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Adjuvant immunotherapy with low-dose interleukin-2 and interferon-a did not significantly improve overall survival or recurrence-free survival of patients with nonmetastatic renal cell carcinoma in a phase III trial.
The findings are disappointing, as no effective adjuvant treatment exists for these patients after radical surgery. The standard approach remains observation, according to Dr. Rodolpho Passalacqua, who reported on behalf of the Italian Oncology Group for Clinical Research. Previous studies have shown no benefit from interferon (IFN)-a, high-dose interleukin (IL)-2, and chemo-immunotherapy, with conflicting results described for autologous tumor cell vaccines.
Subgroup analyses suggested some patients might benefit from the combination of interferon (IFN)-a and high-dose interleukin (IL)-2, but others might fare worse. Adjuvant immunotherapy appeared to benefit patients with at least one of these predictive factors: negative lymph nodes, age less than 60 years, tumor grades 1-2, or tumor stage T3a.
"These factors can be considered predictive of a positive effect of low-dose immunotherapy in the adjuvant setting," said Dr. Passalacqua of the Instituti Ospitalieri, Cremona, Italy.
To assess their impact, the investigators stratified the population into two cohorts. In patients with two or more predictive factors—60% of the study population—adjuvant therapy significantly improved recurrence-free survival (hazard ratio 0.44, P less than .01), and showed a small trend toward improving overall survival (HR 0.66, P = .25).
Of the remaining patients with fewer than two predictive factors, adjuvant therapy had a detrimental effect on recurrence-free survival (HR 1.81, P = .10) and overall survival (HR 2.28, P = .042). "This category of patients should not be treated with adjuvant immunotherapy," Dr. Passalacqua cautioned.
From July 1994 to March 2006, the investigators randomized 310 surgically treated patients with renal cell carcinoma to low-dose immunotherapy for 5 years or observation. Immunotherapy consisted of a 4-week cycle of subcutaneous IL-2 at a dose of 1 million IU/m² given every 12 hours on days 1 and 2 and once a day on days 3, 4, and 5; and IFN-a 1.8 million IU/m² given on days 3 and 5. Cycles were repeated every 4 months for the first 2 years, and every 6 months for the remaining 3 years. Each patient received 12 cycles.
There were 59 deaths and 77 recurrences at a median follow-up of 72 months. Seven patients were not eligible for analysis. Recurrence-free survival (P = .36) and overall survival (P = .79) rates were not statistically different.
Over the 5 years, 14% of patients stopped treatment due to adverse events. Flulike syndrome was the main toxicity (grade 1/2, 35%; grade 3/4, 14%). The treatment was well tolerated, Dr. Passalacqua said.
Discussant Dr. Arlene Siefker-Radtke called the benefits observed in the subset analysis "hypothesis-generating," and need to be comfirmed by randomized trials. Optimal dose and schedule also remain unresolved.
Adjuvant therapy has a future in renal cell tumors, including use of new less toxic agents that allow for more chronic administration, said Dr. Siefker-Radtke of the University of Texas M.D. Anderson Cancer Center in Houston. Results also are pending from the ASSURE trial comparing sorafenib to sunitinib and a phase III trial of Rencarex (WX-G250), a monoclonal antibody, in renal cell carcinoma, she noted.
Passalacqua R. et al. Adjuvant low-dose interleukin-2 (IL2) plus interferone-alfa (IFN) in operable renal cell cancer (RCC). A phase III, randomized, multicenter, independent trial of the Italian Oncology Group for Clinical Research (GOIRC). Abstract LBA5028.