Trial Outcomes & Findings for Higher Per Daily Treatment-Dose Radiation Therapy or Standard Per Daily Treatment Radiation Therapy in Treating Patients With Early-Stage Breast Cancer That Was Removed by Surgery (NCT NCT01349322)

Last Updated: 2025-10-24

Results Overview

In-breast recurrence (IBR) is defined as any of the following: invasive local recurrence-ipsilateral breast (within treatment field); invasive local recurrence-ipsilateral breast (outside treatment field); non-invasive local recurrence-ipsilateral breast (within treatment field); or non-invasive local recurrence-ipsilateral breast (outside treatment field). Time to IBR is defined as time from randomization to the date of first IBR, last known follow-up (censored), or death without IBR (competing risk). IBR rates are estimated using the cumulative incidence method, while treatment effect comparisons are based on cause-specific hazards. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. 5-year rates are provided.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

2354 participants

Primary outcome timeframe

From randomization to last follow-up. Evaluated weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. Five-year rates are reported here.

Results posted on

2025-10-24

Participant Flow

Participant milestones

Participant milestones
Measure	Whole Breast Irradiation + Sequential Boost Standard fractionation whole breast irradiation (WBI) with sequential boost. Standard fractionation whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Sequential boost: 6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.	Hypofractionated Whole Breast Irradiation + Concurrent Boost Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost Hypofractionated whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Concurrent boost: 15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.
Overall Study STARTED	1169	1185
Overall Study Eligible Population	1124	1138
Overall Study Adverse Event Population	1100	1123
Overall Study Quality of Life Population	429	449
Overall Study COMPLETED	1124	1138
Overall Study NOT COMPLETED	45	47

Reasons for withdrawal

Reasons for withdrawal
Measure	Whole Breast Irradiation + Sequential Boost Standard fractionation whole breast irradiation (WBI) with sequential boost. Standard fractionation whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Sequential boost: 6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.	Hypofractionated Whole Breast Irradiation + Concurrent Boost Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost Hypofractionated whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Concurrent boost: 15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.
Overall Study Protocol Violation	45	47

Baseline Characteristics

Higher Per Daily Treatment-Dose Radiation Therapy or Standard Per Daily Treatment Radiation Therapy in Treating Patients With Early-Stage Breast Cancer That Was Removed by Surgery

