Emmanouil Fokas1,2,3,4, Michael Allgäuer5, Bülent Polat6, Gunther Klautke7, Gerhard G Grabenbauer8, Rainer Fietkau9, Thomas Kuhnt10, Ludger Staib11, Thomas Brunner12,13, Anca-Ligia Grosu12, Wolff Schmiegel14, Lutz Jacobasch15, Jürgen Weitz2,16,17, Gunnar Folprecht2,16,17, Anke Schlenska-Lange2, Michael Flentje6, Christoph-Thomas Germer6, Robert Grützmann9, Matthias Schwarzbach18, Vittorio Paolucci19, Wolf O Bechstein1, Tim Friede20, Michael Ghadimi20, Ralf-Dieter Hofheinz21, Claus Rödel1,2,3,4. 1. University of Frankfurt, Frankfurt, Germany. 2. German Cancer Research Center, Heidelberg, Germany. 3. German Cancer Consortium, Frankfurt, Germany. 4. Frankfurt Cancer Institute, Frankfurt, Germany. 5. Barmherzige Brüder Hospital Regensburg, Regensburg, Germany. 6. University Hospital of Würzburg, Würzburg, Germany. 7. Poliklinik Chemnitz, Chemnitz, Germany. 8. DiaCura, Klinikum Coburg, Coburg, Germany. 9. University of Erlangen-Nürnberg, Erlangen, Germany. 10. University of Leipzig, Leipzig, Germany. 11. Klinikum Esslingen, Esslingen, Germany. 12. University of Freiburg, Freiburg, Germany. 13. University of Magdeburg, Magdeburg, Germany. 14. Ruhr-University Bochum, Bochum, Germany. 15. Praxis of Haematology and Oncology, Dresden, Germany. 16. University of Dresden, Dresden, Germany. 17. German Cancer Consortium, Dresden, Germany. 18. Klinikum Frankfurt Höchst, Frankfurt, Germany. 19. Ketteler Krankenhaus, Offenbach, Germany. 20. University Medical Center Göttingen, Göttingen, Germany. 21. University Hospital Mannheim, Mannheim, Germany.
Abstract
PURPOSE:Total neoadjuvant therapy is a new paradigm for rectal cancer treatment. Optimal scheduling of preoperative chemoradiotherapy (CRT) and chemotherapy remains to be established. PATIENTS AND METHODS: We conducted a multicenter, randomized, phase II trial using a pick-the-winner design on the basis of the hypothesis of an increased pathologic complete response (pCR) of 25% after total neoadjuvant therapy compared with standard 15% after preoperative CRT. Patients with stage II or III rectal cancer were assigned to group A for induction chemotherapy using three cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy) or to group B for consolidation chemotherapy after CRT. Secondary end points included toxicity, compliance, and surgical morbidity. RESULTS: Of the 311 patients enrolled, 306 patients were evaluable (156 in group A and 150 in group B). CRT-related grade 3 or 4 toxicity was lower (37% v 27%) and compliance with CRT higher in group B (91%, 78%, and 76% v 97%, 87%, and 93% received full-dose radiotherapy, concomitant fluorouracil, and concomitant oxaliplatin in groups A and B, respectively); 92% versus 85% completed all induction/consolidation chemotherapy cycles, respectively. The longer interval between completion of CRT and surgery in group B (median 90 v 45 days in group A) did not increase surgical morbidity. A pCR in the intention-to-treat population was achieved in 17% in group A and in 25% in group B. Thus, only group B (P < .001), but not group A (P = .210), fulfilled the predefined statistical hypothesis. CONCLUSION: Up-front CRT followed by chemotherapy resulted in better compliance with CRT but worse compliance with chemotherapy compared with group A. Long-term follow-up will assess whether improved pCR in group B translates to better oncologic outcome.
