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)

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/m 2 every 28 days) plus IFN-α2a/b (3 MIU/m 2 , twice on day 1, once daily from days 2 to 5; 5 MIU/m 2 3 times a week from week 2 to 4) with or without IL-2 (4.5 MIU/m 2 for 3 hours i.v. on day 3; 9.0 MIU/m 2 i.v. day 3/4; 4.5 MIU/m 2 s.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 http://www.bjcancer.com

Systemic Therapy for Unresectable Metastatic Melanoma: Impact of Biochemotherapy on Long-Term Survival

“…The contribution of biotherapy including IL-2 to the efficacy of biochemotherapy has been evaluated in several Phase III trials. These trials varied in sample size, choice of chemotherapy regimen, dose schedule of IL-2, and choice of control arm (Khayat et al, 1993;Johnston et al, 1998;Rosenberg et al, 1999;Hauschild et al, 2001;Atzpodien et al, 2002;Eton et al, 2002;Atkins et al, 2003;Keilholz et al, 2005).…”

“…In three prospectively randomized trials, patients received BCDT (dacarbazine, cisplatin, carmustine, tamoxifen [BCDT]) regimen with or without IL-2, the response rates and survival duration of the patients treated with either regimen were similar (Johnston et al, 1998;Hauschild et al, 2001;Keilholz et al, 2005). Keilholz et al (2005) reported on a Phase III trial involving 362 patients with metastatic melanoma who were randomized to receive the dacarbazine, cisplatin, and IFNα combination alone or with IL-2 (Atzpodien et al, 2002).…”

“…We observed that biochemotherapy (combination of IL-2, interferon, and CVD chemotherapy regimen) is associated with better response rates and survival duration than other multi-drug regimens (Richards et al, 1992;Khayat et al, 1993;Atkins et al, 1994;Legha et al, 1996Legha et al, , 1998Thompson et al, 1997;Johnston et al, 1998;O'Day et al, 1999;Flaherty et al, 2001;Hauschild et al, 2001;Atzpodien et al, 2002;Keilholz et al, 202 BEDIKIAN ET AL. 2005). However, the prospectively-randomized Phase III trials failed to firmly establish the superiority of IL-2-based regimens over chemotherapy Hauschild et al, 2001;Atzpodien et al, 2002;Eton et al, 2002;Atkins et al, 2003).…”

“…However, the prospectively-randomized Phase III trials failed to firmly establish the superiority of IL-2-based regimens over chemotherapy Hauschild et al, 2001;Atzpodien et al, 2002;Eton et al, 2002;Atkins et al, 2003). In this retrospective study, we reviewed our 15-year experience with biochemotherapy and other regimens we used to treat patients with metastatic melanoma, and compared the outcomes.…”

Biochemotherapy for the Treatment of Metastatic Malignant Melanoma: A Clinical Practice Guideline

“…Of the nine eligible trials, six compared various regimens of chemotherapy with biochemotherapy 4-9 , two compared chemotherapy plus IFN with biochemotherapy 10,11 , and one trial compared biochemotherapy with a combination of IFN and IL-2 12 . Dose and method of administration varied from trial to trial.…”