Hyperthermic isolated perfusion with melphalan in the treatment of advanced malignant melanoma of the lower limb

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

The use of isolated limb perfusion to manage recurrent malignant melanoma

Hyperthermic isolated limb perfusion (ILP) effectively treats locally recurrent metastatic disease in malignant melanoma of the extremities. The goal of ILP is to decrease the rate of further recurrent disease and eradicate tumor load to achieve wound hygiene and preservation of limb function. This article reviews the development over the last 45 years of ILP in the treatment of malignant melanoma, describes the surgical technique of ILP, and reviews the results of clinical trials with various chemotherapeutic agents. It discusses the recent addition of tumor necrosis factor alpha to the list of drugs currently being explored in hyperthermic ILP, in the ongoing attempt to improve the treatment for recurrent malignant melanoma of the extremities.     

Isolated limb infusion for melanoma: a simple alternative to isolated limb perfusion.

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

Efficacy of hyperthermic isolated limb perfusion for extremity-confined recurrent melanoma

Background: Recurrent melanoma of the extremity has been treated by local excision, systemic chemotherapy, amputation, or a combination of these approaches. Hyperthermic isolated limb perfusion (HILP) provides a method of limb preservation through isolation, allowing the administration of chemotherapy in higher doses than is possible through systemic treatment. Methods: An experimental group of 59 HILP patients with melanoma recurrences of the extremity was studied prospectively. A control group of 248 melanoma patients with similar recurrences was excluded from HILP because their recurrences were in non-extremity locations. The experimental group underwent HILP and excision; the control group had excision only. The experimental procedure consisted of vascular isolation of the affected extremity and a 1-hour perfusion with melphalan. Temperatures were maintained at 40°C in the perfusion circuit. Results: The HILP patients had a lower rate of locoregional recurrence (P=.028) and demonstrated increased survival (P=.026) compared to the control group. In multivariate regression analysis, which included age, ulceration and thickness of the primary, and the treatment variable of perfusion, age (P=.02) and perfusion for the treatment of recurrence (P=.006) were significant predictors of survival. Conclusions: HILP improves prognosis by sterilizing the treated extremity, controlling locoregional disease, and perhaps preventing metastasis, thus having a positive impact on overall survival. Presented at the 50th Annual Cancer Symposium of the Society of Surgical Oncology, Chicago, Illinois, March 20–23, 1997.     

Relation between limb toxicity and treatment outcomes after isolated limb perfusion for recurrent melanoma

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

Hyperthermic perfusion with chemotherapy for melanoma of the extremities

A prospective randomized study was carried out to evaluate the effectiveness of additional regional cytostatic perfusion of the extremities in patients with malignant melanoma. In a control group (n=54), the tumors were widely excised, and regional lymph nodes were dissected. The patients in the perfusion group (n=53) received additional hyperthermic (42°C) perfusion with Melphalan. The disease-free survival time was chosen as the criterion for evaluation. An intermediate analysis revealed a highly significant difference between the 2 groups (21 recurrences in the control group and 4 recurrences in the perfusion group,p< 0.001). Therefore, the study was discontinued prematurely.In an analysis of the data performed after a median observation time of 5 years and 11 months, 26 recurrences were diagnosed in the control group, whereas 6 recurrences were noted in the perfusion group (p< 0.001). The retrospective breakdown into different risk groups according to tumor thickness also demonstrates a significant difference. For patients with a primary tumor of 1.5—3.0-mm in thickness, 2 of 25 in the perfusion group and 10 of 25 in the control group have relapsed. For those with a primary tumor of greater than 3.0-mm in thickness, 4 of 28 in the perfusion group and 16 of 29 in the control group have relapsed. Eleven patients in the control group and 3 patients in the perfusion group have died due to metastatic spread of the melanoma (p<0.01).The results most clearly demonstrate the benefits of additional hyperthermic cytostatic perfusion.

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Resumen Se realizó un estudio prospectivo randomizado para valorar la efectividad de la perfusión citostática regional adicional en pacientes con melanoma maligno de las extremidades. En un grupo control (n=54) los tumores fueron ampliamente resecados junto con disección ganglionar regional. Los pacientes en el grupo de la perfusión (n=53) recibieron perfusión hipertérmica adicional (42°C) con Melphalan. El período de supervivencia libre de enfermedad fue seleccionado como el criterio de evaluación. Un análisis intermedio reveló una diferencia altamente significativa entre los 2 grupos (21 recurrencias en el grupo control y 4 recurrencias en el grupo de perfusión,p< 0.001), por lo cual el estudio fue prematuramente descontinuado.En el análisis de los datos realizado después de un perfodo promedio de observación de 5 años y 11 meses, se diagnosticaron 26 recurrencias en el grupo control, contra 6 en el grupo de perfusión (p<0.001). La separación retrospectiva de los pacientes según el grosor del tumor también demuestra una diferencia significativa. Entre los pacientes con un tumor primario de 1.5–3.0-mm de grosor, 2 de 25 del grupo de perfusión y 10 de 25 del grupo control han hecho relapso. Entre aquellos con tumor primario de más de 3.0 mm, 4 de 28 del grupo de perfusión y 16 de 29 del grupo control han hecho relapso. Once pacientes del group control y 3 del grupo de perfusión han muerto como resultado de extensión metastásica (p<0.01).Los resultados demuestran claros beneficios de la perfusión citostática hipertérmica adicional.

