Emmanouil Fokas1,2,3, Anke Schlenska-Lange4, Bülent Polat5, Gunther Klautke6, Gerhard G Grabenbauer7, Rainer Fietkau8, Thomas Kuhnt9, Ludger Staib10, Thomas Brunner11, Anca-Ligia Grosu12,13, Simon Kirste12,13, Lutz Jacobasch14, Michael Allgäuer15, Michael Flentje5, Christoph-Thomas Germer16, Robert Grützmann17, Guido Hildebrandt18, Matthias Schwarzbach19, Wolf O Bechstein20, Heiko Sülberg21, Tim Friede22, Jochen Gaedcke23, Michael Ghadimi23, Ralf-Dieter Hofheinz24, Claus Rödel1,2,3. 1. Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany. 2. German Cancer Research Center, German Cancer Consortium, Frankfurt, Germany. 3. Frankfurt Cancer Institute, Frankfurt, Germany. 4. Department of Haematology and Oncology, Barmherzige Brüder Hospital, Regensburg, Germany. 5. Department of Radiation Oncology, University of Würzburg, Würzburg, Germany. 6. Department of Radiation Therapy, Poliklinik Chemnitz GmbH, Chemnitz, Germany. 7. Department of Radiation Oncology and Radiotherapy, DiaCura & Klinikum Coburg, Coburg, Germany. 8. Department of Radiation Therapy, University of Erlangen-Nürnberg, Erlangen, Germany. 9. Department of Radiation Therapy, University of Leipzig, Leipzig, Germany. 10. Department of General and Visceral Surgery, Klinikum Esslingen, Germany. 11. Department of Radiation Therapy, University of Magdeburg, Magdeburg, Germany. 12. Department of Radiation Oncology, Medical Center University of Freiburg, Faculty of Medicine, Freiburg, Germany. 13. German Cancer Research Center, German Cancer Consortium, Freiburg, Germany. 14. Praxis of Haematology and Oncology, Dresden, Germany. 15. Department of Radiotherapy, Barmherzige Brüder Hospital Regensburg, Regensburg, Germany. 16. Department of General and Visceral Surgery, University of Würzburg, Würzburg, Germany. 17. Department of General and Visceral Surgery, University of Erlangen-Nürnberg, Erlangen, Germany. 18. Department of Radiotherapy and Oncology, University of Rostock, Rostock, Germany. 19. Department of General and Visceral Surgery, Klinikum Frankfurt Höchst, Germany. 20. Department of General and Visceral Surgery, University of Frankfurt, Frankfurt, Germany. 21. X-act Cologne Clinical Research GmbH, Cologne, Germany. 22. Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany. 23. Department of General and Visceral Surgery, University Medical Center Göttingen, Göttingen, Germany. 24. Department of Medical Oncology, University Hospital Mannheim, Mannheim, Germany.
Abstract
IMPORTANCE: Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established. OBJECTIVE: To report the long-term results of the secondary end points prespecified in the Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy (CAO/ARO/AIO-12 trial) for Locally Advanced Rectal Cancer. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a randomized clinical trial included 311 patients who were recruited from the accrued CAO/ARO/AIO-12 trial population from June 15, 2015, to January 31, 2018, from 18 centers in Germany. Patients with cT3-4 and/or node-positive rectal adenocarcinoma were included in the analysis. Data were analyzed from June 15, 2015, to January 31, 2018. The follow-up analysis was conducted between January 31, 2018, and November 30, 2020. INTERVENTIONS: Patients were randomly assigned to group A for 3 cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy), or to group B for CRT before chemotherapy. Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant therapy in both groups. MAIN OUTCOMES AND MEASURES: The end points assessed in this secondary analysis included long-term oncologic outcomes, chronic toxicity, patient-reported outcome measures for global health status (GHS) and quality of life (QoL), and the Wexner stool incontinence score. RESULTS: Of the 311 patients enrolled, 306 were evaluable, including 156 in group A (mean [SD] age, 60 [11] years; 106 men [68%]) and 150 in group B (mean [SD] age, 62 [10] years; 100 men [67%]). After a median follow-up of 43 months (range, 35-60 months), the 3-year disease-free survival was 73% in both groups (hazard ratio, 0.95; 95% CI, 0.63-1.45, P = .82); the 3-year cumulative incidence of locoregional recurrence (6% vs 5%, P = .67) and distant metastases (18% vs 16%, P = .52) were not significantly different. Chronic toxicity grade 3 to 4 occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B at 3 years. The GHS/QoL score decreased after total mesorectal excision but returned to pretreatment levels 1 year after randomization with no difference between the groups. Stool incontinence deteriorated 1 year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels. CONCLUSIONS AND RELEVANCE: This secondary analysis of a randomized clinical trial showed that CRT followed by chemotherapy resulted in higher pathological complete response without compromising disease-free survival, toxicity, QoL, or stool incontinence and is thus proposed as the preferred total neoadjuvant therapy sequence if organ preservation is a priority. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02363374.
IMPORTANCE: Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established. OBJECTIVE: To report the long-term results of the secondary end points prespecified in the Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy (CAO/ARO/AIO-12 trial) for Locally Advanced Rectal Cancer. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a randomized clinical trial included 311 patients who were recruited from the accrued CAO/ARO/AIO-12 trial population from June 15, 2015, to January 31, 2018, from 18 centers in Germany. Patients with cT3-4 and/or node-positive rectal adenocarcinoma were included in the analysis. Data were analyzed from June 15, 2015, to January 31, 2018. The follow-up analysis was conducted between January 31, 2018, and November 30, 2020. INTERVENTIONS: Patients were randomly assigned to group A for 3 cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy), or to group B for CRT before chemotherapy. Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant therapy in both groups. MAIN OUTCOMES AND MEASURES: The end points assessed in this secondary analysis included long-term oncologic outcomes, chronic toxicity, patient-reported outcome measures for global health status (GHS) and quality of life (QoL), and the Wexner stool incontinence score. RESULTS: Of the 311 patients enrolled, 306 were evaluable, including 156 in group A (mean [SD] age, 60 [11] years; 106 men [68%]) and 150 in group B (mean [SD] age, 62 [10] years; 100 men [67%]). After a median follow-up of 43 months (range, 35-60 months), the 3-year disease-free survival was 73% in both groups (hazard ratio, 0.95; 95% CI, 0.63-1.45, P = .82); the 3-year cumulative incidence of locoregional recurrence (6% vs 5%, P = .67) and distant metastases (18% vs 16%, P = .52) were not significantly different. Chronic toxicity grade 3 to 4 occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B at 3 years. The GHS/QoL score decreased after total mesorectal excision but returned to pretreatment levels 1 year after randomization with no difference between the groups. Stool incontinence deteriorated 1 year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels. CONCLUSIONS AND RELEVANCE: This secondary analysis of a randomized clinical trial showed that CRT followed by chemotherapy resulted in higher pathological complete response without compromising disease-free survival, toxicity, QoL, or stool incontinence and is thus proposed as the preferred total neoadjuvant therapy sequence if organ preservation is a priority. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02363374.
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Authors: Maximilian Fleischmann; Markus Diefenhardt; Adele M Nicolas; Franz Rödel; Michael Ghadimi; Ralf-Dieter Hofheinz; Florian R Greten; Claus Rödel; Emmanouil Fokas Journal: Clin Transl Radiat Oncol Date: 2022-04-06