Breast Cancer
Conditions
Brief summary
This is a randomized controlled trial to determine the safety of 15 fraction vs 25 fraction pencil beam scanning proton radiotherapy after mastectomy in patients requiring regional nodal irradiation. Proton therapy is recognized as a standard option for the delivery of radiotherapy for breast cancer.
Interventions
RADIATIONHypofractionation
40 Gy (RBE) in 15 daily fractions
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years * Histologic confirmation of breast cancer resected by mastectomy with or without immediate reconstruction and chest wall and regional nodal irradiation planned. * pStage T1-T4N0-N3M0 or ypStage T0-4N0-N3M0 Note: The axilla must be staged by sentinel node biopsy alone, sentinel node biopsy followed by axillary node dissection, or axillary lymph node dissection alone * ECOG Performance Status (PS) 0 to 2. (Appendix I). * Negative pregnancy test done ≤7 days prior to registration, for women of childbearing potential only. * Radiotherapy must begin within 12 weeks of last surgery (breast or axilla) or last chemotherapy. Note: Breast implants and expanders allowed * Able to and provides IRB approved study specific written informed consent * Ability to complete questionnaire (s) by themselves or with assistance * Able to complete all mandatory tests listed in section 4.0 * Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study) * Willing to provide tissue and blood samples for correlative research purposes. * Rochester and Arizona patients: Willing to sign consent onto the Mayo Clinic Radiotherapy Patient Outcomes Registry and Biobanking study, IRB number 15-000136 * Rochester patients: Willing to sign consent onto Evaluation of cardiac function in patients undergoing proton beam or photon radiotherapy, IRB number 15-007443
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 or women of childbearing potential who are sexually active and not willing/able to use medically acceptable forms of contraception * Prior receipt of ipsilateral breast or chest wall radiation that would result in significant overlap of radiation therapy fields. Prior contralateral radiotherapy for breast cancer is allowed. * Positive margins after definitive surgery * 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 * Inflammatory breast cancer * Recurrent Breast Cancer * Boosts to the chest wall after mastectomy. Nodal boosts are allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complication Rate | 24 months | Will be defined as the percentage of women randomized who develop one or more of the following events: grade 3 or higher late adverse events; unplanned surgical intervention (not including planned serial fat grafting) in patients who undergo mastectomy with reconstruction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Late Adverse Events | 5 years | Late adverse events are defined using CTCAE version 4. Grade 1 or 2 events occurring in at least 10% of patients are reported along with all grade 3 or higher events. |
| Reconstruction Failure | 5 years | A failure is defined as loss of the tissue expander or implant with the inability to replace it resulting in no final reconstruction or conversion to autologous reconstruction or revised with the addition of autologous reconstruction. |
| Quality of Life - Breast Cancer Outcomes | 5 years | measured by cosmesis evaluation and the Breast Cancer Treatment Outcome Scale (BCTOS) |
| Cosmesis | baseline, 2 years, and 5 years | measured by reviewing digital photographs and the 4 point (excellent, good, fair, poor) adaptation of the Harvard Cosmesis Scale |
| Incidence of Acute Adverse Events | 5 years | Acute adverse events are defined using Common Terminology Criteria for Adverse Events (CTCAE) version 4. Grade 1 or 2 events occurring in at least 10% of patients are reported along with all grade 3 or higher events. |
| Distant Recurrence Incidence | 5 years | Will assess metastatic cancer that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer at 5 years. The percentage of patients with a distant recurrence is defined as the number of patients that have a distant recurrence divided by the number of patients treated in each arm. |
| Regional Recurrence Incidence | 5 years | Defined as invasive breast cancer in the axilla, regional lymph nodes, chest wall, and skin of the ipsilateral breast at 5 years. The percentage of patients with a regional recurrence is defined as the number of patients that have a regional recurrence divided by the number of patients treated in each arm. |
| Disease-free Survival (DFS) at 3 Years | 3 years post radiotherapy, up to 38 months | DFS is defined as the time from study registration until the occurrence, if any, of one of the following events: invasive IBTR, regional invasive breast cancer recurrence, distant breast cancer recurrence, death due to any cause, contralateral invasive breast cancer, and second primary non-breast invasive disease. DFS at 3 years will be reported as the percent of patients without a DFS event at 3 years post radiotherapy. |
| Overall Survival (OS) at 3 Years | 3 years post radiotherapy, up to 38 months | Overall survival is defined as the time from registration to death due to any cause. OS at 3 years is reported as the percentage of patients still alive and in follow up at 3 years post radiotherapy. |
| Ipsilateral Breast Tumor Recurrence (IBTR) Incidence | 5 years | Will be defined as local recurrence from trial registration as a first event at 5 years. The IBTR cumulative incidence will be estimated using a competing risks method by treatment arm. The competing risks will be regional/distant breast cancer recurrence and death. The percentage of patients with IBTR is defined as the number of patients that have a IBTR divided by the number of patients treated in each arm. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Conventional Fractionation 50.0 Gy (RBE) in 25 daily fractions | 41 |
| Hypofractionation 40 Gy (RBE) in 15 daily fractions\> Hypofractionation: 40 Gy (RBE) in 15 daily fractions | 41 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Hypofractionation | Total | Conventional Fractionation |
|---|---|---|---|
| Age, Continuous | 54 years | 52 years | 50 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 79 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 39 Participants | 79 Participants | 40 Participants |
| Sex: Female, Male Female | 41 Participants | 82 Participants | 41 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 44 | 2 / 44 |
| other Total, other adverse events | 41 / 44 | 41 / 44 |
| serious Total, serious adverse events | 2 / 44 | 3 / 44 |
Outcome results
Primary
Complication Rate
Will be defined as the percentage of women randomized who develop one or more of the following events: grade 3 or higher late adverse events; unplanned surgical intervention (not including planned serial fat grafting) in patients who undergo mastectomy with reconstruction.
