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Cytoreductive nephrectomy in the current treatment algorithm

The two recent prospective randomized trials CARMENA and SURTIME have changed the therapy paradigm of metastatic renal cell carcinoma. The CARMENA trial was conducted to investigate whether cytoreductive nephrectomy (CN) is required in the targeted therapy area, whereas SURTIME studied whether deferred CN in combination with sunitinib can be used to identify patients with inherent targeted therapy resistance. In the current review, we provide a comprehensive discussion of two randomized studies and the current evidence with up-do-date algorithms for treating primary metastatic clear-cell renal cell carcinoma in the era of targeted therapy and immune-checkpoint inhibition.


Introduction
CARMENA 1 and SURTIME 2 were two randomized controlled trials (RCTs) initiated in 2010 to investigate the necessity and sequence of cytoreductive nephrectomy (CN) in the era of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Both trials presented data that superseded previous evidence that supported CN followed by interferon (IFN)-α. The European Association of Urology (EAU) renal cell carcinoma guideline panel considered data from CARMENA to be practice changing and has recently updated their recommendation for patients with primary clear-cell renal cell carcinoma (ccRCC) with the primary tumour in situ. 3 Both CARMENA and SURTIME experienced their difficulties with patient recruitment. Although CARMENA recruited substantially more patients than SURTIME, both trials did not meet the planned inclusion of their calculated sample size. Meanwhile first-line treatment paradigms of treatment-naïve metastatic renal cell carcinoma (mRCC) changed with the approval of the combination of ipilimumab and nivolumab 4

in the United States (US) and
Europe and other combinations, including atezolizumab plus bevacizumab, 5 avelumab plus axitinib 6 and pembrolizumab and axitinib. 7 Despite the very recent evidence from CARMENA and SURTIME, the question arises whether the management of patients with primary mRCC needs re-investigation in the era of immunecheckpoint inhibitors (ICIs). We review the current evidence and discuss potential future management of patients with primary mRCC and the tumour in place. Although kidney cancer comprises several subtypes, the highest levels of evidence exists for ccRCC only. For other subtypes CN is associated with great uncertainty and no recommendations are currently available.
The evidence prior to CARMENA and SURTIME In the past, CN was performed in patients with single-or oligometastatic disease, either in combination with complete metastasectomy or to observe metastatic sites which very rarely disappeared after nephrectomy of the tumour-bearing kidney. 8 In the cytokine era, when median overall survival (OS) of mRCC was less than 1 year, 9 two trials formally assessed the efficacy of CN and randomized patients to CN plus IFN-α versus IFN-α alone. Both studies were reported in 2001 and demonstrated a 3 month and 10 month survival benefit in the larger US study and in the smaller European study, respectively. 10,11 A pooled analyses of both trials revealed an advantage of approximately half a year regarding OS among those who underwent CN. 12 Several hypotheses have been suggested to explain why CN might have a beneficial effect but none of these have been substantiated. Removal of the 'immunologic sink' 13 that is, diminished production of growth factors and cytokines by the tumour in situ, 14,15 postponed metastatic progression 16 and nephrectomy-activated azotaemia 17 are among several suggested potential mechanisms.
The introduction of VEGFR-targeted therapy resulted in a considerable increase in mRCC OS, from less than 1 year 18 to more than 2 years for intermediate prognostic risk patients receiving several lines of targeted therapies. 19 Based on the two randomized trials in the cytokine era, CN continued to be offered by default. In a recent systematic review on CN in the targeted therapy era, 56 studies were identified with a moderate or serious risk of bias in 50. 20 Of note, CN demonstrated an OS advantage in patients with mRCC in 10 retrospective comparative trials. However, these studies were biased towards a more favourable population undergoing CN when compared with those who did not undergo surgery. It was therefore uncertain whether the improvement in outcome observed with systemic therapy would benefit from an additional CN at all. To understand and investigate the contradictory indication of CN combined with VEGFR-targeted therapy, two prospective RCTs were initiated in 2010. 1,2

