Multiinstitutional home-therapy trial of recombinant human interleukin-2 and interferon alfa-2 in progressive metastatic renal cell carcinoma.

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.

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confidence: 82%

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

“…The pivotal role of the cytokine interleukin 2 (IL-2) in the immune system has promoted trials of IL-2 in patients with solid cancers such as melanoma and renal cell carcinoma (Atzpodien et al, 1995). IL-2 effectively stimulates the anti-tumour activity of natural killer (NK) cells and other cytotoxic cells in the majority of treated patients (Caligiuri et al, 1993), but the effects on tumour burden and on the survival of patients have, as yet, been disappointing.…”

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confidence: 99%

The response of Dunning R3327 prostatic adenocarcinoma to IL-2, histamine and radiation

Johansson

Landström²,

Hellstrand³

et al. 1998

Summary A syngeneic, androgen-sensitive Dunning R3327 rat prostatic adenocarcinoma was transplanted bilaterally in the flanks of male Copenhagen Fisher rats. Approximately 3 months after implantation, when the tumours had a median volume of 150 mm3, one group of rats was treated with histamine alone (4 mg kg-1 subcutaneously on week days), another group with human recombinant interleukin 2 (IL-2) alone (425 IU kg-' continuous infusion) and a third group with both histamine and IL-2 during 6 weeks. Tumours on one flank were irradiated (6 Gy once daily for 3 days to a total dose of 18 Gy) beginning 1 week after the onset of treatment with histamine and / or IL-2. The contralateral tumour served as the intra-animal control. The tumour volumes were determined weekly. The growth curves showed that all three drug treatments were effective in delaying growth, but when used individually did not cause tumour shrinkage. Radiation was the most effective single agent, but when used alone the shrinkage did not occur until 2 weeks after irradiation. When combined with the drugs, more rapid and extensive growth delay and/or shrinkage was seen. The growth curves showed clear differences between the different treatments. The combination of the three agents was the most effective of all. The most striking difference between radiation alone and radiation plus biotherapy was the time at which a tumour response was detectable. Thus, active biotherapy alone and especially in a combination with histamine and radiotherapy warrants further investigation as a potential therapeutic approach to prostate cancer.

“…Overall, the toxicity was graded 0-2 according to the WHO toxicity scale in the majority of the patients. However, grade 3-4 toxicity was seen in a substantial amount of patients and was more common in the IL-2/IFN-atreated patients (Table 5) (Rosenberg et al, 1993;Besana et al, 1994;Oliver, 1994;Atzpodien et al, 1995;Facendola et al, 1995;Savage, 1995;Wagstaff et al, 1995;Hanninen et al, 1996). Recombinant cytokines, notably IL-2 and IFN-a, appear to have had encouraging results, and have led to approval by several national drug agencies in the management of RCC.…”

Section: Final Analysismentioning

confidence: 99%

“…RCC is one of the few tumours with a known propensity for spontaneous regression (Katz et al, 1982;Oliver et al, 1989 (Rosenberg et al, 1993;Oliver, 1994;Atzpodien et al, 1995;Facendola, 1995;Savage, 1995;Wagstaff et al, 1995;Hanninen et al, 1996). Although these treatment options can induce objective responses, they are associated with significant sideeffects and considerable expense (Oliver, 1994;Facendola et al, 1995;Savage, 1995;Wagstaff et al, 1995).…”

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confidence: 99%

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

Henriksson

Nilsson²,

Colleen³

et al. 1998

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...