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Originally published as JCO Early Release 10.1200/JCO.2004.01.998 on February 23 2004 © 2004 American Society of Clinical Oncology.
Better Survival With Interleukin-2-Based Regimens? Possibly Only in Highly Selected PatientsDepartment of Medicine, Centre Léon Bérard, Lyon, France In this issue of the Journal of Clinical Oncology, Atzpodien et al1 report interesting but surprising results of a randomized multicenter trial of chemoimmunotherapy in patients with metastatic renal carcinoma. Patients were randomly assigned to receive either a triple combination of subcutaneous interleukin-2 (IL-2) and interferon (IFN) with IV fluorouracil (FU), or the same combination combined with oral 13-cis-retinoic acid (po-13cRA); the control group was treated with IFN combined with vinblastine. The response rates, which were the primary end point of the study, were not different among the treatment groups. Both combinations of FU, IL-2, and IFN, with or without po-13cRA, demonstrated a survival advantage compared with the control arm; the largest difference was seen with FU, IL-2, IFN, and po-13cRA. By the survival curves, the largest differences in survival seem to occur about 1 year after treatment starts, but these differences dramatically diminish after 4 to 5 years. These results are surprising for several reasons. First, it is not often that treatments of metastatic cancer lead to an advantage in patient survival without a significant difference in response rates. In fact, the opposite is more common, including in studies of patients with metastatic kidney cancer.2-5 This observation is important because the demonstration of a survival gain without significant improvement of response rates means that the main treatment effect is more likely due to tumor growth inhibition than to tumor reduction. Such an effect is generally expected from treatments administered over a prolonged period of time and also from treatments that are mainly active through blocking mechanisms of tumor growth factors. These are not the usual mechanisms of action identified with IL-2 and FU, which seem to be the most important components in these combinations. The median duration of treatments was 2.2 months, which is rather short. Moreover, other authors recently published in this journal a study demonstrating that prolonged exposure to a combination of cytokines failed to improve disease-free or overall survival in patients with metastatic renal cancer.6 As a consequence, if we analyze the results of this trial, we must consider that the inhibition of tumor growth was a delayed effect of treatment. These results are also unexpected because most previous attempts using combinations of various cytokines alone or cytokines plus chemotherapy have failed to show any survival advantage with IL-2-based regimens. Combinations of IL-2 and IFN were not superior to each cytokine alone3,7 or to tamoxifen.8 Finally, the addition of FU to IL-2 and IFN in another randomized trial did not improve results, compared with the combination of cytokines.9 Only one previous study from the same group had reported a survival gain in favor of the combination of IL-2, IFN, and FU, compared with tamoxifen. These results, however, were not definitive, because they had been obtained from a limited number of patients.10 One important difference between the present trial and previous studies is the selection of patients at enrollment; indeed, only favorable risk groups were recruited. The effect of this selection is evidenced by the rather high median survival observed in the control group (16 months), clearly higher than most median survival data previously reported with IFN.2,3,8,11 It is, therefore, possible that the survival advantages associated with these treatments could only be observed in a similarly favorably selected population. This hypothesis has two major consequences. First, these conclusions may not be applicable to the general population of metastatic renal cancer patients. Second, patients may need to be selected using the rather complex risk score used in this trial, not currently used in routine practice. In the current trial, the greatest benefit was obtained with the quadruple combination, which included po-13cRA. This compound was previously investigated in a well designed controlled trial that did not demonstrate any survival advantage for the combination of po-13cRA and IFN, compared with IFN alone.12 The current study concludes that po-13cRA adds no survival benefit, but the trial was not designed to address this question. Finally, faced with these surprising results, we must be sure that no other biases could be responsible for the observed differences. For example, there is the possibility that the results might be due to a detrimental effect from one treatment. The answer to this point is rather simple and clear: previous reports of combinations of IFN and vinblastine identical to that used in the control group in this trial have demonstrated a survival benefit or, at least, an absence of survival disadvantage in patients with metastatic renal cancer.2,13 A second important question that should be asked when evaluating any clinical study is whether it included a sufficient number of patients and whether the follow-up was long enough. In this trial, the follow-up time appears to be sufficient, but the authors express no baseline assumption regarding expected survival rates (ie, the expected 20% difference could well be between 20% and 40% or between 50% and 70%). Besides, they give no explanations or literature reference regarding the statistical method that would justify the sample size calculation suitable for survival comparison. Another condition for a valid study is that the treatment arms are