At SUO 2018, several powerhouses in renal cell carcinoma research gathered on stage to discuss this issue. In a panel led by Dr. Vitaly Margulis, medical oncologist Dr. Robert Figlin and urologist Dr. Robert Flanigan joined the CARMENA lead author Dr. Arnaud Mejean on stage. Figlin was a pioneer in systemic therapy for metastatic RCC and was the senior author on the pivotal phase III trial that led to sunitinib’s FDA approval. Flanigan, on the other hand, holds one of the most often cited manuscripts related to cytoreductive nephrectomy in the cytokine era. His study, done through the Southwest Oncology Group, employed a similar randomization to cytoreductive nephrectomy or not but used interferon-alfa (the standard at the time) as the systemic therapy regimen. Figlin pulled no punches, stating that CARMENA was “incredibly flawed” and citing inherent biases in patient inclusion. Specifically, he noted that patients with low volume metastatic burden and high volume primary disease may have been taken out of the randomization. In several case discussions, Flanigan echoed these opinions. The importance of risk stratification was emphasized, and Flanigan stated his preference for the MD Anderson criteria reported by Culp et al (Cancer 2010) over other criteria commonly applied in metastatic disease (e.g., Heng or Motzer criteria).
Seeing these giants on stage criticizing the data for CARMENA reaffirmed my feelings on the trial. Recently, Dr. Sumeet Bhanvadia (USC Urology) and I put together a commentary in Nature Reviews Urology on the topic. Above the issue of selection bias, we discussed the relatively high rates of attrition from protocol-defined therapy. A large number of patients assigned to cytoreductive nephrectomy never received the procedure, and similarly, a large number of patients assigned to sunitinib alone received surgical intervention. Perhaps the biggest issue, however, is that the field of kidney cancer has moved far beyond sunitinib. Our first line considerations include nivolumab ipilimumab and cabozantinib and soon will extend to include combinations of tyrosine kinase inhibitors (TKIs) and immunotherapy. We will need to move towards pragmatic trial designs to assess the relevance of cytoreductive nephrectomy in this setting.
To this end, Drs. Ulka Vaishampayan (Karmanos) and Hyung Kim (Cedars Sinai) have proposed an innovative trial through SWOG. Patients with de novo metastatic RCC with received either nivolumab/ipilimumab alone or with cytoreductive nephrectomy. Some may question why a TKI with immunotherapy would not be considered the preferred regimen – my stance on the matter is that TKIs may cloud the benefit of nephrectomy by either causing would healing issues or potentially delaying initiating of systemic treatment. In contrast, I’ve developed a certain comfort level with allowing for surgery alongside systemic therapy. I’m hoping that the study launches soon. There are, of course, efforts underway to develop novel immunotherapy combinations – it would be important to launch the SWOG trial before these become the established standard of care. If the upcoming SWOG trial accrues over the same timeframe as CARMENA (8 years!) it will surely face the same fate – the clinical data will lose relevance due to a shift in systemic therapy paradigm. Good luck Ulka and Hyung!
Written by: Sumanta Kumar Pal, MD
Further Related Content:
Watch: CARMENA: Practice Changing Strategies for Kidney Cancer
Watch: Treatment Strategies in Kidney Cancer and the Results of CARMENA