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Résumé Une étude prospective randomisée a été réalisée pour évaluer l'efficacité d'une perfusion cytostatique régionale des patients porteurs de mélanomes malins des extrémités. Dans un groupe témoin (n=54), on a largement excisé la tumeur avec lymphadénectomie. Le groupe testé (perfusé) (n=53) a reçu en plus une perfusion hyperthermique (42°C) avec du Melphalan. Le critère de jugement a été l'intervalle libre sans maladie. Une analyse intermédiaire a montré qu'il y avait une différence hautement significative entre les 2 groupes (21 récidives dans le groupe contrôle pour 4 récidives dans le groupe perfusé,p< 0.001). L'étude a donc été interrompue prématurément.Dans une analyse réalisée après une période d'observation médiane de 5 ans et 11 mois, on a diagnostiqué 26 récidives dans le groupe témoin, et 6 récidives dans le group perfusé (p< 0.001). L'analyse selon le sous groupe de risque et selon l'épaisseur de la tumeur a mis en évidence une différence significative. Chez les patients ayant une tumeur primitive entre 1.5 et 3.0 mm, on a observé une récidive chez 2 de 25 patients dans le groupe perfusion, et chez 10 des 25 dans le groupe témoin. Lorsque l'épaisseur de la tumeur dépassait 3 mm, on a observé une récidive chez 4 des 28 patients dans le groupe perfusion et chez 16 des 29 patients dans le groupe contrôle. Onze patients dans le groupe témoin et 3 patients dans le groupe perfusé sont morts de métastase de leur mélanome (p<0.01). Ces résultats sont nettement en faveur d'une perfusion hyperthermique complémentaire dans le traitement des mélanomes malins des extrémités.

     

The role of isolated limb perfusion for melanoma confined to the extremities

Isolated limb perfusion with Melphalan is the best treatment option to control symptomatic multiple small in-transit metastases. When lesions are bulky, Isolated Limb Perfusion (ILP) with Tumor Necrosis Factor (TNF) + Melphalan is superior as in soft tissue sarcoma. TNF changes the pathophysiology, greatly enhances the uptake of Melphalan and destructs selectively the vasculature of large tumors. To date, ILP is not indicated in an adjuvant setting.     

Safety and efficacy of isolated limb perfusion in elderly melanoma patients

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

Prognostic scoring in patients with melanoma after adjuvant isolated limb perfusion

BACKGROUND: The clinical course in melanoma is variable. The aim of the present study was to assess adjuvant isolated limb perfusion (ILP) efficacy using a surrogate comparison of observed survival versus Cochran-predicted survival. MATERIALS AND METHODS: All patients in a single university hospital with primary, non-ulcerated limb melanoma who had undergone adjuvant ILP over 10 years (1986-1995) were studied. Clinical and pathological details including follow-up and survival were prospectively recorded in a national database. All patients were risk scored, as described by Cochran et al., to yield individual survival probability at the end of 3, 5 and 10 years and this was compared with observed survival at corresponding intervals. RESULTS: There were 85 patients who had adjuvant ILP for primary non-ulcerated limb melanoma. Of these, 14 deaths were observed (O) within the 10-year follow-up period. The Cochran score predicted (E) 20 deaths within 10 years (O/E ratio 0.7). The O/E ratios for deaths in the 0 to 3, 3 to 5, and 5 to 10 year intervals were 8/7.4, 5/6.0, and 1/6.5, respectively; prediction of late deaths tended to be overestimated. When patients were grouped by predicted 10-year mortality (<20%, 20-40%, >40%) the overestimation was found to occur mainly in the highest risk group: O/E ratios were 6/5.9, 6/8.4, and 2/5.6, respectively (P = 0.10, Hosmer-Lemeshow test). CONCLUSION: The observed and expected survival in patients receiving adjuvant ILP at the end of 3 and 5 years are comparable. The Cochran scoring system overestimated deaths during the 5 to 10 year interval. It is not clear whether this observation is a consequence of ILP efficacy or inaccuracy of the Cochran score.     

Long-term results of hyperthermic, isolated limb perfusion for melanoma: a reflection of tumor biology

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

Isolated limb perfusion for unresectable melanoma of the extremities

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

Optimization of isolated hyperthermic limb perfusion

During isolated limb perfusion, we studied the impact of limb temperature on the concentration of cytostatic drugs in the tissue to identify a possible selective absorption of cytostatic agents by the various tissues. Ten consecutive patients with malignant melanoma were randomly divided into two different groups and perfused with 1 mg cisplatin per kg body weight. In one group the cytostatic agents were injected under hyperthermic conditions (39.5°C) and in the other group under normothermic conditions (37°C). The platinum concentration in the melanoma was twice as high in the hyperthermic group as in the group under normothermic conditions. In the tumor-free tissue the platinum concentration decreased with temperature while it remained constant in the musculature. This selective concentration of cisplatin in the tumor under hyperthermic conditions is accompanied by fewer side effects. Follow-up will show whether the oncological results will be improved in the hyperthermic conditions as one might expect.

