Tyrosine kinase inhibitors (TKIs) have been widely used in the management of patients with metastatic renal cell carcinoma (RCC). However, the use of systemic therapies in the adjuvant setting of localized and locally advanced RCC has shown conflicting results across the literature. Therefore, we aimed to conduct an updated systematic review and meta-analysis comparing the efficacy and safety of TKIs in the adjuvant setting for patients with localized and locally advanced RCC.
The MEDLINE and EMBASE databases were searched in December 2020 to identify phase III randomized controlled trials of patients receiving adjuvant therapies with TKI for RCC. Disease-free survival (DFS) and overall survival (OS) were the primary endpoints. The secondary endpoints included treatment-related adverse events (TRAEs) of high and any grade.
Five trials (S-TRAC, ASSURE, PROTECT, ATLAS, and SORCE) were included in our meta-analysis comprising 6,531 patients. The forest plot revealed that TKI therapy was associated with a significantly longer DFS compared to placebo (pooled HR: 0.88, 95% CI: 0.81-0.96, P= 0.004). The Cochrane's Q test (P = 0.51) and I2 test (I2 = 0%) revealed no significant heterogeneity. Adjuvant TKI was not associated with improved OS compared to placebo (pooled HR: 0.93, 95% CI: 0.83-1.04, P= 0.23). The Cochrane's Q test (P = 0.74) and I2 test (I2 = 0%) revealed no significant heterogeneity. The forest plot revealed that TKI therapy, compared to placebo, was associated with higher rates of high grade TRAEs (OR: 5.20, 95% CI: 4.10-6.59, P< 0.00001) as well as any grade TRAEs (OR: 3.85, 95% CI: 1.22-12.17, P= 0.02). The Cochrane's Q tests (P < 0.0001 and P < 0.00001, respectively) and I2 tests (I2 = 79% and I2 = 90%, respectively) revealed significant heterogeneity.
The findings of our analyses suggest an improved DFS in patients with localized and locally advanced RCC receiving adjuvant TKI as compared to placebo; however, this did not translate into any significant OS benefit. Additionally, TKI therapy led to significant toxicity. Adjuvant TKI does not seem to offer a satisfactory risk and/orbenefit balance for all patients. Select patients with very poor prognosis may be considered in a shared decision-making process with the patient. With the successful arrival of immune-based therapies in RCC, these may allow a more favorable risk/benefit profile.
Urologic oncology. 2021 Aug 14 [Epub ahead of print]
Ekaterina Laukhtina, Fahad Quhal, Keiichiro Mori, Reza Sari Motlagh, Benjamin Pradere, Victor M Schuettfort, Hadi Mostafaei, Satoshi Katayama, Nico С Grossmann, Pawel Rajwa, Irene Resch, Dmitry Enikeev, Pierre I Karakiewicz, Shahrokh F Shariat, Manuela Schmidinger
Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, King Fahad Specialist Hospital, Dammam, Saudi Arabia., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, The Jikei University School of Medicine, Tokyo, Japan., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, University Hospital Zurich, Zurich, Switzerland., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, Medical University of Silesia, Zabrze, Poland., Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia., Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Canada., Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia; Department of Urology, Weill Cornell Medical College, New York, NY, USA; Department of Urology, University of Texas Southwestern, Dallas, TX, USA; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Karl Landsteiner Institute of Urology and Andrology, Vienna, Austria; Division of Urology, Department of Special Surgery, Jordan University Hospital, The University of Jordan, Amman, Jordan. Electronic address: .