Corresponding Author: Jun Gong, MD, Samuel Oschin Cancer Center, 8700 Beverly Blvd., Los Angeles, CA 90048. Email address: firstname.lastname@example.org
The survival benefit of cytoreductive nephrectomy (CN) was demonstrated in patients with metastatic renal cell carcinoma (mRCC) in randomized control trials of interferon alfa. Since 2005, the development of targeted therapies with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) has prompted investigations into the benefit of CN in patients treated with these standard agents in mRCC. With the advent of immune checkpoint inhibitors (ICIs) that have now been approved as new first-line treatments in mRCC, the role of CN in this population remains even more undefined. In this review, we highlight seminal studies of CN in mRCC patients treated with VEGF-TKIs. We also discuss early evidence on the impact of CN in patients with mRCC in the immunotherapy era. We end with a discussion on factors that could potentially aid the selection of mRCC candidates for CN.
Renal cell carcinoma (RCC) is among the top 10 most frequently diagnosed cancers in men and women worldwide with >140,000 RCC-related deaths yearly.1 Although the majority of RCC cases are diagnosed at a localized stage, nearly one third of cases present with regional or distant metastases where the 5-year survival is 53% for patients with locoregional (stage III) disease and a dismal 8% for metastatic disease.2 Two randomized control trials demonstrated the survival benefit of cytoreductive nephrectomy (CN) followed by interferon alfa over interferon alfa alone in patients with metastatic RCC (mRCC) in the cytokine era.3,4 In a pooled analysis of these studies including a total of 331 patients with mRCC and primary tumors deemed resectable, the median overall survival (OS) was 13.6 months for CN plus interferon vs. 7.8 months for interferon alone (31% reduced risk of death, P=0.002).5
Since 2005, the advent of targeted therapies involving vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors led to a paradigm shift in the systemic treatment of mRCC with improvements in OS to nearly 40 months for targeted therapy in the contemporary era compared to a median OS of 10 months in the cytokine era.6,7 To provide level 1 evidence on the role of CN for mRCC in the targeted therapy era, 2 randomized controlled trials CARMENA and SURTIME were conducted.8,9
The CARMENA (Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques) trial was a randomized, multicenter, open-label phase III trial randomizing (1:1 fashion) 450 treatment-naïve patients with metastatic clear-cell RCC to receive CN within 28 days of randomization followed by sunitinib treatment (3-6 weeks after nephrectomy) or sunitinib alone (50 mg daily for 4 weeks on, 2 weeks off) within 21 days of randomization.9 The primary endpoint was OS and 226 patients were randomized to the CN plus sunitinib arm and 224 to the sunitinib alone arm. At a median follow-up of 50.9 months (95% confidence interval or CI 44.0-56.9), the sunitinib-alone group had a longer median OS (18.4 months, 95% CI 14.7-23.0) than those in the CN-sunitinib group (13.9 months, 95% CI 11.8-18.3) in the intention-to-treat (ITT) population with a hazard ratio (HR) for death of 0.89 (95% CI 0.71-1.10). Given that the upper boundary of the 95% CI for the HR did not exceed the fixed noninferiority limit of 1.20, sunitinib alone was deemed not inferior to CN followed by sunitinib. In the CN-sunitinib group, 55.6% and 44.4% were in the Memorial Sloan Kettering Cancer Center (MSKCC) intermediate-risk and poor-risk groups, respectively, while in the sunitinib-alone group, the corresponding values were 58.5% and 41.5%. In both intermediate-risk and poor-risk groups, the median OS was longer in the sunitinib-alone group than in the CN-sunitinib group (23.4 vs. 19.0 months in the intermediate-risk subgroup and 13.3 vs. 10.2 months in the poor-risk group). Notably, 16 patients (7.1%) did not undergo nephrectomy and 40 (17.7%) never received sunitinib. In the sunitinib-alone group, 11 patients (4.9%) never received sunitinib and 38 (17.0%) underwent subsequent nephrectomy a median of 11.1 months after randomization for the control of symptoms.
