Breast Cancer, Colorectal Cancer
Conditions
Keywords
Colorectal, Breast, Insulin, Exercise
Brief summary
Metformin is a medication that is commonly used in the treatment of diabetes. Recently small studies in cancer patients without diabetes suggest that metformin may benefit in lowering insulin levels. In those studies of patients with cancer but not diabetes, glucose (or sugar) levels in the blood are generally no lowered. Insulin and insulin-like growth factors affect the growth of cancer cells. This randomized study will compare different interventions; exercise, exercise and metformin, metformin alone, or a control arm. The investigators are not directly testing how either exercise or metformin affects your disease. The investigators are testing how they affect insulin levels in your body as well as other blood markers. The investigators believe that these blood tests may either be related to cancer recurrences or be an early sign of cancer recurrences and they are testing how both exercise and metformin may change those markers.
Detailed description
Subjects will be randomized into one of four groups: exercise training, exercise training and metformin, metformin alone, or control arm. All subjects will have lifestyle measurements, interviews regarding activity level, diet questionnaires, and blood tests. Subjects randomized to exercise training will participate in two supervised exercise sessions per week with an exercise physiologist for 3 months. They will also be asked to exercise on their own for up to an additional 120 minutes each week. Subjects randomized to exercise training and metformin will participate in two supervised exercise sessions per week and will take metformin. Metformin will be taken once daily for the first two weeks and then twice daily for 3 months. Subjects randomized to metformin will take metformin once daily for the first two weeks and then twice daily. Subjects on the control arm will receive a packet of educational information on nutrition and physical activity developed by the National Cancer Institute and American Cancer Society. In addition to education information, they will be offered two supervised sessions with an exercise physiologist as well as a pedometer 3 months after enrollment in the study.
Interventions
BEHAVIORALExercise training
Two supervised exercise sessions per week
DRUGMetformin
Oral metformin QD for two weeks, then BID
educational information
Sponsors
Dana-Farber Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed stage I-III colorectal or breast cancer * Undergone curative-intent complete surgical resection and completed all adjuvant therapy (if indicated) at least 2 months prior to enrollment * Note: Breast cancer subjects on hormonal therapy or trastuzumab only therapy and colorectal cancer subjects on adjunctive therapies not considered cytotoxic chemotherapy (including those participating in CALGB 80702 receiving only celecoxib/placebo) are eligible. * Participants will be allowed to receive concomitant adjuvant endocrine therapy for breast cancer; however, all endocrine agents must be initiated at least 1 month prior to enrollment in the study and continued throughout the duration of study participation. * Less than 120 minutes of exercise per week * Approval by oncologist or surgeon * English speaking and able to read English * No planned surgery anticipated in the 3 month intervention period * At least one month from any major surgery to start of intervention including colostomy reversal
Exclusion criteria
* Concurrent other malignancy or history of other malignancy treated within the past 3 years (other than non-melanoma skin cancer or in-situ cervical cancer) * Metastatic disease * Scheduled to receive any form of further adjuvant cancer therapy * Currently on medication for diabetes treatment * Pregnant or breast-feeding * Any condition associated with increased risk of metformin-associated lactic acidosis (prior renal failure or liver failure, history of acidosis of any type; habitual intake of 3 or more alcoholic beverages per day) * Known hypersensitivity or intolerance to metformin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Insulin Level | 0 and 3 months (change between 0 and 3 months) | Determine whether supervised exercise training alone and metformin, either alone or in combination can decrease fasting insulin level from baseline to 3 months in patients who completed standard therapy for stage I-III colorectal or breast cancer. Fasting insulin levels in blood will be drawn at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Other Insulin-Related Biomarkers | 0 and 3 months (change between 0 and 3 months) | Markers related to insulin and insulin-like growth factors (including insulin-like growth factor 1 \[IGF-1\], IGF binding protein-1 \[IGFBP-1\], IGF binding protein-3 \[IGFBP-3\], leptin) will be measured by a blood draw at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value. |
| Change in Fasting Glucose Level | 0 and 3 months (change between 0 and 3 months) | Determine whether supervised exercise training alone and metformin, either alone or in combination can decrease fasting Glucose level from baseline to 3 months in patients who completed standard therapy for stage I-III colorectal or breast cancer. Fasting Glucose levels in blood will be drawn at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in Body Composition by Treatment Arm - Weight | 0 and 3 months (change between 0 and 3 months) | Negative least square means indicate a decrease at 3 month comparing to baseline value. |
| Changes in Body Composition by Treatment Arm - BMI | 0 and 3 months (change between 0 and 3 months) | Negative least square means indicate a decrease at 3 month comparing to baseline value. |
| Changes in Body Composition by Treatment Arm - Waist to Hip Ratio | 0 and 3 months (change between 0 and 3 months) | Negative least square means indicate a decrease at 3 month comparing to baseline value. |
Countries
United States
Participant flow
Recruitment details
In a phase 2 RCT, stage I-III CRC & BC survivors at least 2 months from completing standard therapy were randomized. Major eligibility included absence of recurrence, absence of diabetes (glucose \< 160 (random) or \< 126 (fasting) mg/dl), and exercising \< 120 min/wk. 1,426 patients screened, and 139 enrolled from September 2011 to December 2015.
Pre-assignment details
Stratification factors: BMI (\< 30 v \> 30), gender, tumor site (CRC v BC)
Participants by arm
| Arm | Count |
|---|---|
| Exercise Training With Metformin Exercise training with exercise physiologist with oral metformin
Exercise training plus metformin: Two supervised exercise sessions per week. Oral metformin QD for 2 weeks, then BID | 35 |
| Exercise Training Exercise training with exercise physiologist
Exercise training: Two supervised exercise sessions per week | 35 |
| Metformin Metformin
Metformin: Oral metformin QD for two weeks, then BID | 35 |
| Control Educational information
Educational information: educational information | 34 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 4 | 0 |
| Overall Study | Lost to Follow-up | 3 | 0 | 5 | 10 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 |
| Overall Study | Unrelated sickness | 0 | 2 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 6 | 6 | 3 |
Baseline characteristics
| Characteristic | Exercise Training With Metformin | Control | Metformin | Exercise Training | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53 years | 56 years | 55 years | 58 years | 55 years |
| BMI | 27.7 kg/m^2 | 28.4 kg/m^2 | 28.8 kg/m^2 | 28.5 kg/m^2 | 28.5 kg/m^2 |
| Cancer Stage stage I | 14 Participants | 12 Participants | 14 Participants | 11 Participants | 51 Participants |
| Cancer Stage stage II | 8 Participants | 12 Participants | 9 Participants | 11 Participants | 40 Participants |
| Cancer Stage stage III | 13 Participants | 9 Participants | 12 Participants | 12 Participants | 46 Participants |
| Cancer Stage Unknown stage | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 33 Participants | 34 Participants | 35 Participants | 133 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 0 Participants | 0 Participants | 5 Participants |
| Prior Chemotherapy No | 10 Participants | 11 Participants | 12 Participants | 9 Participants | 42 Participants |
| Prior Chemotherapy Unknown | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 5 Participants |
| Prior Chemotherapy Yes | 25 Participants | 22 Participants | 23 Participants | 22 Participants | 92 Participants |
| Prior Radiation Therapy No | 18 Participants | 17 Participants | 21 Participants | 15 Participants | 71 Participants |
| Prior Radiation Therapy Unknown | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 5 Participants |
| Prior Radiation Therapy Yes | 17 Participants | 16 Participants | 14 Participants | 16 Participants | 63 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 3 Participants | 1 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) White | 28 Participants | 26 Participants | 29 Participants | 30 Participants | 113 Participants |
| Region of Enrollment United States | 35 participants | 34 participants | 35 participants | 35 participants | 139 participants |
| Sex: Female, Male Female | 29 Participants | 29 Participants | 29 Participants | 29 Participants | 116 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 6 Participants | 6 Participants | 23 Participants |
| Study Site DFCI | 28 Participants | 25 Participants | 24 Participants | 22 Participants | 99 Participants |
| Study Site Duke | 4 Participants | 6 Participants | 5 Participants | 4 Participants | 19 Participants |
| Study Site Yale | 3 Participants | 3 Participants | 6 Participants | 9 Participants | 21 Participants |
| Tumor Location Breast Cancer | 22 Participants | 22 Participants | 22 Participants | 21 Participants | 87 Participants |
| Tumor Location Colorectal Cancer | 13 Participants | 12 Participants | 13 Participants | 14 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 | 0 / 35 | 0 / 34 |
| other Total, other adverse events | 21 / 35 | 0 / 0 | 23 / 35 | 0 / 0 |
| serious Total, serious adverse events | 0 / 35 | 0 / 35 | 0 / 35 | 0 / 34 |
Outcome results
Primary
Change in Fasting Insulin Level
Determine whether supervised exercise training alone and metformin, either alone or in combination can decrease fasting insulin level from baseline to 3 months in patients who completed standard therapy for stage I-III colorectal or breast cancer. Fasting insulin levels in blood will be drawn at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value.
