.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Dacarbazine; Doxorubicin; Female; Humans; Leiomyosarcoma; Melphalan; Middle Aged; Parity; Postoperative Care; Prognosis; Radiotherapy Dosage; Retrospective Studies; Sarcoma; Uterine Neoplasms; Vincristine

Open-field gamma-beam therapy using grid filters was used for 53 patients with Stage III-III stomatopharyngeal tumors. Besides, to compare therapeutic efficacy the 2nd group was taken (52 persons with Stage III-IV) where chemotherapy was used simultaneously. Single and summary radiation doses did not lower. A chemotherapeutic agent dose was equal to 1/2 up to 2/3 of the standard one. Powerful substitution and hemostimulation therapy and a great variety of drugs were employed not to induce deep changes of hemopoiesis and immunosuppression. A single focal dose in gamma-beam therapy varied from 1.6 to 2.5 Gy, the summary dose from 55 to 70 Gy depending on the stage of disease and the histological structure of a tumor. The prescription of one or another chemotherapeutic agent was mainly determined by the morphological structure of a tumor.

Topics: Adult; Aged; Carcinoma; Combined Modality Therapy; Cyclophosphamide; Gamma Rays; Humans; Melphalan; Methotrexate; Middle Aged; Oropharyngeal Neoplasms; Pharyngeal Neoplasms; Prognosis; Sarcoma; Thiotepa

Topics: Antineoplastic Combined Chemotherapy Protocols; Arm; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Doxorubicin; Female; Hot Temperature; Humans; Leg; Male; Melanoma; Melphalan; Neoplasm Metastasis; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms

Topics: Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dactinomycin; Extremities; Humans; Hyperthermia, Induced; Injections, Intravenous; Melanoma; Melphalan; Perfusion; Sarcoma; Soft Tissue 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

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

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

Topics: Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Drug Therapy, Combination; Extremities; Female; Hot Temperature; Humans; Male; Melanoma; Melphalan; Paralysis; Remission, Spontaneous; Sarcoma; Soft Tissue Neoplasms

Topics: Antineoplastic Agents; Bone Neoplasms; Cyclophosphamide; Doxorubicin; Drug Evaluation; Drug Therapy, Combination; Humans; Melphalan; Sarcoma; Vincristine

Topics: Adolescent; Adult; Aged; Amputation, Surgical; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Male; Melphalan; Middle Aged; Prognosis; Sarcoma; Soft Tissue Neoplasms

Description of a case presenting as an inflammatory polyarthritis. A uterine sarcoma was detected one year later and led to the death of the patient. The abnormal protein belonged to the gammal subclass. Biosynthesis experiments, performed on the marrow plasma cells, showed that light chains were not produced and that the molecular weight of the monomeric unit of the serum protein was slightly smaller than that of the protein secreted in vitro, suggesting the occurrence of a secondary and limited extracellular proteolysis.

Topics: Arthritis; Cyclophosphamide; Female; Heavy Chain Disease; Humans; Immunoglobulin A; Immunoglobulin Heavy Chains; Immunoglobulin M; Melphalan; Middle Aged; Molecular Weight; Prednisone; Sarcoma; Uterine Neoplasms

Nine patients with regionally inoperable malignant melanoma or soft tissue sarcoma were treated with combinations of intra-arterial chemotherapy, immunotherapy and operation or irradiation or both. Three of the heretofore untreatable patients with melanoma remain clinically free of detectable metastases at three years, three and one-half years and one and one-half years from their recurrence. One nodular melanoma remains well controlled two years after diagnosis, while an additional patient is free of disease several months after therapy. Two of the patients with melanoma died within a year of the onset of the recurrence but maintained the affected limb in useful condition until the time of their death. Two of the three patients with sarcoma remain free of disease at ten and four years. One patient who was known to have distant metastatic disease at the onset of the treatment currently is hospitalized for further therapy for tumor in the para-aortic lymph nodes.

