Cytoreductive nephrectomy (CN) has returned to the headlines following a recent publication in Journal of Urology1 by Poojha Ghatalia, MD, and her colleagues from the Fox Chase Cancer Center in Philadelphia.
The report documents the authors’ effort to investigate the role of CN in the era of tyrosine kinase inhibitors (TKIs) and immunotherapy.
The Beginnings of CN Use
The introduction begins with a review of the important historical role of CN. In 2001 and 2004, two published randomized phase 3 trials supported the use of CN before administration of interferon-α. These studies showed improved overall survival (OS) in patients who received a CN prior to interferon-α compared with those who received interferon-α alone.2,3
These results were called into question by the landmark CARMENA trial, published in 2018 in the New England Journal of Medicine.4 CARMENA was a phase 3 noninferiority trial that found no significant benefit to patients who received an upfront CN prior to sunitinib treatment when compared with patients who received sunitinib without surgery. Additionally, SURTIME, a prospective randomized trial comparing deferred CN to upfront CN in patients receiving sunitinib, found that OS may have been better in those who received a deferred nephrectomy.5
Conversely, several large retrospective studies have indicated improved OS for patients who received a CN and affirmed the benefit of deferred versus upfront nephrectomy. These divergent findings, which have painted a confusing picture of the role of CN in patients with metastatic renal cell cancer (mRCC), led Ghatalia et al to evaluate “real-world data from an electronic health record [EHR]-based database…to evaluate the role of upfront CN versus systemic therapy alone, including immunotherapy and tyrosine kinase inhibitor-treated patients, and the role of upfront CN versus deferred CN.”1
Analyzing CN Versus Systemic Therapy
The EHR comprised data from 800 sites of care, most of which were community medical oncology clinics or academic medical centers. Approximately 9000 cases of mRCC, reported between 2011 and 2020, were included for analysis. Other variables assessed included age, sex, race, body mass index, date of metastatic diagnosis, stage, laboratory values, drugs administered, date of CN, Eastern Cooperative Oncology Group (ECOG) performance status, and insurance type. Survival outcomes were determined by radiographic or clinical progression, and date of death, or last structured office visit.
All patients included had intermediate or poor risk status according to the International Metastatic RCC Database Consortium (IMDC) definition. The primary outcome was to compare OS in the patients who received upfront CN versus systemic therapy (including immunotherapy, TKIs, or mammalian target of rapamycin [mTOR] inhibitors). The key secondary outcome was the association between OS and receipt of upfront versus deferred CN. Several methods of analysis were used to reduce the introduction of bias into the results.
After eligibility and study criteria were met, 1910 patients were included in the study. Participants were predominantly White and male, with a mean age of 65 years. The investigators were unable to ascertain IMDC risk in 46% (n=880) of patients, who were classified as intermediate/poor risk; of the remaining 1030 patients, 28% had intermediate risk and 72% had poor risk.
A total of 51% of patients received systemic therapy without undergoing nephrectomy, 32% had received an upfront CN, 7% received a deferred nephrectomy, and 10% received a CN but no systemic therapy. Patients who only received systemic therapy were older and had poorer performance status and poorer risk compared with patients who received a CN. Of the patients given immunotherapy, one-third received either an upfront or deferred CN; these patients tended to be younger with better performance status and less-poor risk disease. The researchers also evaluated the variability of systemic treatment. Most patients received targeted therapy (n=1155), with the remainder receiving combinations of immunotherapy or immunotherapy plus a targeted treatment.
Procedure Effects on Survival
Ghatalia et al performed several analyses to describe the effect that CN had on survival. After balancing (via inverse probability of treatment weighing [IPTW]) pertinent potential biasing factors, including age and IMDC score, median OS was 26 months for patients receiving upfront CN compared with 1 year for those who did not. To further reduce the influence of bias-specifically immortal time bias-a first-treatment analysis, landmark analysis, and time-varying covariate analysis were performed.
The first-treatment analysis showed significant findings for upfront versus deferred CN in OS (26.6 vs 14.6 months) and improved progression-free survival (7.5 vs 5.1 months). Landmark analysis showed similar benefit and a median OS of 36 months in patients receiving upfront CN versus 21.1 months with deferred CN. Additionally, the time-varying covariate analysis found a hazard ratio of 0.83 for upfront CN compared to systemic therapy alone.
Of the patients who received a CN, 81% underwent upfront CN compared with 19% who had a deferred CN. Median OS was 26.1 months with upfront CN compared to 36.5 months with deferred CN, but the findings were seen resulting from immortal time bias, and upon analysis, no statistically significant difference in median OS was revealed.
Overall Survival in CN
In their discussion, the researchers commented that they found upfront CN significantly impacted and improved OS when accounting for many patients’ specific factors, as well as multiple analyses models. They emphasized they designed the conduct of the study in an to attempt to re-create the CARMENA trial’s intention-to-treat analysis, while also replicating a “real-world scenario.”1
They noted that the OS benefit shown in the study was lower than that seen in other studies,6 but that this might be attributable to the strict inclusion criteria and analyses in their study. Although they attempted to identify the ideal candidate to undergo a CN, based on patient-related factors and the therapeutic regimen the patient would be receiving, they could not reach a firm conclusion. Thus, they reiterated that “individualized decisions between the surgeon, oncologist, and patient in regard to the appropriateness of CN in each case remains critical.”1
Ghatalia et al noted some limitations of their study, including not having data on patients if they received a CN at another hospital that was not incorporated in the EHR, which led to patients suspected of possibly having a CN at another center (based on missed surgery date or extensive time between diagnosis and starting on systemic therapy) being excluded from the analysis. The median OS for patients in this study who received just systemic therapy was only 12 to 13 months, which is less than what was expected.
The authors posited that this was likely due to drawing the study population from as early as 2011 and including some patients with poor initial comorbidities and prognoses. Although the researchers attempted to reduce the risk of bias, the retrospective nonrandomized design of the study means that selection bias represents another possible limitation. Further and ongoing prospective trials will further inform on the role and timing of a CN in the setting of patients who are receiving immunotherapy.
- Ghatalia P, Handorf EA, Geynisman DM, et al. The role of cytoreductive nephrectomy in metastatic renal cell carcinoma: a real-world multi-institutional analysis. J Urol. 2022;208(1):71-79. doi: 10.1097/JU.0000000000002495
- 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(3):1071-1076. doi: 10.1097/01. ju.0000110610.61545.ae
- Mickisch GH, Garin A, van Poppel H, de Prijck L, 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
- 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
- Bex A, Mulders P, Jewett M, et al. Comparison of Immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial [published correction appears in JAMA Oncol. 2019;5(2):271. doi: 10.1001/jamaoncol.2019.0117]. JAMA Oncol. 2019;5(2):164-170. doi: 10.1001/jamaoncol.2018.5543
- 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