Survival in renal cell carcinoma-a randomized evaluation of tamoxifen vs interleukin 2, α-interferon (leucocyte) and tamoxifen

Abstract

Survival in renal cell carcinoma -a randomized evaluation of tamoxifen vs interleukin 2, a-interferon (leucocyte) and tamoxifen R Henriksson', S Nilsson2, S Colleen3, P WersaII4, M HeIsing5, R Zimmerman6 and K Engman7 'Department of Oncology, UmeA University Hospital; 2Department of Oncology, Uppsala University Hospital; 4Karolinska Institute, 6Sbdersjukhuset, Stockholm, 5Orebro Hospital; 3Department of Urology, Lund University Hospital, Sweden; and 7BioNative AB, Umec, Sweden Summary Metastatic renal cell carcinoma (RCC) has a poor prognosis. Conventional treatment strategies, including chemotherapy and hormonal therapy, have limited value. Although encouraging results have been achieved in terms of objective response using immunological manipulations, no conclusive studies yet exist with a controlled comparative evaluation of survival. Therefore, the present study was undertaken, which compared one of the present (and presumed best) treatments, interleukin 2/interferon-a (IL-2/IFN-a) and tamoxifen, with a control arm of tamoxifen only. Tamoxifen has been shown to potentiate in vivo anti-tumour activity of IL-2, and because of its non-toxic behaviour it was included in both groups. The study was open, randomized and included seven institutions in Sweden. The patients were stratified according to the different centres involved. An interim analysis was planned when a minimum of 100 patients were evaluable. The 128 patients finally included had a histologically documented metastatic RCC, with a life expectancy of more than 3 months, a performance status WHO 0-2 and no prior chemo-or immunotherapy. Informed consent was obtained from each patient. The patients randomized to the control arm (n = 63) received only tamoxifen 40 mg p.o. daily for at least 1 year or until progression. The patients (n = 65) randomized to biotherapy received subcutaneous recombinant IL-2, leucocyte IFN-a in a treatment cycle of 42 days, as well as tamoxifen p.o. In the absence of undue toxicity or disease progression, these patients received one additional treatment cycle of 42 days followed by maintenance treatment, consisting of 5 days therapy every 4 weeks, for 1 year, or until proven progression. Only two patients in the tamoxifen-only group received immunotherapy when the disease progressed, but without any beneficial effect. All patients received appropriate local treatment when indicated. The interim analysis demonstrated no survival advantage for either group, and therefore further inclusion of patients was stopped. The median follow-up was 11 months (range 0.4-48 months). The final survival analysis showed no significant differences between the two treatment arms in so far as comparison from the day of diagnosis of primary disease, from the day of first evidence of metastatic spread, or from the onset of treatment. This was valid both when the evaluation was performed with regard to intention to treat and when the analysis was directed only to patients that managed at least one treatment cycle (42 days) of IL-2/IFN-a. The adver...

Immunotherapy of Metastatic Renal Cell Cancer

“…A trial comparing tamoxifen 40 mg with or without IFN-α and IL-2 was closed to accrual when interim evaluation showed no survival difference, and final evaluation confirmed that result. 54 A three-arm trial by Négrier et al 34 compared subcutaneous IL-2 (18 mIU/m 2 per day via continuous intravenous infusion for four 5-day courses) vs IFN-α (18 mIU given 3 times per week) vs a combination of IL-2 (same) and subcutaneous IFN-α (6 mIU given 3 times per week). Higher response rates were achieved in the combination arm at week 10 (7.7% vs 7.8% vs 21.3% of the evaluable patients, P=.01), and at week 25 (2.9% vs 6.1% vs 13.6%, P=.001).…”

Interleukin-2 in the treatment of unresectable or metastatic renal cell cancer: a systematic review and practice guideline

“…[10][11][12][13][14][15][16] We excluded 1 of the 7 eligible trials because most of the patients (58%) were lost to follow-up. 11 All 6 trials were published as full reports in journals.…”

“…Median survival data were reported in 4 trials 10,12,14,15 and extracted from survival curves in 2 trials.…”

“…10,12 In the trial by Atzpodien and colleagues, 10 median survival was longer for patients treated with a combination of IL-2 and IFN-a with either 5-FU (25 mo; p = 0.04) or 13cRA (27 mo; p = 0.02), compared with patients receiving combined treatment with IFN-a2a and vinblastine (16 mo). In the earlier trial by Atzpodien and colleagues, 12 a statistically significant longer median survival was observed with IL-2 combined with IFN-a and 5-FU over tamoxifen (24 v. 13 mo; p = 0.03).One-year mortality data were reported in one trial 14 and were extracted from survival curves in 5 trials 10,[12][13][14][15] (Table 2). When the data were pooled in a metaanalysis, no statistically significant difference was observed between IL-2-based regimens and non-IL-2 controls (RR = 0.94; 95% CI, 0.67-1.30; p = 0.69) (Fig.…”

“…Four of the 6 trials reported the method of randomization used. 10,12,14,15 The method of allocation concealment was not reported in any of the trials, and none of the trials were blinded. All of the trials presented baseline demographic and clinical characteristics for treatment and control arms, and 4 stated that randomization achieved balance in the distribution of those characteristics between arms.…”