Topics: Adult; Aged; BCG Vaccine; Chemotherapy, Cancer, Regional Perfusion; Dacarbazine; Dactinomycin; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Middle Aged; Sarcoma

Topics: Bone Neoplasms; Cyclophosphamide; Giant Cell Tumors; Humans; Liver; Melphalan; Osteoma, Osteoid; Osteosarcoma; Radiation Effects; Radiotherapy; Radiotherapy Dosage; Sarcoma; Sarcoma, Ewing

Topics: Aged; Amputation, Surgical; Arm; Bone Neoplasms; Cartilage; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Female; Fibrosarcoma; Hemangiosarcoma; Humans; Leg; Liposarcoma; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Sarcoma

Topics: Adult; Antibiotics, Antineoplastic; Antineoplastic Agents; Cyclophosphamide; Drug Therapy, Combination; Fibrosarcoma; Hemangiosarcoma; Humans; Leiomyosarcoma; Liposarcoma; Male; Melphalan; Neoplasm Metastasis; Neurilemmoma; Nitrogen Mustard Compounds; Sarcoma; Sarcoma, Synovial; Thiotepa

Topics: Bence Jones Protein; Cyclophosphamide; Humans; Immunoglobulin A; Immunoglobulin G; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Sarcoma

Topics: Animals; Bone Neoplasms; Dog Diseases; Dogs; Melphalan; Sarcoma

Topics: Adult; Aged; Arm; Chemotherapy, Cancer, Regional Perfusion; Female; Hemangiosarcoma; Humans; Leg; Male; Melanoma; Melphalan; Middle Aged; Oxygenators; Sarcoma; Sarcoma, Kaposi

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: Administration, Oral; Adolescent; Aged; Chemotherapy, Cancer, Regional Perfusion; Cyclophosphamide; Female; Fibrosarcoma; Humans; Knee; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Retroperitoneal Neoplasms; Sarcoma; Stomach Neoplasms

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antiviral Agents; Ascites; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Cyclophosphamide; Depression, Chemical; Injections, Intraperitoneal; Injections, Subcutaneous; Leukemia, Experimental; Mechlorethamine; Melphalan; Mice; Neoplasms, Experimental; Nitrogen Mustard Compounds; Rats; Sarcoma; Sarcoma 180; Thiotepa; Uracil

Topics: Adolescent; Adult; Aged; Child; Fibrosarcoma; Giant Cell Tumors; Hemangiosarcoma; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Maxillary Neoplasms; Melphalan; Middle Aged; Myxosarcoma; Osteosarcoma; Radioisotope Teletherapy; Sarcoma; Thiotepa

Topics: Animals; Autoradiography; Body Weight; Depression, Chemical; DNA, Neoplasm; In Vitro Techniques; Melphalan; Mice; Rats; Sarcoma; Sarcoma 180; Thymidine; Tritium

Topics: Arm; Burns; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Edema; Femoral Neoplasms; Foot Diseases; Hemangiosarcoma; Hemoglobinuria; Hemolysis; Hot Temperature; Humans; Leg; Melanoma; Melphalan; Neoplasm Metastasis; Sarcoma; Sarcoma, Ewing; Sarcoma, Kaposi; Time Factors

Topics: Adrenalectomy; Aged; Antineoplastic Agents; Breast Neoplasms; Bronchial Neoplasms; Cortisone; Cyclophosphamide; Drug Synergism; Ethinyl Estradiol; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Hydrazines; Hypophysectomy; Kidney Neoplasms; Lung Neoplasms; Male; Melanoma; Melphalan; Mesothelioma; Methotrexate; Middle Aged; Nandrolone; Neoplasm Metastasis; Ovarian Neoplasms; Podophyllin; Sarcoma; Thiotepa; Vinblastine

Topics: Adenocarcinoma; Ameloblastoma; Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Carcinoma; Carcinoma, Squamous Cell; Cyclophosphamide; Ethylenediamines; Facial Neoplasms; Fibrosarcoma; Glioma; Humans; Infusions, Parenteral; Mechlorethamine; Melanoma; Melphalan; Meningioma; Methotrexate; Osteosarcoma; Perfusion; Quinones; Retinoblastoma; Rhabdomyosarcoma; Sarcoma; Thiotepa

Topics: Antineoplastic Agents; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Fluorouracil; Head; Head and Neck Neoplasms; Humans; Leucovorin; Melanoma; Melphalan; Methotrexate; Mouth Neoplasms; Nasopharyngeal Neoplasms; Paranasal Sinus Neoplasms; Sarcoma; Thiotepa; Vinblastine

Topics: Amputation, Surgical; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Extremities; Humans; Lymph Node Excision; Melanoma; Melphalan; Osteosarcoma; Sarcoma; Thiotepa

