“Location, location, location.” Anyone in the market looking at real estate is likely to hear this mantra-like advice. But what if you had a patient with metastatic renal cell carcinoma (mRCC) staring at the prospect of initial cytoreductive nephrectomy or initial targeted therapy as options. As a medical oncologist or urologist evaluating this case in the targeted therapy era, you should be accustomed to following what might be another mantra—“selection, selection, selection.” Yes, cytoreductive nephrectomy is the preferred standard in selected patients. And yet, targeted therapy may be the appropriate choice for other patients. In any case, the selection of patients plays a critical role in day-to-day patient care as well as in clinical trial design.
The Plenary Session at the 2018 meeting of the American Society of Clinical Oncology (ASCO) is likely to have a lasting and significant impact on the management of mRCC. For those of us who have closely followed the debate over the initial use of CN in the targeted therapy era, then “selection, selection, selection” of appropriate candidates for each modality should be the buzz words guiding the decision making process. But one can argue that this has always been true. Guidelines from the National Comprehensive Cancer Network (NCCN) and other groups have touted the importance of careful selection of patients undergoing nephrectomy on the basis of published risk models such as the Memorial Sloan-Kettering Cancer Center (MSKCC) paradigm. At the Plenary Session, there were four studies deemed to have the greatest potential impact on patient care out of the more than 5,800 abstracts featured as part of the 2018 ASCO Annual Meeting. One of these studies is the CARMENA (Cancer du Rein Metastatique Nephrectomie et Antiangiogeniques) trial.
A comprehensive report on CN in the targeted therapy era is presented in this issue of the Kidney Cancer Journal by my esteemed colleague, Michael Blute, MD, who has analyzed virtually all of the current studies leading up to CARMENA. Like other presentations at ASCO over the years, the CARMENA trial is a striking phenomenon, debunking myths and in some cases shattering preconceptions of long standing standards of care. Is it pivotal? Probably. Can it markedly change the paradigm as a so-called landmark trial? Not so fast, and here’s why.
Let’s not rush to judgement on this issue. In his enthusiasm to usher in the results of this trial, the lead author of CARMENA, Arnaud Mejean, MD, a urologist at the Department of Urology, Hôpital Européen Georges-Pompidou – Paris Descartes University in Paris, said: .“Our study is the first to question the need for surgery in the era of targeted therapies and clearly shows that surgery for certain people with kidney cancer should no longer be the standard of care.” The pitfall lies in the propensity to extrapolate the results to a segment of the patient population for which CN may still be the standard of care, and this needs to be emphasized. These pitfalls are expertly described in an Editorial in a June issue of the New England Journal of Medicine (Motzer RJ, Russo P. Cytoreductive nephrectomy—patient selection is key. N Engl J Med. DOI: 10.1056/NEJMe1806331).
As Motzer and Russo point out, interpretation of the results is complicated for a number of reasons. Although CARMENA is pivotal and will soon be followed by other reports addressing the same questions, Motzer and Russo drill down into its data and methodology and enable us to question assumptions some observers have made and clarify its implications. One caveat: a slow and incomplete enrollment over 8 years at 79 centers in Europe raises the possibility that many centers saw few patients with stage IV disease. Or, when surgeons saw patients with intermediate-risk disease who were likely to benefit from combination therapy, they were unwilling for them to undergo randomization and instead treated them outside the trial.
The Editorial delves into other considerations possibly confounding the results, all of which serve to call us back to fundamental standards of care, namely, not to abandon nephrectomy but instead carefully select patients undergoing nephrectomy on the basis of published and well recognized risk models.
Robert A. Figlin, MD