In today’s era of targeted therapy, CN is viewed as part of a multimodality management strategy that combines both surgery and systemic therapy. However, patients demonstrating rapid disease progression despite multimodal therapy, would not benefit from CN. Therefore, the proper selection of patients for CN, the optimal timing for this procedure, and individual choice of systemic therapy, are the main goals of current clinical research.
The underlying mechanisms resulting in the survival of patients undergoing CN is not clear. Suggested models include elimination of the source of circulating tumor cells, or elimination of cytokine signaling and proangiogenic growth factors, which potentially enhance metastatic seeding, and stimulate tumor growth at the metastatic sites. Mouse model of mammary carcinoma suggested that immunosuppression induced by the primary tumor can be reversed and returned to baseline after its removal. Simple disruption of these processes by removal of the primary tumor may be beneficial for mRCC patients, and provide a rationale as to why CN prolongs survival.
However, patient selection is the most important factor in the resulting outcomes. The most non-controversial indication for CN is in patients with solitary and oligo metastases, in whom complete resection of all metastatic lesions can be achieved. Complete metastasectomy may provide cure or significant delay in the start of the systemic treatment, thus decreasing toxicity and cost of targeted therapy. In contrast, the benefit of CN in patients with advanced disseminated metastatic disease is questionable at best.
According to the European Association of Urology (EAU) guidelines, CN is currently recommended in mRCC patients with good performance status (PS), large primary tumors, and low metastatic volume. CN is not recommended in patients with poor PS or International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) or Memorial Sloan Kettering Cancer Center (MSKCC) poor-risk disease, with relatively small primary tumors, and high metastatic volume, or with sarcomatoid tumors.
One of the significant drawbacks of immediate CN in mRCC setting is a delay in systemic therapy. Approximately one third of patients undergoing CN do not go on to receive systemic therapy due to rapid disease progression, patient refusal and perioperative death.
Therefore, as mentioned earlier, proper selection of patients is crucial. In the absence of predictive biomarkers, pre-surgical strategy has been proposed to identify good responders to targeted therapy, who are potentially long-term survivors, and can benefit from CN. On the other hand, it is imperative to avoid surgery in non-responders. Approximately 20% of patients with mRCC are refractory to first-line therapy and progress rapidly. These patients will unlikely benefit from CN.
A randomized EORTC trial (SURTIME) was designed to investigate whether the sequence of CN and systemic therapy in patients who receive sunitinib has an effect on patient outcome. Due to poor accrual a revised statistical design was proposed which assessed progression free survival at 28 weeks in patients who underwent immediate vs delayed CN after 3 cycles of sunitinib. Unfortunately the sample size precluded definitive conclusions, although a trend to OS improvement was seen for deferred CN. Results from another randomized controlled trial, CARMENA are expected to come out next year and provide additional clinical data on the role of CN.3 Better understanding of the biology of mRCC and new biomarkers are of paramount importance to aid patient stratification and consequent treatment choice.
Speaker: Vsevolod Matveev, MD Department of Urology, N.N. Blokhin Cancer Research Center, Moscow, Russia
Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at The 15th Meeting of the EAU Section of Oncological Urology ESOU18 - January 26-28, 2018 - Amsterdam, The Netherlands
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2. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. The New England journal of medicine 2001; 345(23): 1655-9.
3. Stewart GD, Aitchison M, Bex A, et al. Cytoreductive Nephrectomy in the Tyrosine Kinase Inhibitor Era: A Question That May Never Be Answered. European urology 2017; 71(6): 845-7.