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

• ClinicalTrials.gov Identifier: NCT03795493
• Recruitment Status: Enrolling by invitation
• First Posted: January 7, 2019
• Last Update Posted: January 5, 2023
• Sponsor: University of Alberta
• Collaborators: Canadian Cancer Society (CCS); Canadian Institutes of Health Research (CIHR)
• Information provided by (Responsible Party): University of Alberta

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Behavioral: Short-term diet and exercise intervention	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: Diet Restriction and Exercise-induced Adaptations in Metastatic Breast Cancer
• Actual Study Start Date: April 23, 2019
• Estimated Primary Completion Date: December 31, 2023
• Estimated Study Completion Date: December 31, 2023

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Tumor size change after 6 cycles (mm) [ Time Frame: 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 ]
   Change in tumor size measured by computerized tomography after 6 cycles.

Secondary Outcome Measures :

1. Tumor response to therapy by magnetic resonance imaging (mm²/s) [ Time Frame: 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 ]
   Magnetic resonance imaging (MRI) derived water apparent diffusion coefficient within the tumor
2. Tumor size change after 3 cycles (mm) [ Time Frame: 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 ]
   Change in tumor size measured by computerized tomography after 3 cycles.

Other Outcome Measures:

1. Left ventricular ejection fraction (%) [ Time Frame: 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 ]
   MRI-derived left ventricular ejection fraction
2. Left ventricular global longitudinal strain (%) [ Time Frame: 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 ]
   MRI-derived left ventricular global longitudinal strain
3. Left ventricular mass (g/m²) [ Time Frame: 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 ]
   MRI-derived left ventricular mass
4. Liver fat fraction (%) [ Time Frame: 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 ]
   Percent of fat in liver derived by PROFIT1 chemical-shift encoded MRI
5. Liver T1 relaxation time (ms) [ Time Frame: 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 ]
   MRI-derived relaxation time from healthy liver
6. Thigh skeletal muscle T1 relaxation time (ms) [ Time Frame: 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 ]
   MRI-derived skeletal muscle T1 relaxation time at mid-thigh
7. Thigh muscle volume (mL) [ Time Frame: 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 ]
   PROFIT1 chemical-shift encoded MRI of the mid-thigh will be used to assess thigh muscle volume
8. Thigh skeletal muscle fat fraction % [ Time Frame: 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 ]
   Percent of intermuscular fat in thigh muscle derived by PROFIT1 chemical-shift encoded MRI
9. Patient-reported treatment symptoms [ Time Frame: 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 ]
   Patient-reported treatment symptoms assessed using the Rotterdam Symptom Checklist
10. Self reported quality of life [ Time Frame: 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 ]
    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.
11. Fatigue [ Time Frame: 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 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.
12. Progression-free survival (months) [ Time Frame: Two years after study enrollment ]
    Progression-free survival time extracted from Cancer Control Alberta's electronic database
13. Overall survival (months) [ Time Frame: Two years after study enrollment ]
    Overall survival time extracted from Cancer Control Alberta's electronic database

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Canada, Alberta

University of Alberta

Edmonton, Alberta, Canada, T6G 2E1

Sponsors and Collaborators

University of Alberta

Canadian Cancer Society (CCS)

Canadian Institutes of Health Research (CIHR)

Investigators

• Principal Investigator: Carla Prado, PhD; University of Alberta
• Principal Investigator: Richard Thompson, PhD; University of Alberta

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University of Alberta
• ClinicalTrials.gov Identifier: NCT03795493
• Other Study ID Numbers: HREBA.CC-18-0657
• First Posted: January 7, 2019
• Last Update Posted: January 5, 2023
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Alberta:

Exercise; Nutrition; Caloric Restriction; Chemotherapy

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases