The role of cytoreductive nephrectomy in metastatic renal cell carcinoma in the modern era

The treatment landscape of metastatic renal cell carcinoma (mRCC) has experienced tremendous advancement in the last three decades. Immunotherapy, in the form of cytokine therapy with interferons and high-dose IL-2, was first investigated in RCC after several studies showed a lack of response with conventional chemotherapy (1,2). In this setting, upfront cytoreductive nephrectomy (CN) proved to have a clinical benefit in patients receiving cytokine-based therapy, with an improvement in overall survival (OS) compared to systemic therapy alone (3,4). The rationale behind the improved outcomes seen with CN is thought to be secondary to decreased systemic immune suppression associated with the primary tumor and eradication of subclones resistant to systemic therapy (5).

Sunitinib, a VEGF-tyrosine kinase inhibitor (TKI), was shown to improve median progression-free survival (PFS) and OS compared to interferon alfa in patients with previously untreated mRCC (6). This introduced the TKI era, shifting away from cytokine therapy. Following this, other VEGF-TKI, such as sorafenib, were introduced to the treatment landscape of mRCC (7).

In this setting, two phase-3 clinical trials aimed to assess the role of CN in patients with mRCC in the TKI era, as multiple retrospective analyses suggested a clinical benefit for this approach. The CARMENA trial aimed to assess the role of upfront CN in patients treated with sunitinib. The trial enrolled a total of 450 patients, of which 226 were assigned to undergo upfront CN and receive sunitinib, and 224 were assigned to receive sunitinib alone. It is essential to mention that approximately 43% of the patients enrolled in this study had poor International mRCC Database Consortium (IMDC) risk disease, and 18% of patients assigned to the CN plus sunitinib arm never received systemic therapy. This study failed to show a significant difference in OS or PFS. The results of this study, although suggesting that sunitinib monotherapy was not inferior to CN followed by sunitinib, need to be interpreted cautiously, as there was an over-representation of poor IMDC risk patients in the evaluated population, and a large percentage of patients who were allocated to the upfront CN arm never received systemic therapy (8).

Similarly, the SURTIME trial aimed to compare upfront to deferred CN in patients with mRCC treated with sunitinib. The primary outcome of this study was PFS. This trial enrolled 99 patients, of whom 49 were allocated to the deferred CN arm and 50 to the upfront CN arm. Most patients in this study (88%) were intermediate risk; however, the Memorial Sloan-Kettering Cancer Center (MSKCC) score was utilized for risk stratification, not the IMDC score as in the CARMENA trial. Of the patients randomized to the upfront CN arm, 20% never received systemic treatment with sunitinib. The PFS hazard ratio (HR) for the deferred vs. immediate CN was 0.88 [95% confidence interval (CI): 0.56–1.37; P=0.57], suggesting that there is not a significant difference in PFS between patients undergoing upfront vs. deferred CN in patients with and sunitinib. Although OS was assessed as a secondary endpoint of the study, this trial was not powered to assess OS. Likewise, in a per-protocol population analysis, OS was not statistically different between upfront and deferred CN (HR, 0.71; 95% CI: 0.40–1.24; P=0.23) (9). The results of this trial have somewhat modeled current practice, with a more selective approach in selecting patients who might benefit from CN nephrectomy. For instance, given that there is no difference in outcomes on upfront vs. deferred CN, the current practice trend favors initiating systemic therapy followed by offering CN to patients who demonstrate an appropriate response to systemic therapy. This approach avoids the performance of CN in patients with aggressive disease, who will not likely benefit from this intervention.

Although the CARMENA and SURTIME trials failed to show a clinical benefit of upfront vs. deferred CN in patients treated with sunitinib, large retrospective studies have suggested a possible clinical benefit of CN in patients treated with VEGF-TKIs (10-12). For example, a large (n=1,658) study led by the IMDC showed improved survival in patients with mRCC treated with VEGF-TKI who underwent CN. A post-hoc analysis of CARMENA showed that patients with one IMDC risk factor had a numerically better OS with upfront CN followed by sunitinib when compared to sunitinib alone [median OS (mOS) 31.4 vs. 25.2 months]; however, this was not statistically significant (HR, 1.30; 95% CI: 0.85–1.98; P=0.2). This study also suggested that patients with two or more IMDC risk factors have better survival when treated with sunitinib alone rather than with nephrectomy followed by sunitinib (HR, 0.65; 95% CI: 0.44–0.97; P=0.03) (8-10,13). This heterogeneity in results suggests a strong selection bias that perhaps accounts for this inter-study discordance and introduces uncertainty in the role of CN in patients with mRCC.

