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The benefit of any treatment for any disease should be judged by whether it improves either survival or its quality. For adjuvant treatment of cancer, effects on overall survival (OS) are paramount: Patients and their oncologists are willing to accept substantial toxicity and short-term deficits in quality of life, if long-term survival can be improved. Assessment of the validity of randomized controlled trials (RCTs) evaluating adjuvant therapy requires that be addressed. If selection of patients and random assignment are appropriate, important questions are as follows:

• If the primary end point is not OS, is it a valid surrogate for OS?

• Is there evidence of bias in outcomes on the basis of the potential surrogate? Specifically, if the primary end point is disease-free survival (DFS), is there unequal loss of patients between the arms of the trial leading to informative censoring of patients before disease recurrence is recorded?

• Did the patients in the trial receive optimal therapy after disease recurrence?

• How consistent are the results of the trial with those of RCTs evaluating identical or similar treatments?

People who present with renal cell cancer (RCC) should, if possible, undergo surgery to remove all evident disease. A variety of prognostic models have estimated risk of recurrence and death on the basis of clinical characteristics of the tumor: For patients classified as high-risk -- e.g., stage 2 (>7 cm) with poor histology or invasion into surrounding tissue, or positive lymph nodes -- this risk is high, with 50% or more of patients eventually dying of their disease. Thus, there is a substantial need for effective adjuvant therapy to improve survival.

Recommendation of adjuvant pembrolizumab for high-risk RCC is now included in several guidelines, including those of the National Comprehensive Cancer Network and European Society for Medical Oncology, but the European Association of Urology regards (appropriately) the evidence of benefit as weak.

On the basis of the above critical review, we suggest that there is no proven role for adjuvant therapy with pembrolizumab or any other drug after nephrectomy for patients with high-risk RCC. Recommendations might change if follow-up of current trials reveals substantial improvement in OS, with assurance that most control patients received optimal therapy after relapse.

Future trials of adjuvant therapy should avoid the problems summarized in the figure by specifying OS as the primary end point and providing optimal treatment free of charge to control patients who relapse.

Read an interview about the "Comments and Controversies" review here and expert commentary about it here.