well balanced in patient characteristics and prognostic factors. Here the characteristics of the different groups appear well balanced. However, the control group presents some unfavorable features, such as an excess of 7% to 8% of patients with bone metastases, which have previously been identified by these authors and others as an unfavorable prognostic factor.14 There is also a 12% to 14% excess of nonnephrectomized patients, and nephrectomy has recently been associated with improved patient survival.15,16 Finally, the statistical analysis must be well conducted. In this trial, the log-rank test, a standard for comparing survivals, was not used, and survival rates and median survival times are expressed without indicating 95% CIs. Because of these limitations, we cannot be completely assured that the results reported are only due to the effect of treatment. In conclusion, this first demonstration of a survival advantage in favor of IL-2-based regimens in patients with metastatic renal cancer comes rather late, long after this cytokine has been introduced into treatment. Indeed, 15 years have elapsed since the first report of a therapeutic efficacy of IL-2 in the treatment of metastatic renal cancer.17 Since that time, new compounds have been developed, and more can hopefully be expected. Some have already demonstrated promising results, and others are presently under investigation in clinical trials.18 Most are biologic compounds whose main mode of action is thought to be prolonged inhibition of tumor growth, targeting tumor growth factors or their cell receptors. We hope that the development of these promising new agents will be more straightforward than that of IL-2, but we already know that clear answers regarding their usefulness will only be obtained from randomized trials, with survival as the primary end point and with appropriate control groups, including a placebo whenever possible. The results provided by Atzpodien et al raise at least as many questions as they answer, and should therefore be considered with much caution. As the pragmatic Dr Watson suggested when, in helping Sherlock Holmes in his quest for truth, he asked, "Would you think me impertinent if I were to put your theories to a more severe test?"19 we believe these results need to be validated though a rigorous controlled trial before they can be considered as a potential reference treatment for future trials. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Sylvie Negrier, Genentech, GlaxoSmithKline. REFERENCES
1. Atzpodien J, Kirchner H, Jonas U, et al: Interleukin-2- and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: Results of a prospectively randomized trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). J Clin Oncol 22:1188-1194, 2004
2. Fossa SD, Martinelli G, Otto U, et al: Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: Results of a European multi-center phase III study. Ann Oncol 3:301-305, 1992
3. Négrier S, Escudier B, Lasset C, et al: Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma: Groupe Francais d'Immunotherapie. N Engl J Med 338:1272-1278, 1998
4. Rosenberg SA, Lotze MT, Yang JC, et al: Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst 85:622-632, 1993
5. Yang JC, Sherry RM, Steinberg SM, et al: Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 21:3127-3132, 2003
6. Tourani JM, Pfister C, Tubiana N, et al: Subcutaneous interleukin-2 and interferon alfa administration in patients with metastatic renal cell carcinoma: Final results of SCAPP III, a large, multicenter, phase II, nonrandomized study with sequential analysis design-the Subcutaneous Administration Propeukin Program Cooperative Group. J Clin Oncol 21:3987-3994, 2003 7. Sparano JA, Fisher RI, Sunderland M, et al: 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. J Clin Oncol 10:1969-1977, 1993 8. Henriksson R, Nilsson S, Colleen S, et al: Survival in renal cell carcinoma: A randomized evaluation of tamoxifen vs interleukin 2, alpha-interferon (leucocyte) and tamoxifen. Br J Cancer 77:1311-1317, 1998[Medline]
9. Négrier S, Caty A, Lesimple T, et al: Treatment of patients with metastatic renal carcinoma with a combination of subcutaneous interleukin-2 and interferon alfa with or without fluorouracil—Groupe Francais d'Immunothérapie, Fédération Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol 18:4009-4015, 2000
10. Atzpodien J, Kirchner H, Illiger HJ, et al: IL-2 in combination with IFN-
11. Motzer RJ, Mazumdar M, Bacik J, et al: Effect of cytokine therapy on survival for patients with advanced renal cell carcinoma. J Clin Oncol 18:1928-1935, 2000
12. Motzer RJ, Murphy BA, Bacik J, et al: Phase II trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol 18:2972-2980, 2000
13. Pyrhonen S, Salminen E, Ruutu M, et al: Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 17:2859-2867, 1999 14. Atzpodien J, Royston P, Reitz M: Metastatic renal carcinoma extended staging system. Br J Cancer 88:348-353, 2003[CrossRef][Medline] 15. Mickisch GH, Garin A, van Poppel H, et al: Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: A randomised trial. Lancet 358:966-970, 2001[CrossRef][Medline]
16. Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 345:1655-1659, 2001 17. Rosenberg SA, Lotze MT, Muul LM, et al: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316:889-897, 1987[Abstract]
18. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003 19. Doyle, Arthur Conan: The Sign of Four, in: Sherlock Holmes: Selected Stories. Oxford, UK, Oxford University Press, 1998
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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and 5-FU versus tamoxifen in metastatic renal cell carcinoma: Long-term results of a controlled randomized clinical trial. Br J Cancer 85:1130-1136, 2001
