Abstract
In patients with advanced or recurrent melanoma confined to a limb, hyperthermic isolated limb perfusion (ILP) with melphalan produces complete remission in 35–40% of cases and partial remission in a further 35–40%. Mild or moderate limb toxicity is usual, but severe toxic reactions in the limb sometimes occur. After preliminary reports suggested that cisplatin administered by ILP was even more effective than melphalan yet less toxic, a study was undertaken to further assess the value of hyperthermic ILP with cisplatin in the management of limb melanoma. Ten patients were treated. The procedure failed to eliminate melanoma in the limb in 5 of the 6 who received therapeutic ILPs for recurrent disease, and recurrence developed in 2 of the 4 patients who received prophylactic ILPs. Toxicity in the perfused limbs was unacceptably high, with 2 of the 10 patients having severe reactions, one necessitating amputation. We conclude from the results of this study and from a review of literature that neither cisplatin nor any other drug or drug combination so far used for ILP in melanoma patients achieves results which are clearly superior to those achieved with melphalan. Studies are currently in progress investigating double perfusion protocols, new strategies with regional hyperthermia, and the administration by ILP of biological response modifiers such as tumor necrosis factor and interferon. However, for the present, hyperthermic ILP with melphalan remains the treatment most likely to be successful in eliminating or controlling advanced or recurrent melanoma in a limb.
Résumé
Chez les patients atteints de mélanome évolué ou récidivant localisé aux membres, la perfusion sur membre isolé hyperthermique de Melphalan entraîne une rémission complète dans 35 à 40% des cas et une rémission partielle dans 35 à 40% des autres cas. Des études préliminaires ont suggéré que le cisplatin administré sur membre hyperthermique isolé était non seulement plus efficace mais aussi moins toxique que le melphalan. Une étude a donc été entreprise pour évaluer d'avantage l'efficacité des perfusions, sur membre isolé hyperthermique, de cisplatin dans le traitement des mélanomes des membres. Dix patients ont été traités. Le procédé n'a pas réussi à éradiquer le mélanome des membres chez 5 des 6 patients qui étaient traités pour une récidive de la maladie et une rechute est survenue ches 2 des 4 patients traités de façon préventive. La toxicité au niveau des membres perfusés était élevée de façon inacceptable. Deux des 10 patients ont eu des réactions sévères, un a nécessité une amputation. Il faut déduire des résultats de cette étude et à partir des données de la littérature que jusque là par perfusion sur membres isolés hyperthermiques, ni le cisplatin, ni aucune autre drogue utilisée seule ou en combinaison, n'ont démontré une efficacité clairement supérieure à celle du melphalan. Des études sont en cours, testant des protocoles de double perfusion, des stratégies nouvelles utilisant l'hyperthermie locorégionale et la perfusion sur membre isolé de modificateur de la résponse biologique comme le facteur de nécrose tumorale et l'interféron. Toutefois, à l'heure actuelle, la perfusion sur membre hyperthermique isolé de melphalan reste le traitement qui semble le plus efficace pour l'éradication ou le contrôle d'un mélanome évolué ou récidivant des membres.
