Alessandro Gronchi1, Sylvie Bonvalot2, Andres Poveda Velasco3, Dusan Kotasek4, Piotr Rutkowski5, Peter Hohenberger6, Elena Fumagalli1, Ian R Judson7, Antoine Italiano8, Hans J Gelderblom9, Frits van Coevorden10, Nicolas Penel11, Hans-Georg Kopp12, Florence Duffaud13, David Goldstein14, Javier Martin Broto15, Eva Wardelmann16, Sandrine Marréaud17, Mark Smithers18, Axel Le Cesne19, Facundo Zaffaroni17, Saskia Litière17, Jean-Yves Blay20, Paolo G Casali1,21. 1. Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. 2. Institute Curie, Paris, France. 3. Instituto Valenciano De Oncologia, Valencia, Spain. 4. Adelaide Cancer Centre, Kurralta Park, and Division of Medicine, University of Adelaide, Adelaide, Australia. 5. Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland. 6. Mannheim University Medical Center, Mannheim, Germany. 7. Royal Marsden Hospital, London, England. 8. Institut Bergonie, Bordeaux, France. 9. Leiden University Medical Center, Leiden, the Netherlands. 10. The Netherland Cancer Institute, Amsterdam, the Netherlands. 11. Centre Oscar Lambret, Lille, France. 12. Medizinische Universitätsklinik II, Tübingen, Germany. 13. Hôpital La Timone, Aix-Marseille Université, Marseille, France. 14. Prince of Wales Hospital, Sydney, Australia. 15. Hospital Universitario Viergen del Rocio Sevilla, Seville, Spain. 16. University Hospital Münster, Münster, Germany. 17. EORTC Headquarters, Brussels, Belgium. 18. Princess Alexandra Hospital, The University of Queensland, Brisbane, Australia. 19. Institute Gustave Roussy, Villejuif, France. 20. Department of Medicine, NetSARC and LYRIC, Centre Leon Berard, Lyon, France. 21. Oncology and Hemato-Oncology Department, University of Milan, Milan, Italy.
Abstract
Importance: The association between quality of surgery and overall survival in patients affected by localized gastrointestinal stromal tumors (GIST) is not completely understood. Objective: To assess the risk of death with and without imatinib according to microscopic margins status (R0/R1) using data from a randomized study on adjuvant imatinib. Design, Setting, and Participants: This is a post hoc observational study on patients included in the randomized, open-label, phase III trial, performed between December 2004 and October 2008. Median follow-up was 9.1 years (IQR, 8-10 years). The study was performed at 112 hospitals in 12 countries. Inclusion criteria were diagnosis of primary GIST, with intermediate or high risk of relapse; no evidence of residual disease after surgery; older than 18 years; and no prior malignancies or concurrent severe/uncontrolled medical conditions. Data were analyzed between July 17, 2017, and March 1, 2020. Interventions: Patients were randomized after surgery to either receive imatinib (400 mg/d) for 2 years or no adjuvant treatment. Randomization was stratified by center, risk category (high vs intermediate), tumor site (gastric vs other), and quality of surgery (R0 vs R1). Tumor rupture was included in the R1 category but also analyzed separately. Main Outcomes and Measures: Primary end point of this substudy was overall survival (OS), estimated using Kaplan-Meier method and compared between R0/R1 using Cox models adjusted for treatment and stratification factors. Results:A total of 908 patients were included; 51.4% were men (465) and 48.6% were women (440), and the median age was 59 years (range, 18-89 years). One hundred sixty-two (17.8%) had an R1 resection, and 97 of 162 (59.9%) had tumor rupture. There was a significant difference in OS for patients undergoing an R1 vs R0 resection, overall (hazard ratio [HR], 2.05; 95% CI, 1.45-2.89) and by treatment arm (HR, 2.65; 95% CI, 1.37-3.75 with adjuvant imatinib and HR, 1.86; 95% CI, 1.16-2.99 without adjuvant imatinib). When tumor rupture was excluded, this difference in OS between R1 and R0 resections disappeared (HR, 1.05; 95% CI, 0.54-2.01). Conclusions and Relevance: The difference in OS by quality of surgery with or without imatinib was associated with the presence of tumor rupture. When the latter was excluded, the presence of R1 margins was not associated with worse OS. Trial Registration: ClinicalTrials.gov Identifier: NCT00103168.
RCT Entities:
Importance: The association between quality of surgery and overall survival in patients affected by localized gastrointestinal stromal tumors (GIST) is not completely understood. Objective: To assess the risk of death with and without imatinib according to microscopic margins status (R0/R1) using data from a randomized study on adjuvant imatinib. Design, Setting, and Participants: This is a post hoc observational study on patients included in the randomized, open-label, phase III trial, performed between December 2004 and October 2008. Median follow-up was 9.1 years (IQR, 8-10 years). The study was performed at 112 hospitals in 12 countries. Inclusion criteria were diagnosis of primary GIST, with intermediate or high risk of relapse; no evidence of residual disease after surgery; older than 18 years; and no prior malignancies or concurrent severe/uncontrolled medical conditions. Data were analyzed between July 17, 2017, and March 1, 2020. Interventions: Patients were randomized after surgery to either receive imatinib (400 mg/d) for 2 years or no adjuvant treatment. Randomization was stratified by center, risk category (high vs intermediate), tumor site (gastric vs other), and quality of surgery (R0 vs R1). Tumor rupture was included in the R1 category but also analyzed separately. Main Outcomes and Measures: Primary end point of this substudy was overall survival (OS), estimated using Kaplan-Meier method and compared between R0/R1 using Cox models adjusted for treatment and stratification factors. Results: A total of 908 patients were included; 51.4% were men (465) and 48.6% were women (440), and the median age was 59 years (range, 18-89 years). One hundred sixty-two (17.8%) had an R1 resection, and 97 of 162 (59.9%) had tumor rupture. There was a significant difference in OS for patients undergoing an R1 vs R0 resection, overall (hazard ratio [HR], 2.05; 95% CI, 1.45-2.89) and by treatment arm (HR, 2.65; 95% CI, 1.37-3.75 with adjuvant imatinib and HR, 1.86; 95% CI, 1.16-2.99 without adjuvant imatinib). When tumor rupture was excluded, this difference in OS between R1 and R0 resections disappeared (HR, 1.05; 95% CI, 0.54-2.01). Conclusions and Relevance: The difference in OS by quality of surgery with or without imatinib was associated with the presence of tumor rupture. When the latter was excluded, the presence of R1 margins was not associated with worse OS. Trial Registration: ClinicalTrials.gov Identifier: NCT00103168.
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Authors: Matthew P Doepker; Zachary J Thompson; Kate J Fisher; Maki Yamamoto; Kevin W Nethers; Jennifer N Harb; Matthew A Applebaum; Ricardo J Gonzalez; Amod A Sarnaik; Jane L Messina; Vernon K Sondak; Jonathan S Zager Journal: Ann Surg Oncol Date: 2016-03-08 Impact factor: 5.344