Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage I Breast Cancer AJCC v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7, Stage II Breast Cancer AJCC v6 and v7, Stage IIIA Breast Cancer AJCC v7
Conditions
Brief summary
This randomized phase III trial studies how well hypofractionated radiation therapy works in preventing the return of tumor cells in breast cancer patients following surgery. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects.
Detailed description
PRIMARY OBJECTIVES: I. To determine the 24-month complication rate of 5 fraction whole radiotherapy +/- concurrent boost as compared to 15 fraction radiotherapy +/- sequential boost. SECONDARY OBJECTIVES: I. To evaluate acute and late toxicity. II. To estimate the 5-year locoregional control, invasive disease-free survival and overall survival. TERTIARY OBJECTIVES: I. To evaluate fatigue, and other patient-reported outcomes. II. To evaluate clinical features, treatment technique, dose-volume parameters, histologic and genetic variants associated with fair and poor cosmetic outcomes or unplanned surgical intervention. III. To evaluate the costs and comparative effectiveness of treatment. IV. Compare the use of photon therapy with spot scanning proton therapy in two different hypo-fractionated whole breast schemas. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Within 12 weeks of breast cancer surgery or adjuvant chemotherapy, patients undergo radiation therapy in 15 daily fractions for 10 days. ARM II: Within 12 weeks of breast cancer surgery or adjuvant chemotherapy, patients undergo hypofractionated radiation therapy in 5 daily fractions for 5 days. After completion of study treatment, patients are followed up to 5 years.
Interventions
RADIATIONHypofractionated Radiation Therapy
Undergo hypofractionated radiation therapy
OTHERQuality-of-Life Assessment
Ancillary studies
RADIATIONRadiation Therapy
hypofractionated radiation therapy
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological confirmation of breast cancer * Pathologic stage T0-T3N0-N1M0 * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2 * Able to and provides Institutional Review Board (IRB) approved study specific written informed consent * Study entry must be within 12 weeks of last surgery (breast or axilla) or last chemotherapy (if applicable) * Able to complete all mandatory tests * Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study) * Fair, good or excellent cosmesis, as determined by trained nurse assessment using the Harvard Cosmetic Scale * Radiotherapy must begin within 12 weeks of the last breast cancer surgery or the last dose of adjuvant chemotherapy * Breast conserving surgery and indications for whole breast radiotherapy
Exclusion criteria
* Medical contraindication to receipt of radiotherapy * Severe active co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements or providing informed consent * Active systemic lupus or scleroderma * Pregnancy * Prior receipt of ipsilateral breast or chest wall radiation * Positive margins on ink after definitive surgery either for ductal carcinoma in situ (DCIS) or invasive cancer * History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior study entry * Recurrent breast cancer * Indications for comprehensive regional nodal irradiation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complication Rate, Defined as the Percentage of Women Who Develop Grade 3 or Higher Late Adverse Event and/or Deterioration of Cosmesis From Excellent/Good to Fair/Poor or From Fair to Poor | 24 months | The complication rate will be reported by arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cause-specific Survival | 1 year | Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Estimates will be given for one year with 95% CIs. Comparison between arms will employ a log-rank test. |
| Overall Survival | 1 year | Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Estimates will be given for one year along with 95% CIs. Comparison between arms will employ a log-rank test. |
| Number of Patients Experiencing Distant Recurrence | 5 years | Distant recurrence defined as metastatic cancer that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer |
| Number of Patients Experiencing Acute (Grade 3+) Adverse Events (AEs) | 3 months | The maximum grade for each type of acute (grade 3+) AE will be recorded for each patient. Data will be summarized as frequencies and relative frequencies by treatment arm. The relationship of the adverse event(s) to the study treatment will be taken into consideration. Number of patients experiencing one or more grade 3+ events will be compared between arms using chi-squared tests. Adverse events were assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. |
| Percent of Patients With Locoregional Recurrence | 5 years | The cumulative incidence of locoregional recurrence will be estimated using a competing risks method by treatment arm. The competing risks will be distant breast cancer recurrence and death. Comparison between arms will employ Fine-Gray regression. Locoregional recurrence is clinically diagnosed invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast at 5 years. |
| Disease-Free Survival | 5 years | Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Median disease free survival time and standard error will be estimated. Comparison between arms will employ a log-rank test. |
| Number of Patients Experiencing Grade 3+ Late Adverse Events | 24 months | The maximum grade for each type of late AE will be recorded for each patient. Data will be summarized as frequencies and relative frequencies by treatment arm. The relationship of the adverse event(s) to the study treatment will be taken into consideration. Number of patients experiencing one or more grade 3+ late AEs will be compared between arms using chi-squared tests. |
| Invasive Disease-free | 5 years | Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Median invasive disease-free time will be given along with standard error. Comparison between arms will employ a log-rank test. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Patient Reported Outcomes/Quality of Life | Up to 5 years | The subscales of the Breast Cancer Treatment Outcomes Scale (BCTOS), elements from Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and other patient reported measures such as fatigue, breast pain, breast shape, and arm related morbidity outlined in the appendix will be summarized as the mean +/- standard deviation and median (minimum value, maximum value). Mixed models will be used to estimate changes at fixed time points. |
| Patient Self-reported Cosmesis | Baseline up to 5 years | Will evaluate fatigue, breast pain, arm function. The values of the cosmesis instruments (patient self-reported and panel-assessed) will be summarized with the frequencies and confidence intervals of fair or poor cosmesis events at baseline, 2 years, and 5 years by treatment arm. Comparisons between arms will employ chi-squared tests. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 (Radiation Therapy, 15 Fractions) Within 12 weeks of breast cancer surgery or adjuvant chemotherapy, patients undergo standard radiation therapy in 15 daily fractions for 10 days.
