Cytoreductive Nephrectomy for MRCC: ICIs and Targeted Therapy

It is time for an update on the ever-changing landscape of the use of cytoreductive nephrectomy for metastatic renal cell carcinoma (RCC) in the era of immunotherapy. In a recent retrospective study from the Dana-Farber Cancer Institute and Harvard Medical School, Bakouny et al presented data from the International Metastatic RCC Database Consortium (IMDC). The findings address the role of upfront cytoreductive nephrectomy for patients with metastatic RCC who are treated with immune checkpoint inhibitor (ICI) or targeted therapy.¹

Efficacy of Cytoreductive Nephrectomy

The authors began by detailing the historical data that underlie the controversy around the role of cytoreductive nephrectomy for metastatic disease. At a time when patients with metastatic RCC were being treated primarily with interferon-based therapy, several studies reported consistent improved overall survival (OS) results when patients received cytoreductive nephrectomy in addition to systemic therapy.^2,3 By contrast, the CARMENA trial found that in patients with intermediate- and poor-risk metastatic disease, the addition of cytoreductive nephrectomy to sunitinib yielded no improvement in OS.⁴

However, a subgroup analysis stratifying patients using IMDC criteria⁵ and other retrospective studies have demonstrated a benefit with cytoreductive nephrectomy.⁶ Importantly, the standard of care for the management of metastatic RCC has changed since many of these studies were conducted; the disease is now managed primarily with ICIs. In their study, Bakouny et al sought to evaluate the benefit of upfront cytoreductive nephrectomy in the age of targeted or ICI-based therapies.

The IMDC is a prospectively maintained database of patients with metastatic RCC and was reviewed retrospectively in this study. The authors noted 3 important criteria for inclusion in the database. Patients had to be diagnosed with de novo RCC or had to not have received a nephrectomy for localized RCC. Patients had to have been treated with a first-line ICI or targeted therapy, and first-line systemic therapy had to be initiated on or after January 2009.

Study Layout and Results

Patients were divided into 2 cohorts based on whether they had received an ICI or systemic therapy and were subdivided based on whether or not they had undergone upfront cytoreductive nephrectomy. The primary outcome investigated in the study was OS. Multivariable logistic regression models were used to identify predictor variables to ascertain whether patients were more or less likely to undergo cytoreductive nephrectomy.

A total of 4639 patients met the eligibility criteria, of whom 4202 were treated with targeted therapy and 437 were treated with ICIs. Of patients who underwent targeted therapy, 62% had been treated with sunitinib, and 50% of patients who received ICI therapy had been treated with a combination of nivolumab and ipilimumab. Additionally, 55% of patients in the targeted therapy group and 54% of those in the ICI group had received an upfront cytoreductive nephrectomy. The authors note that after undergoing cytoreductive nephrectomy, the median time to initiation of systemic therapy was 3.1 months for the targeted therapy cohort and 2.5 months for the ICI cohort. For patients who had received cytoreductive nephrectomy, the mean age was 60 years in the ICI cohort and 61 years in the targeted therapy cohort, whereas it was 63 years in both cohorts for patients who did not receive cytoreductive nephrectomy.

The authors noted that “the IMDC prognostic profiles of patients who received cytoreductive nephrectomy were better in both treatment groups, with 72% and 60% of the patients belonging to the intermediate risk group in the immune checkpoint inhibitor and targeted therapy groups, respectively, as compared with 47% and 46% who did not receive cytoreductive nephrectomy, respectively.”1 On multivariable logistic regression analysis, older age (≥65 years), the presence of metastasis involving bone, brain, or liver, a low Karnofsky performance scale score (<80), and poor IMDC risk factors were associated with less likelihood of undergoing cytoreductive nephrectomy.

Bakouny et al also evaluated the relationship between receiving cytoreductive nephrectomy and OS. There were 2927 deaths reported in the targeted therapy group and 123 deaths in the ICI group. For surviving patients, the median follow-up time was 24 months for the targeted therapy group and 12 months for the ICI group. Median OS for patients in the ICI group was 54 months (95% CI, 34-not reached) for those who received cytoreductive nephrectomy versus 22 months (95% CI, 17-25) for those who did not; in the targeted therapy group, the median was 25 months (95% CI, 23-26) for those who received cytoreductive nephrectomy versus 13 months (95% CI, 12-14) for those who did not.

