Pre-operative Exercise During Neoadjuvant Chemotherapy in Patients With Breast Cancer

Study Overview
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Brief Summary
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The Neo-Train study is a randomized controlled trial investigating the effects of supervised pre-operative aerobic and resistance exercise in patients with breast cancer during neoadjuvant chemotherapy.

Detailed Description
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The long neoadjuvant chemotherapy period in patients with breast cancer brings a time window of opportunity to investigate the potential of pre-operative exercise to increase treatment efficacy with improved tumour regression. A possible improvement in chemotherapy completion, lift in physical function, alleviated toxicities as well as changes in biological markers can also be investigated. 120 patients with newly diagnosed breast cancer who start neoadjuvant chemotherapy will be randomized to the intervention arm (n=60) and control arm (n=60). Participants in the intervention arm will be prescribed a prehabilitation program consisting of thrice weekly combined supervised aerobic and resistance exercise during the neoadjuvant chemotherapy period. Participants will be screened for psychological distress four times and in case of moderate-severe distress be advised to visit the local Cancer Society Support Center where participants will be assessed and offered free services based on their psychosocial needs and available offers. Participants in the control arm will receive usual care. Outcomes will be measured at baseline (diagnosis), during neoadjuvant chemotherapy, during the week before breast surgery, at breast surgery and at 3 months follow up. The participants will receive the recommended neoadjuvant chemotherapy regimens in Denmark - currently up to 24 weeks. With expected chemotherapy dose delays, the time of breast surgery is expected to be within 30 weeks from baseline. The treatment plans will be individually modified based on tumour response and expected side effects to treatment. A subgroup of participants may change neoadjuvant chemotherapy regimen and be referred to breast surgery early. In these participants, the last measurement during chemotherapy will be used, and the 3 months follow up measurement will still be scheduled at 3 months after breast surgery. The study procedures will be pre-tested in a pilot study with 6 patients who will all receive the prehabilitation program.

Official Title
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Neo-Train: Pre-operative Exercise During Neoadjuvant Chemotherapy in Patients With Breast Cancer - a Randomized Controlled Trial

Conditions
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Breast Cancer

Intervention / Treatment
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* Behavioral: Prehabilitation program


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients newly diagnosed with histologically verified breast cancer and scheduled for neoadjuvant chemotherapy Female gender Aged ≥ 18 years old Signed informed consent Exclusion Criteria: Patients ineligible for or who have declined to receive neoadjuvant chemotherapy Contraindications to magnetic resonance imaging (MRI) Physical or cognitive disabilities preventing exercise or physical testing Inability to read and understand Danish Based on clinical judgement, the physician assesses that the patient is not suitable for inclusion