The SURTIME (Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer) was originally a randomized, multicenter, open-label phase III trial conducted during a similar time period as CARMENA that randomized (1:1 fashion) a total of 99 patients with untreated, clear-cell mRCC to immediate CN followed by sunitinib (50 mg daily 4 weeks on, 2 weeks off) or 3 cycles of sunitinib followed by CN (sunitinib was stopped day before nephrectomy) and resumption of sunitinib (delayed CN arm.8 Sunitinib was started in both arms 4 weeks after surgery, and in the case of systemic progressive disease (PD) in the deferred CN arm, CN was not recommended and left to the discretion of the investigator. The primary endpoint was the 28-week progression-free rate (PFR). Of note, the trial was originally powered for 458 patients, but suffered from poor accrual resulting in a downsizing to 98 patients. At a median follow-up of 3.3 years (range 0-6.2 years), a total of 87 (88%) met MSKCC intermediate risk criteria, and the 28-week PFR in the ITT population was 42% (90% CI 30-55%) in the immediate CN arm vs. 43% (90% CI 31-56%) in the deferred CN arm (1-sided Fisher test p=0.61). The PFS HR for deferred vs. immediate CN was 0.88 (95% CI 0.56-1.37, P=0.57), while for OS the HR for deferred vs. immediate CN was 0.57 (95% CI 0.34-0.95, P=0.03). The median OS was 32.4 months (95% CI 14.5-65.3 months) in the deferred CN arm vs. 15.0 months (95% CI 9.3-29.5 months) in the immediate CN arm. In the per-protocol population, OS was higher in the deferred CN arm than the immediate CN group (HR 0.71, 95% CI 0.40-1.24), but the difference was not statistically significant (P=0.23).
Delayed Cytoreductive Nephrectomy
The results of SURTIME, when placed in the context of CARMENA, appear to support that upfront CN does not result in additional survival benefit with potential to even be harmful in patients with primary clear cell mRCC who require treatment with sunitinib. Instead, there was evidence to suggest that deferred CN conferred a greater survival benefit than immediate CN, particularly in those who are MSKCC intermediate risk. SURTIME, however, suffered from poor accrual and was ultimately grossly underpowered and therefore its results should be considered exploratory. To further provide evidence in support of deferred CN in mRCC, 2 large studies, albeit retrospective, using prospectively collected data were recently conducted.10,11
The first was a retrospective pooled analysis of 3 single-arm prospective phase II studies (12-14) and n=20 patients from the deferred CN experimental arm of SURTIME.11 The goal was to compare patients with MSKCC intermediate-risk primary clear cell mRCC receiving presurgical VEGF-TKIs (sunitinib or pazopanib) followed by delayed CN in the absence of systemic PD vs. upfront CN followed by VEGF-TKIs where treatment-naïve patients received VEGF-TKIs 12-18 weeks prior to planned CN. This deferred CN cohort was compared to a European upfront CN cohort from 4 centers planned to receive VEGF-TKI after surgery between 2006-2016. The pooled deferred CN included 189 patients (57% received sunitinib and 43% pazopanib) where 144 (76%) patients were MSKCC intermediate risk and 42 (22%) poor risk. From 244 patients who received upfront CN, a final 149 patients were included after excluding favorable-risk and non-clear cell mRCC. Of these, 131 patients (88%) were intermediate risk and 18 (12%) were poor risk, while the majority (76%) of patients received sunitinib. For intermediate-risk patients, OS in the deferred CN cohort was 33.0 months (95% CI 25.0-51.0) vs. 22.8 months (95% CI 17.9-30.6) in the upfront CN cohort (HR for death 0.72, 95% CI 0.52-0.996, P = 0.047). In the overall cohort, OS was 24.3 months (95% CI 20.8-34.8) vs. 18.4 months (95% CI 14.4-26.9, P=0.09) in the deferred CN and upfront CN arms, respectively. Notably, 66 (35%) patients in the deferred CN cohort did not undergo CN (24% in the intermediate-risk and 52% in the poor-risk group), while following nephrectomy in the upfront CN group, 34 MSKCC intermediate-risk patients (25.9%) had a short cancer-specific survival of <6 months with 10 (7%) never going on to receive a VEGF-TKI, 8 due to rapid PD.
To further evaluate the benefit of deferred CN in mRCC using International mRCC Database Consortium (IMDC) risk criteria, a retrospective analysis of the prospectively maintained IMDC database was conducted for patients with mRCC diagnosed between 2006-2018 across 33 international centers (10). Patients with mRCC whose first systemic therapy was sunitinib were included whereas patients were excluded if first treatment (sunitinib or upfront CN) occurred >12 months after diagnosis, patients were on surveillance for >6 months after upfront CN (i.e., sunitinib given >6 months after upfront CN), and timing of deferred CN was unknown. Patients were stratified by receipt of upfront CN followed by sunitinib, sunitinib alone, or deferred CN (defined as any CN after receipt of upfront sunitinib) with primary outcome being OS. A final 1541 patients with newly diagnosed mRCC were included, 805 received upfront CN followed by sunitinib, 651 received sunitinib alone, and 85 received sunitinib followed by delayed CN at a median of 7.8 months (interquartile range or IQR 4.8-12.6) from the date of initiation of sunitinib. A majority 85% were clear-cell with 40% of cases being IMDC poor-risk.
With a median follow-up from first treatment initiation of 25 months (IQR 10-49), the median OS for patients treated with sunitinib alone, CN followed by sunitinib, and sunitinib followed by CN were 10 (IQR 4–20), 19 (IQR 9–46), and 46 (IQR 25–67) months, respectively. On multivariable analysis, upfront CN followed by sunitinib was significantly associated with improved OS vs. sunitinib alone (HR 0.60, 95% CI 0.53-0.68, P<0.001), as did deferred CN vs. sunitinib alone (HR 0.45, 95% CI 0.33-0.60, P<0.001. Among CN-treated patients, deferred CN was associated with improved OS vs. upfront CN followed by sunitinib (HR 0.52, 95% CI 0.39-0.70, P<0.001). Similar findings were seen with time to treatment failure (TTF) in favor of deferred CN. On sensitivity analyses excluding patients with PD and among patients receiving upfront sunitinib, median OS without and with deferred CN were 16 (IQR 9-32) and 46 (IQR 25-67) months, respectively (P<0.001), while median TTF without and with deferred CN were 8 (IQR 5-16) and 14 (IQR 9-27) months, respectively (P<0.001). On multivariable analysis adjusted for responses, deferred CN remained significantly associated with OS (HR 0.58, 95% CI 0.40-0.84, P=0.004).
Candidates for Cytoreductive Nephrectomy
The evidence thus far including data from CARMENA and SURTIME has tempered enthusiasm towards initial CN, particularly in unselected patients, with growing evidence to support a deferred CN approach in those with intermediate risk mRCC who require systemic therapies for VEGF-TKIs. It is worthwhile to note that in CARMENA, there was an element of deferred CN in the sunitinib-alone arm whereby 38 patients (17%) underwent secondary CN for acute symptoms or near-complete response at a median of 11.1 months from randomization to CN.9 In an update and post hoc analysis of CARMENA, 40 patients in the sunitinib-only arm had a secondary nephrectomy with a median OS of 48.5 months (95% CI 27.9-64.4) vs. 15.7 months (95% CI 13.3-20.5) in patients who did not have nephrectomy.15 Although this finding was likely a reflection of patient selection bias towards those with more favorable disease course, this updated analysis of CARMENA reclassified patients based on IMDC risk groups instead of MSKCC risk groups15 and highlights: 1) the role for CN after sunitinib with an OS achieved in intermediate-risk patients that should not be underestimated and 2) the importance of selection given that the secondary nephrectomy rate was even higher (25%-30%) among patients who survived long enough.
