Metastatic clear cell renal carcinoma (ccRCC) is the most common type of kidney cancer. Cytoreductive nephrectomy has been a part of the standard of care for decades, with observational studies reporting a correlation between positive survival outcomes and cytoreductive nephrectomy in patients with ccRCC.

Though informative, the previously conducted observational studies did not account for confounding by surgical indication, according to Nicholas H. Chakiryan, MD, and colleagues. The decision to proceed with surgical intervention is nuanced and based on a range of considerations, including patient frailty, surgical complexity, and the site and volume of the metastases. “These observational studies did not account for selection bias related to unmeasured confounding by surgical indication, and as such their results may not accurately reflect the effectiveness of the intervention,” wrote Dr Chakiryan, and colleagues in JAMA Network Open.


Adjusting for Bias

The researchers conducted a study to analyze the effectiveness of cytoreductive nephrectomy for patients with metastatic ccRCC, adjusting for unmeasured confounding by using instrumental variable analysis. They then compared these results with those generated by usual adjustments for selection bias.

National Cancer Database (NCDB) records from January 1, 2006 to December 31, 2016 were used to identify cases of ccRCC. Inclusion was based on the following criteria: clinical stage IV metastatic ccRCC at diagnosis, age 18-100 years, availability of complete staging and demographic data, and receipt of targeted therapy as first-line treatment.  The final study population included 12,766 patients with a median age of 63; 68% were male and 88% were white. Cytoreductive nephrectomy was performed on 39% of the study group.

Dr. Chakiryan and colleagues applied Wilcoxon rank-sum testing to compare continuous variables, and the χ2 test of independence was used to compare categorical variables. A multivariable Cox proportional hazards regression was performed on the overall cohort using several covariates. Additional variable adjustments were also included.


Significant Survival Advantage With Cytoreductive Nephrectomy?

Conventional adjustments for selection bias demonstrated a significant overall survival benefit associated with cytoreductive nephrectomy (multivariable Cox proportional hazards regression: HR, 0.49; 95% CI, 0.47-0.51; propensity score matching: HR, 0.48; 95% CI, 0.46-0.50). However, the instrumental variable estimates determined by this study did not demonstrate a survival advantage for patients with ccRCC who underwent cytoreductive nephrectomy (HR, 0.92; 95% CI, 0.78-1.09). “This discrepancy likely reflects the fact that surgical indication for cytoreductive nephrectomy is primarily driven by factors that are not commonly measured or available in observational data sets,” wrote Dr. Chakiryan and team.