melphalan and Soft-Tissue-Neoplasms

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

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

Interdigitating dendritic cell sarcoma is a rare neoplasm forming part of the group of malignancies derived from histocytic cell line. This nosological unit can be detected only by special immunohistochemical exams. A young man aged 25 found a tumorous swelling in the proximal part of his left crus. The pathological process affected proximal tibial epiphysis and adjacent soft tissues. The first FDG-PET examination performed in the process of determining the clinical stage of the disease showed a high activity in the site of primary tumour (SUV 7.71) and in the site of regional inguinal node (SUV 4.25). Histological examination of a diagnostic excision specimen of the tumour in the tibia and the extirpated enlarged regional nodes in the left groin led to the diagnosis of interdigitating dendritic cell sarcoma. The diagnosis was confirmed pathologically by another two centres in the Czech Republic and, due to the unusual nature of the diagnosis, also in Regensburg, Germany. Treatment started with chemotherapy, applied to patients with aggressive lymphomas in the framework of clinical studies, i.e. a combination of MegaCHOP. After 4 cycles, however, there was no visible response on the site of primary tumour. MegaCHOP therapy was therefore discontinued after the 4 cycles. Subsequently, we referred the patient for a high-dose chemotherapy with autologous bone marrow transplantation, similarly to aggressive lymphomas. The collection of blood producing stem cells from peripheral blood was successfully performed after ESHAP chemotherapy. A verificatoin FDG-PET examination was performed before high-dose chemotherapy. Increased activity was detected only in left proximal crus, with an SUV of 4.6. One month after ESHAP chemotherapy, BEAM high-dose chemotherapy with autologous transplantation of blood forming tissue was performed. High-dose chemotherapy was followed up by radiotherapy targeted on the primary tumour in the crus (70 Gy). The third verification FDG-PET examination was performed 3 months after radiotherapy. The examination showed a continuing higher activity in the region of the primary tumour (SUV 2.69) and a new centre of activity was detected in the left inguinal nodes region (SUV4.09). The activity corresponded to the presence of viable tumour tissue in the primary nidus and new metastases in inguinal nodes, without proofs of further proliferation at the time. Nodes of the left groin were removed. Histological examination showed affection of the nod

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carmustine; Cytarabine; Dendritic Cell Sarcoma, Interdigitating; Drug Resistance, Neoplasm; Etoposide; Humans; Leg; Male; Melphalan; Peripheral Blood Stem Cell Transplantation; Positron-Emission Tomography; Soft Tissue Neoplasms; Tibia; Tomography, X-Ray Computed

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

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

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

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

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

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

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

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

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

This study was designed to estimate the partial and complete response rates (CR and PR) of two novel drug pairs (vincristine and melphalan vs. ifosfamide and etoposide) and to improve overall survival of previously untreated patients with metastatic rhabdomyosarcoma.. One hundred twenty-eight patients were randomly assigned to phase II window therapy consisting of vincristine and melphalan (VM-containing regimen) or ifosfamide and etoposide (IE-containing regimen). Brief window therapy (12 wks) was immediately followed-up by vincristine, dactinomycin, and cyclophosphamide (VAC), chemotherapy, surgery, and irradiation, with continuation of either VM or IE in patients with initial response. Major endpoints were initial CR and PR rates after the phase II window phase of therapy, failure-free survival (FFS), and survival.. Patients who received the VM-containing regimen experienced significantly more anemia, neutropenia, thrombocytopenia, and had more cyclophosphamide dose reductions. The initial PR and CR rates were not significantly different for patients treated with either regimen (VM, 74%; IE, 79%; P = 0.428). However, FFS and overall survival (OS) at 3 years were significantly better with the IE-containing regimen (FFS: 33% vs. 19%; P = 0.043; OS: 55% vs. 27%; P = 0.012).. Although the VM-containing regimen produced a high response rate, inclusion of melphalan appeared to limit the cyclophosphamide dose that could be administered, and ultimately, this regimen was associated with a significantly worse outcome than was the IE-containing regimen. Also, the IE-containing regimen was associated with a gratifyingly high survival rate at 3 years (55%), which is significantly higher than has been observed on any previous Intergroup Rhabdomyosarcoma Study Group regimen for similar patients. We believe that this promising outcome indicates that this drug pair merits further randomized testing in metastatic rhabdomyosarcoma.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Bronchiolitis Obliterans; Chemotherapy, Adjuvant; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dactinomycin; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Humans; Ifosfamide; Infant; Kidney Diseases; Life Tables; Male; Melphalan; Neoplasm Metastasis; Radiotherapy, Adjuvant; Remission Induction; Rhabdomyosarcoma; Sepsis; Soft Tissue Neoplasms; Survival Analysis; Treatment Outcome; Vincristine