Immunotherapy is again playing an essential role in the treatment of mRCC, now in the form of immune checkpoint inhibitor (ICI) containing regimens. Most combination trials showed significant improvement in clinical outcomes over sunitinib alone. These combinations include the ICI-ICI combination of nivolumab/ipilimumab and TKI-ICI combinations such as nivolumab/cabozantinib, pembrolizumab/axitinib, pembrolizumab/lenvatinib (14-18). With these regimens, the mOS of patients with mRCC approaches approximately 4.5 years, which is outstanding compared to the prior mOS of 18 months with VEGF-TKI monotherapy (19,20). Now, with better and more durable disease control, the role of CN in patients undergoing first-line treatment with ICI-ICI or TKI-ICI combination therapy has reemerged as an important clinical question.

The JAVELIN Renal 101 (NCT02684006) was a phase III randomized trial investigating the combination of avelumab plus the VEGF-TKI axitinib vs. sunitinib in patients with treatment-naïve mRCC. Patients were allowed to enroll regardless of their prior nephrectomy status. This study enrolled 886 patients, of which 442 were assigned to the avelumab plus axitinib arm and 444 to the sunitinib arm. The study’s primary endpoints were PFS and OS in patients with PD-L1 positive tumors. The trial’s secondary endpoints were PFS and OS despite PD-L1 expression and objective response rates (ORR). The combination of avelumab plus axitinib showed a longer median PFS (mPFS) (13.8 vs. 7.2 months; HR 0.61; P<0.001) along with a better ORR (55.2% vs. 25%) compared to sunitinib monotherapy. However, the OS was not significantly different between the two groups (HR, 0.82; P=0.38) (21). A recent update of the JAVELIN renal 101 trial again showed an improved mPFS in the combination arm compared to sunitinib monotherapy (13.9 vs. 8.5 months; HR, 0.67; 95% CI: 0.568–0.785; P<0.0001) (22).

In this setting, the study performed by Grimm et al. showed clinically relevant results (23). They conducted a post-hoc analysis of the JAVELIN Renal 101 trial. They aimed to understand the effect of prior CN in previously untreated patients with mRCC patients undergoing treatment with avelumab and axitinib, thus offering the first insight into cytoreductive therapy in the modern era. They evaluated a total of 412 patients with M1 disease at diagnosis of the 886 patients enrolled in the JAVELIN Renal 101 trial. Of these, 126 out of 198 (64%) in the combination arm and 147 out of 214 (69%) in the sunitinib arm had undergone CN before initiating systemic therapy. The authors observed that patients who did not undergo CN were more likely to be older than 65 years, have an Eastern Cooperative Oncology Group (ECOG) performance status greater or equal to 1, and have poor IMDC risk scores. Similarly, patients with no prior CN were less likely to have PD-L1 positive tumors. This strongly suggests a selection bias in patients undergoing CN, similar to prior retrospective analysis. To account for these imbalances, the authors performed a multivariable Cox regression analysis adjusting for baseline characteristics such as age, ECOG status, IMDC risk, geographic region, and PD-L1 status. We should recognize that there are additional unaccounted-for factors that explain the discordance between positive retrospective study results and negative prospective study results.

Their results showed that patients with prior CN who were treated with avelumab and axitinib had an adjusted hazard ratio (aHR) of progression or death of 0.79 (95% CI: 0.53–1.16) and an aHR for death of 0.59 (95% CI: 0.38–0.93) compared to those who did not undergo CN. On the other hand, patients in the sunitinib arm had an aHR for progression or death of 1.15 (95% CI: 0.77–1.70) and an aHR for death of 0.86 (95% CI: 0.55–1.34). Lastly, the authors observed that the odds ratio for response in patients with prior CN compared to those without prior CN was 2.67 (95% CI: 1.32–5.41) in the combination arm and 2.02 (95% CI: 0.82–4.94) in the sunitinib monotherapy arm. However, the interaction test for all assessed outcomes was not significant between treatment arms. The authors proposed that although no firm conclusions can be made from their study given this post-hoc nature, their findings suggest that patients with mRCC treated with avelumab and axitinib may derive a clinical benefit from CN. The results of this study provide solid arguments for CN in patients with mRCC, although future validation is needed.

Previous studies have described that RCC tumor cells release cytokines that increase inflammation and inhibit T-cell function; this immunosuppression can decrease the effectiveness of immunotherapy (24). Based on this observation, it has been hypothesized that CN would decrease this immunosuppressive signal and augment the therapeutic efficacy of immunotherapy. This hypothesis offers a biological explanation for the role of CN in patients treated with ICI-based regimens.

