E Fokas1, R Fietkau2, A Hartmann3, W Hohenberger4, R Grützmann4, M Ghadimi5, T Liersch5, P Ströbel6, G G Grabenbauer7, U Graeven8, R-D Hofheinz9, C-H Köhne10, C Wittekind11, R Sauer2, M Kaufmann12, T Hothorn12, C Rödel13. 1. Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg; German Cancer Consortium (DKTK), Partner Site: Frankfurt, Germany. Electronic address: emmanouil.fokas@kgu.de. 2. Department of Radiation Therapy, University of Erlangen-Nürnberg, Erlangen, Germany. 3. Institute of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany. 4. Department of General and Visceral, University of Erlangen-Nürnberg, Erlangen, Germany. 5. Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany. 6. Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany. 7. Department of Radiation Oncology and Radiotherapy, DiaCura & Klinikum Coburg, Coburg, Germany. 8. Department of Hematology/Oncology, Kliniken Maria Hilf GmbH Mönchengladbach, Mönchengladbach, Germany. 9. Department of Medical Oncology, University Hospital Mannheim, Mannheim, Germany. 10. Department of Medical Oncology, University of Oldenburg, Oldenburg, Germany. 11. Institute of Pathology, University of Leipzig, Leipzig, Germany. 12. Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland. 13. Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg; German Cancer Consortium (DKTK), Partner Site: Frankfurt, Germany.
Abstract
Background: Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial. Patients and methods: Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS. Results: After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106-7.020; P < 0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P = 0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4. Conclusion: Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.
RCT Entities:
Background: Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial. Patients and methods: Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS. Results: After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106-7.020; P < 0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P = 0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4. Conclusion: Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy.
Authors: Thomas J George; Aaron J Franke; A Bapsi Chakravarthy; Prajnan Das; Arvind Dasari; Bassel F El-Rayes; Theodore S Hong; Timothy J Kinsella; Jerome C Landry; James J Lee; Arta M Monjazeb; Samuel A Jacobs; David Raben; Osama E Rahma; Terence M Williams; Christina Wu; C Norman Coleman; Bhadrasain Vikram; Mansoor M Ahmed Journal: Cancer Date: 2019-04-24 Impact factor: 6.860
Authors: Séan M O'Cathail; Steven Davis; Jane Holmes; Richard Brown; Kerry Fisher; Leonard Seymour; Richard Adams; James Good; David Sebag-Montefiore; Tim Maughan; Maria A Hawkins Journal: Radiat Oncol Date: 2020-06-12 Impact factor: 3.481