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

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

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

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

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

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

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

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

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

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

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

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

Kaposi sarcoma (KS) is a rare soft tissue sarcoma. In case of locally advanced disease, mutilating surgery such as amputations or major reconstructive procedures are sometimes inevitable. The aim of this study was to evaluate the effectiveness of isolated limb perfusion (ILP) in patients with locally advanced KS of the extremities.. All patients who underwent ILP for KS between 1996 and 2018 at Erasmus MC, Rotterdam were identified. Clinical data was obtained from either a prospectively maintained database or retrospective assessment of patient files.. A total of 14 primary ILP's were performed in 11 patients. Median follow-up from primary ILP was 30 months (range, 5-98). The overall response rate of primary ILP was 100%, with a complete response (CR) rate of 50%. Only minimal local toxicity (Wieberdink I-III) was observed. Local progressive disease occurred after eight primary ILP's (57%) with a median local progression free survival (PFS) of 18 months (95% confidence interval [CI]: 7.0-28.9). Subsequently, four (46%) patients received a total of 5 recurrent ILP's. After the recurrent ILP on the same leg, the overall response rate was 75% and a CR-rate of 50%. One patient needed amputation post-operatively resulting in a limb salvage rate of 91%. One (9%) patient developed metastases four months after ILP.. ILP is a highly effective treatment modality with very limited morbidity rates for patients with locally advanced KS of the extremity. ILP should be considered as a treatment modality for locally advanced KS of the extremities.

Topics: Aged; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Extremities; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Progression-Free Survival; Retrospective Studies; Sarcoma, Kaposi; Soft Tissue Neoplasms; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha

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

Angiosarcomas are rare and aggressive soft-tissue sarcomas. The only potential curative treatment is complete surgical excision. This study reports the outcome of isolated limb perfusion (ILP) with high-dose melphalan and tumour necrosis factor α for locally advanced angiosarcoma.. All patients who underwent an ILP for angiosarcomas between 1991 and 2016 in three tertiary referral centres were identified from prospectively maintained databases.. A total of 39 patients were included, with a median follow-up of 18 months (interquartile range 6.1-60.8). Of these patients, 23 (58.9%) patients had a complete response (CR) after ILP, 10 (25.6%) had a partial response, 4 (10.3%) had stable disease and 2 (5.1%) patients had progressive disease immediately after ILP. A total of 22 patients developed local progression (56.4%), whereas nine (23.1%) developed distant metastases. The patients with CR had a significantly prolonged median local progression-free survival (PFS) (15.4 versus 7.3 months, p = 0.015) when compared with non-CR patients, and a trend towards better median overall survival (81.2 versus 14.5 months, p = 0.054). Six patients underwent multiple ILPs, whereby the CR rate of the first, second and third ILPs were 60%, 80% and 67%, respectively. Thirteen (33.3%) patients needed further surgical intervention, consisting of resection in eight patients (20.5%) and amputation in five patients (12.8%).. ILP is an effective treatment option for patients with locally advanced angiosarcoma in the extremities, resulting in a high number of CRs, a high limb salvage rate and prolonged local PFS.

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Databases, Factual; Disease Progression; Disease-Free Survival; Extremities; Female; Hemangiosarcoma; Humans; Kaplan-Meier Estimate; Limb Salvage; London; Male; Melphalan; Middle Aged; Netherlands; Proportional Hazards Models; Regional Blood Flow; Retreatment; Retrospective Studies; Risk Factors; Soft Tissue Neoplasms; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Young Adult

