Daniel George, MD
Formal discussant of the CARMENA trial, Daniel George, MD, of Duke University Medical Center, Durham, North Carolina, had reservations about the broad application of these results. “CARMENA was designed to reassess the value and role of nephrectomy in patients who present with metastatic renal cell carcinoma. A noninferiority trial is an appropriate design. However, the study took a long time to accrue because of the strongly held belief that surgery is beneficial to these patients. As such, many patients with low-volume metastatic disease were not included. The patients enrolled represented a more--advanced and poor-risk population, which was not the ideal population. These patients had a high metastatic tumor burden, accounting for about 40% of the total tumor burden. While the results support starting with sunitinib for this patient population, we still do not know whether patients with a low metastatic burden would benefit more from cytoreductive nephrectomy first.”
“This is an important study. It represents our best data on the role of nephrectomy, with almost twice the number of patients in previously reported studies. These results are in line with what we would expect, that sunitinib (Sutent) alone is superior. This will change my practice. For patients with a higher metastatic burden, start with sunitinib. But for patients with low-volume, asymptomatic, metastatic renal cell carcinoma, you could start with sunitinib and consider nephrectomy as consolidation,” Dr. George continued.
“The field has evolved, with more options than never before, including pazopanib (Votrient), ipilimumab (Yervoy)/nivolumab (Opdivo), and cabozantinib (Cabometyx). Prospective randomized trials with these agents would take many years to read out. Based on subgroup analyses, I believe it is reasonable to extrapolate these results to other systemic therapies,” Dr. George said. “With systemic immunotherapy, it makes sense [to forgo nephrectomy] because leaving the primary tumor in place is an abundant source of neoantigens that stimulate the immune system to attack the cancer. In addition, like nephrectomy, initial surgery could result in increased inflammatory and angiogenic cytokine release, which promotes unresected tumor growth and resistance.
The new standard of care for stage IV renal cell carcinoma and high-volume metastasis is systemic therapy as first choice, with palliative nephrectomy and systemic therapy as second choice. For low-volume metastatic disease, the choice can be either nephrectomy with systemic therapy or observation to follow or systemic therapy plus or minus surgery. This will depend on surgeon and patient preference,” Dr. George stated.
Thoughts on Patient Selection
In an accompanying editorial in The New England Journal of Medicine, Robert J. Motzer, MD, and Paul Russo, MD, emphasized the importance of patient selection.1 They stated that there could have been a selection bias, more heavily weighted for poor-risk patients, and that physicians may have decided to treat intermediate-risk patients suitable for combination therapy outside the context of the trial.
Robert J. Motzer, MD
Paul Russo, MD
“The selection of patients plays a critical role in day-to-day patient care as well as in clinical trial design. We think that nephrectomy in properly chosen patients with metastatic renal-cell carcinoma remains an essential component of care,” Drs. Motzer and Russo wrote. They continued: “For practicing surgeons and medical oncologists, these data should not lead to the abandonment of nephrectomy but instead emphasize the importance of careful selection of patients undergoing nephrectomy, on the basis of published risk models. The main focus is on pretreatment risk features, resectability of the primary tumor, status of health, and presence of other medical conditions in determining who is most likely to benefit.” ■
DISCLOSURE: Dr. George is a speaker for Exelixis, Bayer, and Sanofi; a consultant for Astellas, AstraZeneca, Bayer, Exelixis, Innocrin, Janssen, Pfizer, and Sanofi; and has received research support from Bayer, Dendreon, Exelixis, Innocrin, Janssen, Novartis, and Pfizer. Dr. Motzer has received consulting fees or institutional research support from Genentech/Roche, Pfizer, Bristol-Myers Squibb, Novartis, Exelixis, Eisai, and Merck. Dr. Russo reported no conflicts of interest.
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