Subcutaneous interleukin-2, interferon alpha-2b and 5-fluorouracil in metastatic renal cell carcinoma as second-line treatment after failure of previous immunotherapy: a phase II trial

Abstract

The association of interleukin-2 (IL-2), interferon alpha-2a (IFNa), 5-fluorouracil (5-FU) has been reported to induce response in metastatic renal cell carcinoma (MRCC). This study evaluated IL-2, IFNa and 5FU as second-line treatment after failure under immunotherapy. A total of 35 patients received IL-2, at 9 Â 10 6 IU m À2 , once or t.i.d, 5 days a week, every other week. Interferon alpha was administered at 6 MUI, TIW along with IL-2 every week. 5-Fluorouracil was given at 750 mg m À2 day À1 on days 1 -5 every 4 weeks. One cycle lasted 8 weeks. All patients were evaluable for response and toxicity. There were two objective responses (5.7%) and 14 stable diseases (40%). Survival was 14 months. In all, 17 patients experienced grade 3 toxicity. The predictive factor for progression to second-line immunotherapy was the results of first-line immunotherapy, and performance status, delay from primary tumour to metastases and response or stabilisation to chemo-immunotherapy for survival. IL-2, IFNa and 5-FU induce low objective response but stabilisation in patients with MRCC having failed with immunotherapy, and may be considered only in selected patients on performance status, stabilisation or response after first-line immunotherapy and interval from their primary tumour to metastases.

5-fluorouracil enhances the antitumor effect of sorafenib and sunitinib in a xenograft model of human renal cell carcinoma

“…Response rates of immunochemical therapies combining 5FU with IL2 and IFNα ranged from 1.8 to 48% (16,17). Recently, a phase II multicenter trial involving 45 patients with metastatic RCC revealed the efficacy and safety of S-1, an oral fluorinated pyrimidine that includes tegafur, a prodrug of 5FU (18).…”

Expression of Indoleamine 2,3-Dioxygenase in Tumor Endothelial Cells Correlates with Long-term Survival of Patients with Renal Cell Carcinoma

“…Consequently, the current first line therapy for patients with metastasized RCC involves nonspecific immunotherapy with interleukin-2 and/or IFN-a cytokines with or without 5-fluorouracil treatment albeit with only 5% to 10% durable responses (4,5). Immune escape mechanisms may be responsible for the limited success of immunotherapies in patients with RCC (6,7).…”

How Can Second-Line Therapy for Metastatic Renal Cell Carcinoma Help to Define an Overall Management Strategy?

“…Trials in which patients were retreated with cytokines following initial cytokine failure, despite initial promising data from small phase II trials [10], have demonstrated that therapy with a different cytokine or a different cytokine schedule is not active in this patient population [11, 17]. The largest body of evidence on second-line activity of cytokines comes from the CRECY trial.…”

“…Experience of second-line therapy was limited to experimental studies that mostly failed to show any benefit [9,10,11,12,13,14,15,16,17], and not an option for clinical practice, with the only available therapeutic agents, the cytokines IFN and IL-2, having activity in selected patients with untreated mRCC and no activity in patients who had received any prior treatment for their disease [9,10,11, 17]. …”