Debate: Upfront cytoreductive nephrectomy or not?

The EAU20 virtual meeting featured a thematic session looking at the controversy in renal cancer surgery considering the timing and necessity of cytoreductive nephrectomy.

The EAU20 virtual meeting featured a thematic session looking at the controversy in renal cancer surgery considering the timing and necessity of cytoreductive nephrectomy. Prof. Axel Bex (The Royal Free London NHS Foundation Trust, UK) argued that cytoreductive nephrectomy should only be performed in selected patients after systemic treatment1. The counterpoint was provided by Prof. Antonio Finelli (University Health Network, Toronto, Canada) who argued in favor of upfront cytoreductive nephrectomy2.

Prof. Bex commenced his debate by stressing that his arguments only apply to patients who require systemic therapy, such as those diagnosed with metastatic renal cell carcinoma (mRCC). There is evidence from two trials investigating the role and sequence of cytoreductive nephrectomy. The CARMENA trial randomized 450 patients equally to 1 of 2 arms: either upfront nephrectomy followed by adjuvant sunitinib, or upfront sunitinib alone. With a median follow-up of 50.9 months, outcomes from the upfront sunitinib arm were non-inferior to those in the nephrectomy-sunitinib group with regard to overall survival (OS; 18.4 months in the sunitinib-alone group vs 13.9 months in the nephrectomy-sunitinib group; HR 0.89; 95% CI 0.71-1.10), thus the researchers concluded that cytoreductive nephrectomy was not strictly beneficial3

The second trial, SURTIME, assessed upfront nephrectomy versus upfront sunitinib prior to nephrectomy in 99 accrued patients. OS was improved in the deferred cytoreductive nephrectomy arm when compared with immediate surgery (32.4 months vs 15.0 months; HR 0.57; 95% CI 0.34-0.95; P=0.03)4. The 17.4 months survival difference observed by delaying surgery in SURTIME was critical, Prof. Bex argued, because receiving immediate systemic therapy is essential to manage mRCC.

Lastly, a posthoc analysis of CARMENA with a longer follow-up (median 61.5 months) continued to support this trend. Looking specifically at the subgroup of patients with 2 risk factors (51.9% of all participants; most risk factors were low hemoglobin, high corrected calcium, or neutrophils), sunitinib alone had better survival outcomes, with a median OS of 31.2 months compared with 16.6 months for patients receiving nephrectomy + sunitinib (HR 0.61; 95% CI 0.41-0.91; P=0.015)5

In summary, Prof. Bex restated that cytoreductive nephrectomy is not superior to upfront systemic therapy in intermediate- and poor-risk mRCC patients; patients should be given upfront systemic therapy, with the opportunity for deferred nephrectomy upon adequate response and lack of disease progression with upfront systemic therapy. Evolution to upfront immune-oncology monotherapy or combinations, either as an immunotherapy doublet or in combination with a VEGF inhibitor, will likely make upfront cytoreductive nephrectomy even less likely to occur.

Prof. Finelli counter-argued that despite CARMENA and SURTIME, there is still a viable role for cytoreductive nephrectomy. In particular, criticism of SURTIME, which accrued less than one-fourth of the patients for which it was powered, led many experts to claim that the results should be considered exploratory.

Historically, the rationale for cytoreductive nephrectomy has rested on 3 observations. Firstly, targeted therapies or immunotherapy do not typically induce durable responses. Secondly, anecdotal reports of spontaneous metastases regressing after nephrectomy fuels hope. Lastly, we know from the interferon era that surgery meaningfully diminishes the burden of disease in select patients demonstrating an overall survival benefit to cytoreductive nephrectomy. 

One study saw improved 3-month and 6-month survival in mRCC patients treated with initial cytoreductive nephrectomy compared with those treated with targeted therapy prior to cytoreductive nephrectomy6. Furthermore, one study suggests that patients who underwent upfront cytoreductive nephrectomy had a median OS of 20.6 months versus 9.6 months among those not undergoing cytoreductive nephrectomy (HR 0.60; 95% CI 0.52-0.69)7. A recent systematic review on this topic concluded that cytoreductive nephrectomy was associated with improved OS in 10 non-randomized mRCC studies, and CARMENA showed that cytoreductive nephrectomy followed by sunitinib was non-inferior to sunitinib alone8.

In his summarising comments, Prof. Finelli postulated that cytoreductive nephrectomy remains a valuable intervention in mRCC. Although OS remains the gold standard, other outcomes can be equally important to mRCC patients, including the psychological burden of leaving a tumor in situ. Patient selection is key, yet patient stratification and/or biomarker development are still developing fields.

References:
1. Bex A, et al. Cytoreductive Nephrectomy: What Do We Know? Cytoreductive Nephrectomy May Be an Option Only After Response. EAU20 Virtual Congress, 17-26 July 2020, Renal Cancer Controversies Session.
2. Finelli A, et al. Cytoreductive Nephrectomy: What Do We Know? Pro: Upfront Cytoreductive Nephrectomy. EAU20 Virtual Congress, 17-26 July 2020, Renal Cancer Controversies Session.
3. Méjean A, et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. N Engl J Med. 2018;379(5):417-427.  
4. Bex A, et al. Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial [published correction appears in JAMA Oncol. 2019 Feb 1;5(2):271]. JAMA Oncol. 2019;5(2):164-170. 
5. Méjean, A et al. Cytoreductive nephrectomy (CN) in metastatic renal cancer (mRCC): Update on Carmena trial with focus on intermediate IMDC-risk population. ASCO 2019, Abstract 4508.
6. Bhindi B,  et al. Comparative survival following initial cytoreductive nephrectomy versus initial targeted therapy for metastatic renal cell carcinoma. J Urol 2018;200:528-534. 
7. Heng DYC, et al. Cytoreductive nephrectomy in patients with synchronous metastases from Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol 2014;66:704-710.
8. Bhindi B, et al. Systematic review of the role of cytoreductive nephrectomy in the targeted therapy era and beyond: An Individualized Approach to Metastatic renal cell carcinoma. Eur Urol 2019 Jan;75(1):111-128.

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