Breast Cancer, Lymphoma
Conditions
Keywords
Stage I breast cancer, Stage II breast cancer, Stage III breast cancer, Stage I Lymphoma, Stage II Lymphoma, Stage III Lymphoma, Stage IV Lymphoma
Brief summary
The purpose of this research study is to see if Atorvastatin (Lipitor) 40 mg by mouth daily decreases the chance of developing heart problems in individuals receiving adjuvant anthracycline-based chemotherapy for breast cancer of lymphoma.
Detailed description
PRIMARY OBJECTIVES: Specific Aim 1: To determine if Atorvastatin(Lipitor) administration preserves left ventricular ejection fraction (LVEF) 24 months after initiation of Anthracycline-based adjuvant therapy for adjuvant treatment of breast cancer or lymphoma. Specific Aim 2: To determine if baseline to 6-month differences in LVEF predict baseline to 24-month differences in LVEF after Anthracycline-based adjuvant therapy and concomitant atorvastatin therapy. To achieve these aims, we will perform a double-blind, placebo-controlled, randomized clinical trial of 0 or 40 mg of atorvastatin/day in 278 individuals scheduled to receive Anthracycline-based chemotherapy for treatment of Stage I-III breast cancer or lymphoma Stage I-IV with a projected \> 2 year life expectancy. We will use innovative noninvasive magnetic resonance imaging (MRI) procedures to accurately measure LVEF. In addition, we will measure left ventricle (LV) volumes, myocardial strain, fibrosis, aortic pulse wave velocity (PWV) and wall thickness, all factors that can influence LVEF by altering LV pre-load, after-load, and contractility.19,20 Advanced serum biomarkers will be measured that assess for the presence of oxidative/nitrosative stress, systemic inflammation and circulating neurohormones that also may influence LVEF. This study will test a new clinical paradigm to manage breast cancer: primary prevention of Anthracycline-based adjuvant therapy-related LV dysfunction using pre-treatment with low-cost statins. In addition, this trial will be the first systematic collection of data regarding the mechanism(s) and time course by which LV dysfunction and subsequent chronic heart failure (CHF) evolve in individuals given Anthracycline-based chemotherapy for breast cancer or lymphoma. These data will be useful to physicians trying to determine the optimal cardiac protection strategies when administering adjuvant chemotherapeutic regimens to their breast cancer or lymphoma patients. The objective of this research is to use inexpensive medications to preserve cardiovascular (CV) health and thereby improve overall survival in the growing number of breast cancer and lymphoma patients. SECONDARY OBJECTIVES Specific Aim 1: To document the effect of Atorvastatin (Lipitor) on cognitive function using a battery of neurocognitive tests (HVLT, Rey-osterrieth Figure, controlled oral word association test (COWA), Trail-making Parts A and B, Digit Span and Grooved Pegboard) in breast cancer and lymphoma patients receiving an anthracycline. Specific Aim 2: To document the effect of Atorvastatin(Lipitor) on self-reported quality of life using validated questionnaires (PROMIS including: General form, Cog Concerns, Cog Abilities, Fatigue, Pain intensity and interference, Sleep Disturbance, Physical Functioning and Social Functioning) in breast cancer and lymphoma patients receiving an anthracycline.
Interventions
DRUGAtorvastatin
40 mg tablet taken by mouth each morning for 24 months.
DRUGPlacebo
One placebo tablet taken each morning orally for 24 months.