RCT Entities:
PURPOSE: Total neoadjuvant therapy is a new paradigm for rectal cancer treatment. Optimal scheduling of preoperative chemoradiotherapy (CRT) and chemotherapy remains to be established. PATIENTS AND METHODS: We conducted a multicenter, randomized, phase II trial using a pick-the-winner design on the basis of the hypothesis of an increased pathologic complete response (pCR) of 25% after total neoadjuvant therapy compared with standard 15% after preoperative CRT. Patients with stage II or III rectal cancer were assigned to group A for induction chemotherapy using three cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy) or to group B for consolidation chemotherapy after CRT. Secondary end points included toxicity, compliance, and surgical morbidity. RESULTS: Of the 311 patients enrolled, 306 patients were evaluable (156 in group A and 150 in group B). CRT-related grade 3 or 4 toxicity was lower (37% v 27%) and compliance with CRT higher in group B (91%, 78%, and 76% v 97%, 87%, and 93% received full-dose radiotherapy, concomitant fluorouracil, and concomitant oxaliplatin in groups A and B, respectively); 92% versus 85% completed all induction/consolidation chemotherapy cycles, respectively. The longer interval between completion of CRT and surgery in group B (median 90 v 45 days in group A) did not increase surgical morbidity. A pCR in the intention-to-treat population was achieved in 17% in group A and in 25% in group B. Thus, only group B (P < .001), but not group A (P = .210), fulfilled the predefined statistical hypothesis. CONCLUSION: Up-front CRT followed by chemotherapy resulted in better compliance with CRT but worse compliance with chemotherapy compared with group A. Long-term follow-up will assess whether improved pCR in group B translates to better oncologic outcome.
Authors: Markus Diefenhardt; Ethan B Ludmir; Ralf-Dieter Hofheinz; Michael Ghadimi; Bruce D Minsky; Claus Rödel; Emmanouil Fokas Journal: JAMA Oncol Date: 2020-09-01 Impact factor: 31.777
Authors: Seth I Felder; Sebastian Feuerlein; Arthur Parsee; Iman Imanirad; Julian Sanchez; Sophie Dessureault; Richard Kim; Sarah Hoffe; Jessica Frakes; James Costello Journal: Abdom Radiol (NY) Date: 2020-10-28
Authors: Jun Seok Park; Min Kyu Kang; Seung Ho Song; Gyu-Seog Choi; Soo Yeun Park; Hye Jin Kim; Jong Gwang Kim; Byung Woog Kang; Jin Ho Baek; Dong Won Baek; Jae-Chul Kim; Shin-Hyung Park; Seung Hyun Cho; An Na Seo Journal: Int J Colorectal Dis Date: 2021-02-06 Impact factor: 2.571
Authors: Ewa Kosakowska; Lucyna Pietrzak; Wojciech Michalski; Lucyna Kepka; Wojciech Polkowski; Malgorzata Jankiewicz; Bogumila Cisel; Jacek Krynski; Jacek Zwolinski; Lucjan Wyrwicz; Andrzej Rutkowski; Roman Stylinski; Grzegorz Nawrocki; Rafal Sopylo; Marek Szczepkowski; Wieslaw Tarnowski; Krzysztof Bujko Journal: Rep Pract Oncol Radiother Date: 2020-08-16
Authors: Emmanouil Fokas; Ane Appelt; Alexandra Gilbert; David Sebag-Montefiore; Claus Rödel; Robert Glynne-Jones; Geerard Beets; Rodrigo Perez; Julio Garcia-Aguilar; Eric Rullier; J Joshua Smith; Corrie Marijnen; Femke P Peters; Maxine van der Valk; Regina Beets-Tan; Arthur S Myint; Jean-Pierre Gerard; Simon P Bach; Michael Ghadimi; Ralf D Hofheinz; Krzysztof Bujko; Cihan Gani; Karin Haustermans; Bruce D Minsky; Ethan Ludmir; Nicholas P West; Maria A Gambacorta; Vincenzo Valentini; Marc Buyse; Andrew G Renehan Journal: Nat Rev Clin Oncol Date: 2021-08-04 Impact factor: 66.675