The development of targeted molecular therapies offers new avenues for combining pharmacologic and surgical therapies in the treatment of advanced renal cell carcinoma.
San Francisco-The development of targeted molecular therapies offers new avenues for combining pharmacologic and surgical therapies in the treatment of advanced renal cell carcinoma. Results from early trials suggest that nephrectomy plus adjuvant or neoadjuvant drug treatment can be more effective than either treatment alone, but definitive results are still several years away.
The overall 5-year survival rate for metastatic kidney cancer is less than 10%, noted Hendrik Van Poppel, MD, PhD, of University Hospitals Leuven, Belgium.
"Until recently, treatment for metastatic kidney cancer was nephrectomy and toxic and often ineffective immunotherapy," Dr. Van Poppel told the 2010 Genitourinary Cancers Symposium. "Using these agents as adjuvant therapy produced similar outcomes to surgery alone or even worse results. Using them as neoadjuvant therapy gives you poor response and toxicity."
Three randomized double-blind phase III adjuvant trials are currently in progress, Dr. Van Poppel said. ASSURE began in May 2006 to test adjuvant sorafenib or sunitinib in unfavorable RCC. SORCE, which compares sorafenib with placebo in patients with resected primary RCC at high or intermediate risk of relapse, began in June 2007. S-TRAC, which compares efficacy and safety of sunitinib versus placebo for the treatment of patients at high risk of recurrent RCC, began in July 2007.
S-TRAC is expected to be completed in December 2010, and results could be released in 2011. SORCE is expected to run through August 2012 and ASSURE through April 2016.
Concerns over therapies persist
Proposals to use these agents as neoadjuvant therapy have generated significant controversy, Dr. Van Poppel said. Opponents note the lack of well-defined endpoints to determine the optimal time of nephrectomy. There are also concerns that targeted agents may impair wound healing and contribute to perioperative bleeding or thromboembolic events.
Proponents counter that neoadjuvant therapy could facilitate patient selection for nephrectomy: If there is no response, there will be no nephrectomy. Tumor response would mean downstaging or downsizing the primary tumor, which would facilitate surgery.
Small studies have found that neoadjuvant therapy can reduce the size of the primary tumor and primary tumor thrombus, bulky lymph nodes, and metastatic lesions.
"Most of the data in neoadjuvant use have been from case studies," Dr. Van Poppel said. "But cases have been presented with a complete pathological remission-the tumor completely disappears. We have evidence that it can work."
A retrospective analysis of neoadjuvant sunitinib in 19 patients with advanced RCC at Cleveland Clinic found that 42% of primary tumors shrank an average of 24% at 6 months (J Urol 2009; 181:518-23). The primary adverse events were fatigue (74%), dysgeusia (43%), hand-foot skin reaction (32%), and diarrhea (31%). There were no perioperative complications related to sunitinib therapy, and there were no problems with wound healing, bleeding, or thromboembolic events. A larger prospective phase II trial in patients with advanced unresectable primary tumors is under way.
A trial with 30 patients found that neoadjuvant sorafenib, used for a median of 32 days, decreased primary tumor size by a median of 9.6% and produced a 13% median loss of intratumoral enhancement (J Clin Oncol 2010; 28:1502-7). Researchers concluded that neoadjuvant sorafenib is safe and feasible. An early report from 44 patients given neoadjuvant bevacizumab or sunitinib at M.D. Anderson Cancer Center, Houston, concluded that neoadjuvant treatment is safe and does not increase surgical morbidity or perioperative complications (J Urol 2008; 180:94-8). Several retrospective analyses of neoadjuvant targeted therapies reported positive clinical responses.
Two phase III trials are under way. CARMENA is an open-label trial with sunitinib designed to address two questions: Is nephrectomy clinically beneficial in patients treated with targeted agents, and if nephrectomy is necessary, which intervention should be administered first, surgery or sunitinib? The trial opened in May 2009 and primary completion is expected in May 2015. In the meantime, the European Organization for Research and Treatment of Cancer is seeking regulatory approval for a randomized trial to compare sunitinib as neoadjuvant and adjuvant therapy.
"We do not know whether adjuvant or neoadjuvant treatment strategies will actually benefit our patients or not, but these randomized trials will show the way," Dr. Van Poppel said.
Dr. Van Poppel disclosed that he is a consultant/adviser for Antigenics, AstraZeneca, Bayer, Cougar Biotechnology, Ferring, Gen-Probe, Pfizer, sanofi-aventis, and Wyeth.