Resumen
En pacientes con melanoma avanzado o recurrente confinado a una extremidad, la perfusióon hipertérmica aislada del miembro (PHAM) con melfalán resulta en remisión completa en 35–40% de los casos y remisión parcial en 35–40%. Usualmente se registra toxicidad leve o moderada por parte del miembro perfundido, aunque en ocasiones se ven reacciones severas. Con base en reportes preliminares que sugerían que el cisplatino administrado por perfusión aislada era aún más efectivo que el melfalán y menos tóxico, se emprendió un estudio para valorar el uso de la PHAM con cisplatino en el manejo de melanomas de la extremidad. Diez pacientes fueron tratados. El procedimiento falló en cuanto a eliminar el melanoma de la extremidad en 5 de 6 pacientes que recibieron PHAM terapéutica para enfermedad recurrente, y se observó recurrencia en 2 de 4 pacientes que recibieron PHAM profiláctica. La toxicidad en el miembro perfundido fue inaceptablemente alta, con 2 de 10 pacientes con reacciones severas, uno de los cuales requirió amputacion. La conclusión, después de este estudio y con base en una revisión de la literatura, es que ni el cisplatino ni ninguna otra droga o combinación de drogas hasta ahora utilizadas para perfusión aislada logra resultados claramente superiores a los obtenidos con melfalán. Actualmente hay estudios en progreso destinados a investigar protocolos de doble perfusión, nuevas estrategias con hipertermia regional y la administración por vía de perfusión aislada de agentes capaces de modificar la respuesta biológica, tales como el factor necrotizante tumoral y el interferón. Sin embargo, hasta la fecha, la PHAM con melfalán sigue siendo el tratamiento que con mayor probabilidad resulta exitoso en cuanto a eliminar o controlar un melanoma o recurrente de una extremidad.
Similar content being viewed by others
References
Creech, O., Krementz, E.T., Ryan, R.F., Winblad, J.: Chemotherapy of cancer: Regional perfusion utilizing an extracorporeal circuit. Ann. Surg.148:616, 1958
Stehlin, J.S., Clark, R., White, E.: Regional chemotherapy for cancer: Experiences with 116 perfusions. Ann. Surg.151:605, 1960
Krementz, E.T., Ryan, R.F., Carter, R.D., Sutherland, C.M., Reed, R.J.: Hyperthermic regional perfusion for melanoma of the limbs. In Cutaneous Melanoma, C.M. Balch, G.W. Milton, editors, Philadelphia, J.B. Lippincott, 1985, pp. 171–195
Krementz, E.T.: Regional perfusion: Current sophistication, what next? Cancer57:416, 1986
Ghussen, F., Kruger, I., Groth, W., Stutzer, H.: The role of regional hyperthermic cytostatic perfusion in the treatment of extremity melanoma. Cancer61:654, 1988
Kroon, B.B.: Regional isolation perfusion in melanoma of the limbs; accomplishments, unsolved problems, future. Eur. J. Surg. Oncol.14:101, 1988
Lejeune, F.J., Lienard, D., El Douaihy, M., Seyedi, J.V., Ewalenko, P.: Results of 206 isolated limb perfusions for malignant melanoma. Eur. J. Surg. Oncol.15:510, 1989
Santinami, M., Belli, F., Cascinelli, N., Rovini, O., Vaglini, M.: Seven years experience with hyperthermic perfusions in extracorporeal circulation for melanoma of the extremities. J. Surg. Oncol.42:201, 1989
Edwards, M.J., Soong, S.J., Boddie, A.W., Balch, C.M., McBride, C.M.: Isolated limb perfusion for localized melanoma of the extremity: A matched comparison of wide local excision with isolated limb perfusion and wide local excision alone. Arch. Surg.125:317, 1990
Van Geel, A.N., Van Wijk, J., Wieberdink, J.: Functional morbidity after regional isolated perfusion of the limb for melanoma. Cancer63:1092, 1989
