Renal Cell Cancer: Role of Cytoreductive Nephrectomy Remains Unclear in Targeted Therapy Era; Retrospective Analysis Suggests Benefit

GU Cancers ConferenceSAN FRANCISCO––Patients with metastatic renal cell carcinoma (RCC) who undergo cytoreductive nephrectomy prior to treatment with VEGF-targeted therapy may have longer overall survival than patients who do not have surgery, according to a relatively large retrospective analysis presented here at the Genitourinary Cancers Symposium. Experts at the multidisciplinary meeting cosponsored by ASCO, ASTRO, and the Society of Urologic Oncology, however, emphasized the need for prospective randomized trials to definitively answer the question and described trials already ongoing in Europe. Prospective randomized trials demonstrated that cytoreductive nephrectomy extended overall survival by approximately six months in patients with metastatic renal cell cancer during the era of cytokine therapy, but the value of the surgery needs to be reexamined following the introduction of VEGF-targeted therapies. To begin to consider the issue, Toni K. Choueiri, MD, a medical oncologist at Dana-Farber Cancer Institute and an instructor at Harvard Medical School, and colleagues examined data from the Renal Cell Cancer Consortium, which includes seven institutions in the United States and Canada.TONI K. CHOUEIRI, MD: “In this retrospective analysis, cytoreductive nephrectomy improved overall survival in patients with metastatic RCC treated with VEGF-targeted agents even after controlling for known prognostic factors. However, the benefit seems to be marginal in patients in the poor-risk group or with a poor Karnofsky performance status.”A total of 314 patients with metastatic RCC were identified who had not received VEGF-targeted therapy or cytoreductive nephrectomy for earlier disease and who received sorafenib, sunitinib, or bevacizumab for metastatic disease. Of those, 201 had undergone cytoreductive nephrectomy and 113 had not. The patients who had surgery tended to be younger, have a better Karnofsky performance status, and a longer time between diagnosis and treatment initiation. After a median follow-up time of 28.5 months, patients who underwent nephrectomy had a median overall survival of 19.8 months compared with 9.4 months for patients who did not have surgery. The surgery was associated with a statistically significant 56% reduction in the risk of death. Using the same database, Dr. Choueiri and colleagues previously identified independent predictors of poor overall survival in the era of targeted therapy (Heng et al; JCO 2009:27:5794-5799). The predictors included Karnofsky performance status lower than 80, less than one year between diagnosis and initiation of therapy, anemia, hypercalcemia, neutrophilia, and thrombocytosis. The prognostic factors identified are very similar to the criteria included in the Motzer risk factors. When the researchers divided the 314 patients into favorable-, intermediate-, and poor-risk groups based on the number of adverse prognostic factors, the intermediate-risk group was found to have the largest detectable benefit from surgery. Nearly all of the patients (22 of 23) in the favorable-prognosis group underwent surgery, disallowing a comparison of survival. There was, however, a 54% improvement in overall survival associated with the surgery in the 143 patients in the intermediate-risk group. In contrast, there was no statistically significant benefit associated with surgery for poor-risk patients. Dr. Choueiri said that because many physicians rely heavily on a patient's performance status when deciding whether to recommend surgery, the researchers examined the impact of cytoreductive nephrectomy on patients with a good or poor performance status. Those with a Karnofsky performance status of 80 or above had a statistically significant improvement in survival associated with the surgery (23.9 months with surgery vs 14.5 months without surgery).PAUL RUSSO, MD, noted that randomized trial data are needed because it is not an easy decision whether to send patients to surgery. “It is a very tough call…..So now we have more spectacular drugs that show early and tremendous responses. The surgeon doesn't want to do an operation and debilitate a patient and render them unable to ever get the medicine—that defeats the purpose. So the stubborn use of cytoreductive nephrectomy would defeat you….In the absence of definitive prospective data to guide surgery decisions, very strong clinical judgment is integral to the decision-making process.”In contrast, the difference in survival was not statistically different in patients with a Karnofsky performance status less than 80 (10.1 months with surgery vs 6 months without surgery). “In this retrospective analysis, cytoreductive nephrectomy improved overall survival in patients with metastatic RCC treated with VEGF-targeted agents even after controlling for known prognostic factors,” Dr. Choueiri concluded. “However, the benefit seems to be marginal in patients in the poor-risk group or with a poor Karnofsky performance status.” Prospective Trials in the Works Two prospective randomized Phase III trials are currently enrolling patients in Europe. In the CARMINA trial, investigators will randomize 576 patients with metastatic RCC to either cytoreductive nephrectomy followed by sunitinib or to sunitinib alone. The results, which are expected in 2015, should answer the basic question about the role of surgery in the era of targeted therapies. The second trial, sponsored by the European Organization for Research and Treatment of Cancer, will examine the order of therapy, with 440 metastatic RCC patients randomly assigned to sunitinib followed by surgery or surgery followed by sunitinib. The primary endpoint of both trials is progression-free survival, and Hein van Poppel, MD, PhD, Chairman and Professor of Urology at University Hospitals Leuven in Belgium, described the trials in an Educational Session at the meeting. During the discussion at the end of the talk, one of the co-primary investigators for the CARMINA trial asked Dr. Choueiri why American investigators have neither launched a trial of their own to answer this question nor joined the European trials. He said he was surprised by the lack of participation and pointed out that US participation would speed recruitment and lead to a more rapid answer. Although Dr. Choueiri declined to comment on whether trials were being designed in the United States, the co-chair of the session, Paul Russo, MD, a surgeon on the Urology Service at Memorial Sloan-Kettering Cancer Center, later told OT that the cooperative groups are working on such trials. Randomized trial data are needed because it is not an easy decision whether to send patients to surgery, he said. “It is a very tough call.” In a historical series that looked at cytoreductive nephrectomy in patients treated at the National Cancer Institute, investigators found that approximately 40% of the patients never recovered sufficiently from their surgery to receive cytokine therapy. “So now we have more spectacular drugs that show early and tremendous responses,” Dr. Russo continued. “The surgeon doesn't want to do an operation and debilitate a patient and render them unable to ever get the medicine—that defeats the purpose. So the stubborn use of cytoreductive nephrectomy would defeat you.” In the absence of definitive prospective data to guide surgery decisions, Dr. Russo says “very strong clinical judgment” is integral to the decision-making process. And, he said that in his mind, that was what Dr. Choueiri was exploring by looking at factors that indicate good health versus poorer health. Dr. van Poppel concurs that Dr. Choueiri's findings, although retrospective, support the continued use of cytoreductive nephrectomy in favorable- and intermediate-risk patients. US Investigators Should Participate That said, during an interview he emphasized the need for the US cooperative groups to participate in trials. “It is a bit disappointing that there is so little involvement with the American experts in randomized trials,” he said. “The accrual of these [European] trials is fairly good, but I think we could just speed up the process and come to evidence-based propositions more quickly if the Americans would participate in these trials.” In the absence of that evidence, though, he thinks there is no reason to change one's approach. “There is no reason, because we have the targeted agents not to do cytoreductive nephrectomy,” Dr. van Poppel said. “I am very happy with the presentation made by Dr. Choueiri, which again confirms that the outcome of the patients who can have cytoreductive nephrectomy—this is good- and intermediate-risk groups—do better when the kidney is out.”

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