Author's response to reviews

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1 Author's response to reviews Title: Effects on quality of life, anti-cancer responses, breast conserving surgery and survival with neoadjuvant docetaxel: A randomised study of sequential weekly versus three-weekly docetaxel following neoadjuvant doxorubicin and cyclophosphamide in women with primary breast cancer Authors: Leslie G Walker (l.g.walker@hull.ac.uk) Jennifer M Eremin (jennifer.eremin@ulh.nhs.uk) Mark M Aloysius (mark.aloysius@nottingham.ac.uk) Wichai Vassanasiri (wichai_vassanasiri@yahoo.com) Mary B Walker (m.b.walker@hull.ac.uk) Mohammed El-Sheemy (melsheemy@lincoln.ac.uk) Ged Cowley (ged.cowley@ulh.nhs.uk) Jeanette Beer (jeanette.beer@ulh.nhs.uk) Srila Samphao (ssamphao@hotmail.com) Janice Wiseman (janice.wiseman@ulh.nhs.uk) Jibril A Jibril (jibril.jibril@ulh.nhs.uk) David Valerio (david.valerio@ulh.nhs.uk) David J Clarke (david.clarke@ulh.nhs.uk) Mujahid Kamal (mujahid.kamal@ulh.nhs.uk) Gerald W Thorpe (gerald.thorpe@ulh.nhs.uk) Karin Baria (karin.baria@ulh.nhs.uk) Oleg Eremin (oleg.eremin@ulh.nhs.uk) Version: 3 Date: 14 March 2011 Author's response to reviews: see over

2 Effects on quality of life, anti-cancer responses, breast conserving surgery and survival with neoadjuvant docetaxel: A randomised study of sequential weekly versus three-weekly docetaxel following neoadjuvant doxorubicin and cyclophosphamide in women with primary breast cancer Leslie G. Walker a, Jennifer M. Eremin b, Mark M. Aloysius h*, Wichai Vassanasiri c,d, Mary B. Walker a, Mohamed El-Sheemy c,d,e, Ged Cowley f, Jeanette Beer c, Srila Samphao c, Janice Wiseman c, Jibril A. Jibril d, David Valerio d, David J. Clarke d, Mujahid Kamal g, Gerald W. Thorpe g, Karin Baria b, Oleg Eremin c,d,h a Oncology Health Centres and the Institute of Rehabilitation, University of Hull, Kingston upon Hull, East Riding of Yorkshire HU3 2PG, UK b Department of Clinical Oncology, Lincoln County Hospital, Lincoln LN2 5QY, UK c Research & Development Department, Lincoln County Hospital, Lincoln, UK d Lincoln Breast Unit, Lincoln County Hospital, Lincoln, UK e Department of Health, Life and Social Sciences, University of Lincoln, Lincoln, LN6 7TS, UK f Department of Pathology, Lincoln County Hospital, Lincoln, UK g Department of Radiology, Lincoln County Hospital, Lincoln, UK h Department of Surgery, Nottingham University Hospitals, Nottingham NG7 2UH, UK Corresponding author: Mark M Aloysius Department of Surgery, E Floor West Block, Nottingham University Hospitals, Queen s Medical Centre, Nottingham NG7 2UH Mark.aloysius@nottingham.ac.uk Tel: Fax: This study was presented in part as a poster discussion at the 28 th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005.

3 Dear Editor Thank you for providing us with an opportunity to respond to the Reviewers Report. In particular, we have addressed aspects of the manuscript which have been classified as Minor Essential Revisions. (1) Reviewers Comments Weekly Docetaxel has not shown a similar benefit in the adjuvant setting compared with Docetaxel every three weeks or with Parclitaxel weekly. This could be mentioned since the regimen with weekly Docetaxel is therefore not standard care. This matter has now been discussed in the DISCUSSION section in the revised manuscript (see page 15-17). Also, two new references have been included in the revised manuscript. These changes have been tracked for ease of reference. (2) Reviewers Comments HER status of tumours is not shown. This should be added. Also, HER 2 positive patients show high rates of response when Trastuzumab is added to (neoadjuvant) chemotherapy (eg Untch et al, JCO 2010), which is standard of care in many countries now. This is a limitation of the study results. This should be discussed.

4 Although we now carry out HER 2 analysis in all patients with breast cancer, when this study was carried out this was not routine practice and there are no HER 2 data available. As none of the patients were given Trastuzumab, either pre- or postsurgery, the HER 2 levels are not relevant in this study. The primary objective of this study was to ascertain the quality of life and morbidity with two Docetaxel regimens, 100 mg / m 2 3 weekly versus 33 mg/m 2 weekly. (3) Reviewers Comments When examining the end point DFS and OS, post-surgery treatment (endocrine treatment, radiation therapy) of patients should be described in more detail. Appropriate sections for radiotherapy and endocrine treatment have now been included in the revised manuscript (see P1). The changes have been tracked with the manuscript. Radiotherapy Radiotherapy was given according to cancer centre local guidelines at the time. All patients who had undergone breast conserving surgery had post-operative radiotherapy. This consisted of the following (i) 50 Gy in 25 fractions to the breast over 5 weeks. In addition, those aged 50 years or under received an electron boost of 16 Gy in 8 fractions (ii) Following mastectomy, if more than 3 cm residual tumour was present in the excised specimen there was histological evidence of vascular

5 invasion, or the cancer was T4 on presentation, chest wall irradiation (45 Gy in 20 fractions over 4 weeks) was carried out. If lymph nodes were involved by metastatic disease (assessed by sampling, level I/II dissection), the remaining axillary and supraclavicular lympth nodes were irradiated (45 Gy in 20 fractions over 4 weeks). If clearance was performed (level III) and lymph nodes were involved only the supraclavicular area was irradiated (45 Gy in 20 fractions over 4 weeks). Anti-hormonal All patients with ER +ve and/or PR +ve breast cancers received tamoxifen 20 mg daily for 5 years. (4) Reviewers Comments The rules for dose reduction seem unusual to me since one neutropenia already led to dose reduction in all subsequent cycles. It would be of interest how many patients received a dose reduction and how the delivered dose intensity in the two treatment groups was. There was a dose reduction in only one patient on low dose Docetaxel, from cycle 2 onwards. There was also a dose reduction in only one patient on high dose Docetaxel, from cycle 7 onwards due to a decrease in body surface area (weight loss-induced).

6 We document on p 16 in DISCUSSION that The total intended drug dose and regimen duration in both groups were comparable. (5) Reviewers Comments The number of patients included in the study is rather small. Therefore, it seems possible that differences in the Quality of Life (QoL) - scores and efficacy end-points were not detected. This limitation should be discussed. We acknowledge in our manuscript that the numbers of patients is not large, however, the quality of life measures were carried out over ten time-points (prior to commencement, 3 weekly during chemotherapy and post chemotherapy). We believe this intensive assessment contributed substantially to the reliability and sensitivity of the assessments. The comprehensive range of statistical tests employed ensured the appropriate significance and robustness of the findings (see pages 9 and 10).