Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: Results of a European multi-center phase III study

Fosså, Sophie D.; Martinelli, G.; Otto, Ulrich; Schneider, George; Wander, H.-E.; Oberling, F.; Bauer, H. W.; Achtnicht, U.; Holdener, E. E.

doi:10.1093/oxfordjournals.annonc.a058185

Cited by 120 publications

(38 citation statements)

References 21 publications

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“…Although immunotherapy has been successfully used for treating tumors in animal model, only few types of tumors such as melanoma and renal cell carcinoma responded to immunotherapy using IL-2 and IFN-a [4][5][6]. Systemic administration of cytokines often causes severe adverse effect at higher doses that can induce efficient antitumor effects in several human tumors [7,8].…”

Section: Introductionmentioning

confidence: 99%

Antitumor immune response by CX3CL1 fractalkine gene transfer depends on both NK and T cells

et al. 2005

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The CX3C chemokine fractalkine (CX3CL1) exists as both a membrane-bound form promoting firm cell-cell adhesion and a soluble form chemoattracting leukocytes expressing its receptor CX3CR1. When adenoviral vector expressing mouse fractalkine (AdFKN) was transduced to the tumor cells, fractalkine was expressed as both membrane-bound form on the tumor cells and soluble form in the supernatant in vitro. Intratumoral injection of AdFKN (1Â10 9 PFU/tumor) into C26 and B16F10 tumors resulted in marked reduction of tumor growth compared to control (C26: 86.5%, p<0.001; B16F10: 85.5%, p<0.001). Histological examination of tumor tissues revealed abundant infiltration of NK cells, dendritic cells, and CD8 + T lymphocytes 3 and/or 6 days after treatment with AdFKN. Splenocytes from mice treated by AdFKN developed tumor-specific cytotoxic T cells, and thereby protected from rechallenging with parental tumor cells. Antitumor effects by AdFKN were completely abrogated in both NK celldepleted mice and CD8 -/-mice, and partially blocked in CD4 -/-mice. These data indicated that fractalkine mediates antitumor effects by both NK cell-dependent and T cell-dependent mechanisms. This study suggests that fractalkine can be a suitable candidate for immunogene therapy of cancer because fractalkine induces both innate and adaptive immunity.

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Section: Introductionmentioning

confidence: 99%

Antitumor immune response by CX3CL1 fractalkine gene transfer depends on both NK and T cells

et al. 2005

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“…Median survival was also significantly different between the 2 groups (15.8 mo v. 8.8 mo). Fossa and others 13 randomized 178 patients to receive interferon-α2a or interferon-α2a with vinblastine with the exact same dosages as those used in the study by Pyrhonen and others. 12 Like that study, Fossa and others 13 found vinblastine increased RR (from 11% to 24%), but unlike that study, they found no difference in survival rate between the 2 groups.…”

Section: Interferonsmentioning

confidence: 99%

“…Fossa and others 13 randomized 178 patients to receive interferon-α2a or interferon-α2a with vinblastine with the exact same dosages as those used in the study by Pyrhonen and others. 12 Like that study, Fossa and others 13 found vinblastine increased RR (from 11% to 24%), but unlike that study, they found no difference in survival rate between the 2 groups. Differences in the calculation of survival may explain the difference in conclusions: Pyrhonen and others 12 calculated survival in months, whereas Fossa and others 13 compared the percentage of surviving patients.…”

Section: Interferonsmentioning

confidence: 99%

Current status of cytokine therapy in management of patients with metastatic renal cell carcinoma

Kapoor

Hotte

2012

CUAJ

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Studies examining the efficacy of immunotherapy have used a variety of end points such as response rate (RR), complete response (CR) or partial response (PR); rate of progression; and progression-free and median survival. However, these studies used different definitions of these end points and none was blinded.5 Further, RR has been reported to be an unreliable surrogate of survival. 5A meta-analysis 7 of 1042 patients found that the overall proportion of responses (CR and PR) to interferon-α was 12%. CRs were quite rare. Favourable characteristics of responders included patients with prior nephrectomy and patients with lung metastases. In this particular patient population, the proportion of objective responses was as high as 44%. 7 The average time from the start of treatment to an objective response was about 3-4 months. Metastases of the central nervous system tended not to respond to interferon, and soft-tissue disease tended to respond more readily than bony metastases. Results of a review of more than 1500 patients 8 suggest that the disease RR is between 12% and 15% for patients receiving interferon-α. CRs occurred in 2%-5% patients, usually in those with pulmonary metastases. The recently published Cochrane collaboration review 5 estimated a gain of 3.8 months and a 1-year risk of mortality reduction by 44% for patients randomized to interferon-α2a, compared with patients randomized to control arms. Toxicity with interferon-α includes fever, malaise, flulike symptoms and night sweats, and is markedly less than that with interleukin-2 (IL-2). S28 REVIEW AbstractCytokine therapy with interferon-α and interleukin-2 has arguably been the standard treatment for patients with metastatic renal cell carcinoma for more than 20 years. In this paper, the current evidence for the use of cytokine therapy in this patient population is discussed, including the significant toxicity associated with these agents. A low overall response rate and a marginal survival advantage are observed with interferon-α and interleukin-2; however, these therapies have significant toxicity and impair quality of life. Unlike the current tyrosine-kinase inhibitors, complete tumour responses may be seen with interleukin-2, but again this therapy has significant morbidity and mortality. Newer anti-angiogenesis agents may be combined with current standard cytokine therapy for patients with metastatic renal cell carcinoma.

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“…In this context it is also of interest to emphasize that controlled randomized trials evaluating different approaches of immunotherapy on survival, for example IL-2 vs IL-2 plus lymphokine-activated killer cells or IFN-a vs IFN-a and vinblastin, displayed no significant differences (Fossa et al, 1992;Rosenberg et al, 1993;Kellokumpu-Lehtinen et al, 1995). Furthermore, the advantage of an increased response rate after immunological manipulation has not always been translated to a better chance of survival (Fossaet al, 1992;Facendola et al, 1995).…”

Section: Final Analysismentioning

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

Br J Cancer

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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...

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Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: Results of a European multi-center phase III study

Cited by 120 publications

References 21 publications

Antitumor immune response by CX3CL1 fractalkine gene transfer depends on both NK and T cells

Antitumor immune response by CX3CL1 fractalkine gene transfer depends on both NK and T cells

Current status of cytokine therapy in management of patients with metastatic renal cell carcinoma

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

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