Cancer Adverse Effects PReventIon With Care & Exercise: the CAPRICE Study

Study Design: A single-center, two-arm, parallel group with standard of care controlled trial with a balanced 1:1 randomization will be conducted at University Hospital Inselspital, Berne, Switzerland. A total of 120 women (60 participants per study arm) who are scheduled for first- line Anthracycline based chemotherapy (Anth-bc) presenting either at the Inselspital or Lindenhofspital Berne, the Spital AG Thun or the Bürgerspital Solothurn will be enrolled. After baseline assessments, eligible participants will be randomized to one of two arms including the exercise rehabilitation programme during chemotherapy or the control group (exercise training intervention after conclusion of chemotherapy).

Patient Population: Women and men aged 18 years and older with histologically confirmed breast cancer or lymphoma who are Anth-bC naïve and are scheduled for first-line Anth-bC, Eastern Cooperative Oncology Group (ECOG) grade 0-2, curative or palliative approach with reasonable life expectancy and a willingness to attend exercise sessions twice per week for 12 weeks (24 sessions in total).

Procedures: The following measurements will be collected at the beginning (T0), following the 12 week intervention (T1) and after another 12 weeks (T2). Participants will also be expected to attend two weekly supervised exercise sessions integrated in a multidisciplinary oncology rehabilitation programme at the Inselspital Bern, Spital AG Thun, and Bürgerspital Solothurn, and will be expected to complete one additional exercise training session at home or in the community each week.

T0: All participants will undergo baseline assessments at the University Hospital Inselspital, Berne. This includes cardiac assessment by a skilled clinical cardiac sonographer to obtain left ventricular (LV) global longitudinal strain (GLS) and aortic distensibility. Further, cardiopulmonary exercise testing (CPET) will be completed on a cycle ergometer to obtain VO2peak and to calculate corresponding training zones. Standard measures conducted during the intake process including height, weight, body composition (assessed by bio-impedance- measurement) and waist circumference will also be collected. Blood samples will be obtained from each participant and analyzed for biomarkers of myocardial injury as well as lipid profile and HbA1C. Following each visit, twenty-four-hour ambulatory blood pressure monitoring and 24h Holter ECG will be performed. The questionnaires for physical activity patterns (GPAQ) and fatigue (FACIT-F), a health history questionnaire and the activity tracking devices will also be administered by the research coordinator upon their initial visit.

T1: All measurements from T0 will be repeated. Additionally, patients from the ExEarly (experimental) group will be interviewed by the study coordinator to assess barriers for missed exercise sessions. Simultaneously, patients from the ExStandard group will be asked to anticipate barriers which may impede their participation in regular exercise training during the next 12 weeks. It will further be assessed whether it would have been feasible for them to complete the exercise programme concurrently to chemotherapy.

T2: All measurements from T0 will be repeated. Additionally, patients from the ExStandard (active comparator) group will be interviewed by the study coordinator to assess barriers for missed exercise sessions. Simultaneously, patients from the ExEarly group will be asked to indicate their preferred time point for the completion of the exercise programme.

Throughout the programme: Information regarding adherence to the exercise programme will also be collected by the research coordinator each month via the exercise training diaries and activity tracking devices from each participant. The study coordinator will also assess reasons for missed exercise sessions. Lastly, chemotherapy adherence will be assessed by dose adjustments in percent of the intended dose and reason for adjustment.

Intervention (ExEarly): The 12-week exercise training programme will be integrated in a multidisciplinary oncology rehabilitation programme at the Inselspital Bern, Spital AG Thun, and Bürgerspital Solothurn. The exercise programme will comprise 2 weekly exercise sessions lasting 90 min, supervised by experienced exercise therapists. The sessions start with approximately 40 min cycling on an ergometer at moderate intensity, increasing on a weekly basis if possible. After the cycling training, patients continue the exercise session with 40 min of strength training, stretching, relaxation, coordination and balance training. In addition, patients will be instructed to perform at least one additional endurance-related activity per week in their own time with a duration of 30-60 min at moderate intensity levels (e.g. walking, bicycling). In the ExEarly group, patients start in the week preceding the first dose of Anth-bC. They perform exercise training therapy for 12 weeks during which they will normally have 4 cycles of Anth-bC.

Control Group (ExStandard): Participants who are randomized to the control group will undergo baseline and follow up assessments at 13 and 26 weeks. They will be encouraged to continue with their regular physical activity routine and will be medically managed as per standard of care by their Cardiologist and Oncologists. All participants will also complete the GPAQ Questionnaire to determine if there are potential increases in physical activity in the exercise and control group, which may account for changes in all outcome measures. 1-4 weeks after completion of their last dose of Anth-bc the participants will commence exercise training. All participants in both groups will also be asked to wear an activity-tracking device, namely a step counter (Fitbit Zip) during the intervention and control period (25 weeks) to objectively quantify their daily physical activity.

Randomization: Randomization will occur at the central site, the University Hospital, Inselspital Berne, using minimisation based on strata recruiting center, age, therapy (adjuvant/ neoadjuvant), Global Longitudinal Strain (GLS), HER2 status and metastases, with an allocation ratio of 1:1.

Blinding: The participants will not be blinded to their intervention arm. Assessors of outcome data and analysis will be blinded to the study arm.

Analytical Plan: The primary outcome, change in global longitudinal strain (GLS) from before Anth-bC to immediately after Anth-bC (T1 vs T0), will be compared between the two groups (ExEarly and ExStandard) by independent one-sided t-test (or Wilcoxon two-sample test as appropriate) with alpha set at 0.05. Values from baseline (before Anth-bC, T0), completion of Anth-bC (week 13, T1), and follow-up (T2) will be compared between groups using ANCOVA with repeated measures (or mixed models in case of missing data) including baseline values as covariate and post-hoc testing for different time points. Intention-to-treat (ITT) analysis will be performed with group allocation according to randomization to assess the effectiveness of ExEarly in the clinical setting. Per-protocol analysis will be performed with patients allocated with regard to time period they completed more supervised sessions in, with a minimum requirement of 15 of the 24 (60%) scheduled training sessions within one or the other time period to assess the potential effects of an optimal training. Linear models will be performed to find independent baseline parameters to predict negative outcome of cardiac function (LV GLS, NT-proBNP, hsTnT). Secondary endpoints will be analysed accordingly. Statistical analyses will be performed using the software R (Version 3.3.1, R Core Team, 2016).

Significance: Outcomes from this project will improve long term care of patients with early breast cancer and lymphoma as well as other cancers, such that patients can be offered the possibility of active involvement towards mitigating undesirable side effects of a very effective cancer treatment. The assessment of barriers to training therapy may help to adapt the offered physical training programmes to reduce these barriers.