Increasing the evidence for surveillance of metastatic renal cancer

Abstract

Harrison et al are to be applauded for their prospective observational study of active surveillance (AS) for patients with metastatic renal cell carcinoma (mRCC) (the Metastatic Renal Cell Cancer Registry [MaRCC] study), which was conducted across a broad range of community and academic centers and is reported in this issue of Cancer. The authors provide baseline characteristics and outcome data from an orphan group of patients who have slowly progressing metastases that can be best described as too much for resection or focal treatment but too little for systemic therapy and can be temporarily managed by AS. Often, these patients were not enrolled in systemic therapy trials because inclusion frequently required documentation of progressive disease. Only 1 prospective, singlearm trial has investigated a strategy of AS in 48 patients with treatmentnaive, mRCC in the era of vascular endothelial growth factor (VEGF)targeted therapy. Most patients in that trial had developed metachronous mRCC (98%), and both the observation of asymptomatic patients beyond Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST 1.0) progression and the resection of metastases were allowed. The median time to systemic therapy was 14.9 months. Similarly, we retrospectively analyzed 40 patients (15.9%) from a database of 251 patients with primary mRCC who underwent cytoreductive nephrectomy followed by AS of lowvolume metastasis that was considered not completely resectable. Following a strategy of AS beyond RECIST progression in asymptomatic patients and focal therapy to control the most rapidly progressing lesions, systemic treatment could be deferred by a median of 16 months. In both studies, patients who had fewer metastatic sites or lower numbers of International Metastatic Database Consortium (IMDC) adverse risk factors had a longer AS period. It deserves mentioning that Harrison et al included 45 patients (32%) in the AS cohort who were previously diagnosed with metastases but had no evidence of disease (NED) present. This subgroup presumably underwent complete resection or received focal therapy for a single metastasis or oligometastatic disease before AS and is clinically not comparable to the 89 patients (69%) on AS who had metastases present. In the absence of effective adjuvant therapy, current guidelines recommend AS as the standard of care for patients who previously had a metastatic diagnosis but are without measurable disease after focal therapy. According to the authors, the enrolment of patients with mRCC on the MaRCC study who were resected to NED is a consequence of the protocol, which required prior radiographic or pathologic evidence of metastatic disease for inclusion, but not current measurable disease. In contrast patients who previously were diagnosed with metastases but have NED, the characteristics and outcome of patients with mRCC who undergo AS and have measurable metastases present remain illdefined because of the paucity of contemporary data. Therefore, additional realworld data for these patients are important for several reasons. First, they provide practical information who of these patients may be a candidate for AS of treatmentnaive mRCC. In the era of VEGFtargeted therapy, a randomised controlled phase 3 trial of pazopanib versus placebo in treatmentnaive mRCC which allowed crossover into the active treatment arm upon progression demonstrated no statistically significant difference in final overall survival (OS) between pazopanibtreated and placebotreated patients (22.9 vs 20.5 months, respectively; hazard ratio [HR], 0.91; 95% CI, 0.711.16; P = .224). Although this was not the objective of the trial, these are the only data from an OS analysis in a randomised setting suggesting that delaying effective VEGFtargeted therapy in treatmentnaive mRCC is not harmful in terms of survival. Immune checkpoint inhibitor (ICI) combination therapy has now replaced VEGFtargeted monotherapy in the firstline; however, despite an approximately 10% complete response rate, these combinations remain essentially noncurative and are associated with treatmentrelated adverse events