"Up-front CN is associated with a survival benefit in selected patients with mRCC treated with either targeted therapy or ICI therapy," writes Badar M. Mian, MD.
In the presence of metastatic renal cell carcinoma (mRCC), up-front removal of the tumor (ie, cytoreductive nephrectomy [CN]) along with the use of interferon and/or interleukins had been the standard of care for a couple of decades. The role of CN was challenged by the advent of more selective and effective systemic therapies for mRCC. The CARMENA trial (NCT00930033) demonstrated that use of sunitinib (Sutent) alone in patients with intermediate- and poor-risk mRCC was associated with similar overall survival (OS) compared with those who received up-front CN followed by sunitinib.1 However, subgroup analyses that stratified patients for certain risk criteria indicated some patients could benefit from CN along with sunitinib. Since that trial, systemic therapy for mRCC has shifted from targeted agents (sunitinib) to immune checkpoint inhibitors (ICIs) as the preferred option at many centers. However, the role of CN in patients with mRCC treated with ICI therapy and the timing of CN are not well understood.
Bakouny et al addressed these questions using the International mRCC Database Consortium (IMDC), which includes patients with de novo mRCC who did not undergo nephrectomy and were treated with a first-line ICI or targeted therapy regimen.2 Each systemic therapy cohort (ICI and targeted) was further divided into subcohorts of patients receiving up-front CN or receiving systemic therapy without upfront CN. Patients had to have received systemic therapy after January 1, 2009. The primary outcome of interest was OS as calculated from the start of first-line systemic therapy until death from any cause.
The authors identified 4639 patients with mRCC who were eligible for this retrospective analysis. Of the 4202 patients receiving targeted therapy, 2326 (55%) underwent up-front CN, and of the 437 treated with ICI therapy, 234 (54%) underwent up-front CN. Sunitinib was used in majority of patients receiving targeted therapy, and the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) was most frequently utilized regimen in patients receiving ICI therapy. The median time between CN and starting targeted therapy or ICI therapy was 3.1 months and 2.5 months, respectively.
Patients receiving CN in both systemic cohorts had more favorable prognostic profiles than those who did not undergo CN. For patients undergoing CN, 72% and 60% of patients belonged to the intermediate-risk group in the targeted therapy and ICI therapy cohorts, respectively. Of those not undergoing CN, 47% and 46% had intermediate-risk features in the targeted therapy and ICI therapy cohorts, respectively. Older age; presence of bone, brain, or liver metastases; poor performance status; and IMDC poor-risk factors were associated with a lower likelihood of undergoing CN.
The median OS for patients in the ICI therapy group was 54 months for those receiving CN and 22 months for those not receiving CN. Similarly, the median OS for patients in the targeted therapy group undergoing CN vs patients not undergoing CN was 25 months and 13 months, respectively. The median follow-up in the targeted therapy and ICI therapy groups for surviving patients was 24 and 12 months, respectively.
Multivariable analysis demonstrated an OS benefit in favor of CN in both the ICI therapy (HR, 0.61; P=.013) and the targeted therapy (HR, 0.72; P<.001) cohorts. However, the extent of survival benefit associated with CN was not different between the ICI therapy and targeted therapy groups (interaction, P=.6). Although there were substantial differences in baseline risk factors between the CN and no CN groups, sensitivity analysis using an inverse propensity of treatment weighting approach yielded similar results in both the targeted therapy (HR, 0.74) and the ICI therapy (HR, 0.66) groups.
The study results, using a large, prospectively maintained, multicenter database demonstrate that up-front CN was associated with a significant OS benefit regardless of the type of systemic therapy used. Since the advent of improved systemic therapies, there have been conflicting reports regarding the benefit of CN, with some studies questioning the need for up-front CN and others suggesting a potential benefit in properly selected patients. In the current study, younger patients who had fewer IMDC risk factors, no adverse metastases (bone, brain, or liver), and better performance status were more likely to be treated with up-front CN. The study results suggest that well-selected patients are best suited to realize the benefits from CN in the era of ICIs. The beneficial effects of CN may be a result of the immune-modulating effects of an up-front CN. It has been well-established that primary RCC is associated with the release of cytokines that inhibit T cells, thus blunting the systemic antitumor immune response. It is entirely conceivable that up-front CN may facilitate a more robust immune response in patients being treated with ICI therapy for mRCC.
The reason for the delay of 2.5 to 3 months before systemic therapy could be initiated also warrants further evaluation. With minimally invasive surgery and relatively favorable performance status, most patients should be able to initiate systemic therapy 1.5 months after surgery. It’s unclear whether this near doubling of time between surgery and systemic therapy has any detrimental effect on survival. The study results are subject to potential confounders including nonrandomized data and patient factors or symptoms that can affect the likelihood of receiving up-front CN (renal function, hematuria, pain, inferior vena caval thrombus, tumor extent). Furthermore, delayed nephrectomy after a period of initial systemic therapy in those not suitable for up-front CN also requires further discussion.
While we await the results of several randomized clinical studies, this study provides useful data to guide contemporary clinical practice. Up-front CN is associated with a survival benefit in selected patients with mRCC treated with either targeted therapy or ICI therapy. This is especially true for patients younger than 65 years without metastases to brain, bone, and liver and with good functional capacity.
1. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379:417-427. doi:10.1056/NEJMoa1803675
2. Bakouny Z, El Zarif T, Dudani S, et al. Upfront cytoreductive nephrectomy for metastatic renal cell carcinoma treated with immune checkpoint inhibitors or targeted therapy: an observational study from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol. Published online October 19, 2022. doi:10.1016/j.eururo.2022.10.004