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

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)

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)

“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

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 650-800kcal +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 650-800kcal +5 days week Mediterranean diet cal

CER Mediterranean diet 7 days /week to meet estimated energy requirements

Outcomes assessed 3 weeks after final chemotherapy

n = 172

Scheduled to receive adjuvant or neoadjuvant chemotherapy

• 2 day / week IER (& physical activity)

• Individual face to face advice

• Telephone support (alternate weeks)

• Mailings (alternate weeks)

IER n=86

CER n=86

• Continuous energy restricted diet (&

physical activity)

• Individual face to face advice

• Telephone support (alternate weeks)

• Mailings (alternate weeks)

Study design 4

.5 –

6 m

onth

s o

f chem

oth

era

py

Inclusion criteria • Scheduled to have standard adjuvant or neoadjuvant chemotherapy

• Breast cancer stage I–III

• Any age >18 years

• BMI>19 kg / m2. 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

Recruitment

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)

Number screened in 11 cancer centres

n = 662

Baseline characteristics

IER ( n = 86) CER (n = 86)

Age (years) 51.3(9.0) 52.6(10.1)

BMI (Kg/m2) 28.1(6.1) 28.4(6.1)

Overweight/ obese/ normal wt - % 69/ 31 71/ 29

Premenopausal % 56 55

Ethnicity, Caucasian-% 96 88

Grade Invasive 1/2/3 /DCIS -% 4/ 30/ 64/ 2 5 / 43 / 51/ 1

ER +/ER- % 31 / 69 33 / 67

Chemotherapy -%

FEC –docetaxel

FEC-paclitaxel

Other

59

13

28

56

13

31

Adjuvant / neoadjuvant % 93/ 7 93/ 7

Current smoker % 7 3.5

Mean (SD)

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

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

Adherence

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

Prevent Breast Cancer

Breast Cancer Research Trust

Our Trial Participants

Funding Lifestyle Research

Team

Co- investigators

Sacha Howell

Tony Howell

Anne Armstrong

Nigel Bundred

Lee Graves

Mark Mattson

Judy Adams

Louise Gorman

Mary Pegington

Nina Brogden

Claire Lindsay

Kath Sellers

Grace Cooper

Debbie McMullen

Pam Coates

Lesley Coates

Cheryl Barlow

Prevent BC Volunteers

PI’s & research nurses in

recruiting centres