SURTIME
The first of these trials, presented in August 2017, was SURTIME, a randomized trial investigating three cycles of sunitinib prior to the decision to perform CN in the absence of systemic progression compared with immediate CN followed by sunitinib. Patients with mRCC were randomized into either immediate CN followed by sunitinib versus three cycles sunitinib followed by CN and sunitinib. Inclusion criteria required ccRCC, a resectable primary tumour and ⩽3 risk factors associated with CN as previously reported by Culp and colleagues. 21 Initially planned as a phase III randomized trial to include 458 patients with progression-free survival (PFS) as a primary endpoint, insufficient accrual led the Independent Data Monitoring Commission to recommend to report the intention-to-treat (ITT) 28-week progression-free rate as a primary endpoint instead, for which 98 patients were needed. Secondary endpoints were OS, adverse event rates and postoperative progression. The concept of reversing the sequence of CN and targeted therapy that SURTIME investigated was based on results from previous phase II studies of VEGFR-TKIs for 2-3 months of pretreatment before CN. In these studies, the Memorial Sloan Kettering Cancer Center (MSKCC) poor-risk subgroup patients had inferior outcomes regardless of surgery, whereas the response in those patients with MSKCC intermediate-risk disease could be used as litmus test to aid decisions about CN, leading to excellent survival data. 22 SURTIME was closed after 5.7 years of accrual with 99 patients included and showed no difference in PFS. However, the ITT OS hazard ratio (HR) of deferred versus immediate CN was 0.57 [95% confidence interval (CI): 0.34-0.95, p = 0.032] with a median OS of 32.4 (95% CI: 14.5-65.3) and 15.0 months (95% CI: 9.3-29.5), respectively. In the deferred arm, all patients except one received sunitinib, whereas in the immediate CN arm 20% received no systemic therapy, mainly due to rapid disease progression and deterioration of performance. Despite being an underpowered trial, SURTIME supported the rationale that postponing systemic treatment by performing CN upfront may be questionable for those patients, who need early control of their progressive disease.

CARMENA
In contrast with SURTIME that investigated the sequence of CN and systemic targeted therapy, CARMENA, a phase III non-inferiority RCT, investigated the role of immediate CN followed by sunitinib versus sunitinib alone. Results of this landmark trial were reported in June 2018. The trial showed that sunitinib alone did not result in inferior survival when compared with CN followed by sunitinib. CARMENA enrolled 450 patients with metastatic ccRCC of intermediate and poor MSKCC risk, of whom 226 were randomized to immediate CN followed by sunitinib and 224 to sunitinib alone. Patients in both arms were evenly distributed and had a median of two metastatic sites and a mean tumour burden of 140 ml of measurable disease by RECIST 1.1 criteria, of which approximately 80 ml accounted for but may be observed instead. 28 In these cases, immediate CN may be justified, as prospective single-arm studies have shown that the time of observation of the metastases until progression requires systemic treatment can be substantial 28 (Figure 1). For patients with a primary tumour in place, good performance status and resectable single-or oligometastasis it is generally accepted that CN and focal therapy, which can be metastasectomy, ablation or stereotactic body radiotherapy, should be employed to render them disease-free.

Future CN trials
Future trials investigating CN will be challenging to perform in view of the rapid evolvement of new treatment paradigms. Like the previous SWOG and EORTC trials in the cytokine era, both CARMENA and SURTIME took 8 years to accrue enough patients for academically valid information on how these patients should be best managed. Both trials, however, did not reach full accrual which was especially apparent in the more complex designed SURTIME trial. With new treatment options replacing sunitinib as first-line treatment of mRCC, the continued conduct of both CARMENA and SURTIME would have introduced ethical dilemmas and both trials had to stop, let alone for reasons of poor accrual. The current changes in treatment paradigms are likely to appear at a faster pace than previously anticipated. Anyone designing and embarking on a phase III RCT with primary metastatic patients, needs to consider the changed epidemiology with fewer patients eligible than 20 years ago as well as a high likelihood that the first-line therapy chosen at the outset of the trial will change during its course. Based on past experience, it is therefore doubtful whether we should be conducting these large trials in this very selective, but heterogeneous, patient population anymore. In addition, both trials revealed the detrimental effect of immediate CN in patients who require systemic therapy. Based on the ratio of priming the immune system through pretreatment of tumour tissue, it would be more appropriate to try to answer whether deferred CN is superior to no CN. Alternatively, studies could be downsized according to certain biomarker profiles which would enable calculation of smaller sample sizes based on higher HRs that could lead to faster read-outs of study results.

Funding
The authors received no financial support for the research, authorship, and/or publication of this article.