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Phase II Trial of Interleukin 2, Interferon , and 5-Fluorouracil in Metastatic Renal Cell Cancer: A Cytokine Working Group Study¹

Albert Einstein Cancer Center, Bronx, New York [J. P. D.]; University of Pittsburgh, Pittsburgh, Pennsylvania 15260 [T. L., M. L.]; Indiana University, Indianapolis, Indiana 85012 [M. G.]; Loyola University, Chicago, Illinois 60612 [J. S., J. C.]; University of Texas, San Antonio, Texas [G. W.]; City of Hope Medical Center, Duarte, California 91010 [K. M.]; Chiron Corp., Emeryville, California 94608 [T. P.]; and Tufts-New England Medical Center, Boston, Massachusetts 02111 [J. M., M. A.]

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-2B followed by 4 weeks of 5-fluorouracil plus IFN-2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1–4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m² twice daily on days 3–5, and the dosage for IFN-2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m² on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m² on days 1, 3, and 5, and the dosage for IFN-2B was 6 MIU/m² on days 1, 3, 5. During weeks 5–8, 5-fluorouracil (750 mg/m²) was administered once weekly by i.v. infusion, and IFN-2B (9 MIU/m²) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated.

There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10–25). The median response duration was 8 months (range, 3–51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1–53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during treatment with IL-2/IFN were fatigue, nausea/vomiting, anorexia, skin reaction, diarrhea, fever, and liver enzyme elevations. One-third had central nervous system toxicity (headache, depression, insomnia). During 5FU/IFN treatment, 49 of 50 patients experienced grade 2/3 myelosuppression during course 1. Eight patients experienced grade 4 toxicities. In conclusion, the activity of this alternating regimen is similar to that of IL-2/IFN alone, given in 4- week cycles. The addition of 5FU/IFN failed to increase the efficacy and added new toxicity (myelosuppression). This report does not confirm the results previously reported for either alternating or simultaneous administration of these three agents. Because 5FU does not appear to add to the antitumor activity of IL-2-based therapy for renal cancer, current efforts are directed toward a Phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment versus treatment with outpatient s.c. injection of IL-2 plus IFN.

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