Tim Eisen1, Eleni Frangou2, Bhavna Oza2, Alastair W S Ritchie2, Benjamin Smith2, Rick Kaplan2, Ian D Davis3, Martin R Stockler4, Laurence Albiges5, Bernard Escudier5, James Larkin6, Axel Bex7,8, Steven Joniau9, Barry Hancock10, Gregers G Hermann11, Joaquim Bellmunt12, Elizabeth Hodgkinson13, Grant D Stewart14, Jim Barber15, Janet Brown16,17, Rhona McMenemin18, Paul Nathan19, Lisa M Pickering6, Mahesh K B Parmar2, Angela Meade2. 1. Department of Oncology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, United Kingdom. 2. Medical Research Council Clinical Trials Unit at University College London (UCL), Institute of Clinical Trials and Methodology, London, United Kingdom. 3. Monash University and Eastern Health, Box Hill, Victoria, Australia. 4. National Health and Medical Research Council Clinical Trials Centre, Central Clinical School, Department of Medicine, University of Sydney, Sydney, New South Wales, Australia. 5. Institut Gustave Roussy, Villejuif, France. 6. The Royal Marsden Hospital, London, United Kingdom. 7. Royal Free London NHS Foundation Trust UCL, Division of Surgery and Interventional Science, London, United Kingdom. 8. Netherlands Cancer Institute, Amsterdam, the Netherlands. 9. Department of Development and Regeneration, Urogenital, Abdominal, and Plastic Surgery, University Hospitals Leuven, Leuven, Belgium. 10. University of Sheffield, Academic Unit of Clinical Oncology, Weston Park Cancer Centre, Sheffield, United Kingdom. 11. Urology Research Unit, Department of Urology, Herlev/Gentofte Hospital, Herlev, Denmark. 12. Beth Israel Deaconess Medical Center-IMIM Research Lab, Boston, MA. 13. Pharmacy Department, Weston Park Hospital, Sheffield, United Kingdom. 14. Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom. 15. Velindre Cancer Centre, Cardiff, United Kingdom. 16. Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, Sheffield, United Kingdom. 17. Institute of Cancer and Pathology, St James's University Hospital, University of Leeds, Leeds, United Kingdom. 18. Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, United Kingdom. 19. Mount Vernon Cancer Centre, Northwood, United Kingdom.
Abstract
PURPOSE: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.
PURPOSE: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.
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