Diet Restriction and Exercise-induced Adaptations in Metastatic Breast Cancer (DREAM)

Fifty patients with metastatic breast cancer will be randomly assigned to an acute intervention consisting of both aerobic exercise and caloric restriction administered acutely prior to each of six chemotherapy cycles, or to usual care. The aerobic exercise intervention will consist of a single supervised recumbent cycle ergometer session performed concurrent to each chemotherapy infusion. The diet intervention consists of provision of meals freshly prepared in a metabolic kitchen with caloric content equivalent to 50% of measured energy requirements and low carbohydrate content for 48-72 hours prior to each chemotherapy infusion. Tumor outcomes will be assessed via CT scan (tumor size) and MRI (novel marker of tumor regression), while treatment side effects will be assessed by MRI and treatment symptoms and quality of life will be assessed via questionnaire before, during and after up to six chemotherapy cycles of a consistent treatment protocol. Progression-free and overall survival will be tracked for two years after diagnosis.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Behavioral: Short-term diet and exercise intervention

Detailed Description

Despite major advances in recent decades in treatment for early stage breast cancer leading to an 89% 5-year survival rate, metastatic breast cancer is still considered incurable due to resistance to most available treatments. As such, 5-year survival rate for metastatic breast cancer is only 22%. One mechanism for resistance to cancer therapies and promotion of metastasis in solid tumors is that their vascular system is impaired causing diminished delivery of systemic therapy and oxygen. Furthermore, toxicity can be quite high with metastatic regimens, which can limit the dose received. Both diet and exercise have been used to attenuate treatment toxicity, but the promising preclinical evidence showing their potential to enhance chemotherapy efficacy and survival has not been studied in humans. For example, a single bout of aerobic exercise substantially increased tumor blood flow and oxygen delivery, suggesting that chemotherapy delivery to the tumor would be enhanced. Short periods of fasting or caloric restriction also appear to be safe and effective strategies to inhibit tumor growth and enhance chemotherapy efficacy, while also promoting resistance to chemotherapy in healthy cells. Furthermore, combining aerobic exercise and caloric restriction can elicit synergistic effects on outcomes relevant to cancer, including body composition, aerobic fitness, fasting insulin and glucose, insulin-like growth factor, and tumor promoter pathways.

Study Design: With preclinical proof-of-principle and clinical safety and feasibility of each intervention independently established, this study will be a phase II, two-arm, single blind, randomized controlled trial. Fifty patients will be randomly assigned to an acute intervention consisting of both caloric restriction administered acutely prior to and aerobic exercise during each treatment of six chemotherapy cycles, or to usual care.

Approach: Participants will include adults with metastatic breast cancer with measurable metastases that will receive intravenous chemotherapy. The aerobic exercise intervention will consist of a single supervised recumbent cycle ergometer session performed concurrent to each chemotherapy infusion. The diet intervention consists of provision of meals freshly prepared in a metabolic kitchen with caloric content equivalent to 50% of measured energy requirements and low carbohydrate content for 48-72 hours prior to each chemotherapy infusion. The diet period will be reduced from 72 to 48 hours when there are <7 days between infusions (ie weekly protocols) to avoid inducing a sustained caloric deficit leading to weight loss. This acute intervention does not lead to long-term nutritional imbalances. Exercise intensity and meals will be individualized to participant abilities and preferences. All participants, regardless of group assignment, will receive a one-time phone consultation with a registered dietitian and a certified exercise physiologist to enhance recruitment and retention. Tumor outcomes will be assessed via CT scan (tumor size) and MRI (novel marker of tumor regression), while treatment side effects will be assessed by MRI and treatment symptoms and quality of life will be assessed via questionnaire before, during and after up to six chemotherapy cycles of a consistent treatment protocol. Progression-free and overall survival will be tracked for two years after diagnosis.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2E1
      • University of Alberta

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of stage IV or metastatic breast cancer;
• Measurable metastases.
• Age >18
• Starting (or having only received one treatment of) any type of intravenously administered chemotherapy;
• Eastern Cooperative Oncology Group (ECOG) Score < 3
• Oncologist approval to participate
• Able to communicate and read and understand English;
• Willing and able to adhere to the study interventions and assessments;

Exclusion Criteria:

• Limitations to sustained exercise (including bone metastases in the femur neck);
• Clinical evidence of cachexia (oncologist's discretion, study team will use body mass index <18.5kg/m² as a flag to highlight concern to treating oncologist);
• Body mass >109 kg at time of enrollment;
• Diabetes;
• Severe food allergies;
• History of eating disorder (diagnosed or self-reported);
• Strict diet restrictions including vegetarian or vegan;
• Unable to provide informed consent (i.e. cognitive impairment);
• Supplemental oxygen requirement;
• Uncontrolled pleural effusions (oncologists approval if pleural effusions exists and are controlled);
• Bilirubin >30 umol/L;
• Creatinine >120 umol/L;
• Pregnant;
• Contraindications to 3T MRI for research purposes

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Group; Standard chemotherapy treatment and oncology care plus short-term diet and exercise intervention.	Behavioral: Short-term diet and exercise intervention; Participants assigned to the intervention group will perform both the diet and acute exercise interventions. The interventions will be applied prior to up to six chemotherapy cycles of a consistent protocol. The total number of treatments of a given protocol received prior to treatment conclusion is dependent on patient condition and oncologic care preferences.
No Intervention: Control Group; Standard chemotherapy treatment and oncology care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor size change after 6 cycles (mm)	Change in tumor size measured by computerized tomography after 6 cycles.	0-6 weeks before the first chemotherapy treatment of the first cycle and 1-4 weeks after the last chemotherapy treatment of the last cycle

