Clinical trial NCT03795493: Diet Restriction and Exercise-induced Adaptations in Metastatic Breast Cancer
Official title: Diet Restriction and Exercise-induced Adaptations in Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Breast Cancer
Keywords: Exercise
Nutrition
Caloric Restriction
Chemotherapy
Lead sponsor: University of Alberta
Sponsor class: OTHER
Collaborators: name: Canadian Cancer Society (CCS)
name: Canadian Institutes of Health Research (CIHR)
First posted: 2019-01-07
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.

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.

Eligibility 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

Primary outcomes:
measure: Tumor size change after 6 cycles (mm)
timeFrame: 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 outcomes:
measure: Tumor response to therapy by magnetic resonance imaging (mm²/s)
timeFrame: 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
measure: Tumor size change after 3 cycles (mm)
timeFrame: 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 outcomes:
measure: Left ventricular ejection fraction (%)
timeFrame: 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
measure: Left ventricular global longitudinal strain (%)
timeFrame: 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
measure: Left ventricular mass (g/m²)
timeFrame: 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
measure: Liver fat fraction (%)
timeFrame: 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
measure: Liver T1 relaxation time (ms)
timeFrame: 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
measure: Thigh skeletal muscle T1 relaxation time (ms)
timeFrame: 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
measure: Thigh muscle volume (mL)
timeFrame: 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
measure: Thigh skeletal muscle fat fraction %
timeFrame: 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
measure: Patient-reported treatment symptoms
timeFrame: 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
measure: Self reported quality of life
timeFrame: 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
measure: Fatigue
timeFrame: 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
measure: Progression-free survival (months)
timeFrame: Two years after study enrollment
measure: Overall survival (months)
timeFrame: Two years after study enrollment
Locations:
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
Study officials:
affiliation: University of Alberta
name: Carla Prado, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alberta
name: Richard Thompson, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.