In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown.
To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib.
This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied.
Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy.
Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points.
The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P = .61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P = .03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%).
Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib.
ClinicalTrials.gov identifier: NCT01099423.
JAMA oncology. 2018 Dec 13 [Epub ahead of print]
Axel Bex, Peter Mulders, Michael Jewett, John Wagstaff, Johannes V van Thienen, Christian U Blank, Roland van Velthoven, Maria Del Pilar Laguna, Lori Wood, Harm H E van Melick, Maureen J Aarts, J B Lattouf, Thomas Powles, Igle Jan de Jong, Sylvie Rottey, Bertrand Tombal, Sandrine Marreaud, Sandra Collette, Laurence Collette, John Haanen
The Netherlands Cancer Institute, Amsterdam, the Netherlands., Department of Urology, Radboud University Hospital, Nijmegen, the Netherlands., Department of Urology, Princess Margaret Hospital, Toronto, Ontario, Canada., Department of Oncology, Cardiff Hospital, Wales, United Kingdom., Department of Urology, Institut Jules Bordet, Brussels, Belgium., Department of Urology, Amsterdam Medical Center, Amsterdam University, Amsterdam, the Netherlands., Division of Medical Oncology, QEII Health Sciences Center, Halifax, Nova Scotia, Canada., Department of Urology, Saint Antonius Hospital, Nieuwegein, the Netherlands., Department of Oncology, Maastricht University Medical Center, Maastricht, the Netherlands., Department of Surgery-Urology, University of Montreal Hospital Center, Quebec, Ontario, Canada., Department of Oncology, The Royal Free Hospital and Queen Mary University, London, United Kingdom., Department of Urology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium., Department of Urology, Cliniques Universitaires Saint-Luc, Brussels, Belgium., Department of Statistics, European Organisation for Research and Treatment of Cancer, Brussels, Belgium.