Sponsors
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Wake Forest University Health Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Stage I-III breast cancer (including inflammatory and newly diagnosed recurrent breast cancer) or lymphoma Stage I-IV. (Patients should have a \> 2 year life expectancy) * Scheduled to receive adjuvant chemotherapy with an Anthracycline (doxorubicin and epirubicin) * 21 years of age or older * LVEF \> 50% (Most recent within the last 5 years) * Prior administration of anthracyclines is acceptable if therapy was completed \> 6 months prior to study enrollment * Patients that are receiving or have received chemotherapy regimens are allowed * Able to hold breath for 10 seconds * Prior cancers allowed if no evidence of disease in last 5 years * Eastern Cooperative Oncology Group (ECOG) 0 or 1
Exclusion criteria
* Prior use of lipid-lowering therapy within the last 6 months * Current postmenopausal hormone-replacement therapy * Uncontrolled hypertension (systolic blood pressure \>190 mm Hg or diastolic blood pressure \>100 mm Hg) * Scheduled to receive neoadjuvant chemotherapy with an anthracycline * No active liver disease allowed * Uncontrolled hypothyroidism * Recent history (within past 3 years) of alcohol or drug abuse, inflammatory conditions such as lupus or inflammatory bowel disease, use of immunosuppressant agents, or another medical condition that might compromise safety or the successful completion of the study. * Patients with ferromagnetic cerebral aneurysm clips or other intraorbital/intracranial metal;pacemakers, defibrillators, functioning neurostimulator devices or other implanted electronic devices. * Unstable angina; significant ventricular arrhythmias (\>20 premature ventricular complexes (PVCs)/min due to gating difficulty) atrial fibrillation with uncontrolled ventricular response; coronary artery disease; acute myocardial infarction within 28 days * Current use of Cytochrome P450 (CYP3A4) inhibitors. These include Clarithromycin, HIV protease inhibitors, Itraconazole, grapefruit juice, Cyclosporine, Rifampin or Digoxin * Current or history of hepatic dysfunction * Unable to provide informed consent * Claustrophobia * Planning to move within 24 months of trial enrollment * Pregnant or breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Left Ventricular Ejection Fraction (LVEF) | 24 months | 24 month estimated values of clinical measurements obtained from Cardiac MRI left ventricular ejection fraction by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| End Systolic Volume | 24 months | 24 month estimated values of clinical measurements obtained from Cardiac MRI End Systolic Volume by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data. |
| Stroke Volume | 24 months | 24 month estimated values of clinical measurements obtained from Cardiac MRI Stroke Volume by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data. |
| Left Ventricular (LV) Mass | 24 months | 24 month estimated values of clinical measurements obtained from Cardiac MRI left ventricular mass by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data. |
| Pulse Wave Velocity | 24 months | 24 month estimated values of clinical measurements obtained from Cardiac MRI pulse wave velocity by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data. |
| End Diastolic Volume | 24 months | 24 month estimated values of clinical measurements obtained from Cardiac MRI End Diastolic Volume by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data. |
| Controlled Oral Word Association (COWA) | 24 months | 24 month estimated values Controlled Oral Word Association (COWA) by group. Linear model adjusts for baseline value and group assignment. No missing imputation performed. The COWA uses the three letter set of C, F, and L to assess phonemic fluency. Individuals are given 1 min to name as many words as possible beginning with one of the letters. The procedure is then repeated for the remaining two letters. Ranges from 0 to the total number of correct words that begin with one of the letters in the set. There is no ceiling of a maximum score. Higher numbers reflect better verbal fluency. |
| Patient-reported Outcomes Measurement (PROMIS) Questionnaire - Applied Cognition - General Concerns - Short Form 4a | 24 months | Patient reported quality of life outcomes obtained from patient-reported outcomes measurement (PROMIS) questionnaire - Applied Cognition - General Concerns - Short Form 4a . Scores range from 4-20 and then adjusted by t-scores ranging from 30.1-63.8. Higher scores reflect better cognition. Linear models include baseline assessment and group and multiple imputation was utilized. |
| Patient-reported Outcomes Measurement (PROMIS) Questionnaire - Fatigue Short Form 41 | 24 months | Patient reported quality of life outcomes obtained from patient-reported outcomes measurement (PROMIS) questionnaire - Fatigue Short Form 41. Scores range from 4-20 and then adjusted by t-scores ranging from 33.7-75.8. Higher scores reflect worse fatigue. Linear models include baseline assessment and group and multiple imputation was utilized. |
| Hopkins Verbal Learning Test (HVLT) Total Recall | 24 months | 24 month estimated values Hopkins Verbal Learning test (HVLT) total recall by group. Linear model adjusts for baseline value and group assignment. No missing imputation performed. Ranges from 0 to 36 and higher numbers reflect better recall. |
Countries
United States
Participant flow
Pre-assignment details
No reason for exclusion prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 - Atorvastatin One 40 mg Atorvastatin tablet each morning by mouth for 24 months
Atorvastatin: 40 mg tablet taken by mouth each morning for 24 months. | 139 |
| Arm 2 - Placebo One placebo tablet each morning by mouth for 24 months.