Time frame: 24 months
Population: All treated patients were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conventional Fractionation | Complication Rate | 15 percentage of participants |
| Hypofractionation | Complication Rate | 20 percentage of participants |
Secondary
Cosmesis
measured by reviewing digital photographs and the 4 point (excellent, good, fair, poor) adaptation of the Harvard Cosmesis Scale
Time frame: baseline, 2 years, and 5 years
Secondary
Disease-free Survival (DFS) at 3 Years
DFS is defined as the time from study registration until the occurrence, if any, of one of the following events: invasive IBTR, regional invasive breast cancer recurrence, distant breast cancer recurrence, death due to any cause, contralateral invasive breast cancer, and second primary non-breast invasive disease. DFS at 3 years will be reported as the percent of patients without a DFS event at 3 years post radiotherapy.
Time frame: 3 years post radiotherapy, up to 38 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conventional Fractionation | Disease-free Survival (DFS) at 3 Years | 89.4 percentage of patients |
| Hypofractionation | Disease-free Survival (DFS) at 3 Years | 92.4 percentage of patients |
Secondary
Distant Recurrence Incidence
Will assess metastatic cancer that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer at 5 years. The percentage of patients with a distant recurrence is defined as the number of patients that have a distant recurrence divided by the number of patients treated in each arm.
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conventional Fractionation | Distant Recurrence Incidence | 10 percentage of patients |
| Hypofractionation | Distant Recurrence Incidence | 7 percentage of patients |
Secondary
Incidence of Acute Adverse Events
Acute adverse events are defined using Common Terminology Criteria for Adverse Events (CTCAE) version 4. Grade 1 or 2 events occurring in at least 10% of patients are reported along with all grade 3 or higher events.
Time frame: 5 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Conventional Fractionation | Incidence of Acute Adverse Events | Breast infection | 1 event occurrence |
| Conventional Fractionation | Incidence of Acute Adverse Events | Oedema of the limbs | 5 event occurrence |
| Conventional Fractionation | Incidence of Acute Adverse Events | Breast oedema | 9 event occurrence |
| Conventional Fractionation | Incidence of Acute Adverse Events | Radiation dermatitis | 39 event occurrence |
| Conventional Fractionation | Incidence of Acute Adverse Events | Oesophagitis | 5 event occurrence |
| Conventional Fractionation | Incidence of Acute Adverse Events | Stroke | 0 event occurrence |
| Conventional Fractionation | Incidence of Acute Adverse Events | Skin hyperpigmentation | 32 event occurrence |
| Conventional Fractionation | Incidence of Acute Adverse Events | Non-cardiac chest pain | 2 event occurrence |
| Conventional Fractionation | Incidence of Acute Adverse Events | Joint range of motion decreased | 11 event occurrence |
| Hypofractionation | Incidence of Acute Adverse Events | Non-cardiac chest pain | 2 event occurrence |
| Hypofractionation | Incidence of Acute Adverse Events | Joint range of motion decreased | 7 event occurrence |
| Hypofractionation | Incidence of Acute Adverse Events | Breast infection | 3 event occurrence |
| Hypofractionation | Incidence of Acute Adverse Events | Oesophagitis | 8 event occurrence |
| Hypofractionation | Incidence of Acute Adverse Events | Breast oedema | 4 event occurrence |
| Hypofractionation | Incidence of Acute Adverse Events | Skin hyperpigmentation | 21 event occurrence |
| Hypofractionation | Incidence of Acute Adverse Events | Oedema of the limbs | 2 event occurrence |
| Hypofractionation | Incidence of Acute Adverse Events | Radiation dermatitis | 40 event occurrence |
| Hypofractionation | Incidence of Acute Adverse Events | Stroke | 1 event occurrence |
Secondary
Incidence of Late Adverse Events
Late adverse events are defined using CTCAE version 4. Grade 1 or 2 events occurring in at least 10% of patients are reported along with all grade 3 or higher events.