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial with an intervention arm and a control arm
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention arm<br>Prehabilitation program | Behavioral: Prehabilitation program<br>* The prehabilitation program includes combined high-intensity interval training on a cycle ergometer and machine-based resistance exercise of large muscle groups supervised by a physiotherapist. Exercise sessions will take place in physiotherapy departments at local hospitals or in municipality rehabilitation centres 3 times a week during the neoadjuvant chemotherapy period and ending in the week before breast surgery (maximum estimated 29 weeks depending on number of chemotherapy cycles, dose delays and time of breast surgery). Participants will be screened for psychological distress four times and in case of moderate-severe distress be advised to visit the local Cancer Society Support Center where participants will be assessed and offered free services based on their psychosocial needs and available offers. Participation will be monitored.<br>|
| No Intervention: Control arm<br>Usual care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumour size | Change in the maximum diameter of the tumour visualized by magnetic resonance imaging (MRI). | Sequential MRI scans follow the individual treatment plan in a period of up to 30 weeks from baseline (diagnostic MRI before start of neoadjuvant chemotherapy) to MRI performed by the end of the course of neoadjuvant chemotherapy before breast surgery. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative dose intensity of neoadjuvant chemotherapy | Relative dose intensity in percentage defined as the ratio of received mg/m2 per week compared to planned mg/m2 per week according to standard guidelines. | Baseline to time of breast surgery estimated up to 30 weeks | 
| Number of participants with neoadjuvant chemotherapy dose reductions | Measured in percentage | Baseline to time of breast surgery estimated up to 30 weeks | 
| Number of participants with neoadjuvant chemotherapy dose delays | Measured in percentage | Baseline to time of breast surgery estimated up to 30 weeks | 
| Number of participants with early discontinuation of neoadjuvant chemotherapy | Measured in percentage | Baseline to time of breast surgery estimated up to 30 weeks | 
| Number of hospital admissions during neoadjuvant chemotherapy | Measured in percentage | Baseline to time of breast surgery estimated up to 30 weeks | 
| Total length of hospital admissions during neoadjuvant chemotherapy | Measured in days | Baseline to time of breast surgery estimated up to 30 weeks | 
| Changes in total body mass | Changes from baseline measured by bioelectrical impedance analysis. | Baseline, during the week before breast surgery, 3 months after breast surgery | 
| Changes in lean body mass | Changes from baseline measured by bioelectrical impedance analysis. | Baseline, during the week before breast surgery, 3 months after breast surgery | 
| Changes in fat mass | Changes from baseline measured by bioelectrical impedance analysis. | Baseline, during the week before breast surgery, 3 months after breast surgery | 
| Changes in physical fitness | Changes in VO2 max estimated from maximum power output from baseline measured by a progressive cycle ergometer test (watt max test). | Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery | 
| Changes in muscle strength | Changes in 1 repetition maximum strength from baseline measured on leg press and pull down. | Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery | 
| Changes in physical function | Changes in hand grip strength from baseline measured by hand-held dynamometer in kilograms. Maximum kilograms obtained of 3 measurements on each hand. | Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery | 
| Changes in level of physical activity | Changes in activity data measured by a wearable objective measurement device. | Baseline, during the week before breast surgery, 3 months after breast surgery | 
| Changes in health-related quality of life | Changes in self-reported health-related quality of life from baseline assessed on the Functional Assessment of Cancer Therapy - Breast Cancer (FACT-B). | Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery | 
| Changes in general anxiety | Changes in self-reported general anxiety from baseline assessed on the Generalised Anxiety Disorder 7-item (GAD-7). | Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery | 
| Changes in depression | Changes in self-reported depression from baseline assessed on the Patient Health Questionnaire-9 (PHQ-9). | Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery | 
| Changes in psychological distress | Changes in self-reported psychological distress from baseline assessed on the Distress Thermometer (DT). | Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery | 
| Post-operative referral to and participation in municipal rehabilitation programs | Frequency of participants referred to municipal rehabilitation, participation and types of activities attended identified from a self-reported questionnaire. | Breast surgery to 3 months after breast surgery | 
| Tumour size | Assessed by doctors' clinical examination of the breast. | Sequential clinical examinations of the breast following the individual treatment plan in a period of up to 30 weeks from baseline to time of breast surgery | 
| Tumour size | Measured by a pathologist from the tumour surgical specimen at breast surgery. | At time of breast surgery estimated to take place within 30 weeks from baseline | 
| Pathological response grade | Assessed by a pathologist from the tumour surgical specimen at breast surgery. | At time of breast surgery estimated to take place within 30 weeks from baseline | 
| Tumour infiltrating lymphocyte population | Description of tumour infiltrating lymphocyte population (percentage of cells) evaluated by a pathologist from the tumour surgical specimen at breast surgery. | At time of breast surgery estimated to take place within 30 weeks from baseline | 
| Tumour vascularity | Description of tumour vascularity density and structure evaluated by a pathologist from the tumour surgical specimen at breast surgery. | At time of breast surgery estimated to take place within 30 weeks from baseline | 
| Liquid biopsies | Changes in cell free DNA from blood samples. Furthermore, circulating tumour DNA will be investigated if possible. | Baseline, approximately week 7, 13 and 19, 3 months after breast surgery | 
| Metabolic and inflammatory markers | Changes in glucose, hba1c, zinc, magnesium, phosphate and C reactive protein (CRP) levels from blood samples. | Baseline, approximately week 13 and 19, 3 months after breast surgery | 
| Cytokines | Changes in cytokines from blood samples before, during and after neoadjuvant chemotherapy. | Baseline, approximately week 13 and 19, 3 months after breast surgery | 
| Cell proliferation | In vitro cell proliferation response with sera collected from blood samples before and after exercise. | Approximately between week 1-4 during neoadjuvant chemotherapy and within 6 weeks before breast surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prehabilitation, Pre-operative exercise, Breast cancer, Tumour regression, Neoadjuvant chemotherapy