Abstract
In several phase II-trials encouraging tumour responses rates in advanced metastatic melanoma (stage IV; AJCC-classification) have been reported for the application of biochemotherapy containing interleukin 2. This study was designed to compare the efficacy of therapy with dacarbazine (DTIC) and interferon α (IFN-α) only to that of therapy with DTIC and IFN-α with the addition of interleukin 2 (IL-2) in terms of the overall survival time and rate of objective remissions and to provide an elaborated toxicity profile for both types of therapy. 290 patients were randomized to receive either DTIC (850 mg/m2every 28 days) plus IFN-α2a/b (3 MIU/m2, twice on day 1, once daily from days 2 to 5; 5 MIU/m23 times a week from week 2 to 4) with or without IL-2 (4.5 MIU/m2for 3 hours i.v. on day 3; 9.0 MIU/m2i.v. day 3/4; 4.5 MIU/m2s.c. days 4 to 7). The treatment plan required at least 2 treatment cycles (8 weeks of therapy) for every patient. Of 290 randomized patients 281 were eligible for an intention-to-treat analysis. There was no difference in terms of survival time from treatment onset between the two arms (median 11.0 months each). In 273 patients treated according to protocol tumour response was assessable. The response rates did not differ between both arms (P = 0.87) with 18.0% objective responses (9.7% PR; 8.3% CR) for DTIC plus IFN-α as compared to 16.1% (8.8% PR; 7.3% CR) for DTIC, IFN-α and IL-2. Treatment cessation due to adverse reactions was significantly more common in patients receiving IL-2 (13.9%) than in patients receiving DTIC/IFN-α only (5.6%). In conclusion, there was neither a difference in survival time nor in tumour response rates when IL-2, applied according to the combined intravenous and subcutaneous schedule used for this study, was added to DTIC and IFN-α. However, toxicity was increased in melanoma patients treated with IL-2. Further phase III trials with continuous infusion and higher dosages must be performed before any final conclusions can be drawn on the potential usefulness of IL-2 in biochemotherapy of advanced melanoma. © 2001 Cancer Research Campaign
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References
Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L and Rosenberg SA (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17: 2105–2111
Atzpodien J, Korfer A, Evers P, Franks CR, Knuver-Hopf J, Lopez-Hanninen E, fischer M, Mohr H, Dallmann I and Hadam M (1990a) Low-dose subcutaneous recombinant interleukin-2 in advanced human malignancy: a phase II outpatient study. Mol Biother 2: 18–26
Atzpodien J, Korfer A, Franks CR, Poliwoda H and Kirchner H (1990b) Home therapy with recombinant interleukin-2 and interferon-alpha 2b in advanced human malignancies. Lancet 335: 1509–1512
Buzaid AC, Ross MI, Balch CM, Soong S, McCarthy WH, Tinoco L, Mansfield P, Lee JE, Bedikian A, Eton O, Plager C, Papadpoulos N, Legha SS and Benjamin RS (1997) Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system. J Clin Oncol 15: 1039–1051
Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro A, Panageas K, Begg C, Agarwala S, Schluchter L, Ernsthoff M, Houghton A and Kirkwood J (1999) Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17: 2745–2751
Dréno B, Cupissol D and Joly P (1995) Ambulatory treatment of metastatic melanoma associating subcutaneous dacarbazine, interferon α and interleukin-2. JEADV 4: 248–253
Dummer R, Gore ME, Hancock BW, Guillou PJ, Grobben HC, Becker JC, Oskam R, Dieleman JP and Burg G (1995) A mulicenter phase II clinical trial using dacarbazine and continuous infusion interleukin-2 for metastatic melanoma. Clinical data and immunomonitoring. Cancer 75: 1038–1044
Falkson CI, Falkson G and Falkson HC (1991) Improved results with the addition of interferon alfa-2b to dacarbazine in the treatment of patients with metastatic malignant melanoma. J Clin Oncol 9: 1403–1408
Falkson CI, Ibrahim J, Kirkwood JM, Coates AS, Atkins MB and Blum RH (1998) Phase III trial of dacarbazine versus dacarbazine with tamoxifen versus dacarbazine with interfron alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 16: 1743–1751
