Journal of Clinical Oncology, Vol 11, 661-670, Copyright © 1993 by American Society of Clinical Oncology

ARTICLES

Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma

MB Atkins, J Sparano, RI Fisher, GR Weiss, KA Margolin, KI Fink, L Rubinstein, A Louie, JW Mier and R Gucalp
Division of Hematology/Oncology, New England Medical Center, Boston, MA 02111.

PURPOSE: To determine better the activity of high-dose interleukin-2 (IL-2) either alone or in combination with interferon alfa-2b (IFN; Schering-Plough, Kenilworth, NJ) in patients with metastatic renal cell carcinoma, the IL-2 Working Group initiated a randomized phase II trial. PATIENTS AND METHODS: Patients were randomly assigned to receive treatment with either IL-2 (Chiron Corp, Emeryville, CA) 1.33 mg/m2 (approximately 600,000 IU/kg) alone or IL-2 0.8 mg/m2 and IFN 3 x 10(6) U/m2 administered by bolus intravenous injection every 8 hours, days 1 to 5 and 15 to 19 (maximum, 28 doses). All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and normal organ function. After 28 patients were entered onto each arm, the IL-2/IFN arm was closed because of a failure to meet predetermined efficacy criteria. An additional 43 patients (total, 71) were assigned to receive IL-2 alone. RESULTS: Toxicities were similar for both study arms. Hypotension requiring pressors was the most frequent dose- limiting toxicity. Only 11 of 99 patients experienced severe toxicity; there were no irreversible side effects or treatment-related deaths. Responses were seen in three of 28 patients (11%) on IL-2/IFN (three partial responses [PRs] lasting 14, 7, and 7 months) and 12 of 71 patients (17%) on IL-2 alone (four complete responses [CRs] and eight PRs). Six of the partial responders on IL-2 and two on IL-2/IFN experienced greater than 90% reduction in tumor mass. Ten of the 12 responders to IL-2 have ongoing responses of 12+ to 26+ months in duration. CONCLUSION: We conclude that both IL-2 and IL-2/IFN therapy have activity in metastatic renal cell carcinoma. In particular, therapy with high-dose IL-2 alone produces meaningful and durable responses with manageable and reversible toxicity. This study supports the contention that high-dose IL-2 represents the treatment of choice in selected patients with advanced renal cell carcinoma.

This article has been cited by other articles:

				G. Hudes, M. Carducci, P. Tomczak, J. Dutcher, R. Figlin, A. Kapoor, E. Staroslawska, J. Sosman, D. McDermott, I. Bodrogi, et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma N. Engl. J. Med., May 31, 2007; 356(22): 2271 - 2281. [Abstract] [Full Text] [PDF]

				M. S. Ernstoff, T. S. Crocenzi, J. D. Seigne, N. A. Crosby, B. F. Cole, J. L. Fisher, J. C. Uhlenhake, D. Mellinger, C. Foster, C. J. Farnham, et al. Developing a Rational Tumor Vaccine Therapy for Renal Cell Carcinoma: Immune Yin and Yang Clin. Cancer Res., January 15, 2007; 13(2): 733s - 740s. [Abstract] [Full Text] [PDF]

				M. Parton, M. Gore, and T. Eisen Role of Cytokine Therapy in 2006 and Beyond for Metastatic Renal Cell Cancer J. Clin. Oncol., December 10, 2006; 24(35): 5584 - 5592. [Abstract] [Full Text] [PDF]

				D. F. McDermott and M. M. Regan In Reply: J. Clin. Oncol., September 1, 2005; 23(25): 6268 - 6269. [Full Text] [PDF]

				D. F. McDermott, M. M. Regan, J. I. Clark, L. E. Flaherty, G. R. Weiss, T. F. Logan, J. M. Kirkwood, M. S. Gordon, J. A. Sosman, M. S. Ernstoff, et al. Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients With Metastatic Renal Cell Carcinoma J. Clin. Oncol., January 1, 2005; 23(1): 133 - 141. [Abstract] [Full Text] [PDF]

				B. I. Rini, S. Halabi, J. Taylor, E. J. Small, and R. L. Schilsky Cancer and Leukemia Group B 90206: A Randomized Phase III Trial of Interferon-{alpha} or Interferon-{alpha} Plus Anti-Vascular Endothelial Growth Factor Antibody (Bevacizumab) in Metastatic Renal Cell Carcinoma Clin. Cancer Res., April 15, 2004; 10(8): 2584 - 2586. [Abstract] [Full Text] [PDF]