Quality-of-Life Assessment: Ancillary studies
Radiation Therapy: hypofractionated radiation therapy | 54 |
| Arm 2 (Hypofractionated Radiation Therapy, 5 Fractions) Within 12 weeks of breast cancer surgery or adjuvant chemotherapy, patients undergo hypofractionated radiation therapy in 15 daily fractions for 10 days.
Quality-of-Life Assessment: Ancillary studies
Hypofractionated Radiation Therapy: Undergo hypofractionated radiation therapy | 53 |
| Total | 107 |
Baseline characteristics
| Characteristic | Total | Arm 2 (Hypofractionated Radiation Therapy, 5 Fractions) | Arm 1 (Radiation Therapy, 15 Fractions) |
|---|---|---|---|
| Age, Continuous | 62.8 years STANDARD_DEVIATION 8.5 | 62.9 years STANDARD_DEVIATION 9.3 | 62.7 years STANDARD_DEVIATION 7.7 |
| Bilateral disease No | 106 Participants | 52 Participants | 54 Participants |
| Bilateral disease Yes | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 96 Participants | 48 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 2 Participants | 4 Participants |
| Multiple lesions No | 90 Participants | 41 Participants | 49 Participants |
| Multiple lesions Yes | 17 Participants | 12 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 99 Participants | 49 Participants | 50 Participants |
| Region of Enrollment United States | 107 participants | 53 participants | 54 participants |
| Sex: Female, Male Female | 107 Participants | 53 Participants | 54 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Study breast Left | 58 Participants | 30 Participants | 28 Participants |
| Study breast Right | 49 Participants | 23 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 54 | 0 / 53 |
| other Total, other adverse events | 50 / 54 | 51 / 53 |
| serious Total, serious adverse events | 0 / 54 | 0 / 53 |
Outcome results
Primary
Complication Rate, Defined as the Percentage of Women Who Develop Grade 3 or Higher Late Adverse Event and/or Deterioration of Cosmesis From Excellent/Good to Fair/Poor or From Fair to Poor
The complication rate will be reported by arm.
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 (Radiation Therapy, 15 Fractions) | Complication Rate, Defined as the Percentage of Women Who Develop Grade 3 or Higher Late Adverse Event and/or Deterioration of Cosmesis From Excellent/Good to Fair/Poor or From Fair to Poor | 2 Participants |
| Arm 2 (Hypofractionated Radiation Therapy, 5 Fractions) | Complication Rate, Defined as the Percentage of Women Who Develop Grade 3 or Higher Late Adverse Event and/or Deterioration of Cosmesis From Excellent/Good to Fair/Poor or From Fair to Poor | 3 Participants |
Secondary
Cause-specific Survival
Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Estimates will be given for one year with 95% CIs. Comparison between arms will employ a log-rank test.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 (Radiation Therapy, 15 Fractions) | Cause-specific Survival | 100 percentage of patients |
| Arm 2 (Hypofractionated Radiation Therapy, 5 Fractions) | Cause-specific Survival | 100 percentage of patients |
p-value: 1Log Rank
Secondary
Disease-Free Survival
Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Median disease free survival time and standard error will be estimated. Comparison between arms will employ a log-rank test.
Time frame: 5 years
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Arm 1 (Radiation Therapy, 15 Fractions) | Disease-Free Survival | 2.9569 years | Standard Error 0.0225 |
| Arm 2 (Hypofractionated Radiation Therapy, 5 Fractions) | Disease-Free Survival | 3.17 years | Standard Error 0.0282 |
p-value: 0.54Log Rank
Secondary
Invasive Disease-free
Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Median invasive disease-free time will be given along with standard error. Comparison between arms will employ a log-rank test.
