Adjuvant Vaccine for Renal Carcinoma: Finally!
Abstract & Commentary
Synopsis: In this phase III, randomized, multicenter trial, renal carcinoma patients with organ-confined tumors were randomized after radical nephrectomy to receive autologous renal tumor cell vaccine or observation. The primary clinical outcome was the time to tumor recurrence. Patients who received the vaccine had greater 5-year and 70-month progression-free survival rates and lower tumor progression hazard rates than those in the control group.
Source: Jocham D, et al. Lancet. 2004;363:594-599.
At present, 3% of all malignant tumors in adults develop in the kidney. Of these, 85% can be considered renal-cell carcinomas with the tumor originating from cells of the proximal tubules. After radical nephrectomy, organ-confined renal-cell carcinoma is associated with tumor progression in up to 50% of patients. Several adjuvant protocols, including radiotherapy, interferon alfa, interleukin 2, and medroxyprogesterone acetate, have been used in attempt to halt this progression. However, none have been effective in improving progression-free survival or overall survival in patients with renal-cell carcinoma.1 Jocham and colleagues from the University of Lübeck Medical School in Germany examined the effect of an autologous renal tumor cell vaccine on the risk of tumor progression in 379 patients with stage pT2-3b pN0-3 M0 renal-cell carcinoma scheduled for radical nephrectomy. All patients were centrally randomized to receive autologous renal tumor cell vaccine (6 intradermal applications at 4-week intervals postoperatively) or no adjuvant therapy (control group). Patients were then assessed at 6-month intervals for a minimum of 4.5 years.
Overall, the patients who received the vaccine had better outcomes than those in the control group. In the vaccine group, 5-year and 70-month progression-free survival rates for patients at all tumor stages were 77.4% and 72%, respectively and 67.8% and 59.3%, respectively for the control group. At 5-year and 70-month follow-up, the hazard ratios for tumor progression were 1.58 (95% CI, 1.05-2.37) and 1.59 (1.07-2.36) respectively, in favor of the vaccine group (P = .0204, log-rank test). The vaccine was well tolerated, with only 12 adverse events among the 177 patients who received, in total, 1053 vaccine doses.
After subgroup analysis in which tumor size was among various features examined, Jocham et al conclude that autologous renal tumor cell vaccine is a beneficial approach, particularly for those undergoing radical nephrectomy due to organ-confined renal-cell carcinoma of more than 2.5 cm in diameter.
Comment by William B. Ershler, MD
The single greatest chance for long-term survival in patients with renal cell carcinoma is early detection and surgical excision before metastatic disease is apparent. The NCI SEER data indicate that 54% of renal carcinoma is localized at the time of diagnosis, and yet for these, nearly half will have recurrent disease. Various measures have been used, including chemotherapy, radiation and immunotherapy, in the adjuvant setting to diminish recurrences, but none have proven efficacious.1
The current study is remarkable for a number of reasons. First, it is a large study of a relatively uncommon tumor (renal carcinoma accounts for 3% of malignancies in adults)2 and Jocham et al should be credited for a job well done with regard to community participation and patient recruitment. Secondly, the coordination of autologous vaccine preparation and administration for a relatively large number of individuals at multiple centers throughout the country must also have been logistically complex and may wrongly have been considered unfeasible by some at the outset. Again, Jocham et al should take credit for this outstanding effort. Finally, and most importantly, the findings are of great significance with regard to the role of vaccine therapy for this disease. For a tumor that characteristically is resistant to both chemotherapy and radiation, it is encouraging to demonstrate a beneficial response to immunotherapy, and with little toxicity.
There were some methodological concerns raised in an accompanying editorial,3 such as a rather steep post-randomization attrition rate, particularly from the vaccine group, and the lack of data on overall survival.3 However, these do not diminish the importance of the findings reported, but just raise a cautionary warning before we adopt a cumbersome and expensive approach as a clinical standard. With this trial as a starting point, additional studies should be designed to confirm the salutary effect in terms of overall survival and to identify which subsets of patients are likely to be protected. Furthermore, it would be of great value to determine the mechanisms of vaccine-induced protection and ultimately to develop more global vaccines that do not rely on the processing of autologous tumor tissues.
1. Motzer RJ, Russo P.
J Urol. 2000;163:408-417.
2. Figlin RA. J Urol. 1999;161:381-387.
3. Fishman M, Antonia S. Lancet. 2004;363: 583-584.
William B. Ershler, MD INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC, is Editor of Clinical Oncology Alert.