Time frame: 0 and 3 months (change between 0 and 3 months)
Population: 11 patients are excluded for missing baseline blood samples.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exercise Training With Metformin | Change in Fasting Insulin Level | -2.47 mU/L | Standard Error 1.07 |
| Exercise Training | Change in Fasting Insulin Level | -0.08 mU/L | Standard Error 1.06 |
| Metformin | Change in Fasting Insulin Level | -1.16 mU/L | Standard Error 1.18 |
| Control | Change in Fasting Insulin Level | 2.79 mU/L | Standard Error 1.27 |
Comparison: Null hypothesis: decrease of insulin in treatment arm is greater than the control arm.p-value: <0.0001Mixed Models Analysis
Comparison: Null hypothesis: decrease of insulin in treatment arm is greater than the control arm.p-value: 0.003Mixed Models Analysis
Comparison: Null hypothesis: decrease of insulin in treatment arm is greater than the control arm.p-value: 0.01Mixed Models Analysis
Comparison: Null hypothesis: decrease of Insulin in combined arm is greater than the exercise-only or metformin-only arm.p-value: 0.03Mixed Models Analysis
Secondary
Change in Fasting Glucose Level
Determine whether supervised exercise training alone and metformin, either alone or in combination can decrease fasting Glucose level from baseline to 3 months in patients who completed standard therapy for stage I-III colorectal or breast cancer. Fasting Glucose levels in blood will be drawn at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value.
Time frame: 0 and 3 months (change between 0 and 3 months)
Population: 11 patients are excluded for missing baseline blood samples.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exercise Training With Metformin | Change in Fasting Glucose Level | -0.09 mg/dL | Standard Error 2.11 |
| Exercise Training | Change in Fasting Glucose Level | 2.93 mg/dL | Standard Error 2.08 |
| Metformin | Change in Fasting Glucose Level | -4.11 mg/dL | Standard Error 2.32 |
| Control | Change in Fasting Glucose Level | 4.92 mg/dL | Standard Error 2.44 |
Comparison: Null hypothesis: decrease of Glucose in treatment arm is greater than the control arm.p-value: 0.0004Mixed Models Analysis
Comparison: Null hypothesis: decrease of Glucose in treatment arm is greater than the control arm.p-value: 0.007Mixed Models Analysis
Secondary
Changes in Other Insulin-Related Biomarkers
Markers related to insulin and insulin-like growth factors (including insulin-like growth factor 1 \[IGF-1\], IGF binding protein-1 \[IGFBP-1\], IGF binding protein-3 \[IGFBP-3\], leptin) will be measured by a blood draw at baseline, 3 months and 6 months. Negative least square means indicate a decrease at 3 month comparing to baseline value.
Time frame: 0 and 3 months (change between 0 and 3 months)
Population: 11 patients are excluded for missing baseline blood samples.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exercise Training With Metformin | Changes in Other Insulin-Related Biomarkers | IGFBP-1 | -0.22 ng/mL | Standard Error 0.57 |
| Exercise Training With Metformin | Changes in Other Insulin-Related Biomarkers | IGF-I | -1.29 ng/mL | Standard Error 2.98 |
| Exercise Training With Metformin | Changes in Other Insulin-Related Biomarkers | Leptin | -5.09 ng/mL | Standard Error 1.21 |
| Exercise Training With Metformin | Changes in Other Insulin-Related Biomarkers | IGFBP-3 | -178.8 ng/mL | Standard Error 82 |
| Exercise Training | Changes in Other Insulin-Related Biomarkers | IGFBP-3 | 53.4 ng/mL | Standard Error 80.7 |
| Exercise Training | Changes in Other Insulin-Related Biomarkers | IGFBP-1 | 0.09 ng/mL | Standard Error 0.56 |
| Exercise Training | Changes in Other Insulin-Related Biomarkers | Leptin | -0.54 ng/mL | Standard Error 1.19 |
| Exercise Training | Changes in Other Insulin-Related Biomarkers | IGF-I | 8.22 ng/mL | Standard Error 2.94 |
| Metformin | Changes in Other Insulin-Related Biomarkers | Leptin | -2.56 ng/mL | Standard Error 1.33 |
| Metformin | Changes in Other Insulin-Related Biomarkers | IGF-I | -2.66 ng/mL | Standard Error 3.28 |
| Metformin | Changes in Other Insulin-Related Biomarkers | IGFBP-1 | -1.20 ng/mL | Standard Error 0.63 |
| Metformin | Changes in Other Insulin-Related Biomarkers | IGFBP-3 | 25.9 ng/mL | Standard Error 90.2 |
| Control | Changes in Other Insulin-Related Biomarkers | IGF-I | -3.05 ng/mL | Standard Error 3.46 |
| Control | Changes in Other Insulin-Related Biomarkers | Leptin | -0.20 ng/mL | Standard Error 1.4 |
| Control | Changes in Other Insulin-Related Biomarkers | IGFBP-3 | -96.9 ng/mL | Standard Error 94.9 |
| Control | Changes in Other Insulin-Related Biomarkers | IGFBP-1 | 0.78 ng/mL | Standard Error 0.66 |
Comparison: Null hypothesis: decrease of leptin in treatment arm is greater than the control arm.p-value: 0.0002Mixed Models Analysis
Comparison: Null hypothesis: decrease of IGFBP\_1 in treatment arm is greater than the control arm.p-value: 0.002Mixed Models Analysis
Comparison: Null hypothesis: decrease of IGFBP\_1 in treatment arm is greater than the control arm.p-value: 0.02Mixed Models Analysis
Comparison: Null hypothesis: decrease of Leptin in combined arm is greater than the exercise-only or metformin-only arm.p-value: 0.0002Mixed Models Analysis
Comparison: Null hypothesis: decrease of Leptin in combined arm is greater than the exercise-only or metformin-only arm.p-value: 0.02Mixed Models Analysis
Other Pre-specified
Changes in Body Composition by Treatment Arm - BMI
Negative least square means indicate a decrease at 3 month comparing to baseline value.
