The LISA randomized trial of a weight loss intervention in postmenopausal breast cancer

Trial design

A Phase III randomized trial was conducted in the adjuvant BC setting, randomizing women who had received standard breast cancer treatment (1:1) to a lifestyle-based weight loss intervention with educational materials versus educational materials only. Enrolment was discontinued when 338 of 2150 subjects had been enrolled and the protocol was amended to allow completion of the study intervention and follow-up, with analysis of the impact of the intervention on disease-free survival (DFS) and overall survival (OS) planned after all patients had a minimum follow-up of eight years. The study design has been previously reported9 and is summarized briefly below.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee; the primary ethics committee was the Ontario Cancer Research Ethics Board with oversight by the Principal Investigator (PG) at Mount Sinai Hospital, Toronto. Informed consent was obtained from all individual participants included in the study.

Patient population

Randomization occurred August 2007–December 2009. Subjects were required to be postmenopausal, with Stage I, II, or IIIa, (T1–3, pN0-3, M0) estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) BC within the previous 15 months, with a body mass index [BMI = weight (kg)/height (m2)] between 24 and 40 kg/m2. In June 2008 entry criteria were changed to allow women with any BMI over 24 kg/m2 diagnosed with BC within the previous 36 months to participate and to exclude patients with N3 disease. Patients were required to be on adjuvant letrozole at entry and to be fluent in English or French. Patients were excluded if they had experienced a BC recurrence, had a life expectancy less than 5 years, were unable to walk at least two blocks (self-reported), had insulin requiring diabetes, or other conditions that precluded participation in the intervention. We excluded patients with a prior history of cancer apart from (i) adequately treated non-melanoma ski n cancer, (ii) curatively treated in situ carcinoma of the cervix, or (iii) other solid tumors curatively treated with no evidence of disease for ≥5 years.

Randomization was performed centrally (at the Ontario Clinical Oncology Group) using computer generated sequences stratified for (i) BMI (< versus ≥ 30 kg/m2), (ii) prior chemotherapy (yes versus no), and (iii) language of the intervention (English versus French).

Interventions

The study interventions have been previously described.9 Both arms received educational material that addressed healthy diets, physical activity, breast cancer, compliance with therapy, osteoporosis and other general medical issues; women also received a 2-year subscription to the Canadian Health Magazine. The lifestyle intervention goals included (i) 10% weight loss to a BMI not less than 21 kg/m/2, (ii) caloric reduction to attain a 500–1000 kcal per day deficit with fat intake of ~20% of calories and (iii) a gradual increase in moderate intensity aerobic physical activity (usually walking) to 150–200 min per week, coupled with home-based resistance and stretching exercises. Behavioral components addressed motivation, relapse prevention, emotional distress, time management, and barriers. The intervention was delivered in English or French by trained lifestyle coaches at the University of Ottawa supervised by RS. Nineteen contacts were delivered over 2 years. Calls last ed 30–60 min and were scripted, semi-structured, and standardized; they were based on a participant workbook. Standardization involved training and supervision, recruitment of a Lead Coach, scripting of telephone calls, and recording and centralized review of at least 50% of phone calls.

Measurements

Women were weighed in indoor clothing, without shoes, at clinic visits at baseline, 6, 12, 18, and 24 months then annually. Height was obtained at baseline.

Outcomes

The primary outcome was DFS; events included local and regional recurrences (including chest wall), distant recurrence, new primary breast cancers and death, with time from randomization to an outcome event compared in the primary analysis. Secondary outcomes included OS, as well as weight change, quality of life and a composite "other medical" endpoint (diabetes and hospitalization for cardiac or cerebrovascular events, orthopedic events).

Statistical analysis

DFS and OS were calculated from the date of randomization. Patients were censored on their last follow-up date. Following the intent-to-treat principle, all tests were performed based on randomized allocation. Descriptive statistics were used to summarize patient characteristics and outcomes. Change in weight from baseline was calculated as the absolute change in kg and the percent change from baseline (absolute change/baseline weight × 100). Similar analyses were performed for physical activity and QOL. Differences in QOL and activity level between intervention arms were tested using the Wilcoxon rank sum test at each follow-up time point with data available. The Kaplan–Meier method was used to estimate time-to-event outcomes (DFS, OS). Cox proportional hazards regression was used to investigate factors potentially prognostic of DFS and OS. All analyses included adjustments for stratification factors. Given the reduced power due to early suspension of accrual, no multivari able analyses were performed. A landmark analysis was performed exploring weight loss up to 24 months as a prognostic factor of DFS, including only the subset of patients alive, disease-free and on-study beyond 24 months. The following supportive analyses were performed: using change in BMI instead of change in weight for the landmark analysis, including site as an additional stratification factor, analysis with no stratification factors, and excluding ineligible patients or those who received the incorrect intervention or no intervention. Results were similar, except when site was included as a stratification (all factors statistically not significant). All tests were two-sided and a p-value of 0.05 or less was considered statistically significant, with no p-value adjustment for multiple testing.

Sample size

At the time of study design, it was assumed that 5-year disease-free survival in the control would be 85% and the HR for patients receiving the 24-month intervention would be 0.75. Assuming a total of 8 years of follow-up, a two-sided, α = 0.05, log-rank would have >80% statistical power with 2150 patients accrued.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.