				J.-M. Tourani, C. Pfister, N. Tubiana, M. Ouldkaci, G. Prevot, V. Lucas, S. Oudard, M. Malet, P. Cottu, J.-M. Ferrero, 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., November 1, 2003; 21(21): 3987 - 3994. [Abstract] [Full Text] [PDF]

				J. I. Clark, M. B. Atkins, W. J. Urba, S. Creech, R. A. Figlin, J. P. Dutcher, L. Flaherty, J. A. Sosman, T. F. Logan, R. White, et al. Adjuvant High-Dose Bolus Interleukin-2 for Patients With High-Risk Renal Cell Carcinoma: A Cytokine Working Group Randomized Trial J. Clin. Oncol., August 15, 2003; 21(16): 3133 - 3140. [Abstract] [Full Text] [PDF]

				J. I. Clark, T. M. Kuzel, T. M. Lestingi, S. G. Fisher, P. Sorokin, B. Martone, M. Viola, and J. A. Sosman A multi-institutional phase II trial of a novel inpatient schedule of continuous interleukin-2 with interferon {alpha}-2b in advanced renal cell carcinoma: major durable responses in a less highly selected patient population Ann. Onc., April 1, 2002; 13(4): 606 - 613. [Abstract] [Full Text] [PDF]

				E. Jonasch and F. G. Haluska Interferon in Oncological Practice: Review of Interferon Biology, Clinical Applications, and Toxicities Oncologist, February 1, 2001; 6(1): 34 - 55. [Abstract] [Full Text]

				S. Negrier, A. Caty, T. Lesimple, J.-Y. Douillard, B. Escudier, J.-F. Rossi, P. Viens, and F. Gomez Treatment of Patients With Metastatic Renal Carcinoma With a Combination of Subcutaneous Interleukin-2 and Interferon Alfa With or Without Fluorouracil J. Clin. Oncol., December 15, 2000; 18(24): 4009 - 4015. [Abstract] [Full Text] [PDF]

				J. P. Dutcher, T. Logan, M. Gordon, J. Sosman, G. Weiss, K. Margolin, T. Plasse, J. Mier, M. Lotze, J. Clark, et al. Phase II Trial of Interleukin 2, Interferon {{alpha}}, and 5-Fluorouracil in Metastatic Renal Cell Cancer: A Cytokine Working Group Study Clin. Cancer Res., September 1, 2000; 6(9): 3442 - 3450. [Abstract] [Full Text]

				J. I. Clark, E. R. Gaynor, B. Martone, S. C. Budds, R. Manjunath, R. C. Flanigan, W. B. Waters, and J. A. Sosman Daily Subcutaneous Ultra-Low-Dose Interleukin 2 with Daily Low-Dose Interferon-{{alpha}} in Patients with Advanced Renal Cell Carcinoma Clin. Cancer Res., September 1, 1999; 5(9): 2374 - 2380. [Abstract] [Full Text] [PDF]

				R. A. Figlin, J. A. Thompson, R. M. Bukowski, N. J. Vogelzang, A. C. Novick, P. Lange, G. D. Steinberg, and A. S. Belldegrun Multicenter, Randomized, Phase III Trial of CD8+ Tumor-Infiltrating Lymphocytes in Combination With Recombinant Interleukin-2 in Metastatic Renal Cell Carcinoma J. Clin. Oncol., August 1, 1999; 17(8): 2521 - 2521. [Abstract] [Full Text] [PDF]

				B. Escudier, C. Chevreau, C. Lasset, J. Y. Douillard, A. Ravaud, M. Fabbro, A. Caty, J. F. Rossi, P. Viens, J. P. Bergerat, et al. Cytokines in Metastatic Renal Cell Carcinoma: Is It Useful to Switch to Interleukin-2 or Interferon After Failure of a First Treatment? J. Clin. Oncol., July 1, 1999; 17(7): 2039 - 2039. [Abstract] [Full Text] [PDF]

				R. C. Young Metastatic Renal-Cell Carcinoma: What Causes Occasional Dramatic Regressions? N. Engl. J. Med., April 30, 1998; 338(18): 1305 - 1307. [Full Text]