Tumor necrosis factor alpha (TNF) and melphalan-based isolated limb perfusion (TM-ILP) is one of the most effective treatment modalities for unresectable soft tissue sarcoma (STS) of the extremities. Liposarcomas (LS) are a large and heterogeneous subgroup of STS with different biological behavior and prognoses. The aim of this study was to evaluate LS and the different subentities with respect to their responsiveness towards TM-ILP.. We matched our ILP database with our pathology database to identify patients who received TM-ILP due to STS followed by resection of the residual tumor. We identified 126 patients who matched these inclusion criteria. In this patient group we identified 24 patients with a LS. Histopathological regression was assessed from all resection specimens and was compared between groups: LS vs. non-LS and for myxoid and non-myxoid LS subgroups.. There were no significant differences in the overall tumor regression comparing non-LS (median 95%, mean 77%) and LS (median 90%, mean 74%). For the subgroup analysis, a higher grade of regression after TM-ILP was found in myxoid-LS (median 95%, mean 79% ± 31.5) compared to the non-myxoid LS (median 75%, mean 72% ± 24.6). Atypical lipomatous tumors (ALT) were less responsive to TM-ILP treatment (median 40%, mean 40%).. The histopathological response of LS toward TM-ILP is equally good compared to non-lipomatous STS. Myxoid LS seem to have a tendency towards a better response to TM-ILP compared to non-myxoid LS and ALT showed the lowest response rate in the liposarcoma subgroup. Furthermore, we found that TM-ILP seems to facilitate successful R0 resection. Due to the low number of cases in the subgroups we advocate further research on this topic.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Liposarcoma; Male; Melphalan; Middle Aged; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm, Residual; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

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

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

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

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

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

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

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

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

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

Hyperthermic isolated limb perfusion (ILP) (2 mg, TNF-alpha and 100mg, melphalan) was performed for an irresectable right thigh desmoid tumor with calf extension in a 49-year-old man. The patient had a history of four resections since the age of 19 years. Local ILP toxicity appeared with extensive edema and common peroneal neurologic impairment including paresis that remained severe 10 months later. One of the most troublesome side effects of perfusion is peripheral nerve damage, which has been reported at a rate of between 1 and 48% of perfused patients. ILP is an effective treatment in recurrence situations or where resection threatens loss of function; it, however, requires administration in specialized centers, progress in standardization and close monitoring to avoid locoregional toxicity, the mechanisms of which merit further investigation. Emergency compartmental pressure measurement may indicate fasciotomy, can be of great interest.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Electromyography; Fibromatosis, Aggressive; Follow-Up Studies; Humans; Magnetic Resonance Imaging; Male; Melphalan; Middle Aged; Neoplasm Staging; Paralysis; Peroneal Nerve; Risk Assessment; Severity of Illness Index; Soft Tissue Neoplasms; Thigh; Treatment Outcome; Tumor Necrosis Factor-alpha

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

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

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

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

Addition of high-dose tumor necrosis factor-alpha to melphalan-based isolated limb perfusion enhances anti-tumor effects impressively. Unfortunately, the mechanism of action of tumor necrosis factor-alpha is still not fully understood. Here, we investigated the effects of tumor necrosis factor-alpha on the tumor microenvironment and on secondary immunological events during and shortly after isolated limb perfusion in soft-tissue sarcoma-bearing rats. Already during isolated limb perfusion, softening of the tumor was observed. Co-administration of tumor necrosis factor-alpha in the isolated limb perfusion with melphalan induced a six-fold enhanced drug accumulation of melphalan in the tumor compared with isolated limb perfusion with melphalan alone. In addition, directly after perfusion with tumor necrosis factor-alpha plus melphalan, over a time-frame of 30 min, vascular destruction, erythrocyte extravasation and hemorrhage was detected. Interstitial fluid pressure and pH in the tumor, however, were not altered by tumor necrosis factor-alpha and no clear immune effects, cellular infiltration or cytokine expression were observed. Taken together, these results indicate that tumor necrosis factor-alpha induces rapid damage to the tumor vascular endothelial lining resulting in augmented drug accumulation. As other important parameters were not changed (e.g. interstitial fluid pressure and pH), we speculate that the tumor vascular changes, and concurrent hemorrhage and drug accumulation are the key explanations for the observed synergistic anti-tumor response.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Capillary Permeability; Chemotherapy, Cancer, Regional Perfusion; Cytokines; Hindlimb; Humans; Leukocytes; Macrophages; Male; Melphalan; Models, Animal; Rats; Rats, Inbred BN; Sarcoma, Experimental; Soft Tissue Neoplasms; 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

