The B-AHEAD 2 Trial. Randomised controlled trial of intermittent versus continuous energy restriction during adjuvant chemotherapy:

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Bryan Grant
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chemotherapy: Dr Michelle Harvie Research Dietitian The

1 The B-AHEAD 2 Trial Randomised controlled trial of intermittent versus continuous energy restriction during adjuvant chemotherapy: Dr Michelle Harvie Research Dietitian The Nightingale and Prevent Breast Cancer Centre University Hospital of South Manchester

2 Background Excess weight at diagnosis and weight gain after diagnosis increase risk of recurrence and mortality (Chan et al Ann Oncology 2014 Daily energy restriction and exercise is only partially effective for weight control in pts receiving chemotherapy for early breast cancer (-0.8Kg) (Harvie et al B AHEAD study) We have reported greater weight loss with intermittent vs. standard daily energy restriction in healthy overweight / obese women (Harvie et al Br J Cancer 2013) Animal studies and case series suggest intermittent energy restriction reduce chemotherapy toxicity (Brandhorst & Metabolism & Cancer Springer 2016)

3 Aim To test whether IER is feasible amongst women receiving chemotherapy for early breast cancer. To compare intermittent energy restriction vs. continuous energy restriction for : Primary endpoints Changes in weight, body fat and fat free mass (DXA) Chemotherapy toxicity: -Self reported CTCAE scores, dose reduction, dose delay, hospitalisation, -Blood toxicity biomarkers; serum CK18 (epithelial toxicity) & plasma FLT 3 ligand (myelosuppression) (n = 55)

4 Research findings may be coupled with suggestions and guesses to build up concepts which by pyramided repetition become accepted Tannenbaum & Silverstone 1953 Early intermittent fasting researchers Dept of Cancer research Michael Reese Hospital Chicago, USA

5 The IER and CER diets 70% of subjects Overweight / obese Aim to lose weight Overall 25% energy restriction IER 2 days low carb, 50-70% ER/wk kcal +5 days week Mediterranean diet CER 25% energy restricted Mediterranean diet 7 days /week 30% of subjects Normal weight Aim to maintain weight i.e. prevent wt gain No energy restriction IER 2 days low carb, 50-70% ER/wk kcal +5 days week Mediterranean diet cal CER Mediterranean diet 7 days /week to meet estimated energy requirements

6 4.5 6 months of chemotherapy Study design n = 172 Scheduled to receive adjuvant or neoadjuvant chemotherapy IER n=86 CER n=86 2 day / week IER (& physical activity) Individual face to face advice Telephone support (alternate weeks) Mailings (alternate weeks) Continuous energy restricted diet (& physical activity) Individual face to face advice Telephone support (alternate weeks) Mailings (alternate weeks) Outcomes assessed 3 weeks after final chemotherapy

7 Inclusion criteria Scheduled to have standard adjuvant or neoadjuvant chemotherapy Breast cancer stage I III Any age >18 years BMI>19 kg / m 2. We aim to prevent weight gain (normal wt) & promote wt loss (overweight / obese) Resident within Greater Manchester or Cheshire area Clear routine staging CT scan (for patients scheduled to receive neoadjuvant chemotherapy & patients with 4 or more axillary nodes) Exclusion criteria Metastatic disease Had previous chemotherapy within the last 2 years Serious cardiovascular, respiratory, musculoskeletal, digestive or psychiatric condition Medications affecting weight e.g. daily steroids (2-3 days with chemotherapy ok) Diabetics on insulin or sulphonylureas as could cause hypoglycaemia on 2 day diet Already commenced current course of chemotherapy

8 Recruitment Number screened in 11 cancer centres n = 662 Not eligible n = 192 (29%) 25% - Already started chemotherapy 19% - Co morbidities 7% - Metastatic disease 5% - Low BMI 6% - IDDM 7% - Language 31% - Other 470 eligible Not want to join n = 298 (45%) 18% - Did not want extra appts 15% - Not interested 12% - Too anxious 9% - Travel issues 5% - Not want to diet during chemo 3% - Already eats healthily 1% - Not want to be randomised 27% - Unknown 36% uptake of eligible women (8-50% in the centres)

9 Baseline characteristics IER ( n = 86) CER (n = 86) Age (years) 51.3(9.0) 52.6(10.1) BMI (Kg/m 2 ) 28.1(6.1) 28.4(6.1) Overweight/ obese/ normal wt - % 69/ 31 71/ 29 Premenopausal % Ethnicity, Caucasian-% Grade Invasive 1/2/3 /DCIS -% 4/ 30/ 64/ 2 5 / 43 / 51/ 1 ER +/ER- % 31 / / 67 Chemotherapy -% FEC docetaxel FEC-paclitaxel Other Adjuvant / neoadjuvant % 93/ 7 93/ 7 Current smoker % Mean (SD)

Other illness / feels too unwell 19 9 Total 22% 10% % Withdrawn Adherence IER n = 86 CER n = 86 Calls received 7.

10 Retention to trial Intermittent Continuous Withdrawn 2 1 Excluded after consent as not eligible 1 0 Developed mets during study 1 2 Too busy/too many appts 6 3 Loss of contact 3 1 Not coping with chemo 2 2 Not tolerate diet 4 0 Other illness / feels too unwell 19 9 Total 22% 10% % Withdrawn Adherence IER n = 86 CER n = 86 Calls received 7.6/10 7.5/10 % compliance with IER 2 days/ week during trial All patients (n = 86) Completers only (n = 67) 57% 62% N/A

11 Conclusion Good uptake and retention show diet & exercise interventions are feasible & welcomed amongst chemotherapy patients IER is feasible amongst chemotherapy patients Further analysis will inform the safety, harms of IER & CER i.e. dose information, hospitalisation, quality of life & objective blood markers of toxicity

Acknowledgements Our Trial Participants Co- investigators Sacha Howell Tony Howell Anne Armstrong Nigel Bundred Lee Graves Mark Mattson Judy Adams Louise Gorman Lifestyle Research Team Mary Pegington

12 Acknowledgements Our Trial Participants Co- investigators Sacha Howell Tony Howell Anne Armstrong Nigel Bundred Lee Graves Mark Mattson Judy Adams Louise Gorman Lifestyle Research Team Mary Pegington Nina Brogden Claire Lindsay Kath Sellers Grace Cooper Debbie McMullen Pam Coates Lesley Coates Cheryl Barlow Prevent BC Volunteers Funding Prevent Breast Cancer Breast Cancer Research Trust PI s & research nurses in recruiting centres

Breast Cancer: Weight and Exercise. Anne McTiernan, MD, PhD. Fred Hutchinson Cancer Research Center Seattle, WA

Breast Cancer: Weight and Exercise Anne McTiernan, MD, PhD Fred Hutchinson Cancer Research Center Seattle, WA Associations of Obesity with Overall & Breast Cancer Specific Survival Survival Obese vs. Non-obese