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Randomized Study of Intravenous versus Subcutaneous Interleukin-2, and IFN in Patients with Good Prognosis Metastatic Renal Cancer

Authors' Affiliations: ¹ Université de Lyon, Centre Léon Bérard, Medical Oncology Department and Cytokines and Cancer Research Unit, Institut National de la Sante et de la Recherche Medicale U.590 and ² Biostatistics Unit, Centre Léon Bérard, Lyon Cedex 08, France; ³ Hôpital Saint André, University Hospital, Bordeaux Cedex, France; ⁴ Centre Jean Perrin, Clermont-Ferrand, France; ⁵ Hôpital Européen Georges Pompidou, Paris Cedex 15, France; ⁶ Centre Georges-François Leclerc, Dijon, France; ⁷ Centre Paul Papin, Angers Cedex, France; ⁸ Groupe Hospitalier Saint Joseph, Paris, France; ⁹ Institut Paoli Calmettes, Marseilles, France; and ¹⁰ Institut Gustave Roussy, Villejuif, France

Requests for reprints: Sylvie Négrier, Université de Lyon, Centre Léon Bérard, Medical Oncology Department and Cytokines and Cancer Research Unit, Institut National de la Sante et de la Recherche Medicale U.590, 28 rue Laennec, 69373 Lyon Cedex 08, France. Phone: 33-478-78-27-51; Fax: 33-478-78-27-16; E-mail: reynaud{at}lyon.fnclcc.fr.

Purpose: Metastatic renal cancer patients with a single metastatic site are potentially amenable to interleukin 2 (IL-2) + IFN-. A French immunotherapy intergroup multicenter trial assessed the potential benefit of i.v. over s.c. administration of IL-2 in this combination.

Experimental Design: Untreated patients with one metastatic site were randomized to continuous i.v. infusion (18 x 10⁶ IU/m²/d; arm A) or twice daily s.c. injections (9 x 10⁶ or 18 x 10⁶ IU; arm B) of IL-2, associated with s.c. IFN- (6 x 10⁶ IU) 3 days per week in both arms. Tumor response was assessed (WHO criteria) at weeks 12 and 24 to 26. The primary end point was overall survival, with an expected 15% improvement at 4 years with i.v. IL-2. The planned sample size was 220 (80% power, 5% significance, one-sided test). Intent-to-treat analysis was done and survivals were compared using log-rank tests.

Results: From January 2000 to January 2005, 80 and 75 patients were randomized to arms A and B, respectively. Enrollment was stopped early because of low accrual; analysis was done at 42.5 months median follow-up. Patient characteristics were well balanced between groups. Response rates were 17.9% versus 21.3% in arms A and B. Progression-free survival rates were not significantly different. Overall survival difference was not significant: median 33 months (95% confidence interval, 27.0-40.2; P = 0.202).

Conclusions: In combination with IFN- in selected, good prognosis metastatic renal cell carcinoma patients, i.v. IL-2 offers no significant advantage over s.c. IL-2 and induces higher toxicity. Although i.v. IL-2 induced longer responses, it seems unreasonable to continue recommending this regimen after the recent introduction of more effective therapies.