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

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

Desmoid tumours are soft tissue sarcomas with local aggressive behaviour and a high rate of local recurrence after treatment. Although they do not tend to metastasise systemically, the local aggressiveness can lead to situations in which limb-preserving surgery cannot be performed without severe disability. As isolated limb perfusion (ILP) with TNF and melphalan has proven to be extremely effective in the treatment of soft tissue sarcoma, we studied its potential in locally advanced extremity desmoid tumours.. Prospectively maintained database in a tertiary referral centre. Between 1991 and 2003, 12 ILP procedures were performed in 11 patients for locally advanced desmoid tumours. Local surgical therapy with preservation of limb function was impossible in all patients due to large or multifocal tumours, multiple recurrences or extensive previous treatment. Perfusions were performed with 4-3mg TNF and 10-13 mg/l limb volume melphalan form leg and arm perfusions, respectively.. Overall response rate was 75%: Two complete responses were recorded (17%) and seven patients had a partial response (58%). Amputation could be avoided in all cases. Local control was obtained after 10/12 ILPs and in the other two patients through repeat ILP and systemic chemotherapy, thus leading to an overall local control rate of 100%. Local toxicity was mild and systemic toxicity was absent in all patients.. ILP is a very effective treatment option in the multimodality treatment of limb desmoid tumours. It should be considered in patients with aggressive and disabling disease where resection without important functional sacrifice is impossible.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Dermoid Cyst; Disease Progression; Female; Humans; Limb Salvage; Lower Extremity; Male; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Remission Induction; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha; Upper Extremity

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

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

We report three cases of massive chest wall plasmacytoma, each greater than 10 cm in diameter, without evidence of overt myeloma, whom we treated with a combination of VAD chemotherapy consolidated by high-dose melphalan and autologous peripheral blood stem cell transplantation and radical radiotherapy. All three patients completed all components of their therapy without experiencing any major side effects and one patient has had a durable remission. The other two patients have had disease progression but at sites other than the original tumour.

Topics: Antineoplastic Agents, Alkylating; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Plasmacytoma; Remission Induction; Soft Tissue Neoplasms; Thoracic Wall

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The authors review their experience of 4 years with isolated limb perfusion for the application of high dose TNF-alpha associated to IFN-gamma and melphalan for the treatment of regionally advanced tumours such as malignant melanoma, soft tissue sarcoma and epidermoid carcinoma. In malignant melanoma, the complete remission rate reaches 91%. In irresectable soft tissue sarcoma, this treatment when used as a neoadjuvant treatment saves the limb from amputation in 87.5% of the cases. Similar results are obtained for epidermoid carcinoma. With the regional application of high doses of TNF-alpha associated to chemotherapy and IFN-gamma, it has been possible to validate the concept of a strategy based on a dual targeting, that is the selective impact of the intratumoral vessels by TNF-alpha and of the tumour cells by chemotherapy. This approach appears to be the treatment of choice for locally advanced tumours of the limbs. However, as a single therapy, this procedure should be considered in melanoma as an induction therapy, and in sarcoma, as a preoperative treatment.

Topics: Antineoplastic Agents, Alkylating; Arm; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Drug Therapy, Combination; Follow-Up Studies; Humans; Interferon-gamma; Leg; Melphalan; Neoplasm Staging; Sarcoma, Clear Cell; Soft Tissue Neoplasms; 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

The treatment of a patient with soft-tissue sarcoma was evaluated with FDG-PET. A limb-saving complete remission of a locally advanced liposarcoma of the left thigh was achieved with isolated regional perfusion of the limb with tumor necrosis factor alpha, interferon gamma and melphalan.. PET with 18F-FDG before perfusion showed high glucose consumption in the tumor. After perfusion, glucose metabolism in the tumor was absent. Subsequent excision confirmed complete necrosis of the tumor.. FDG-PET may be useful in evaluating the results of isolateral regional limb perfusion for soft-tissue sarcomas.

Topics: Chemotherapy, Cancer, Regional Perfusion; Contrast Media; Deoxyglucose; Fluorodeoxyglucose F18; Humans; Interferon-gamma; Leg; Liposarcoma; Male; Melphalan; Middle Aged; Soft Tissue Neoplasms; Tomography, Emission-Computed; 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

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Doxorubicin; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Soft Tissue Neoplasms

Nine patients with soft tissue tumours of the lower limb not amenable to treatment other than by isolated limb perfusion or amputation underwent hyperthermic isolated limb perfusion at the level of the superficial femoral vessels, using a combination of recombinant tumour necrosis factor (TNF) alpha and melphalan. In seven patients with superficial tumours, necrosis and sloughing was 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. Three patients ultimately required amputation because of the large soft tissue defects that resulted from necrosis of the tumour and overlying skin.