Time frame: 0 and 3 months (change between 0 and 3 months)
Population: 2 patients are excluded for missing baseline measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exercise Training With Metformin | Changes in Body Composition by Treatment Arm - BMI | -0.51 kg/m^2 | Standard Error 0.2 |
| Exercise Training | Changes in Body Composition by Treatment Arm - BMI | 0.27 kg/m^2 | Standard Error 0.2 |
| Metformin | Changes in Body Composition by Treatment Arm - BMI | -0.33 kg/m^2 | Standard Error 0.21 |
| Control | Changes in Body Composition by Treatment Arm - BMI | 0.70 kg/m^2 | Standard Error 0.22 |
Comparison: Null hypothesis: decrease of BMI in treatment arm is greater than the control arm.p-value: <0.0001Mixed Models Analysis
Comparison: Null hypothesis: decrease of BMI in treatment arm is greater than the control arm.p-value: 0.02Mixed Models Analysis
Comparison: Null hypothesis: decrease of BMI in treatment arm is greater than the control arm.p-value: <0.0001Mixed Models Analysis
Other Pre-specified
Changes in Body Composition by Treatment Arm - Waist to Hip Ratio
Negative least square means indicate a decrease at 3 month comparing to baseline value.
Time frame: 0 and 3 months (change between 0 and 3 months)
Population: 2 patients are excluded for missing baseline measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exercise Training With Metformin | Changes in Body Composition by Treatment Arm - Waist to Hip Ratio | -0.007 ratio | Standard Error 0.01 |
| Exercise Training | Changes in Body Composition by Treatment Arm - Waist to Hip Ratio | 0.006 ratio | Standard Error 0.01 |
| Metformin | Changes in Body Composition by Treatment Arm - Waist to Hip Ratio | 0.012 ratio | Standard Error 0.01 |
| Control | Changes in Body Composition by Treatment Arm - Waist to Hip Ratio | 0.016 ratio | Standard Error 0.01 |
Comparison: Null hypothesis: decrease of Waist to Hip Ratio in treatment arm is greater than the control arm.p-value: 0.01Mixed Models Analysis
Other Pre-specified
Changes in Body Composition by Treatment Arm - Weight
Negative least square means indicate a decrease at 3 month comparing to baseline value.
Time frame: 0 and 3 months (change between 0 and 3 months)
Population: 2 patients are excluded for missing baseline measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exercise Training With Metformin | Changes in Body Composition by Treatment Arm - Weight | -1.41 kg | Standard Error 0.53 |
| Exercise Training | Changes in Body Composition by Treatment Arm - Weight | 0.70 kg | Standard Error 0.54 |
| Metformin | Changes in Body Composition by Treatment Arm - Weight | -0.91 kg | Standard Error 0.57 |
| Control | Changes in Body Composition by Treatment Arm - Weight | 1.97 kg | Standard Error 0.6 |
Comparison: Null hypothesis: decrease of Weight in treatment arm is greater than the control arm.p-value: <0.0001Mixed Models Analysis
Comparison: Null hypothesis: decrease of Weight in treatment arm is greater than the control arm.p-value: <0.0001Mixed Models Analysis
Comparison: Null hypothesis: decrease of Weight in treatment arm is greater than the control arm.p-value: 0.01Mixed Models Analysis