Deferred CN is a favorable approach for other reasons as well. As described in SURTIME, a deferred CN approach allows a greater proportion of patients who are otherwise in need of systemic therapy to receive such therapy as all patients in the ITT deferred CN arm received systemic therapy compared to 87% in immediate CN arm.8 Safety was reassuring as the surgical complication rate was similar in patients who underwent CN after 3 months of pretreatment with sunitinib compared with those who underwent immediate surgery. A deferred CN route also allows a selecting out of patients with aggressive biology or inherent resistance to VEGF-TKIs, i.e., individuals who would have been unlikely to benefit from CN in the first place. For example, an exploratory landmark analysis in SURTIME at week 16 of OS according to treatment arm and progression status suggested that patients who had PD in the deferred CN arm before planned surgery or ≤16 weeks of immediate CN had similar poor survival prognosis.8 In the deferred CN group, 8 of 48 (16.7%) experienced PD by 3 cycles of sunitinib. At the 4-week post-CN restaging assessment, 9 of 46 patients (20%, 95% CI 9-33%) had PD in the immediate CN arm vs. 8 of 34 patients (24%, 95% CI 11-41%) in the deferred CN arm.8
With this evidence in mind, it may be practical and logical to initiate all patients with mRCC in need of VEGF-TKIs on a delayed CN pathway to select for the best candidates for CN and avoid unnecessary surgery in those who are unlikely to benefit from CN. However, as many groups have contended, the optimal selection of candidates for CN is difficult to generalize to all mRCC patients.16,17 There are still mRCC patients in need of immediate CN even if CN was not initially planned (e.g., palliation for symptoms). Others have argued that upfront CN still may have a role in those with good performance status and limited metastatic burden amenable to surveillance or metastectomy.16 Many agree that initial treatment with systemic therapy is preferred in those with MSKCC/IMDC poor risk disease, poor performance status, and/or large-volume metastatic burden.16,17 It has been noted that current risk stratification criteria for mRCC invariably classify all CN candidates into intermediate- or poor-risk categories, and given that those who would benefit from CN are likely to have 3 or less adverse prognostic factors, we are essentially focusing our debate on optimal selection of CN candidates within the MSKCC or IMDC intermediate-risk disease category.17 In the context for guiding the selection of CN in mRCC at presentation, there is certainly a clinical need to redefine low-risk patients.
Lastly, it should be noted that these landmark studies of CN in mRCC were conducted in the era of VEGF-TKIs. The current treatment landscape of mRCC has again shifted in the past 2 years with the advent of immune checkpoint inhibitors (ICIs) whereby dual ICI combinations (ie, nivolumab and ipilimumab) and VEGF-TKI and ICI combinations (ie, axitinib with pembrolizumab or avelumab) have become Food and Drug Administration (FDA) approved for the first-line treatment of mRCC.18-20 With immunotherapy-based regimens now widely recognized as the preferred first-line standards for mRCC, it would be prudent to investigate the role of CN in this population.
Role of CN in the Immunotherapy Era
Data is still fairly limited on the role of CN in the current immunotherapy era. A retrospective analysis of the National Cancer Data Base (NCDB) involving patients with predominantly clear cell mRCC who received modern immunotherapy between 2015 and 2016 was recently conducted to analyze survival after CN in this population.21A total of 96,329 cases were screened but those preceding 2015 were excluded given that the first ICI approval was granted in 2015. The final cohort consisted of 391 mRCC patients (183 diagnosed in 2015, 208 diagnosed in 2016), including 221 (56.5%) who received CN plus immunotherapy and 170 (43.5%) who received immunotherapy only. After a median follow-up of 14.7 months in 183 patients with outcomes data, there were 75 deaths (41%) overall. Patients who received CN had younger age and a larger median primary tumor size, but baseline demographics and Charlson/Deyo comorbidity scores were otherwise similar across groups. In the immunotherapy-only group, the frequency of clinically positive nodes and hepatic metastasis was higher, but the rate of bone, brain, and pulmonary metastases was comparable between groups with no significant difference in the number of known metastatic sites. Sarcomatoid features were seen in 22 cases (5.6%) but this was similarly distributed between groups.
Patients who underwent CN and immunotherapy had significantly improved OS than those who received immunotherapy only (median not reached vs. 11.6 months, HR 0.23, p<0.001). Of the 221 patients who received CN and immunotherapy, 197 underwent upfront CN, while 24 received immunotherapy before CN (including 9 who had continuation of immunotherapy following CN). In a comparison of upfront and delayed CN groups, patients who received immunotherapy first tended to be older and more likely to have bone metastases, but they tended to have lower Fuhrman grade, smaller tumor size, lower pathologic T stage, and lower likelihood of lymphovascular invasion. In contrast, patients who underwent upfront CN were more likely to have pulmonary metastases. The rates of brain, liver, and pathologically positive lymph node (pN1) metastases were similar between groups. Notably, this study was limited by its observational nature with potential for unaccounted confounders. There are also limitations in the data captured by the NCDB including the inability to account for risk stratification that could have affected decisions to offer CN, type of immunotherapy regimen, number of cycles, and duration between last immunotherapy treatment and surgery. With that said, the median OS for the delayed CN group was not reached, compared with 30 months for the upfront CN group (HR 0.25, P=0.139).