Grob JJ, Dreno B, de la Salmoniere P, Delauny M, Cupissol D, Guillot B, Souteyrand P, Sassolas B, Cesarini JP, Lionnet S, Lok C, Chastang C and Bonerandi JJ (1998) Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet 351: 1905–1910
Hill GJ 2d, Krementz ET and Hill HZ (1984) Dimethyl triazeno imidazole carboxamide and combination therapy for melanoma. IV. Late results after complete response to chemotherapy (Central Oncology Group protocols 7130, 7131, and 7131A). Cancer 53: 1299–1305
Hoffmann R, Müller I, Neuber K, Lassmann S, Buer J, Probst M, Oevermann K, Franzke A, Kirchner H, Ganser A and Atzpodien J (1998) Risk and outcome in metastatic malignant melanoma patients receiving DTIC, cisplatin, BCNU and tamoxifen followed by immunotherapy with interleukin 2 and interferon alpha2a. Br J Cancer 78: 1076–1080
Kashani-Sabet M, Sagebiel RW, Collins HE, Glassberg AB, Allen RE, Leong SP and Small EJ (1999) Outpatient combination chemoimmunotherapy for patients with metastatic melanoma. Results of a phase I/II trial. Cancer 86: 2160–2165
Keilholz U (1995) Chemoimmunotherapy of melanoma. Is it time for phase III trials?. Cancer 75: 905–907
Keilholz U, Goey SH, Punt CJ, Proebtsle TM, Salzmann R, Scheibenbogen C, Schadendorf D, Lienard D, Enk A, Dummer R, Hantich B, Geueke AM and Eggermont AM (1997) Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. J Clin Oncol 15: 2579–2588
Keilholz U, Conradt C, Legha SS, Khayat D, Scheibenbogen C, Thatcher N, Goey SH, Gore M, Dorval T, Hancock B, Punt JC, Dummer R, Avril MF, Brocker EB, Benhammouda A, Eggermont AM and Pritsch M (1998) Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients. J Clin Oncol 16: 2961–2969
Kirkwood JM, Strawdermann MH, Ernstoff MS, Smith TJ, Borden EC and Blum RH (1996) Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14: 7–17
Legha SS, Ring S, Eton O, Bedikian A, Buzaid A, Plager C and Papadopoulos N (1998) Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol 16: 1752–1759
Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A, Weiss J, Fraass U, Statkevich P, Muller M and Thatcher N (2000) Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18: 158–166
Pehamberger H, Soyer HP, Steiner A, Kofler R, Binder M, Mischer P, Pachinger W, Aubock J, Fritsch P, Kerl H and Wolff K (1998) Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. J Clin Oncol 16: 1425–1429
Proebstle TM, Fuchs T, Scheibenbogen C, Sterry W and Keilholz U (1998) Long-term outcome of treatment with dacarbazine, cisplatin, interferon-alpha and intravenous dose interleukin-2 in poor risk melanoma patients. Melanoma Res 8: 557–563
Punt CJ (1998) The use of interferon-alpha in the treatment of cutaneous melanoma: a review. Melanoma Res 8: 95–104
Richards JM, Gale D, Mehta N and Lestingi T (1999) Combination of chemotherapy with interleukin-2 and interferon alfa for the treatment of metastatic melanoma. J Clin Oncol 17: 651–657
Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola F, Topalian S, Seipp C, einhorn J and White D Steinberg (1999) Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 17: 968–975
Schomburg A, Menzel T, Korfer A, Heer G, Dallmann I, Kirchner H, Poliwoda H and Atzpodien J (1992) In vivo and ex vivo antitumor activity in patients receiving low-dose subcutaneous recombinant interleukin-2. Nat Immun 11: 133–143
Sertoli MR, Queirolo P, Bajetta E, DelVecchio M, Comella G, Barduagni L, Bernengo MG, Vecchio S, Criscuolo D, Bufalino R, Morabito A and Cascinelli N (1999) Multi-institutional phase II randomized trial of integrated therapy with cisplatin, dacarbazine, vindesine, subcutaneous interleukin-2, interferon alpha2a and tamoxifen in metastatic melanoma. BREMIM (Biological Response Modifiers in Melanoma). Melanoma Res 9: 503–504
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Hauschild, A., Garbe, C., Stolz, W. et al. Dacarbazine and interferon α with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG). Br J Cancer 84, 1036–1042 (2001). https://doi.org/10.1054/bjoc.2001.1731
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DOI: https://doi.org/10.1054/bjoc.2001.1731
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