Cytoreductive Nephrectomy Survival Benefit

These findings were consistent when accounting for multiple confounding variables showing an OS benefit for patients who underwent an upfront cytoreductive nephrectomy in both the ICI (hazard ratio [HR], 0.61; 95 CI, 0.4-0.9; P=0.013) and targeted therapy (HR, 0.72; 95% CI, 0.67- 0.78; P>0.001) cohorts. Of note, there was no detectable significant difference between the 2 cohorts in the survival benefit received from an upfront cytoreductive nephrectomy. The authors then challenged their findings by considering both recognized and unrecognized confounders and found consistent results showing a survival benefit.

Bakouny et al found that “upfront cytoreductive nephrectomy was associated with a significant survival benefit, regardless of the systemic therapy used even after adjusting for potential confounding factors.”¹ In this study, patients were more likely to receive an upfront cytoreductive nephrectomy if they were younger in age, had fewer IMDC risk factors, had a better Karnofsky performance status, and had no adverse sites of metastasis such as bone, brain, or liver. The findings suggest that, in this era of ICI-based therapy, patients who are carefully selected and meet these criteria may benefit from upfront cytoreductive nephrectomy—a benefit the authors speculate could “be due to the immune effects of cytoreductive nephrectomy.”⁷ The idea behind this is that primary RCC tumors may release cytokines that promote inflammation and inhibit T cells, which could impede the systemic antitumor immune response.⁸ Bakouny et al concluded that “the removal of the primary tumor may be potentiating a more effective immune response mounted against the metastatic RCC lesions treated with immune checkpoint inhibitors.”¹

The findings of improved OS with cytoreductive nephrectomy in patients treated with immunotherapy are consistent with results from other recently published studies.^9,10 This study’s strength lies in being a multicenter, large study that performed analyses incorporating potential confounders. However, its limitations include that it was a retrospective, nonrandomized study that did not include all the potential confounders that might have influenced whether a patient received a cytoreductive nephrectomy, and it was largely conducted in an academic cohort that was not necessarily representative of the general population. Nevertheless, in the absence of randomized controlled trials, these findings may help guide clinicians in determining which patients would most benefit from undergoing a cytoreductive nephrectomy.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

References

1. 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. 2022 Oct 19: S0302-2838(22)02713-0. doi: 10.1016/j. eururo.2022.10.004.
2. Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol. 2004; 171:1071-1076. doi: 10.1097/01. ju.0000110610.61545.ae
3. Mickisch GH, Garin A, van Poppel H, Sylvester R ; for the European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358(9286):966-970. doi: 10.1016/s0140-6736(01)06103-7.
4. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417-427. doi: 10.1056/NEJMoa1803675.
5. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy for patients with metastatic renal cell carcinoma: is there still a role for cytoreductive nephrectomy? Eur Urol. 2021;80(4):417-424. doi: 10.1016/j.eururo.2021.06.009.
6. Hanna N, Sun M, Meyer CP, et al. Survival analyses of patients with metastatic renal cancer treated with targeted therapy with or without cytoreductive nephrectomy: a National Cancer Data Base study. J Clin Oncol. 2016 ;34(27):3267-3275. doi: 10.1200/ JCO.2016.66.7931.
7. Dadian G, Riches PG, Henderson DC, et al. Immunological parameters in peripheral blood of patients with renal cell carcinoma before and after nephrectomy. Br J Urol. 1994;74(1):15-22. doi: 10.1111/j.1464-410x.1994.tb16538.x.
8. Flanigan RC. Debulking nephrectomy in metastatic renal cancer. Clin Cancer Res. 2004; 10(18 pt 2):6335S-6341S. doi: 10.1158/1078-0432.CCR-sup-040026.
9. Singla N, Hutchinson RC, Ghandour RA, et al. Improved survival after cytoreductive nephrectomy for metastatic renal cell carcinoma in the contemporary immunotherapy era: an analysis of the National Cancer Database. Urol Oncol. 2020;38(6): 604.e9-604. e17. doi: 10.1016/j.urolonc.2020.02.029.
10. Ghatalia P, Handorf EA, Deng M, et al. Role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2021;39(15 suppl): abstract 4582. doi: 10.1200/JCO.2021.39.15_suppl.4582.