We continue to see retrospective studies suggesting an improvement in survival with CN; as such, it becomes apparent that a population of patients derives a clinical benefit from this approach. Choueiri et al. demonstrated that patients with intermediate and poor IMDC risk scores and those with 1–3 risk factors derived the most significant benefit from CN (10). These findings also suggest that the IMDC score reflects the disease biology rather than purely the burden of the disease. Similarly, another retrospective study led by Larcher et al. assessed the clinical benefit of CN in 317 patients with mRCC stratified by the presence of symptoms. The authors found a significant clinical benefit of CN in patients with signs or symptoms such as hematuria, flank/abdominal pain, weight loss, anemia, and fever (25). Similarly, patients with documented tumor thrombus have shown an improved survival with the addition of CN to systemic therapy (26). Given the survival and clinical benefit seen with CN evidenced in multiple retrospective studies in patients with IMDC intermediate risk, those with 1–3 IMDC risk factors, and patients with symptoms secondary to their disease burden or presence of tumor thrombus, perhaps the key lies in the proper selection of patients to identify those who would derive the most significant benefit from CN.

In other disease states, such as acute myeloid leukemia (AML), minimal residual disease negativity after induction therapy and low disease volume have been associated with improved outcomes (27). Extrapolating from these other pathologies, it could be presumed that the cytoreduction, and therefore, decrease in disease burden, partially accounts for the improved outcomes previously documented by upfront CN in mRCC (10).

Grimm et al. performed the first study to investigate the role of CN in patients with mRCC who undergo treatment with an ICI-TKI regimen. Their findings suggest that there might be a role for CN in patients with mRCC. However, we agree with the authors’ conclusion that this is hypothesis-generating only and should not immediately change clinical practice due to the limitations in accounting for bias in retrospective studies. This should enormously increase our collective enthusiasm to test this hypothesis through prospective clinical trials.

Four ongoing studies are actively recruiting patients and strongly deserve our attention and support. The SEVURO-CN trial (NCT05753839) is a randomized clinical trial evaluating the role of upfront vs. deferred CN in patients with synchronous mRCC and ≤3 IMDC risk features in patients treated with the ICI combination of nivolumab and ipilimumab. The primary outcome of this study is OS. Similarly, the phase III randomized clinical trial PROBE (NCT04510597) is assessing the role of ICI combination regimens with or without deferred CN in patients with mRCC. Patients who have documented a response to systemic therapy will be randomized 1:1 to undergo CN followed by systemic therapy continuation or to continue systemic treatment without CN. The primary endpoint of the trial is also OS. Similarly, the Cyto-KIK trial (NCT04322955) is a phase II clinical trial assessing the role of CN in patients with mRCC after therapy with cabozantinib and nivolumab. The primary endpoint of this trial is complete response rate. Lastly, although not directly assessing the role of CN, the SAMURAI trial (NCT05327686) is investigating the role of stereotactic ablative radiation therapy in patients with mRCC who are candidates to receive IO combination therapy and are not candidates for upfront CN.

In the meantime, what is the current role of CN in patients with mRCC? We strongly encourage personalizing treatment recommendations based on a multidisciplinary discussion. Based on the current evidence, we suggest that this is a systemic disease, and the priority is systemic therapy over surgery, as the results of the SURTIME trial failed to show an improvement in outcome with upfront CN. However, situations to consider upfront CN include patients who are highly symptomatic from their disease burden in whom CN would palliate symptoms and those documented with tumor thrombosis involving the inferior vena cava. Our approach closely mirrors the recent American Society of Clinical Oncology (ASCO) guideline on mRCC (28). Selection of patients who would derive a benefit from delayed CN is also challenging. Based on data from prior retrospective studies, it seems reasonable to consider patients who experience profound responses to ICI-based systemic therapy or with fewer IMDC risk factors, all to augment their treatment response. Perhaps by decreasing disease burden and reducing tumor-mediated immunosuppression, we can provide better long-term disease control. Hopefully, with solid support from the clinical research community, we can answer these questions soon.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-23-646/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-646/coif). B.L.M. has received financial compensation as a paid consultant/advisor to Abbive, Pfizer, AVEO oncology, Janssen, Astellas, Bristol-Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology, Lilly, Sanofi, Telix and Peloton Therapeutics; and Huntsman Cancer Institute has received research funding from Exelixis, Bavarian-Nordic, Clovis and Bristol-Myers Squibb on his behalf. The other author has no conflicts of interest to declare.

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