The CARMENA trial presented at the 2018 ASCO Annual Meeting, published simultaneously in The New England Journal of Medicine,1,2 and reported in this supplement to The ASCO Post, evaluated the role of nephrectomy in patients with metastatic renal cell carcinoma. Formal discussant of the trial, Daniel George, MD, of Duke University Medical Center, Durham, North Carolina, had reservations about the broad application of these results.
Daniel George, MD
“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 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 ever before, including pazopanib, ipilimumab/nivolumab, and cabozantinib. 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. ■
DISCLOSURE: Dr. George is a speaker for Exelixis, Bayer, and Sanofi; a consultant for Astellas, AstraZeneca, Bayer, Exelixis, Innocrin, Janssen, Pfizer, and Sanofi. He has received research support from Bayer, Dendreon, Exelixis, Innocrin, Janssen, Novartis, and Pfizer.
1. Méjean A, Escudier B, Thezenas S, et al: CARMENA: 2018 ASCO Annual Meeting. Abstract LBA3. Presented June 3, 2018.
2. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med 379:417-427, 2018.
In a trial with a modified primary endpoint due to slow accrual reported in JAMA Oncology,1 Axel Bex, MD, PhD, and colleagues found that deferred cytoreductive nephrectomy after sunitinib did not improve the 28-week progression-free rate vs immediate nephrectomy followed by sunitinib in patients...