Significance of Upfront Cytoreductive Nephrectomy Stratified by IMDC Risk for Metastatic Renal Cell Carcinoma in Targeted Therapy Era – a Multi-Institutional Retrospective Study - Beyond the Abstract

Significance of upfront cytoreductive nephrectomy stratified by IMDC risk for metastatic renal cell carcinoma in targeted therapy era – a multi-institutional retrospective study – Beyond the Abstract

Cytoreductive nephrectomy (CN) for metastatic RCC removes the primary kidney tumor and its potential for bleeding and pain. In addition, CN possibly eliminates the primary tumor as a potential source of immunosuppressive or tumor-promoting growth factors, thus minimizing the risk of future metastatic seeding from primary tumors.1 Recently, the CARMENA trial reported no significant prolongation of OS in patients who received initial nephrectomy followed by sunitinib compared to patients with sunitinib alone.2 Although the CARMENA trial is an important and commendable effort to evaluate the impact of CN in patients with metastatic RCC, it should be evaluated within the context of its limitations.3

In the present study, we aimed to verify whether CN or drug therapy should be selected as the first-line therapy by performing analyses comparing patients with upfront CN and those with no CN + deferred CN.

The present study demonstrated that upfront CN confers survival benefits in patients with IMDC intermediate or poor risk, even after adjusting for baseline patient characteristics. To verify whether other systemic therapies contributed to the prolonged OS observed with upfront CN, we performed multivariate analysis including upfront CN and other systemic therapies in IPTW-adjusted Cox proportional hazard regression models. In the subgroup with IMDC inter-mediate risk, upfront CN versus no CN was identified as an independent factor predicting OS prolongation, while other systemic therapies were not associated with OS. Therefore, the option of upfront CN should be considered at the beginning of treatment in patients with IMDC intermediate risk. In patients with IMDC poor risk, upfront CN versus no CN and metastasectomy were independently associated with OS benefit. Therefore, upfront CN may also be indicated in metastatic RCC patients with IMDC poor risk

In our analysis of upfront CN group with IMDC intermediate risk, patients with longer OS had fewer lung metastases than patients with shorter OS (1.7 ± 0.3 versus 3.2 ± 0.3, p < 0.01). In patients with IMDC intermediate risk who had a small volume of lung metastases, targeted therapy after upfront CN may bring survival benefit. In both IPTW-unadjusted and -adjusted analyses of upfront CN group with IMDC poor risk, patients with shorter OS had more bone metastases than patients with longer OS (0.1 ± 0.1 versus 1.2 ± 0.2, p < 0.01). Indications for upfront CN in patients with IMDC poor risk have not yet been established. The present analysis suggests that IMDC poor risk patients who have multiple bone metastases may not benefit from upfront CN in terms of overall survival.

Further study is required to evaluate the survival benefit of upfront CN followed by IO therapy compared to IO therapy alone. Nowadays, IO combination therapies have become the standard of care for metastatic RCC patients. These novel agents are expected to prolong survival after upfront CN.

Written by: Renpei Kato, MD, PhD, Department of Urology, Iwate Medical University School of Medicine, Iwate, Japan


  1. Turajlic S, Xu H, Litchfield K, et al. Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal. Cell. 2018;173(3):581-594.e512.
  2. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. The New England journal of medicine. 2018;379(5):417-427.
  3. Motzer RJ, Russo P. Cytoreductive Nephrectomy - Patient Selection Is Key. The New England journal of medicine. 2018;379(5):481-482.

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