Sunitinib prior to planned cytoreductive nephrectomy: is this the new litmus test for metastatic renal cell carcinoma?

There is currently a paucity of high-level evidence regarding the role of cytoreductive nephrectomy in the era of targeted therapy. Patients diagnosed with metastatic renal carcinoma are confronted with difficult treatment decisions regarding the optimal treatment strategy and the timing of surgery in relation to targeted therapy. Level 1 evidence from two randomized trials has demonstrated improved overall survival with cytoreductive nephrectomy in the immunotherapy era [1–3]. Current clinical guidelines recommend cytoreductive nephrectomy followed by systemic therapy for patients presenting with metastatic renal carcinoma in which the primary tumor is surgically resectable and where the treatment is individualized based on symptoms and extent of metastatic disease [4]. In this issue of the Platinum Journal, Powles et al report a pooled analysis of two single-arm, phase 2 prospective trials and evaluate the efficacy and outcomes of sunitinib prior to cytoreductive nephrectomy [5]. Although the authors previously reported safety with neoadjuvant sunitinib prior to cytoreductive nephrectomy [6], this investigation describes the outcomes for the 66 patients who received two or three cycles of sunitinib prior to surgery. Two principal findings from this study help inform the debate regarding the optimal treatment strategy of targeted therapy and cytoreductive nephrectomy. First, patients who are in the Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate risk group can achieve a lasting response with a median overall survival >2 yr compared with patients harboring poor-risk disease, for whom a markedly shorter median overall survival of 9 mo was observed. These results suggest that patient selection, particularly by MSKCC risk stratification, is paramount in identifying those patients who are most likely to benefit from targeted therapy prior to cytoreductive nephrectomy. Second, the authors also observed that interruptions of sunitinib in preparation for surgery were associated with a high rate of disease progression. Although the study attempted to apply a rigorous protocol to minimize the time off of targeted therapy by reinitiating sunitinib within 2–3 wk following cytoreductive nephrectomy, there was considerable variation in the amount of time off of therapy following surgery. Consequently, 36% of the patients had disease progression by RECIST criteria and eight patients had new metastatic sites during the perioperative convalescence interval without sunitinib. Thus patients treated with sunitinib who plan to stop treatment for surgical intervention should be informed about the risk of disease progression. Although the authors acknowledge the need to validate their findings with a randomized trial, the results of this study suggest that cytoreductive nephrectomy may have limited efficacy in patients who experience disease progression following initiation of sunitinib or in patients with poor MSKCC risk. To date, no level 1 evidence has evaluated the efficacy of cytoreductive nephrectomy and targeted therapy, whether neoadjuvant or adjuvant, in patients presenting with metastatic renal carcinoma. Proponents of cytoreductive nephrectomy have extrapolated the results from randomized trials of sunitinib and immunotherapy in patients who underwent previous nephrectomy and then developed metastatic disease and from the two randomized trials that set the current treatment paradigm of cytoreductive nephrectomy [1–3,7,8]. Currently, an ongoing phase 3 trial is recruiting patients presenting with metastatic renal carcinoma to be randomized to immediate cytoreductive nephrectomy followed by sunitinib or three cycles of sunitinib (4 wk of sunitinib and then 2 wk off) followed by