Author s response to reviews

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1 Author s response to reviews Title: Preoperative chemoradiation with paclitaxel-carboplatin or with fluorouracil-oxaliplatin - folinic acid (FOLFOX) for resectable esophageal and junctional Cancer: the PROTECT-1402, randomized phase 2 trial. Authors: Mathieu Messager (mathieu.messager@chru-lille.fr) Xavier Mirabel (x-mirabel@o-lambret.fr) Emmanuelle Tresch (e-tresch@o-lambret.fr) Amaury Paumier (amaury.paumier@ico.unicancer.fr) Veronique Vendrely (veronique.vendrely@chu-bordeaux.fr) Laetitia Dahan (laetitia.dahan@mail.ap-hm.fr) Olivier Glehen (olivier.glehen@chu-lyon.fr) Frederique Vasseur (f-vasseur@o-lambret.fr) Thomas Lacornerie (t-lacornerie@o-lambret.fr) Guillaume Piessen (guillaume.piessen@chru-lille.fr) Farid El Hajbi (f-elhajbi@o-lambret.fr) William B. Robb (robb.will@gmail.com) Stephanie Clisant (s-clisant@o-lambret.fr) Christophe Mariette (christophe.mariette@chru-lille.fr) Andrew Kramar (a-kramar@o-lambret.fr) Antoine Adenis (a-adenis@o-lambret.fr) Version: 2 Date: 26 Apr 2016

2 Author s response to reviews: Dear BMC Cancer Editor, On April 19th, 2016, as well as on April 22nd, 2016, you informed me that the following manuscript: (BCAN-D R1, Preoperative chemoradiation with paclitaxel-carboplatin or with fluorouracil-oxaliplatin - folinic acid (FOLFOX) for resectable esophageal and junctional Cancer: the PROTECT-1402, randomized phase 2 trial. Messager M et al. BMC Cancer) was found potentially acceptable for publication in BMC Cancer, once minor revisions have been made. Please find as follows our point-by-point response to your comments (all changes in the manuscript have been highlighted in the text in yellow color): 1) Please provide a conclusion section after the Discussion Answer: DONE - See line 344 to line 364 To summarize, in patients with resectable locally advanced esophageal and gastro-esophageal junctional cancers who are eligible for curative treatment, it is of great clinical interest to compare two current standards of neoadjuvant chemotherapy (carboplatin/paclitaxel-based and oxaliplatin/fu-based) combined with a common standardized protocol for concomitant radiotherapy. Before performing a formal phase 3 trial, we first designed this randomized phase 2 trial to investigate the complete resection rate and the severe postoperative morbidity rate of these two regimens. This trial will give us the opportunity to better understand the relative effect and benefit of these two regimens when combined with the delivery of modern radiotherapy and to better estimate the number of patients to be enrolled in a subsequent phase III trial.

3 Conclusion To summarize, in patients with resectable locally advanced esophageal and gastro-esophageal junctional cancers who are eligible for curative treatment, it is of great clinical interest to compare the two current standards of neoadjuvant chemotherapy (carboplatin/paclitaxel-based and oxaliplatin/fu-based) combined with a common standardized protocol for concomitant radiotherapy. Before performing a formal phase 3 trial, we first designed this randomized phase 2 trial to investigate the complete resection rate and the severe postoperative morbidity rate of these two regimens. 2) Please provide a Declarations header after the conclusion Answer: DONE - See line 367 3) Please ensure that the sections. - List of abbreviations - Ethics approval and consent to participate - Consent for publication - Availability of data and materials - Competing interests - Funding - Authors' contributions - Acknowledgements.are included at the end of your manuscript in a Declarations section.

4 Answer: DONE - See Line 368 to line 421 List of abbreviations esophageal cancer (EC), neoadjuvant chemoradiation (ncrt), fluorouracil (FU), oxaliplatin and FU-based regimen (FOLFOX), squamous cell carcinoma (SCC), adenocarcinoma (ADC), Union for International Cancer Control (UICC), Eastern Cooperative Oncology Group (ECOG), performance status (PS), complete resection rate (R0), National Cancer Institute Common Terminology Criteria (NCI-CTC), European Organisation for Research and Treatment of Cancer (EORTC), Dose-Volume-Histogram (DVH), computed tomography (CT), esophageal ultrasound endoscopy (EUS), positon emission tomography (PET-CT). Ethics approval and consent to participate This study was performed according to the Declaration of Helsinki. Written consent was required from patients. The study protocol has been approved by our local ethics committee (Comité de Protection des Patients Nord-Ouest IV, reference number: 14/53, November 4th, 2014), and by our national regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé, reference number: A-12, August 29th, 2014) Consent for publication Not applicable Availability of data and materials Non applicable (ongoing study) Competing interests The authors declare that they have no competing interests for this study.

5 Funding This study is supported by a grant from the French Ministry of Health (PHRC-K N) Authors' contributions AA, AK, XM, CM designed the study. AA, MM, WR, CM contributed to the drafting of the manuscript. ET and AK were responsible for data collection, data management and statistical analysis. SC was responsible for administrative support. All authors contributed to the revision of the manuscript, and approved it for submission Author details 1Department of digestive and oncological surgery, University hospital, Lille, France. 2University of Lille 2, Lille, France. 3FRench EsoGastric Tumours (FREGAT) working group, Lille, France. 4Department of radiotherapy, Centre Oscar Lambret, Lille, France. 5Methodology and biostatistics Unit, Centre Oscar Lambret, Lille, France. 6Department of radiotherapy, Institut de Cancérologie de l Ouest, Nantes/Angers. 7Department of radiotherapy, University hospital, Bordeaux, France. 8Department of gastroenterology, University hospital, Marseille, France. 9Department of digestive and oncological surgery, HCL Cancer Institute, Lyon, France. 10 Unit of medical physics, Centre Oscar Lambret, Lille, France. 11SIte de Recherche Intégrée sur le Cancer (SIRIC) OncoLille, Lille, France. 12Department of Surgery, Beaumont Hospital and the Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland. 13Clinical research unit, Centre Oscar Lambret, Lille, France. 14Catholic University, Lille, France. 15Department of gastrointestinal oncology, Centre Oscar Lambret, Lille, France. Acknowledgements Not applicable 4) Please include dates of registration after the TRNs at the end of the abstract

6 Answer: DONE - See Line 68 to line 69 Trial Registration: NCT (ClinicalTrials.gov) (registration date: 9 FEB 2015), EudraCT: (registration date: 10 FEB 2014) Hoping these clarifications will help in getting your full agreement for the publication of this work. Best regards Pr Antoine Adenis