Topics: Blood; Blood Cells; Carbon Isotopes; Carcinoma, Krebs 2; Chromatography; Intestinal Absorption; Melphalan; Metabolism; Mice; Neoplasms; Physiology; Radiometry; Rats; Research; Sarcoma; Sarcoma, Yoshida; Toxicology; Urine

Topics: Animals; Antineoplastic Agents; Melphalan; Neoplasms; Neoplasms, Experimental; Pharmacology; Rats; Research; Sarcoma; Sarcoma, Yoshida

Topics: Female; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Melphalan; Multiple Myeloma; Neoplasms; Osteosarcoma; Ovarian Neoplasms; Research; Sarcoma; Sarcoma, Ewing; Testicular Neoplasms; Thymoma

Topics: Animals; Carcinoma 256, Walker; DNA; DNA, Neoplasm; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Mice; Neoplasms; Neoplasms, Experimental; Pharmacology; Phosphorus Isotopes; Rats; Research; RNA; RNA, Neoplasm; Sarcoma; Sarcoma, Yoshida; Tissue Culture Techniques

Topics: Antineoplastic Agents; Cricetinae; Cyclophosphamide; Dactinomycin; Melphalan; Mice; Mitomycin; Mitomycins; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Pharmacology; Research; Sarcoma; Sarcoma, Experimental; Thiotepa

Topics: Animals; Carbon Isotopes; Kidney; Liver; Melphalan; Metabolism; Neoplasm Proteins; Neoplasms, Experimental; Pharmacology; Rats; Research; Sarcoma; Sarcoma, Experimental; Spleen

Topics: Breast Neoplasms; Carcinoma, Bronchogenic; Dysgerminoma; Female; Gastrointestinal Neoplasms; Hodgkin Disease; Humans; Liver Neoplasms; Lymphoma; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melanoma; Melphalan; Multiple Myeloma; Neoplasms; Ovarian Neoplasms; Sarcoma

Topics: Adolescent; Bone Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Child; Chondrosarcoma; Dogs; Femur; Fibula; Hemangiosarcoma; Humans; Melanoma; Melphalan; Mesenchymoma; Neoplasms; Nitrogen Mustard Compounds; Osteosarcoma; Sarcoma; Sarcoma, Ewing; Ulna; Uracil

Topics: Aorta; Aorta, Abdominal; Bone Neoplasms; Carotid Arteries; Chemotherapy, Cancer, Regional Perfusion; Chondrosarcoma; Dactinomycin; Dogs; Fibrosarcoma; Iliac Artery; Iliac Vein; Leiomyosarcoma; Liposarcoma; Lymphoma, Non-Hodgkin; Melphalan; Mesothelioma; Neoplasms; Neuroblastoma; Osteosarcoma; Rhabdomyosarcoma; Sarcoma; Sarcoma, Kaposi; Subclavian Artery; Vena Cava, Inferior

Topics: Adenine; Bone Marrow Transplantation; Breast Neoplasms; DNA; Female; Folic Acid; Humans; Lung Neoplasms; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Neoplasms; Ovarian Neoplasms; Perfusion; Sarcoma; Thiotepa; Triethylenemelamine

Topics: Geriatrics; Hodgkin Disease; Iatrogenic Disease; Leukopenia; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Neoplasms; Radiography, Thoracic; Sarcoma; Thrombocytopenia; Toxicology

Topics: Animals; Antineoplastic Agents; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Carcinoma, Krebs 2; Feeding and Eating Disorders; Leukopenia; Melanoma; Melphalan; Neoplasms; Neoplasms, Experimental; Pharmacology; Research; Sarcoma; Sarcoma, Experimental

Topics: Bone Neoplasms; Elbow; Giant Cell Tumor of Bone; Giant Cell Tumors; Melphalan; Neoplasms; Neoplasms, Radiation-Induced; Pathology; Radiography; Sarcoma

Topics: Chemotherapy, Cancer, Regional Perfusion; Coccidioidomycosis; Dactinomycin; Drug Hypersensitivity; Drug Therapy; Hematologic Diseases; Humans; Melanoma; Melphalan; Mycetoma; Neoplasms; Sarcoma; Sepsis; Toxicology

Topics: Bone Neoplasms; Cobalt Isotopes; Dactinomycin; Drug Therapy; Humans; Mandible; Mandibular Neoplasms; Melphalan; Methotrexate; Neoplasms; Osteomyelitis; Osteosarcoma; Pathology; Radiography; Radium; Sarcoma