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor response to therapy by magnetic resonance imaging (mm²/s)	Magnetic resonance imaging (MRI) derived water apparent diffusion coefficient within the tumor	0-2 weeks before the first chemotherapy treatment of the first cycle and 2-3 weeks after the last chemotherapy treatment of the last cycle
Tumor size change after 3 cycles (mm)	Change in tumor size measured by computerized tomography after 3 cycles.	0-6 weeks before the first chemotherapy treatment of the first cycle and 1-3 weeks after the last chemotherapy treatment of the third cycle

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular ejection fraction (%)	MRI-derived left ventricular ejection fraction	0-2 weeks before the first chemotherapy treatment of the first cycle and 2-3 weeks after the last chemotherapy treatment of the last cycle
Left ventricular global longitudinal strain (%)	MRI-derived left ventricular global longitudinal strain	0-2 weeks before the first chemotherapy treatment of the first cycle and 2-3 weeks after the last chemotherapy treatment of the last cycle
Left ventricular mass (g/m²)	MRI-derived left ventricular mass	0-2 weeks before the first chemotherapy treatment of the first cycle and 2-3 weeks after the last chemotherapy treatment of the last cycle
Liver fat fraction (%)	Percent of fat in liver derived by PROFIT1 chemical-shift encoded MRI	0-2 weeks before the first chemotherapy treatment of the first cycle and 2-3 weeks after the last chemotherapy treatment of the last cycle
Liver T1 relaxation time (ms)	MRI-derived relaxation time from healthy liver	0-2 weeks before the first chemotherapy treatment of the first cycle and 2-3 weeks after the last chemotherapy treatment of the last cycle
Thigh skeletal muscle T1 relaxation time (ms)	MRI-derived skeletal muscle T1 relaxation time at mid-thigh	0-2 weeks before the first chemotherapy treatment of the first cycle and 2-3 weeks after the last chemotherapy treatment of the last cycle
Thigh muscle volume (mL)	PROFIT1 chemical-shift encoded MRI of the mid-thigh will be used to assess thigh muscle volume	0-2 weeks before the first chemotherapy treatment of the first cycle and 2-3 weeks after the last chemotherapy treatment of the last cycle
Thigh skeletal muscle fat fraction %	Percent of intermuscular fat in thigh muscle derived by PROFIT1 chemical-shift encoded MRI	0-2 weeks before the first chemotherapy treatment of the first cycle and 2-3 weeks after the last chemotherapy treatment of the last cycle
Patient-reported treatment symptoms	Patient-reported treatment symptoms assessed using the Rotterdam Symptom Checklist	0-2 weeks before the first chemotherapy treatment of the first cycle, at each chemotherapy treatment, and 2-3 weeks after the last chemotherapy treatment of the last cycle
Self reported quality of life	Quality of life assessed using the total score from the Functional Assessment of Cancer Therapy - Fatigue Questionnaire. Scores can range from 0 - 52 where a high score represents a better quality of life.	0-2 weeks before the first chemotherapy treatment of the first cycle, at the first chemotherapy treatment of 4th cycle, and 2-3 weeks after the last chemotherapy treatment of the last cycle
Fatigue	Fatigue assessed using the total score from the Functional Assessment of Cancer Therapy - Fatigue Questionnaire. Scores can range from 0 - 52 where a high score represents a lower level of fatigue.	0-2 weeks before the first chemotherapy treatment of the first cycle, at the first chemotherapy treatment of 4th cycle, and 2-3 weeks after the last chemotherapy treatment of the last cycle
Progression-free survival (months)	Progression-free survival time extracted from Cancer Control Alberta's electronic database	Two years after study enrollment
Overall survival (months)	Overall survival time extracted from Cancer Control Alberta's electronic database	Two years after study enrollment

Collaborators and Investigators

• Sponsor: University of Alberta
• Collaborators: Canadian Institutes of Health Research (CIHR); Canadian Cancer Society (CCS)
• Investigators: Principal Investigator: Carla Prado, PhD, University of Alberta; Principal Investigator: Richard Thompson, PhD, University of Alberta

Publications and helpful links

General Publications

• Kirkham AA, King K, Joy AA, Pelletier AB, Mackey JR, Young K, Zhu X, Meza-Junco J, Basi SK, Hiller JP, Brkin T, Michalowski B, Pituskin E, Paterson DI, Courneya KS, Thompson RB, Prado CM. Rationale and design of the Diet Restriction and Exercise-induced Adaptations in Metastatic breast cancer (DREAM) study: a 2-arm, parallel-group, phase II, randomized control trial of a short-term, calorie-restricted, and ketogenic diet plus exercise during intravenous chemotherapy versus usual care. BMC Cancer. 2021 Oct 10;21(1):1093. doi: 10.1186/s12885-021-08808-2.

Study record dates

Study Major Dates

• Study Start (Actual): April 23, 2019
• Primary Completion (Actual): December 31, 2023
• Study Completion (Estimated): July 28, 2024

Study Registration Dates

• First Submitted: November 26, 2018
• First Submitted That Met QC Criteria: January 4, 2019
• First Posted (Actual): January 7, 2019

Study Record Updates

• Last Update Posted (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Exercise; Nutrition; Chemotherapy; Caloric Restriction
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: HREBA.CC-18-0657

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No