Time frame: 5 years
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Arm 1 (Radiation Therapy, 15 Fractions) | Invasive Disease-free | 2.9569 years | Standard Error 0.0225 |
| Arm 2 (Hypofractionated Radiation Therapy, 5 Fractions) | Invasive Disease-free | 3.4743 years | Standard Error 0.0298 |
p-value: 0.97Log Rank
Secondary
Number of Patients Experiencing Acute (Grade 3+) Adverse Events (AEs)
The maximum grade for each type of acute (grade 3+) AE will be recorded for each patient. Data will be summarized as frequencies and relative frequencies by treatment arm. The relationship of the adverse event(s) to the study treatment will be taken into consideration. Number of patients experiencing one or more grade 3+ events will be compared between arms using chi-squared tests. Adverse events were assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 (Radiation Therapy, 15 Fractions) | Number of Patients Experiencing Acute (Grade 3+) Adverse Events (AEs) | 1 Participants |
| Arm 2 (Hypofractionated Radiation Therapy, 5 Fractions) | Number of Patients Experiencing Acute (Grade 3+) Adverse Events (AEs) | 0 Participants |
p-value: 0.32Chi-squared
Secondary
Number of Patients Experiencing Distant Recurrence
Distant recurrence defined as metastatic cancer that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer
Time frame: 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 (Radiation Therapy, 15 Fractions) | Number of Patients Experiencing Distant Recurrence | 0 Participants |
| Arm 2 (Hypofractionated Radiation Therapy, 5 Fractions) | Number of Patients Experiencing Distant Recurrence | 0 Participants |
Secondary
Number of Patients Experiencing Grade 3+ Late Adverse Events
The maximum grade for each type of late AE will be recorded for each patient. Data will be summarized as frequencies and relative frequencies by treatment arm. The relationship of the adverse event(s) to the study treatment will be taken into consideration. Number of patients experiencing one or more grade 3+ late AEs will be compared between arms using chi-squared tests.
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 (Radiation Therapy, 15 Fractions) | Number of Patients Experiencing Grade 3+ Late Adverse Events | 1 Participants |
| Arm 2 (Hypofractionated Radiation Therapy, 5 Fractions) | Number of Patients Experiencing Grade 3+ Late Adverse Events | 4 Participants |
p-value: 0.163Chi-squared
Secondary
Overall Survival
Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Estimates will be given for one year along with 95% CIs. Comparison between arms will employ a log-rank test.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 (Radiation Therapy, 15 Fractions) | Overall Survival | 100 percentage of patients |
| Arm 2 (Hypofractionated Radiation Therapy, 5 Fractions) | Overall Survival | 100 percentage of patients |
p-value: 1Log Rank
Secondary
Percent of Patients With Locoregional Recurrence
The cumulative incidence of locoregional recurrence will be estimated using a competing risks method by treatment arm. The competing risks will be distant breast cancer recurrence and death. Comparison between arms will employ Fine-Gray regression. Locoregional recurrence is clinically diagnosed invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast at 5 years.
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 (Radiation Therapy, 15 Fractions) | Percent of Patients With Locoregional Recurrence | 2.3 percentage of patients |
| Arm 2 (Hypofractionated Radiation Therapy, 5 Fractions) | Percent of Patients With Locoregional Recurrence | 5.8 percentage of patients |
p-value: 0.5Gray Test P-value
Other Pre-specified
Patient Reported Outcomes/Quality of Life
The subscales of the Breast Cancer Treatment Outcomes Scale (BCTOS), elements from Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and other patient reported measures such as fatigue, breast pain, breast shape, and arm related morbidity outlined in the appendix will be summarized as the mean +/- standard deviation and median (minimum value, maximum value). Mixed models will be used to estimate changes at fixed time points.
Time frame: Up to 5 years
Other Pre-specified
Patient Reported Outcomes/Quality of Life
The subscales of the Breast Cancer Treatment Outcomes Scale (BCTOS), elements from Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and other patient reported measures such as fatigue, breast pain, breast shape, and arm related morbidity outlined in the appendix will be summarized as the mean +/- standard deviation and median (minimum value, maximum value). Mixed models will be used to compare outcomes between arms.
Time frame: Up to 5 years
Other Pre-specified
Patient Self-reported Cosmesis
Will evaluate fatigue, breast pain, arm function. The values of the cosmesis instruments (patient self-reported and panel-assessed) will be summarized with the frequencies and confidence intervals of fair or poor cosmesis events at baseline, 2 years, and 5 years by treatment arm. Comparisons between arms will employ chi-squared tests.
Time frame: Baseline up to 5 years