Atorvastatin: 40 mg tablet taken by mouth each morning for 24 months.
Placebo: One placebo tablet taken each morning orally for 24 months. | 140 |
| Total | 279 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 1 |
| Overall Study | Lost to Follow-up | 3 | 0 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Withdrawal by Subject | 31 | 33 |
Baseline characteristics
| Characteristic | Total | Arm 2 - Placebo | Arm 1 - Atorvastatin |
|---|---|---|---|
| Age, Continuous | 49.0 years STANDARD_DEVIATION 12 | 49.4 years STANDARD_DEVIATION 11.5 | 48.5 years STANDARD_DEVIATION 12.5 |
| Body Mass Index | 30 kg/m^2 STANDARD_DEVIATION 7 | 31 kg/m^2 STANDARD_DEVIATION 7.4 | 29 kg/m^2 STANDARD_DEVIATION 6.43 |
| Cancer Stage Stage 1 | 46 Participants | 22 Participants | 24 Participants |
| Cancer Stage Stage 2 | 154 Participants | 77 Participants | 77 Participants |
| Cancer Stage Stage 3 | 74 Participants | 40 Participants | 34 Participants |
| Cancer Stage Stage 4 | 5 Participants | 1 Participants | 4 Participants |
| Cancer Type Breast Cancer | 238 Participants | 119 Participants | 119 Participants |
| Cancer Type Lymphoma | 41 Participants | 21 Participants | 20 Participants |
| Education College Degree (Bachelors) | 68 Participants | 32 Participants | 36 Participants |
| Education Doctoral degree | 4 Participants | 3 Participants | 1 Participants |
| Education Grades 1-8 | 2 Participants | 0 Participants | 2 Participants |
| Education Grades 9-11 | 6 Participants | 3 Participants | 3 Participants |
| Education High School/GED | 44 Participants | 16 Participants | 28 Participants |
| Education Masters degree | 37 Participants | 16 Participants | 21 Participants |
| Education Some College/Assoicates | 76 Participants | 49 Participants | 27 Participants |
| Education Some post college | 13 Participants | 7 Participants | 6 Participants |
| Education Unknown | 19 Participants | 8 Participants | 11 Participants |
| Education Vocational/trading school | 10 Participants | 6 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 4 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 270 Participants | 136 Participants | 134 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Income $100,000-$150,000 | 20 Participants | 10 Participants | 10 Participants |
| Income $10,000-$20,000 | 26 Participants | 12 Participants | 14 Participants |
| Income $20,000-$35,000 | 31 Participants | 19 Participants | 12 Participants |
| Income $35,000-$50,000 | 27 Participants | 12 Participants | 15 Participants |
| Income $50,000-$75,000 | 57 Participants | 30 Participants | 27 Participants |
| Income $75,000-$100,000 | 27 Participants | 16 Participants | 11 Participants |
| Income Less than $10,000 | 17 Participants | 6 Participants | 11 Participants |
| Income More than $150,000 | 12 Participants | 5 Participants | 7 Participants |
| Income Unknown | 62 Participants | 30 Participants | 32 Participants |
| Job Status Disabled, unable to work | 14 Participants | 7 Participants | 7 Participants |
| Job Status Employed | 178 Participants | 95 Participants | 83 Participants |
| Job Status Homemaker | 14 Participants | 4 Participants | 10 Participants |
| Job Status Not currently working | 30 Participants | 14 Participants | 16 Participants |
| Job Status Other | 8 Participants | 3 Participants | 5 Participants |
| Job Status Retired | 29 Participants | 14 Participants | 15 Participants |
| Job Status Unknown | 6 Participants | 3 Participants | 3 Participants |
| Marital Status Living in a married like relationship | 12 Participants | 8 Participants | 4 Participants |
| Marital Status Married | 166 Participants | 84 Participants | 82 Participants |
| Marital Status Separated or Divorced | 48 Participants | 25 Participants | 23 Participants |
| Marital Status Single, Never Married | 38 Participants | 15 Participants | 23 Participants |
| Marital Status Unknown | 9 Participants | 5 Participants | 4 Participants |
| Marital Status Widowed | 6 Participants | 3 Participants | 3 Participants |
