CYTOREDUCTIVE NEPHRECTOMY IN THE ERA OF TARGETED THERAPY

An enjoyable benefit of being in this field for as long as I have is seeing the evolution of knowledge and the impact that it has on therapies for our patients. The pendulum has swung several times when it comes to nephrectomy for patients with metastatic renal cell carcinoma. Spontaneous remissions had been reported following nephrectomy in metastatic disease 40 years ago.^[1] Those remissions were rare, however, and no clear prognostic factors were known. As a result, the recommendations in the urologic literature in 1987 were that nephrectomy should not be performed.^[2] The problem, unfortunately, was that we had few other options for therapy.

The addition of immunotherapies, namely interferon and interleukin-2, changed things. Response rates weren't great but they were better than anything we had before. The rationale behind nephrectomy was that the surgery might stimulate the natural immune response, leading to metastatic responses. To address that question further, two clinical trials looked at the addition of nephrectomy to interferon in metastatic patients. In a SWOG trial of 246 patients, the addition of nephrectomy improved overall survival from 8 months to 11 months.^[3] A European Organisation for Research and Treatment of Cancer (EORTC) trial with the same treatment arms showed that adding nephrectomy to interferon more than doubled overall survival, from 7 months to 17 months.^[4]

In 2006, the US Food and Drug Administration approved sunitinib for use in renal cell carcinoma. This was the start of impressive advancement in this disease. We have started to see significant responses and extended survival in patients with metastatic disease, a concept we dared not imagine previously. That seems to also have changed how we think of cytoreductive nephrectomy. The data demonstrating benefit from this approach were with therapies not nearly as effective as the newer treatments. As the use of targeted therapies increased, the use of cytoreductive nephrectomy seemed to decrease. Sarah Psutka, MD, and colleagues^[5] looked at the impact of targeted therapies in a 2015 report and described a fall in cytoreductive nephrectomies from 31% in 2005 to just under 15% in 2010.

Two recent publications suggest that we should rethink things yet again. In the June 20, 2016, issue of Journal of Clinical Oncology, Nawar Hanna, MD,^[6] reported a survival analysis of patients treated with targeted therapy, comparing whether cytoreductive nephrectomy was used or not. They reviewed data from the National Cancer Database on 15,390 metastatic renal cell carcinoma patients treated with targeted therapies, 35% of whom underwent cytoreductive nephrectomy between 2006 and 2013. They found an increase in overall survival from 7.7 months to 17.1 months with the addition of nephrectomy. These results mirror the older data from the EORTC trial. A more impressive view of the data comes from analyzing 3-year survival, which increased from 9.8% to 27.7% with the addition of nephrectomy; 11.6% of the patients underwent nephrectomy following targeted therapy. In those patients, the 3-year survival rate was even better at 35.3%. Granted, there is a real selection bias in this group, but those are impressive data.

Fausto Petrelli, MD, of Treviglio Hospital in Italy, and colleagues^[7] have reported a systematic review and meta-analysis of the same question. The analysis, which included 12 manuscripts with 39,953 patients, found that the use of cytoreductive nephrectomy decreased the hazard ratio of death to 0.46 (95% confidence interval, 0.32-0.64). This benefit was seen, albeit to a small degree, even in non–clear cell pathologies.

Although some guidelines list cytoreductive nephrectomy as an option in metastatic disease, there are no reported prospective data. There is an ongoing prospective trial, however. CARMENA is a French study randomizing the addition of nephrectomy to the use of sunitinib. Various authors have expressed concern that, with a proposed enrollment of 576 patients, the trial may be underpowered. This could be a difficult trial to mount in the United States, but it should at least be considered.