Author s response to reviews

Size: px

Start display at page:

Download "Author s response to reviews"

Allen Chambers
6 years ago
Views:

1 Author s response to reviews Title: Docetaxel, Cisplatin, and 5-fluorouracil (DCF) chemotherapy in the treatment of metastatic or unresectable locally recurrent anal squamous cell carcinoma: a phase II study of French interdisciplinary GERCOR and FFCD Groups (Epitopes-HPV02 study) Authors: Stefano Kim (stefanokim@me.com) Marine Jary (mjary@chu-besancon.fr) Thierry André (thierry.andre@sat.aphp.fr) Véronique Vendrely (veronique.vendrely@chu-bordeaux.fr) Bruno Buecher (bruno.buecher@curie.fr) Eric François (eric.francois@nice.unicancer.fr) François-Clément Bidard (francois-clement.bidard@curie.fr) Sarah Dumont (sarah.dumont@sat.aphp.fr) Emmanuelle Samalin (emmanuelle.samalin@icm.unicancer.fr) Didier Peiffert (d.peiffert@nancy.fnclcc.fr) Simon Pernot (simon.pernot@aphp.fr) Nabil Baba-Hamed (nbaba-hamed@hpsj.fr) Farid El Hajbi (f-elhajbi@o-lambret.fr) Olivier Bouché (obouche@chu-reims.fr) Jérôme Desrame (jerome.desrame@orange.fr) Aurélie Parzy (a.parzy@baclesse.unicancer.fr) Mustapha Zoubir (m.zoubir@gsante.fr) Christophe Louvet (Christophe.LOUVET@imm.fr) Jean-Baptiste Bachet (jean-baptiste.bachet@psl.aphp.fr)

2 Thierry Nguyen Meher Ben Abdelghani Denis Smith Christelle De La Fouchardière Thomas Aparicio Jaafar Bennouna Jean-Marc Gornet Marion Jacquin Franck Bonnetain Christophe Borg Version: 2 Date: 02 Aug 2017 Author s response to reviews: Editor of BMC Cancer Stefano Kim, MD Department of Medical Oncology University Hospital of Besançon 3 Bd A Fleming Besançon CEDEX, France stefanokim@me.com phone: fax: Besançon, August 2nd 2017

3 Dear Editorial Committee, We are very pleased to submit our revised manuscript written by KIM and al. entitled Docetaxel, Cisplatin, and 5-fluorouracil (DCF) chemotherapy in the treatment of metastatic or unresectable locally recurrent anal squamous cell carcinoma: a phase II study of French interdisciplinary GERCOR and FFCD Groups (Epitopes-HPV02 study) to BMC Cancer In this reviewed manuscript, all reviewers' and Editor s comments were taken into account. Please find below a point-by-point responses. Changes were performed in red in the revised manuscript and a clean copy was submitted. Editor s Comments: 1. addresses for all the authors Please provide addresses for all the authors in the title page. We added addresses for all the authors in the title page, in page 2 and 3: *Corresponding author: Stefano KIM Address: Department of Oncology. Jean Minjoz University Teaching Hospital, 3 Boulevard Alexander Fleming, Besancon, F-25030, France. address: stefanokim@me.com Marine Jary: mjary@chu-besancon.fr Thierry André: thierry.andre@sat.aphp.fr Véronique Vendrely: veronique.vendrely@chu-bordeaux.fr Bruno Buecher: bruno.buecher@curie.fr Eric François: eric.francois@nice.unicancer.fr

4 François-Clément Bidard: Sarah Dumont: Emmanuelle Samalin: Didier Peiffert: Simon Pernot: Nabil Baba-Hamed: Farid El Hajbi: Olivier Bouché: Jérôme Desrame: Aurélie Parzy: Mustapha Zoubir: Christophe Louvet: Jean-Baptiste Bachet: Thierry Nguyen: Meher Ben Abdelghani: Denis Smith: Christelle De La Fouchardière: Thomas Aparicio: Jaafar Bennouna: Jean-Marc Gornet: François Ghiringhelli: Melanie Deberne: Marion Jacquin: Franck Bonnetain: Christophe Borg:

5 2. Ethics approval and consent to participate Please remove the below paragraph from the statement as it is not relevant. The results of the study will be presented at scientific national and international meetings, and will be published in a peer-reviewed journal. The main investigator and the coordinator of the study will be the first and the last author of the manuscript, and the remaining authorship will be attributed according to their implications and the journal s guideline. This paragraph has been removed from the Ethics approval and consent to participate section in page Availability of data and materials Please state Not Applicable in this section as this article is a study protocol and doesn't contain any results or raw data. As required by the Editor, the sentence below in Availability of data and material in page 19 was replaced by Not applicable. 4. Clean copy Please ensure that when you upload your revised submission that it is in the final form for publication. Please remove any tracked changes or highlighting and include only a single clean copy of the manuscript (and please ignore any automated requests to show tracked changes). Should you wish to respond to these revision requests, please include the information in the designated input box (Respond to Reviewers) only. A clean copy was uploaded without any tracked changes. Reviewer reports: Kurian Joseph (Reviewer 1): very interesting project We need project like this for metastatic Anal ca Thanks.