| Medicaid | 21 Participants | 11 Participants | 10 Participants |
| Medicare | 26 Participants | 10 Participants | 16 Participants |
| No Health Insurance | 7 Participants | 1 Participants | 6 Participants |
| Private Insurance | 233 Participants | 121 Participants | 112 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 38 Participants | 22 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 4 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 231 Participants | 116 Participants | 115 Participants |
| Sex: Female, Male Female | 256 Participants | 127 Participants | 129 Participants |
| Sex: Female, Male Male | 23 Participants | 13 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 139 | 1 / 140 |
| other Total, other adverse events | 0 / 139 | 0 / 140 |
| serious Total, serious adverse events | 17 / 139 | 18 / 140 |
Outcome results
Primary
Left Ventricular Ejection Fraction (LVEF)
24 month estimated values of clinical measurements obtained from Cardiac MRI left ventricular ejection fraction by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data.
Time frame: 24 months
Population: All those with baseline and 24 month cardiac MRI (multiple imputation utilized for missing data).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Atorvastatin | Left Ventricular Ejection Fraction (LVEF) | 58.1 percent ejected from LV per heartbeat | Standard Error 0.555 |
| Arm 2 - Placebo | Left Ventricular Ejection Fraction (LVEF) | 57.9 percent ejected from LV per heartbeat | Standard Error 0.56 |
Comparison: Linear models adjusting for baseline values and utilized multiple imputation for missing data.p-value: 0.84ANCOVA
Secondary
Controlled Oral Word Association (COWA)
24 month estimated values Controlled Oral Word Association (COWA) by group. Linear model adjusts for baseline value and group assignment. No missing imputation performed. The COWA uses the three letter set of C, F, and L to assess phonemic fluency. Individuals are given 1 min to name as many words as possible beginning with one of the letters. The procedure is then repeated for the remaining two letters. Ranges from 0 to the total number of correct words that begin with one of the letters in the set. There is no ceiling of a maximum score. Higher numbers reflect better verbal fluency.
Time frame: 24 months
Population: Those with data available at baseline and 24 months.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Atorvastatin | Controlled Oral Word Association (COWA) | 41.6 score on a scale | Standard Error 1.07 |
| Arm 2 - Placebo | Controlled Oral Word Association (COWA) | 44.7 score on a scale | Standard Error 1.06 |
Secondary
End Diastolic Volume
24 month estimated values of clinical measurements obtained from Cardiac MRI End Diastolic Volume by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data.
Time frame: 24 months
Population: All those with baseline and 24 month cardiac MRI (multiple imputation utilized for missing data).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Atorvastatin | End Diastolic Volume | 123 milliliters of blood | Standard Error 2.06 |
| Arm 2 - Placebo | End Diastolic Volume | 125 milliliters of blood | Standard Error 2.01 |
Secondary
End Systolic Volume
24 month estimated values of clinical measurements obtained from Cardiac MRI End Systolic Volume by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data.
Time frame: 24 months
Population: All those with baseline and 24 month cardiac MRI (multiple imputation utilized for missing data).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Atorvastatin | End Systolic Volume | 51.8 milliliters of blood | Standard Error 1.27 |
| Arm 2 - Placebo | End Systolic Volume | 52.9 milliliters of blood | Standard Error 1.25 |
Secondary
Hopkins Verbal Learning Test (HVLT) Total Recall
24 month estimated values Hopkins Verbal Learning test (HVLT) total recall by group. Linear model adjusts for baseline value and group assignment. No missing imputation performed. Ranges from 0 to 36 and higher numbers reflect better recall.
