Phase III Study of 5tx vs 15tx of RT (X-rays or Protons) Including RNI in Breast Cancer Patients

Study Overview
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Brief Summary
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This phase III trial investigates the rate of complications of x-ray therapy or proton beam radiation therapy over 5 treatments compared to 15 treatments or more after breast conserving surgery or mastectomy in treating patients with breast cancer. It is not yet known what level of complications x-ray therapy or proton beam radiation therapy have in treating patients with breast cancer when regional nodal irradiation is done

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the 24-month complication rate of 5 fraction radiotherapy compared to 15 or more fractions. SECONDARY OBJECTIVES: I. To evaluate acute toxicity that occur up to 180 days after radiation. II. To evaluate late toxicity that appear or persist 180 days after radiation. III. To estimate the 5-year locoregional control, invasive disease-free survival, disease-free survival, cause-specific survival and overall survival. CORRELATIVE AND EXPLORATORY OBJECTIVES: I. To evaluate patient-reported quality of life outcomes through Mayo Breast Survey, Mayo 10 (Patient-Reported Outcomes [PRO]-Common Terminology Criteria for Adverse Events [CTCAE]), and Mayo Patient Survey. 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 hypo-fractionated whole breast or post-mastectomy chest wall with regional nodal irradiation. V. To evaluated cosmetic outcome with patient-reported measures with elements from the Mayo Breast Patient Survey and panel assess cosmetic outcome with blinded photographs, and the Harvard/National Surgical Adjuvant Breast and Bowel Project (NSABP)/Radiation Therapy Oncology Group (RTOG) Cosmesis Scale. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Within 12 weeks of the last breast cancer surgery or last dose of adjuvant chemotherapy and no sooner than 14 days since the last chemotherapy, patients undergo x-ray therapy over 25 fractions in the absence of disease progression or unacceptable toxicity. Optionally, patients may then receive a 4-fraction boost of x-ray therapy. ARM II: Within 12 weeks of the last breast cancer surgery or last dose of adjuvant chemotherapy and no sooner than 14 days since the last chemotherapy, patients undergo proton beam radiation therapy over 5 fractions in the absence of disease progression or unacceptable toxicity. Optionally, patients may receive a concurrent 5-fraction boost of proton beam radiation therapy. After completion of study treatment, patients are followed up at 12 weeks, at 6, 12, 24, and 36 months, and then at 5 years.

Official Title
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A Phase III Trial of Hypofractionated Radiotherapy to the Whole Breast or Post-Mastectomy Chest Wall Including Regional Nodal Irradiation

Conditions
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Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage IA Breast Cancer AJCC v8, Anatomic Stage IB Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB Breast Cancer AJCC v8, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8

Intervention / Treatment
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* Radiation: Proton Beam Radiation Therapy
* Other: Questionnaire Administration
* Radiation: X-ray Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Histological confirmation of breast cancer Breast conserving surgery or mastectomy (reconstruction is allowed) Clinical or pathologic T1-T4c, N0-3, M0 disease 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 Indications for breast or post mastectomy radiation with regional nodal radiotherapy per the discretion of the treating physician If uncertain of eligibility please consult the principal investigator (PI) 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 or PI, 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 Persistent positive margins on ink after definitive surgery either for ductal carcinoma in situ (DCIS) or invasive cancer No active metastatic disease from other origin Recurrent breast cancer Patient requires bilateral breast radiation treatment cT4d patients (inflammatory breast cancer) Patients that may not be compliant or fit for the study at the discretion of the PI Male patients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I 5 treatments<br>5 tx of x-rays or protons | Other: Questionnaire Administration<br>* Ancillary studies<br>Radiation: X-ray Therapy<br>* Undergo x-ray therapy<br>* Other names: X-ray Radiation Therapy;|
| Experimental: Arm II 15 or more treatmetns<br>15 tx or more of x-rays or protons | Radiation: Proton Beam Radiation Therapy<br>* Undergo proton beam radiation therapy<br>* Other names: Radiation, Proton Beam;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complication rate | Will be defined as the percentage of women evaluable at 24 months who develop one or more of these events: grade 3 or higher late adverse event or unplanned surgeries for cosmetic or treatment related events, including surgeries to remove implant. The complication rate will be estimated using a binomial estimator in both experimental arm and control arm, and a one-sided 90% confidence interval of the difference will be computed with normal approximation. | At 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute adverse events | The maximum grade for each type of acute adverse event will be recorded for each patient. Data will be summarized as frequencies and relative frequencies by treatment arm. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Rates will be compared between arms using chi-squared tests. | Up to 90 days post-radiation therapy | 
| Incidence of late toxicity | Will be defined as any adverse event that occurred or persisted after the first 180 days post-radiation therapy and up to 5 years post-radiation therapy. The maximum grade for each type of late adverse event will be recorded for each patient. Data will be summarized as frequencies and relative frequencies by treatment arm. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Rates will be compared between arms using chi-squared tests. | Up to 5 years post-radiation therapy | 
| Locoregional control | 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. | Up to 5 years post-radiation therapy | 
| Invasive disease-free survival | Invasive disease recurrence is defined by ipsilateral breast tumor recurrence (IBTR), regional recurrence, or distant recurrence. Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Estimates will be given for specific time points along with 95% confidence intervals. Comparison between arms will employ a log-rank test. | From study registration until the time of invasive disease recurrence (not including ductal carcinoma in situ) or death due to any cause, assessed up to 5 years post-radiation therapy | 
| Disease-free survival | Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Estimates will be given for specific time points along with 95% confidence intervals. Comparison between arms will employ a log-rank test. | From study registration until the occurrence of IBTR, regional invasive breast cancer recurrence, distant breast cancer recurrence, or death due to any cause, assessed up to 5 years post-radiation therapy | 
| Cause-specific survival | Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Estimates will be given for specific time points along with 95% confidence intervals. Comparison between arms will employ a log-rank test. | From registration to death due to breast cancer, assessed up to 5 years post-radiation therapy | 
| Overall survival | Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Estimates will be given for specific time points along with 95% confidence intervals. Comparison between arms will employ a log-rank test. | From registration to death due to any cause, assessed up to 5 years post-radiation therapy |