Time frame: 5 years
Population: All patients that were evaluated for adverse events 90 or more days after radiotherapy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Conventional Fractionation | Incidence of Late Adverse Events | Breast oedema | 3 event occurrence |
| Conventional Fractionation | Incidence of Late Adverse Events | Radiation dermatitis | 3 event occurrence |
| Conventional Fractionation | Incidence of Late Adverse Events | Joint range of motion decreased | 11 event occurrence |
| Conventional Fractionation | Incidence of Late Adverse Events | Non-cardiac chest pain | 6 event occurrence |
| Conventional Fractionation | Incidence of Late Adverse Events | Skin hyperpigmentation | 19 event occurrence |
| Conventional Fractionation | Incidence of Late Adverse Events | Superficial soft tissue fibrosis | 5 event occurrence |
| Conventional Fractionation | Incidence of Late Adverse Events | Oedema of the limbs | 6 event occurrence |
| Conventional Fractionation | Incidence of Late Adverse Events | Fibrosis deep connective tissue | 10 event occurrence |
| Conventional Fractionation | Incidence of Late Adverse Events | Breast infection | 0 event occurrence |
| Hypofractionation | Incidence of Late Adverse Events | Fibrosis deep connective tissue | 7 event occurrence |
| Hypofractionation | Incidence of Late Adverse Events | Breast infection | 5 event occurrence |
| Hypofractionation | Incidence of Late Adverse Events | Breast oedema | 10 event occurrence |
| Hypofractionation | Incidence of Late Adverse Events | Skin hyperpigmentation | 22 event occurrence |
| Hypofractionation | Incidence of Late Adverse Events | Joint range of motion decreased | 12 event occurrence |
| Hypofractionation | Incidence of Late Adverse Events | Oedema of the limbs | 10 event occurrence |
| Hypofractionation | Incidence of Late Adverse Events | Radiation dermatitis | 6 event occurrence |
| Hypofractionation | Incidence of Late Adverse Events | Non-cardiac chest pain | 11 event occurrence |
| Hypofractionation | Incidence of Late Adverse Events | Superficial soft tissue fibrosis | 7 event occurrence |
Secondary
Ipsilateral Breast Tumor Recurrence (IBTR) Incidence
Will be defined as local recurrence from trial registration as a first event at 5 years. The IBTR cumulative incidence will be estimated using a competing risks method by treatment arm. The competing risks will be regional/distant breast cancer recurrence and death. The percentage of patients with IBTR is defined as the number of patients that have a IBTR divided by the number of patients treated in each arm.
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conventional Fractionation | Ipsilateral Breast Tumor Recurrence (IBTR) Incidence | 0 percentage of patients |
| Hypofractionation | Ipsilateral Breast Tumor Recurrence (IBTR) Incidence | 2 percentage of patients |
Secondary
Overall Survival (OS) at 3 Years
Overall survival is defined as the time from registration to death due to any cause. OS at 3 years is reported as the percentage of patients still alive and in follow up at 3 years post radiotherapy.
Time frame: 3 years post radiotherapy, up to 38 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conventional Fractionation | Overall Survival (OS) at 3 Years | 94.9 percentage of patients |
| Hypofractionation | Overall Survival (OS) at 3 Years | 95.1 percentage of patients |
Secondary
Quality of Life - Breast Cancer Outcomes
measured by cosmesis evaluation and the Breast Cancer Treatment Outcome Scale (BCTOS)
Time frame: 5 years
Secondary
Reconstruction Failure
A failure is defined as loss of the tissue expander or implant with the inability to replace it resulting in no final reconstruction or conversion to autologous reconstruction or revised with the addition of autologous reconstruction.
Time frame: 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Conventional Fractionation | Reconstruction Failure | 1 Participants |
| Hypofractionation | Reconstruction Failure | 5 Participants |
Secondary
Regional Recurrence Incidence
Defined as invasive breast cancer in the axilla, regional lymph nodes, chest wall, and skin of the ipsilateral breast at 5 years. The percentage of patients with a regional recurrence is defined as the number of patients that have a regional recurrence divided by the number of patients treated in each arm.
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conventional Fractionation | Regional Recurrence Incidence | 0 percentage of patients |
| Hypofractionation | Regional Recurrence Incidence | 2 percentage of patients |