Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma.

The purpose of this study was to evaluate in a randomized phase II trial the efficacy and toxicity of combination biochemotherapy compared with chemotherapy alone in patients with metastatic melanoma. Sixty-five patients with metastatic melanoma (ECOG performance status 0 or 1) were randomized to receive intravenous BCNU 100 mg m(-2) (day 1, alternate courses), cisplatin 25 mg m(-2) (days 1-3), DTIC 220 mg m(-2) (days 1-3) and oral tamoxifen 40 mg (BCDT regimen) with (n = 35) or without (n = 30) subcutaneous interleukin 2 (IL-2) 18 x 10(6) iu t.d.s. (day - 2), 9 x 10(6) iu b.d. (day - 1 and 0) and interferon 2 alpha (IFN-alpha) 9 MU (days 1-3). Evidence for immune activation was determined by flow cytometric analysis of peripheral blood lymphocytes. Treatment was repeated every 4 weeks up to six courses depending on response. The overall response rate of BCDT with IL-2/IFN-alpha was 23% [95% confidence interval (CI) 10-40%] with one complete response (CR) and seven partial responses (PR), and for BCDT alone 27% (95% CI 12-46%) with eight PRs; the median durations of response were 2.8 months and 2.5 months respectively. Sites of response were similar in both groups. There was no difference between the two groups in progression-free survival or overall survival (median survival 5 months for BCDT with IL-2/IFNalpha and 5.5 months for BCDT alone). Although 3 days of subcutaneous IL-2 resulted in significant lymphopenia, evidence of immune activation was indicated by a significant rise in the percentage of CD56- (NK cells) and CD3/HLA-DR-positive (activated T cells) subsets, without any change in the percentage of CD4 or CD4 T-cell subsets. Toxicity assessment revealed a significantly higher incidence of severe thrombocytopenia in patients treated with combination chemotherapy than with chemotherapy alone (37% vs 13%, P = 0.03) and a higher incidence of grade 3/4 flu-like symptoms (20% vs 10%) and fatigue (26% vs 13%). The addition of subcutaneous IL-2 and IFNalpha to BCDT chemotherapy in a randomized phase II trial resulted in immune activation but did not improve response rates in patients with metastatic melanoma, and indeed may increase some treatment-related toxicity.

Section: Methodsmentioning

confidence: 99%

Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-α) and interleukin (IL-2) in patients with metastatic melanoma

Johnston

Constenla²,

Moore³

et al. 1998

“…An NCI Surgery Branch Study, administering high-dose bolus IL-2 (> 30 MIU m-2 day-') and IFN-a found the highest response rates (Rosenberg et al, 1989b). On the other hand, the Extramural IL-2 Working Group, using identical dose, schedule and patient selection criteria, did not observe any evidence of enhanced response with the IL-2/IFN-a combination (Sparano et al, 1993). In summary, a dose-response effect for IL-2 in the treatment of metastatic melanoma is not clear.…”

mentioning

confidence: 88%

“…However, low response rates of 10% or less were observed by others (Olham et al, 1992;Dillman et al, 1993;Sparano et al, 1993). The median response duration in these trials varied between 2 and 11 months, and the median survival was approximately 10 months (Lee et al, 1989;Rosenberg et al, 1989b;Oldham et al, 1992;Dillman et al, 1993;Sparano et al, 1993).…”

mentioning

confidence: 95%

“…Immunotherapy with recombinant interleukin 2 (IL-2) has been reported to yield a 5-27% response rate in metastatic melanoma (Rosenberg et al, 1989a(Rosenberg et al, , 1993Parkinson et al, 1990;Whitehead et al, 1991;Sparano et al, 1993). Interferon x (IFN-() alone in this group of patients has shown response rates of 12-22% (Robinson et al, 1986;Kirkwood, 1991).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Final report of a phase II study of interleukin 2 and interferon α in patients with metastatic melanoma

Kruit

Goey²,

Calabresi³

et al. 1995

Summary Fifty-seven patients with metastatic melanoma were treated with interleukin 2 (IL-2) 7.8 MIU m-day as a continuous infusion for 4 days combined with interferon a (IFN-a) 6 MIU m day-' subcutaneously on days I and 4. The cycle was repeated every 2 weeks for a maximum number of 13 cycles. Of the 51 evaluable patients, one (2%) achieved a complete and seven (14%) a partial response (total response rate 16%: C1 7-29%). Median time to progression and median survival were 2.5 and 11.3 months respectively. This regimen of IL-2 and IFN-a appeared to be only moderately active.

“…IL-2, with or without lymphokine-activated killer cells, yielded response rates from 10-25% (Rosenberg et al, 1989a;Parkinson et al, 1990;Whitehead et al, 1991). With the combination of IL-2 and IFN-a the reported response rates varied between 0-44% (Rosenberg et al, 1989b;Dillman et al, 1993;Sparano et al, 1993;Keilholz et al, 1993;Kruit et al, 1995). A phase I-II study with increasing dose levels of bolus IL-2 and IFN-a produced an objective response in 33% of patients (Rosenberg et al, 1989b).…”

mentioning

confidence: 99%

Dose efficacy study of two schedules of high-dose bolus administration of interleukin 2 and interferon alpha in metastatic melanoma

Kruit¹,

Punt²,

Goey³

et al. 1996

Summary Forty-three patients with metastatic melanoma were treated with a 5 day (18 patients) and a 3 day (25 patients) schedule of high-dose IL-2 11.7 MIU m2 and IFN-a 3 MIU m2 i.v. by bolus administration every 8 h, repeated every 21 days for a total of three courses. The 5 day schedule resulted in a high response rate of 41% (CI 18-67%), but was accompanied by severe cardiotoxicity (41 %) and central nervous system toxicity (28%). The 3 day schedule was associated with manageable toxicity, but yielded a moderate response rate of 20% (CI 7-43%).