6 Sam Lubner (Reviewer 2): The paper as written describes a valuable possible contribution to the science of the treatment of anal cancer. There are no results to report, but as a description of the rationale and entry criteria for the trial, it serves a valuable purpose. The results of the study will be important to establish the underpinnings of a possible phase III study. What is unclear to me is if the intent of the paper is to describe the materials and methods/inclusion-exclusion criteria only. If that is indeed the case, it is acceptable with no edits. I have no critique of the trial design, statistics, or rationale. Please confirm that that is indeed the intent of the submission. It is indeed only the study protocol. Thanks for your comments. Cathy Eng (Reviewer 3): To the author, It is unclear to me the lapse in validation following the initial trial findings from This trial is not novel. It is a trial in progress that would be of limited interest. Our initial findings of potential benefit of DCF regimen was published in 2013 in Annals of Oncology, based in 8 patients treated between 2005 and 2012 in a single center. Then, this prospective multicenter phase II (Epiotpes-HPV02) study was designed which has been submitted to BMC Cancer. This study protocol was approved by the scientific committees of French collaborative groups: Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) Oncology Multidisciplinary Group and Fédération Francophone de Cancérologie Digestive (FFCD) In April 24, 2014, the trial was registered at European Clinical Trials database (EudraCT: ; April 24, 2014) In June 6, 2014, the trial was approved by the independent Est-II French Committee for Protection of Persons. In July 15, 2014, the trial was approved by the French Health Products Safety Agency, fully completing all required procedures to start patient enrolment in France. In November 27, 2014, the trial was registered at clinicaltrials.gov. All these steps are clearly specified in the article in the section Ethics approval and consent to participate in page 18:

7 The study was approved by the independent Est-II French Committee for Protection of Persons (June 6, 2014) and by the French Health Products Safety Agency (July 15, 2014). The University Hospital of Besançon is the legal sponsor of this trial. The trial was registered at European Clinical Trials database (EudraCT: ; April 24, 2014). Thus, the trial fully completed all required procedures to start patient enrolment in France. The first center was activated in September 17, The trial was then registered at clinicaltrials.gov (NCT ; November 27, 2014). Does the study allow HIV+ patients since they will be ones that are commonly affected. Are immunosuppressed patients excluded? e.g., HIV+ HIV+ patients are allowed if their lymphocytes CD4 count is 400/mm3. No other potentially immunosuppressive conditions are considered as an exclusion criterion in this trial. This is described in Patient selection session in METHODS AND ANALYSIS in page 9 and 10 (box1): Exclusion Criteria: HIV positive patient with lymphocyte CD4 count under 400/mm3 Pierfrancesco Franco, MD (Reviewer 4): This is a nice protocol outline. I do not have any particular comment, except a robust revision of English grammar/spelling/quality of written English. This new version of manuscript was fully reviewed and improved MATTHEW WILLIAMS (Reviewer 5): Review of BCAN-D _R1 Docetaxel, Cisplatin, and 5-fluorouracil (DCF) chemotherapy in the treatment of metastatic or unresectable locally recurrent anal squamous cell carcinoma: a phase II study of French interdisciplinary GERCOR and FFCD Groups (EpitopesHPV02 study) This paper describes the rationale and plan for a non-randomised phase II trial of DCF or mdcf chemotherapy in patients with irresectable/ metastatic recurrent anal carcinoma.

8 It is good practice to publish such trial summaries as they are planned, and this trial is potentially important, and therefore I would recommend publication. In this review, I am focusing on the reporting of the trial, NOT on the trial design itself, which I assume has been independently reviewed. Some specific points: 1. References for the expected response in patients receiving conventional treatment would be useful e.g. after the phrase "Indeed, no randomized clinical trials are currently available to determine a standard of care for relapsing or metastatic SCCA patients, and the combination of cisplatin-5fu only demonstrated a modest activity in a small retrospective analysis, with progression-disease before 12 months in the great majority of the patients."" References has been added as recommended by the reviewer in BACKGROND session, in page 8: Indeed, no randomized clinical trials are currently available to determine a standard of care for relapsing or metastatic SCCA patients, and the combination of cisplatin-5fu only demonstrated a modest activity in a small retrospective analysis, with progression-disease before 12 months in the great majority of the patients. [13,14] 2. Is there an EORTC measure specific for patients with anal cancer? In one part of the study it is mentioned, and in another it is not The QoL data of our patients will be measured by the standard EORTC-QLQ-C30. At date, there is no validated specific EORTC module for anal cancer patients. Our main methodologist, professor Bonnetain, was involved in the development of this module as a member of the EORTC QoL group. In fact, the development of this specific module is planned as an ancillary study of Epitopes- HPV02 trial. We clarified this point for a better understanding in secondary analysis session in METHODS AND ANALYSIS in page 13 Patients also participate to an ancillary study for the development of a specific anal module with EORTC QoL group