Topics: Antineoplastic Agents; Electrophoresis; Iontophoresis; Melphalan; Rats; Research; Sarcoma; Sarcoma, Experimental

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Drug Therapy; Hodgkin Disease; Lymphatic System; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mannomustine; Melphalan; Neoplasms; Piperazines; Sarcoma

Topics: DNA; DNA, Neoplasm; Genetics; Melphalan; Neoplasms; Nucleoproteins; Rats; Research; RNA; RNA, Neoplasm; Sarcoma; Sarcoma, Experimental

Topics: Animals; Arteries; Capillaries; Histology; Melphalan; Neoplasm Transplantation; Pathology; Pharmacology; Rats; Research; Sarcoma; Sarcoma, Experimental

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Carbohydrate Metabolism; Carcinoma; Carcinoma, Ehrlich Tumor; Female; Glucose; Humans; Melphalan; Metabolism; Ovarian Neoplasms; Oxidative Phosphorylation; Peptides; Pharmacology; Phosphorylation; Research; Sarcoma; Sarcoma, Experimental; Toxicology

Topics: Animals; Autoradiography; Carbon Isotopes; Carcinoma, Ehrlich Tumor; Chloramphenicol; Culture Media; DNA; DNA, Neoplasm; Female; Humans; Melphalan; Ovarian Neoplasms; Pharmacology; Phenylalanine; Proteins; Research; RNA; RNA, Neoplasm; Sarcoma; Sarcoma, Experimental

Topics: Amino Acids; Animals; Antineoplastic Agents; Carcinoma, Brown-Pearce; Carcinoma, Ehrlich Tumor; Glycine; Histocytochemistry; In Vitro Techniques; Lysine; Melphalan; Methionine; Mice; Neoplasm Proteins; Pharmacology; Proteins; Rabbits; Research; Sarcoma; Sarcoma, Experimental; Thiotepa; Tyrosine

Topics: Brain; Leukopenia; Melphalan; Mice; Neoplasms; Pharmacology; Rabbits; Rats; Research; Sarcoma; Sarcoma, Experimental; Tissue Extracts

Topics: Antineoplastic Agents; Dactinomycin; Humans; Melphalan; Neoplasms; Perfusion; Sarcoma

Topics: Benz(a)Anthracenes; Cellophane; Connective Tissue; Melphalan; Neoplasms; Neoplasms, Connective Tissue; Pharmacology; Rats; Research; Sarcoma; Sarcoma, Experimental; Toxicology; Urethane

Topics: Adolescent; Child; Geriatrics; Head and Neck Neoplasms; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mandibular Neoplasms; Maxillary Neoplasms; Melanoma; Melphalan; Multiple Myeloma; Neoplasms; Orbital Neoplasms; Plasmacytoma; Sarcoma; Sarcoma, Kaposi

Topics: Animals; Carcinoma, Ehrlich Tumor; DNA; DNA, Neoplasm; Melphalan; Metabolism; Mice; Neoplasm Transplantation; Neoplasms; Pharmacology; Phosphorus Isotopes; Rats; Research; RNA; RNA, Neoplasm; Sarcoma; Sarcoma, Yoshida

Topics: Antimetabolites; Antineoplastic Agents; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Dactinomycin; Geriatrics; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Melanoma; Melphalan; Methotrexate; Mouth Neoplasms; Neoplasms; Neoplasms, Muscle Tissue; Nitrogen Mustard Compounds; Sarcoma; Toxicology; Triethylenemelamine

Topics: Antineoplastic Agents; Cytosine; Erythrocyte Count; Leukocyte Count; Melphalan; Neoplasm Metastasis; Neoplasms; Pyrimidines; Rats; Research; Sarcoma; Sarcoma, Experimental; Toxicology

Topics: Animals; Antineoplastic Agents; Melphalan; Sarcoma; Sarcoma, Experimental

Topics: Antineoplastic Agents; Humans; Melphalan; Neoplasms; Oxidoreductases; Sarcoma

Topics: Animals; Mechlorethamine; Melphalan; Nitrogen Mustard Compounds; Rats; Sarcoma; Sarcoma, Experimental

Topics: Hodgkin Disease; Humans; Leukemia; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Mechlorethamine; Melphalan; Multiple Myeloma; Nitrogen Mustard Compounds; Phenylalanine; Plasma Cells; Sarcoma

Topics: Melphalan; Neoplasms; Phenylalanine; Sarcoma; Sarcoma, Experimental