Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)
CN in the era of molecular targeted agents has not been prospectively evaluated but has been generally accepted based on the earlier studies when performed prior to cytokine-based therapy [23, 24]. The current 2015 NCCN guidelines recommend CN in properly selected patients prior to immunotherapy . With regard to patients prior to contemporary systemic targeted therapy, the NCCN guidelines cite retrospective series showing CN continues to play a role in patients treated with VEGF-targeted agents while anticipating the results from contemporary randomized trials [4, 5].
The overwhelming majority (90+%) of patients enrolled in clinical trials of targeted therapies have by default undergone prior CN. The one exception has been in the Global ARCC study of the mammalian target of rapamycin (mTOR) inhibitor, temsirolimus . ARCC was a phase 3 randomized trial of interferon alpha, temsirolimus, or a lower dose combination of both agents in patients with poor risk mRCC of any histology. The primary tumor was not removed in 33% of the patents and 20% had non-clear cell histology. Temsirolimus improved OS among patients with mRCC and poor prognosis features. A subsequent subset analysis of this trial explored the influence of nephrectomy and histology on overall and PFS . The improvement in PFS and OS in patients treated with temsirolimus was seen in both clear and non-clear cell histologies, while nephrectomy status did not impact the PFS or OS. Most of these patients had poor prognostic features and would not have been ideal candidates for CN .
Multiple retrospective analyses of patients treated with targeted therapy have provided conflicting data on the benefit of CN. In a multiinstitutional analysis, Choueiri et al. reported on the outcomes of 314 patients receiving targeted therapy for mRCC . Favorable risk and younger patients were more likely to undergo CN. After adjusting for significant differences in baseline prognostic factors, patients undergoing CN had a significantly improved OS (HR 0.44; CI 0.32–0.59, p < 0.01). As would be expected, this survival advantage did not extend to patients classified as poor risk (similar to Global ARCC).
Heng et al. published a large multi-institutional data set assessing the benefit of CN from patients enrolled on the International Metastatic Renal Cell Carcinoma Database Consortium . A total of 1,658 patients with a diagnosis of synchronous mRCC were included, with 982 of these patients undergoing CN and 676 not receiving surgery. As expected, baseline clinical prognostic factors varied between the groups with those undergoing CN having more favorable clinical features. After adjusting for the prognostic differences between the two groups, the authors reported results favoring CN with the median OS (20.6 vs. 9.5 months; p < 0.0001; Fig. 10.2) and PFS (7.6 vs. 4.5 months; p < 0.001). In this series, patients surviving less than 12 months did not appear to benefit from CN. This study, along with others, highlights the importance of selecting patients most likely to benefit from CN .
There are currently two phase III randomized trials attempting to provide insight into the role of CN in the era of targeted therapy and on the question of timing of nephrectomy with regard to systemic targeted therapies. The CARMENA trial is a randomized phase III trial comparing the first-line treatments of (1) CN followed by sunitinib to sunitinib monotherapy in clear cell RCC . The anticipated enrollment is 576 patients with a primary end point of OS. This study will provide the only level I evidence assessing the role of CN in patients with mRCC treated with contemporary systemic targeted therapies. The second trial is being performed through the EORTC by randomizing patients to either (1) upfront CN followed by sunitinib versus (2) four 6-week cycles of sunitinib (4 + 2 schedule) followed by CN only in patients with non-progressive metastases . The study is attempting to enroll 458 patients with the primary end point being PFS. Given the morbidity of CN and the considerable percentage of patients experiencing progression in the interval between surgery and the start of systemic therapy, this trial may provide evidence supporting the presurgical treatment of mRCC patients as a “litmus test” to further select candidates for CN. Completion of accrual and results from both of these trials are highly anticipated.
Fig. 10.2. Kaplan-Meier overall survival from the initiation of targeted therapy for 1,633 mRCC based on receiving a cytoreductive nephrectomy 
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