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Resumen Hemos estudiado el impacto de la temperatura del miembro en el momento de la inyección de drogas citostásicas midiendo la concentración tisular de platino, con el propósito de identificar una posible absorción selectiva de los agentes cistotásicos por los diferentes tejidos durante la perfusión aislada de una extremidad. Se asignaron, en forma randomizada, 10 pacientes consecutivos con melanoma maligno a dos grupos diferentes que fureon perfundidos con cisplatino 1 mg por 1 kg de peso corporal. En uno de los grupos los agentes citotóxicos fureon inyectados bajo condiciones de hipertermia (39.5°C). La concentración de platino en el menaloma apareció dos veces más alta en el grupo de perfusión hipertérmica que en el grupo normotérmico (37°C). En los tejidos libres de tumor la concentración de platino disminuyó con la temperatura, en tanto que permaneció constante en la masa muscular. Tal concentración selectiva del cisplatino en el tumor bajo condiciones hipertérmicas está acompanada de menos efectos secundarios. El seguimiento habrá de demostrar si los resultados oncológicos son mejores de lo que se pueda esperar.

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Résumé Nous avons mésuré l'impacte de la température ambiante sur la concentration tissulaire en platinum au moment de son injection afin d'identifier une absorption sélective des drogues cytostatiques par les tissues pendant la perfusion isolée des extrémités. Dix patients consécutifs ayant un mélanome malin ont été randomisés pour recevoir une perfusion de cisplatine (1 mg par kg de poids corporel) soit à 39.5°C, soit à 37.0°C. Les concentrations de platinium étaient deux fois plus importantes dans le mélanome du groupe hyperthermique que dans celui du groupe normothermique. Dans les tissus non-tumoraux, les concentrations étaient proportionnellement plus basses, alors que dans les muscles, les concentrations étaient constantes. Cette sélectivité de concentration de cisplatine s'accompagne de moins d'effets secondaires. Il faut attendre l'évolution à plus long terme pour juger des résultats au plan oncologique.

     

Isolated limb perfusion for recurrent melanoma of the extremity.

Recent reports in the literature suggest that hyperthermic isolated limb perfusion (HILP) may be effective in preventing local recurrence in patients with deeply invasive melanoma or in patients with recurrent disease confined to the extremity. It has been used in the past as an adjuvant treatment after resection of the primary melanoma or recurrence, or as a therapeutic measure if all the disease on the extremity cannot be resected. A prospective, nonrandomized trial of 16 patients with melanoma with recurrent disease confined to the extremity underwent HILP. The protocol involved the wide local excision of all recurrent disease when possible, elective or therapeutic node dissection when indicated, and HILP using cisplatin. In 11 patients in whom all recurrent disease could be resected and the HILP was considered prophylactic, only 1 patient's disease has recurred in the perfusion circuit. Before the perfusion, the 11 patients had a total of 19 local or intransit recurrences. Of the 5 patients in whom all recurrent disease could not be resected, disease persisted in 4 patients. When compared with a concurrent control population of patients with extremity melanoma who had a local recurrence and were not perfused, the patients with melanoma who underwent HILP had a significant prolongation of disease-free survival (p less than 0.05), but a similar actuarial survival. In this study, we demonstrate that HILP can prevent local regional recurrences in patients with metastatic melanoma who are at high risk for further recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional perfusion for recurrent malignant melanoma of the extremities

Seventeen patients with a local recurrence or intransit metastases of a malignant melanoma of the arm or leg were treated by normothermic regional perfusion with phenylalanine mustard. Seven of these patients had regional lymph node metastases as well. The follow-up period was either five to eight years or until the time of death. Two years after treatment, eleven of the seventeen patients were still alive. After a five year follow-up, six patients were still alive without demonstrable recurrence or metastases. Only three patients had a recurrence in an extremity; two of these three patients simultaneously showed general metastization.     

Prognostic factors related to survival and groin recurrence following therapeutic lymph node dissection for lower limb malignant melanoma

A retrospective analysis was carried out of 133 patients undergoing therapeutic lymph node dissection for malignant melanoma of the lower limb. A radical ilio-obturator dissection (RID) was performed in 106 patients and a superficial femoral dissection (SFD) in the remaining 27. On univariate analysis five factors were found to be significant indicators of prognosis. These were: Clark level of the primary (P = 0.02); primary melanoma thickness (P = 0.04); total number of positive nodes (P less than 0.001); number of positive femoral nodes (P less than 0.001); and number of positive ilio-obturator nodes (P less than 0.001). On multiple regression analysis only the number of positive nodes in each compartment remained a significant independent factor (P less than 0.001). The morbidity associated with RID was not significantly greater than after SFD. RID was, however, associated with a reduction in subsequent groin recurrence. Radical nodal clearance is the operation of choice. This technique provides maximum prognostic information, reduces the likelihood of local untreatable disease and possibly improves overall survival rates--especially when only one iliac node is involved.