Time frame: 24 months
Population: Those with data available at baseline and 24 months.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Atorvastatin | Hopkins Verbal Learning Test (HVLT) Total Recall | 28.5 score on a scale | Standard Error 0.518 |
| Arm 2 - Placebo | Hopkins Verbal Learning Test (HVLT) Total Recall | 27.5 score on a scale | Standard Error 0.503 |
Secondary
Left Ventricular (LV) Mass
24 month estimated values of clinical measurements obtained from Cardiac MRI left ventricular mass by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data.
Time frame: 24 months
Population: All those with baseline and 24 month cardiac MRI (multiple imputation utilized for missing data).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Atorvastatin | Left Ventricular (LV) Mass | 88.4 gram per meter squared | Standard Error 1.68 |
| Arm 2 - Placebo | Left Ventricular (LV) Mass | 87.5 gram per meter squared | Standard Error 1.65 |
Secondary
Patient-reported Outcomes Measurement (PROMIS) Questionnaire - Applied Cognition - General Concerns - Short Form 4a
Patient reported quality of life outcomes obtained from patient-reported outcomes measurement (PROMIS) questionnaire - Applied Cognition - General Concerns - Short Form 4a . Scores range from 4-20 and then adjusted by t-scores ranging from 30.1-63.8. Higher scores reflect better cognition. Linear models include baseline assessment and group and multiple imputation was utilized.
Time frame: 24 months
Population: Those with baseline and 24 month assessment completed. Multiple imputation was utilized for missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Atorvastatin | Patient-reported Outcomes Measurement (PROMIS) Questionnaire - Applied Cognition - General Concerns - Short Form 4a | 45.57 t-score | Standard Error 1.1 |
| Arm 2 - Placebo | Patient-reported Outcomes Measurement (PROMIS) Questionnaire - Applied Cognition - General Concerns - Short Form 4a | 46.55 t-score | Standard Error 1.14 |
Secondary
Patient-reported Outcomes Measurement (PROMIS) Questionnaire - Fatigue Short Form 41
Patient reported quality of life outcomes obtained from patient-reported outcomes measurement (PROMIS) questionnaire - Fatigue Short Form 41. Scores range from 4-20 and then adjusted by t-scores ranging from 33.7-75.8. Higher scores reflect worse fatigue. Linear models include baseline assessment and group and multiple imputation was utilized.
Time frame: 24 months
Population: Those with baseline and 24 month assessment completed. Multiple imputation was utilized for missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Atorvastatin | Patient-reported Outcomes Measurement (PROMIS) Questionnaire - Fatigue Short Form 41 | 48.17 t-score | Standard Error 1.08 |
| Arm 2 - Placebo | Patient-reported Outcomes Measurement (PROMIS) Questionnaire - Fatigue Short Form 41 | 49.29 t-score | Standard Error 1.12 |
Secondary
Pulse Wave Velocity
24 month estimated values of clinical measurements obtained from Cardiac MRI pulse wave velocity by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data.
Time frame: 24 months
Population: All those with baseline and 24 month cardiac MRI (multiple imputation utilized for missing data).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Atorvastatin | Pulse Wave Velocity | 5.73 m/s | Standard Error 0.247 |
| Arm 2 - Placebo | Pulse Wave Velocity | 5.51 m/s | Standard Error 0.24 |
Secondary
Stroke Volume
24 month estimated values of clinical measurements obtained from Cardiac MRI Stroke Volume by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data.
Time frame: 24 months
Population: All those with baseline and 24 month cardiac MRI (multiple imputation utilized for missing data).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Atorvastatin | Stroke Volume | 71 milliliters per minute | Standard Error 1.58 |
| Arm 2 - Placebo | Stroke Volume | 72.2 milliliters per minute | Standard Error 1.5 |