Aigner, K., Hild, P., Henneking, K., Paul, E., Hundeiker, M.: Regional perfusion with cisplatinum and dacarbazine. Recent Results Cancer Res.86:239, 1983
Klein, E.S., Ben-Ari, G.Y.: Isolation perfusion with cisplatin for malignant melanoma of the limbs. Cancer59:1068, 1987
Roseman, J.M.: Effective management of extremity cancers using cisplatin and etoposide in isolated limb perfusions. J. Surg. Oncol.35:170, 1987
Pommier, R.F., Moseley, H.S., Cohen, J., Huang, C.S., Townsend, R., Fletcher, W.S.: Pharmacokinetics, toxicity, and short-term results of cisplatin hyperthermic isolated limb perfusion for soft-tissue sarcoma and melanoma of the extremities. Am. J. Surg.155:667, 1988
Wieberdink, J., Benckhuysen, C., Braat, R.P., van Slooten, E.A., Olthuis, G.A.: Dosimetry in isolation perfusion of the limbs by assessment of perfused tissue volume and grading of toxic tissue reactions. Eur. J. Cancer Clin. Oncol.18:905, 1982
Thompson, J.F.: Local and regional therapy for metastatic melanoma. Cancer Forum14:16, 1990
Lejeune, F., Krementz, E., Vaglini, M. (study coordinators): Protocol—EORTC Malignant Melanoma Cooperative Group, North American Perfusion Group and WHO Collaborating Centres for evaluation of methods of diagnosis and treatment of melanoma: A randomized trial on prophylactic isolation perfusion for Stage I high risk (>1.5 mm thickness) malignant melanoma of the limbs. Commenced March 1984 (unpublished)
Shiu, M.H., Knapper, W.H., Fortner, J.G., Yeh, S., Horowitz, G., Schnog, J., Guerra, J., Gould-Rossbach, P., Ray, C.: Regional isolated limb perfusion of melanoma in-transit metastases using mechlorethamine (nitrogen mustard). J. Clin. Oncol.4:1819, 1986
Vaglini, M., Belli, F., Marolda, R., Prada, A., Santinami, M., Cascinelli, N.: Hyperthermic antiblastic perfusion with DTIC in stage IIIA – III AB melanoma of the extremities. Eur. J. Surg. Oncol.13:127, 1987
Pfefferkorn, R.O., Didolkar, M.S.: Regional perfusion for melanoma of the extremities. J. Extra Corporeal Technol.14:475, 1982
Ariyan, S., Mitchell, M.S., Kirkwood, J.M.: Regional isolated perfusion of high risk melanoma of the extremities with imidazole carboxamide. Surg. Gynecol. Obstet.158:238, 1984
Didolkar, M.S., Fitzpatrick, J.L., Jackson, A.J., Johnston, G.S.: Toxicity and complications of vascular isolation and hyperthermic perfusion with imidazole carboxamide (DTIC) in melanoma. Cancer57:1961, 1986
Hajarizadeh, H., Mueller, C.R., Woltering, E.A.: Phase I–II trial of hyperthermic isolated limb perfusion with cisplatin in the treatment of high risk malignant melanoma of the extremities. Melanoma Res.1:55, 1991
Coit, D.G., Bajorin, D.F., Menendez-Botet, C.: A phase I trial of hyperthermic isolation limb perfusion (HILP) using cisplatin (CDDP) for metastatic melanoma. Proceedings of ASCO10:294, 1991
Fletcher, W.S.: Cisplatin in isolated limb perfusion (letter). Am. J. Surg.157:366, 1989
Neades, G.T., Shelley, M.D., Fish, R.G., Mansel, R.E.: Evaluation of isolated perfusion with cisplatin for malignant melanoma of the limbs. Reg. Cancer Treat.4:34, 1991
Cox, K.R.: Survival after regional perfusion for limb melanoma. Aust. N. Z. J. Surg.45:32, 1975
Martijn, H., Oldhoff, J., Schraffordt Koops, H.: Hyperthermic regional perfusion with melphalan and a combination of melphalan and actinomycin D in the treatment of locally metastasized malignant melanomas of the extremities. J. Surg. Oncol.20:9, 1982
Binder, J., Henneking, K., Weyers, W.: Regional perfusion in the treatment of the extremity melanoma. Reg. Cancer Treat.4:6, 1991