9 3. The change in QoL measure is unclear - is the minimal change considered to be 10 points or 5% (again, different definitions) Thanks for this remark. Indeed, the minimal clinically important difference was fixed to 10 points, and the sensitivity analysis is planned with 5 points. We have corrected the paragraph in Secondary analyses session in METHODS AND ANALYSIS in page 13 and 14: QoL analysis measured by EORTC-QLQ-C30 & time to QoL score deterioration with a minimal clinically important difference of 5% The time to deterioration of a score of QoL will be defined as the interval of time between the date of enrolment and the appearance of at least 10 points of the QoL score compared to the QoL score at inclusion, without later improvement of more than 10 points compared to the QoL score at inclusion, or death. As exploratory manner, univariate and multivariate Cox models for the 5 targeted-dimensions will be performed. A difference of at least 10 points will be considered as the smallest difference clinically important. Analysis of sensitivity with a difference of at least 5 points will be performed. were replaced by: QoL analysis measured by EORTC-QLQ-C30 & time to QoL score deterioration with a minimal clinically important difference of 10 points. The time to deterioration of a score of QoL will be defined as the interval of time between the date of enrolment and the appearance of at least 10 points deterioration of the QoL score compared to the QoL score at baseline, without later improvement of more than 10 points compared to the QoL score at baseline, or death. [25] As exploratory manner, univariate and multivariate Cox regression models for the 5 targeted-dimensions will be performed. A difference of at least 10 points will be considered as the minimal clinically important difference (MCID). Analysis of sensitivity with a MCID of 5 points will be performed. And one reference has been added: [25] Bonnetain F, Dahan L, Maillard E, Ychou M, Mitry E, Hammel P et al. Time until definitive quality of life score deterioration as a means of longitudinal analysis for treatment trials in patients with metastatic pancreatic adenocarcinoma. Eur J Cancer. 2010; 46: There are numerous areas where the use of English is sub-optimal. This is not a barrier to publication, but the authors may want to consider reviewing some of the wording before

10 publication. In particular, I would consider addressing the matter of tenses. Since the authors are describing a trial that they plan to conduct, I would suggest using the future tense when describing conduct (e.g. "We will enrol x patients; patients will undergo PET-CT at timepoints x and y"). This new version of manuscript was fully reviewed and improved. As recommended by the reviewer, we replaced all conduct describing phrases in future tense in METHODS AND ANALYSIS session in pages 9, 10 and 11 Patient selection The study population consists of patients with SCCA at metastatic stage or with locally advanced recurrence after CRT, non-eligible for salvage surgery due to the extension of the disease. Patients should be eligible to DCF, with performance status ECOG-PS 0 or 1, and with adequate organ function. The local institutional multidisciplinary board of each center will identify eligible patients. The inclusion and exclusion criteria are listed in box 1. DCF treatment Patients will receive 6 cycles of DCF regimen (docetaxel 75 mg/m2 day, CDDP 75 mg/m2 and 5FU at 750 mg/m2/day for 5 days) every 3 weeks or 8 cycles of modified-dcf regimen (mdcf, docetaxel 40 mg/m2 day, CDDP 40 mg/m2 day and 5-FU at 1200 mg/m2/day for 2 days) every 2 weeks, according to their clinical status. The standard DCF regimen is recommended for patients up to 75 years and with ECOG-PS of 0, whereas the mdcf is recommended for those > 75 years-old or ECOG-PS of 1. Granulocyte colony-stimulating factor will be systematically administered as primary prophylaxis of febrile neutropenia for both regimens. Post per-protocol treatment At the end of planned DCF cycles, complementary local treatments like surgery of metastases or radiotherapy will be allowed at the discretion of each local institutional multidisciplinary board s decision. Evaluation, laboratory tests and follow-up

11 CT scans are planned at baseline, after 3rd and 6th cycles of DCF regimen (or after 4th and 8th cycles of modified-dcf regimen) and then every three months until disease progression, or death. Tumour assessment will be carried out according to RECIST criteria version 1.1. A PET scan will be performed before and at the end of chemotherapies. The blood samples for immuno-monitoring will be performed before DCF and at first follow-up visit after the last DCF cycle. The QoL will be measured by EORTC QLQ-C30 questionnaire at inclusion, and every 2 cycles of chemotherapy. Patients will be followed-up every 3 months, up to 3 years from enrolment, or death. A CT-scan, blood analysis, clinical examination, and QoL measurement will be performed at each follow-up visit. Table 1 5. "After the generation of the scores following the EORTC recommendations, the scores will be described at each time of measure using median (standard deviation) and mean (Min- Max)" - I wonder if these are perhaps transposed (usually median (range) and mean (SD)). Thanks for this correction. We have changed these mistakes as recommended by the reviewer in secondary analysis session in METHODS AND ANALYSIS in page 14: After the generation of the scores following the EORTC recommendations, the scores will be described at each time of measure using median (Min-Max) and mean (standard deviation). Overall, these constitute minor corrections. Thanks. Kind regards, Stefano Kim

Author s response to reviews

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