Topics: Adult; Aged; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Hyperthermia, Induced; Leg; Male; Melphalan; Middle Aged; Pilot Projects; Soft Tissue Neoplasms; Tumor Necrosis Factor-alpha

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

Topics: Bone Neoplasms; Carcinoma, Squamous Cell; Chemotherapy, Cancer, Regional Perfusion; Drug Monitoring; Drug Therapy, Combination; Female; Hemodynamics; Humans; Interleukins; Melphalan; Middle Aged; Soft Tissue Neoplasms; Tibia; Time Factors; Tumor Necrosis Factor-alpha

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

From 1975 to 1986, 26 patients with soft tissue tumors of the extremities underwent a total of 29 perfusions. The cytostatics used were doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) (19 perfusions), melphalan (two perfusions), and a combination of these agents (eight perfusions). Before perfusion most patients had been treated by surgical excision(s), radiotherapy, or systemic chemotherapy. Of 17 patients perfused because of local inoperable tumor, four showed prolonged complete remission of the tumor mass, stable disease was seen in three, and ten showed progression. The complete remissions observed in three patients with aggressive fibromatosis and in one with lymphangiosarcoma occurred after perfusion with doxorubicin combined with melphalan. Doxorubicin added to the perfusate as the sole cytostatic was not effective. Local recurrence was observed in five of nine patients treated by adjuvant perfusion, always after dubiously radical tumor excision. Toxicity was high, especially in the first few years. Tissue necrosis necessitated amputation in three cases (in two after perfusion with doxorubicin and melphalan and in one after repeated perfusion with doxorubicin only). This complication was no longer seen after adjustment of the dosage and dose distribution of doxorubicin, but the morbidity after perfusion with doxorubicin remained considerable.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Child; Doxorubicin; Extremities; Female; Humans; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Remission Induction; Soft Tissue Neoplasms

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

Patients with regional metastases of malignant melanoma (75 with Stage IIIA soft tissue metastases, 124 with Stage IIIB nodal metastases and 75 with Stage IIIAB soft tissue and nodal metastases) treated by regional perfusion between 1957 and 1982 were retrospectively studied to identify prognostic factors relating to survival. In patients with Stage IIIB disease, the melanoma specific cumulative survival rates at five years was 72 per cent for one, 33 per cent for two to three and 20 per cent for four or more positive lymph nodes. In patients with Stage IIIAB disease, those with one node had a better survival rate at five years than those with multiple nodes (45 versus 25 per cent). In patients with Stage IIIA melanoma, two groups were identified based upon the results of prior treatment--those with and without prophylactic lymph node dissection (PLND) at the time of primary therapy. The factors associated with decreased survival rates in patients with PLND were: 1, increasing age; 2, presence of subcutaneous or both subcutaneous and dermal metastases, and 3, treatment at normothermic temperatures or earlier date of treatment. No significant factors were found in the group without PLND; however, the survival time was similar to that for patients with Stage IIIAB and one positive node (45 per cent at five years). Knowledge of these factors is important in assessing the prognosis and establishing randomization criteria for prospective studies evaluating various forms of therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Lymphatic Metastasis; Male; Melanoma; Melphalan; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Soft Tissue Neoplasms

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

From March 1979 through December 1983, 15 patients with soft-tissue sarcomas of the extremities were treated by a local excision and an adjuvant regional hyperthermic cytostatic perfusion. Reversible edema in two patients was the only post-operative complication. 14 patients were disease-free after a median follow-up period of 24.2 months. One female patient developed a local recurrence 10 months following surgery. Based on our results and long-term studies of several authors, the adjuvant regional perfusion appears capable of successfully treating patients with soft-tissue sarcomas of the extremities.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arm; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dactinomycin; Female; Hot Temperature; Humans; Leg; Male; Melphalan; Middle Aged; 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

In 171 cases of isolated perfusion of the extremities for treatment of melanomas and soft tissue sarcomas, standardized operation techniques were perfected. The arterial double cannulation makes an iliac cannulation feasible also in cases of second and third perfusion. Cytostatics are dosed per liter of perfused extremity. Cis-Platinum and dacarbacine were recently introduced in isolation perfusion treatment. So-called preheating of the extremity before adding the drugs allows administration of cytostatics besides tumortoxic hyperthermia.

Topics: Arm; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Dacarbazine; Drug Therapy, Combination; Extracorporeal Circulation; Humans; Hyperthermia, Induced; Leg; Mechlorethamine; Melanoma; Melphalan; Postoperative Care; Soft Tissue Neoplasms

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

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: 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