McBride, C.M., McMurtrey, M.J., Copeland, E.M., Hickey, R.C.: Regional chemotherapy by isolation-perfusion. In International Advances in Surgical Oncology, Vol. 1, G.P. Murphy, editor, New York, Alan R. Liss, 1978, pp. 1–9
Golomb, F.M.: Perfusion of melanoma: 133 isolated perfusions in 114 patients. Panminerva Med.18:8, 1976
Busse, O., Aigner, K., Wilimzig, H.: Peripheral nerve damage following isolated extremity perfusion with cis-platinum. Recent Results Cancer Res.86:264, 1983
Aigner, K.R., Jungbluth, A., Link, K.H., Watther, H., Muller, H., Schwemmie, K., Ringenberg, T., Borger, G., Ruppel, R., Illig, L.: Die isolierte hypertherme Extremitaten perfusion mit Vindesin, Dacarbazin und Cis-Platin bei der Behandlung maligner Melanome. Onkologie7:348, 1984
Lienard, D., Lejeune, F., Ewalenko, P.: High dose of rTNFδ combined with rIFN-γ and melphalan administered in isolation perfusion produce 88% of complete remissions in melanoma and sarcoma. Reg. Cancer Treat.4:27, 1991
Semmler, W., Gademann, G., Schlag, P., Bachert-Baumann, P., Zabel, H.J., Lorenz, W.J., Von Kaick, G.: Impact of hyperthermic regional perfusion therapy on cell metabolism of malignant melanoma monitored by 3IP MR spectroscopy. Magn. Reson. Imaging6:335, 1988
Wile, A.G., Guilmette, E., Friedberg, H., Mason, G.R.: A model of isolated limb perfusion using cis-platinum. J. Surg. Oncol.21:37, 1982
Hild, P., Aigner, K., Henneking, K.: Levels of cis-platinum in hyperthermic isolated perfusion. Anticancer Res.2:255, 1982
Wile, A.G., Nahabedian, M.Y., Pumley, D.A., Guilmette, J.E., Mason, G.R.: Experimental hyperthermic isolation perfusion using cis-diamminedichloroplatinum (II). Cancer Res.43:3108, 1983
Vaglini, M., Belli, F., Santinami, M.: Isolation perfusion of the lower limb with platinum. World J. Surg.12:307, 1988
Bonadonna, G., Bernardo, G., Gianni, L., della Cuna, G.R.: Pharmacology, clinical toxicity, dosage and general indications of growth inhibiting compounds. In Handbook of Medical Oncology, G. Bonadonna, G.R. della Cunna, editors, Milan, Masson, 1988, pp. 335–377
Averbuch, S.D.: Nonclassic alkylating agents. In Cancer Chemotherapy: Principles and Practice, B.A. Chabner, J.M. Collins, editors, Philadelphia, J.B. Lippincott, 1990, pp. 314–340
Cavaliere, R., Ciocatto, E.C., Giovanella, B.C., Heidelberger, C., Johnson, R., Margottini, M., Mondovi, B., Rossi-Fanelli, A.: Selective heat sensitivity of cancer cells: Biochemical and clinical studies. Cancer20:1351, 1967
Giovanella, B.C., Stehlin, J.S., Morgan, A.C.: Selective lethal effect of supranormal temperatures on human neoplastic cells. Cancer Res.36:3944, 1976
Stehlin, J.S., Greeff, P.J., de Ipolyi, P.D.: Heat as an adjuvant in the treatment of advanced melanoma: An immune stimulant? Houston Med. J.4:61, 1988
Klaase, J.M., Kroon, B.B.R., van Geel, A.N., Franklin, H.R., Benckjuijsen, C., van Dongen, J.A.: Results of a double perfusion schedule with melphalan for patients with measurable melanoma of the extremities. Reg. Cancer Treat.4:21, 1991
Kroon, B.B.R., Klaase, J.M., van der Zee, J., van Geel, A.N., van der Merwe, S.A., van Dongen, J.A.: Application of hyperthermia in regional isolation perfusion for melanoma. Reg. Cancer Treat.4:24, 1991
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Thompson, J.F., Gianoutsos, M.P. Isolated limb perfusion for melanoma: Effectiveness and toxicity of cisplatin compared with that of melphalan and other drugs. World J. Surg. 16, 227–233 (1992). https://doi.org/10.1007/BF02071525
Issue Date:
DOI: https://doi.org/10.1007/BF02071525