Several retrospective small studies have indicated that survival

Several retrospective small studies have indicated that survival is incrementally better with larger tumor burden removed with CN; therefore, CN should be mainly used in patients where most of the tumor bulk is in the retroperitoneum or kidney [43–46]. In patients with T4 disease, CN is generally associated with poor survival and should mainly be considered as last resort for palliative purposes in this setting [47]. In patients with non–clear cell histology, the results of retrospective studies are contradictory, with some studies showing worse survival in patients with non–clear histology undergoing CN (compared with patients with clear cell RCC undergoing CN) [48], whereas others showing improved survival in patients with non–clear cell RCC undergoing CN (compared with patients with non–clear cell not undergoing CN) [49].

Sequence of CN in setting of multimodal therapy
With the widespread use of targeted therapy agents in the treatment of mRCC, there has been a significant phenomenon observed in many studies that did not occur with the use of immunotherapy agents, and that is the downsizing of some primary tumors. Many retrospective studies have documented 3X FLAG Peptide in largest diameter primary tumor size between 7% and 24%, with 6% to 23% of responses qualifying as partial response according to the RECIST criteria [50], after the use of various targeted agents such as sunitinib, sorafenib, and bevacizumab [51–54]. However, it is also acknowledged that decrease in tumor size may be owing to increase in necrosis or various responses to widely heterogeneous tumor foci; hence, a reduction in size may not represent the best end point in mRCC. Nevertheless, with this observation, the idea of using targeted therapy as preoperative agents for patients with locally advanced and even mRCC has been considered. In the context of mRCC, the term preoperative or presurgical rather than neoadjuvant should be used to imply that the intent targeted therapy is not curative in this setting, hence, it is not truly neoadjuvant therapy before consolidative surgery.
Although there is no definitive evidence to date that can steer the argument one way or another, the theoretical use of preoperative targeted therapy in the metastatic setting includes downsizing of tumor before CN, which may facilitate surgery for locally advanced tumors with bulky lymphadenopathy or decrease in size of IVC tumor thrombus or both. In addition, preoperative therapy allows for timely delivery of systemic therapy to the metastatic disease and act as a litmus test for better patient selection, such that patients who respond to therapy are most likely to benefit from CN, whereas those that rapidly progress on therapy could avoid potential surgical morbidity and remain on medical treatment without undergoing CN. Several small retrospective series have been published that explore the role of preoperative targeted therapy in mRCC. In a study by Rini et al., 28 patients with unresectable RCC, 19 of which had distant metastases, received continuous daily dosing of sunitinib. A 22% median decrease in primary tumor size, corresponding to a median absolute reduction of 1.2cm, was noted. In total, 13 patients (45%) met the primary end point of being able to undergo nephrectomy after preoperative sunitinib. All patients had viable RCC in the surgical specimen, and surgical morbidity was reported to be consistent with prior experience of nephrectomy in patients without preoperative therapy according to the authors [55]. In another study, Powles et al. [56] examined the outcomes or 66 patients with mRCC who received 2 to 3 cycles of sunitinib before surgery. Sunitinib was administered in 6-week cycles with 4 weeks on and 2 weeks off and was stopped a median of 29 days before CN. Overall, 68% of patients had intermediate-risk disease, and CN was not performed in 12 owing to disease progression. The PFS was 6.3 months (95% CI: 5.1–8.5 months), and OS was 15.2 months (95% CI: 10.3-not applicable), with improved OS for the intermediate-risk group vs. poor-risk group, 26.0 months (95% CI: 13.6-not applicable) vs. 9.0 months (95% CI: 5.8–20.5), respectively (P<0.01). Interestingly, 17 (36%) patients progressed during the 2-week treatment break, although the vast majority stabilized once sunitinib was restarted. This study demonstrated improved survival in the intermediate-risk patients compared to the poor-risk group, although there was no control arm and therefore results should not be generalized. Finally, in a multi-institutional retrospective study by Stroup and colleagues, 17 patients with mRCC underwent upfront CN followed by sunitinib, and 18 underwent preoperative sunitinib therapy followed by planned CN [57]. Of these patients, 11 (61%) had PR or SD per the RECIST criteria and underwent CN, and 7 (39%) progressed and did not undergo CN. Mean times to disease-specific death were 29.2 months for the upfront CN group, 28.7 months for the preoperative sunitinib followed by CN group, and 4.6 months for the preoperative sunitinib group that did not respond and therefore did not undergo CN (P = 0.025). Therefore, it appeared that nonresponders had a poor prognosis, and overall, those with preoperative sunitinib who responded and proceeded to CN appeared to fare significantly better than patients receiving upfront CN and then undergoing sunitinib treatment. Although this is a small retrospective study with a small patient population, it helps to shed light on the dilemma of timing of CN in multimodal treatment of mRCC.