Recently, the phase III ADAPT trial investigated the efficacy of Rocapuldencel-T, an autologous dendritic cell-based immuno-therapy designed to capture and present host tumor-specific antigens to elicit antitumor immune responses.22 In this open-labeled, multicenter, randomized trial, a total of 462 patients with IMDC intermediate- or poor-risk, untreated mRCC with a primary tumor in place and predominant clear cell histology were randomized (2:1 fashion) to receive Rocapuldencel-T and sunitinib or sunitinib alone (the standard of care at that time). Rocapuldencel-T was manufactured by isolating autologous tumor total RNA from partial nephrectomy or CN and administered into a single lymph node basin as 3 intradermal injections of 0.2 mL each after completion of at least one 6-week sunitinib cycle followed by 1 dose every 3 weeks for a total of 5 doses (induction phase). This was followed by 1 dose every 3 months until withdrawal study criteria were met with doses administered through 48 weeks irrespective of PD unless unacceptable toxicity occurred, per patient/physician discretion, or ≥2 progression events occurred.
In the ITT population, median OS in the combination arm was 27.7 months (95% CI 23.0-35.9) and 32.4 months (95% CI 22.5-not reached) in the sunitinib arm with an unadjusted HR of 1.10 (95% CI 0.83-1.46). There were 307 subjects enrolled into the Rocapuldencel-T and sunitinib arm and 155 subjects to the sunitinib alone arm in the overall ITT population but 450 patients with clear cell mRCC were randomized to combination therapy or sunitinib alone with or without nephrectomy. Notably, the median OS was 18.4 months for those who did not receive nephrectomy, which was numerically higher but declared noninferior to the median OS of 13.9 months in patients who received nephrectomy. A key takeaway point from this prospective, phase III ADAPT study was that in a population where the majority of patients received immunotherapy-based therapy and were of intermediate-risk classification (>75%), the median OS of those who received nephrectomy (essentially upfront nephrectomy in those receiving experimental immunotherapy given the nature of autologous tumor RNA isolation) was comparably worse than the median OS of the upfront CN group of intermediate-risk mRCC patients of CARMENA.9 Instead, the median OS of those receiving nephrectomies in ADAPT was more comparable to the poor-risk group of patients receiving upfront CN in CARMENA. It is important to note that this would be a cross-study comparison with inherent limitations and that Rocapuldencel-T is different from conventional ICIs that have been established in the first-line treatment of mRCC. Nevertheless, ADAPT provides initial glimpses into the outcomes of mRCC patients receiving nephrectomies and immunotherapy-based regimens in the more current era.
Although evidence seeking to address the role of CN in mRCC in the immunotherapy era is starting to be published, further investigation in ideally large, prospective settings are certainly warranted. It is worthwhile to mention that ongoing phase III studies of CN and ICI-based regimens in mRCC are evaluating the impact of deferred CN (Table), whereby induction with standard ICI-based therapies are performed and if there is absence of PD, then randomization to CN takes place. In NORDIC-SUN, having >3 IMDC risk factors at the time of assessment is deemed not suitable for CN. The study designs of SWOG-1931 and NORDIC-SUN are likely reflective of growing acknowledgement that deferred CN is becoming the preferred approach allowing for a period of assessment of disease response and biology to systemic therapy prior to advancing to CN even in the contemporary immunotherapy era in mRCC.
In patients with mRCC deemed candidates for CN, the initial treatment approach and optimal sequencing of CN and systemic therapy has yet to be definitively established. However, a growing consensus is that nonselective use of CN to treat clear cell mRCC is unlikely to provide a meaningful survival benefit. Selection of candidates for CN should be performed in a multidisciplinary team-based setting incorporating conventional risk or prognostic stratification systems. Based on recent seminal studies of CN in mRCC patients treated with VEGF-TKIs, there is evidence to support that response to presurgical systemic therapy and upfront systemic therapy should be prioritized over surgery. This is reflected in modern phase III study designs whereby the impact of deferred CN is being evaluated in mRCC patients treated with current immunotherapy-based combinations. Results from these ongoing studies are eagerly anticipated as the role of CN in the immunotherapy era remains undefined.
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