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Whole Breast Irradiation + Sequential Boost n=1124 Participants Standard fractionation whole breast irradiation (WBI) with sequential boost. Standard fractionation whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Sequential boost: 6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.	Hypofractionated Whole Breast Irradiation + Concurrent Boost n=1138 Participants Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost Hypofractionated whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Concurrent boost: 15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.	Total n=2262 Participants Total of all reporting groups
Age, Continuous	55 years n=5 Participants	55 years n=7 Participants	55 years n=5 Participants
Age, Customized < 50 years	403 Participants n=5 Participants	400 Participants n=7 Participants	803 Participants n=5 Participants
Age, Customized ≥ 50 years	721 Participants n=5 Participants	738 Participants n=7 Participants	1459 Participants n=5 Participants
Sex: Female, Male Female	1124 Participants n=5 Participants	1138 Participants n=7 Participants	2262 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	57 Participants n=5 Participants	72 Participants n=7 Participants	129 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1046 Participants n=5 Participants	1051 Participants n=7 Participants	2097 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	21 Participants n=5 Participants	15 Participants n=7 Participants	36 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	8 Participants n=5 Participants	8 Participants n=7 Participants	16 Participants n=5 Participants
Race (NIH/OMB) Asian	65 Participants n=5 Participants	62 Participants n=7 Participants	127 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) Black or African American	135 Participants n=5 Participants	131 Participants n=7 Participants	266 Participants n=5 Participants
Race (NIH/OMB) White	887 Participants n=5 Participants	909 Participants n=7 Participants	1796 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	24 Participants n=5 Participants	19 Participants n=7 Participants	43 Participants n=5 Participants
Zubrod Performance Status 0	896 Participants n=5 Participants	943 Participants n=7 Participants	1839 Participants n=5 Participants
Zubrod Performance Status 1	222 Participants n=5 Participants	190 Participants n=7 Participants	412 Participants n=5 Participants
Zubrod Performance Status 2	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Resection Margin Status Negative margins (no tumor at the resected specimen edge)	942 Participants n=5 Participants	942 Participants n=7 Participants	1884 Participants n=5 Participants
Resection Margin Status Close resection margins (>0mm to ≤2mm / Focally positive resection margin)	182 Participants n=5 Participants	196 Participants n=7 Participants	378 Participants n=5 Participants
Axillary Staging Method Sentinel node biopsy alone	883 Participants n=5 Participants	934 Participants n=7 Participants	1817 Participants n=5 Participants
Axillary Staging Method Sentinel node biopsy alone or followed by axillary node dissection	183 Participants n=5 Participants	163 Participants n=7 Participants	346 Participants n=5 Participants
Axillary Staging Method Sentinel node biopsy followed by axillary dissection/minimum 6 axillary nodes	13 Participants n=5 Participants	11 Participants n=7 Participants	24 Participants n=5 Participants
Axillary Staging Method Axillary dissection alone (with a minimum 6 axillary nodes)	30 Participants n=5 Participants	22 Participants n=7 Participants	52 Participants n=5 Participants
Axillary Staging Method None: non-invasive breast cancer	15 Participants n=5 Participants	8 Participants n=7 Participants	23 Participants n=5 Participants
Radiation Therapy Technique (plan at randomization) 3D-CRT	887 Participants n=5 Participants	888 Participants n=7 Participants	1775 Participants n=5 Participants
Radiation Therapy Technique (plan at randomization) IMRT	237 Participants n=5 Participants	250 Participants n=7 Participants	487 Participants n=5 Participants
Received Chemotherapy Yes	678 Participants n=5 Participants	697 Participants n=7 Participants	1375 Participants n=5 Participants
Received Chemotherapy No	446 Participants n=5 Participants	441 Participants n=7 Participants	887 Participants n=5 Participants
Estrogen receptor (ER) Status Negative	335 Participants n=5 Participants	350 Participants n=7 Participants	685 Participants n=5 Participants
Estrogen receptor (ER) Status Positive	789 Participants n=5 Participants	788 Participants n=7 Participants	1577 Participants n=5 Participants
Histologic Grade 1-2	535 Participants n=5 Participants	545 Participants n=7 Participants	1080 Participants n=5 Participants
Histologic Grade 3	589 Participants n=5 Participants	593 Participants n=7 Participants	1182 Participants n=5 Participants
Pathologic Stage Stage 0 (Tis, N0, M0)	36 Participants n=5 Participants	34 Participants n=7 Participants	70 Participants n=5 Participants
Pathologic Stage Stage I (T1/T1mi, N0, M0 or T0/T1/T1mi, N1mi, M0)	683 Participants n=5 Participants	727 Participants n=7 Participants	1410 Participants n=5 Participants
Pathologic Stage Stage II (T0/T1/T1mi, N1, M0 or T2, N0, M0 or T2, N1, M0 or T3, N0, M0)	399 Participants n=5 Participants	376 Participants n=7 Participants	775 Participants n=5 Participants
Pathologic Stage Stage III (T0/T1/T1mi/T2, N2, M0 or T3, N1/N2, M0 or T4, N0/N1/N2, M0 or Any T,N3,M0)	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Pathologic Stage Stage IV (Any T, Any N, M1)	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Oncotype recurrence score > 25 No	1030 Participants n=5 Participants	1014 Participants n=7 Participants	2044 Participants n=5 Participants
Oncotype recurrence score > 25 Yes	94 Participants n=5 Participants	124 Participants n=7 Participants	218 Participants n=5 Participants
Pathologic stage 0 breast cancer wtih nuclear grade 3 DCIS and patient age <50 years No	1092 Participants n=5 Participants	1107 Participants n=7 Participants	2199 Participants n=5 Participants
Pathologic stage 0 breast cancer wtih nuclear grade 3 DCIS and patient age <50 years Yes	32 Participants n=5 Participants	31 Participants n=7 Participants	63 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization to last follow-up. Evaluated weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. Five-year rates are reported here.

Population: Eligible population

Outcome measures

Outcome measures
Measure	Whole Breast Irradiation + Sequential Boost (Arm 1) n=1124 Participants Standard fractionation whole breast irradiation (WBI) with sequential boost. Standard fractionation whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Sequential boost: 6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.	Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) n=1138 Participants Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost Hypofractionated whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Concurrent boost: 15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.
Percentage of Participants With In-breast Recurrence (Local Failure)	2.0 percentage of participants Interval 1.4 to 2.9	1.9 percentage of participants Interval 1.3 to 2.7

SECONDARY outcome

Population: Eligible population

Failure is defined as death due to any cause. Failure time (overall survival time) is defined as the time from randomization to the date of death or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method and distributions between the two arms are compared using the log-rank test. Five-year rates are provided here.

Outcome measures

Outcome measures
Measure	Whole Breast Irradiation + Sequential Boost (Arm 1) n=1124 Participants Standard fractionation whole breast irradiation (WBI) with sequential boost. Standard fractionation whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Sequential boost: 6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.	Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) n=1138 Participants Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost Hypofractionated whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Concurrent boost: 15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.
Percentage of Participants Alive	95.7 percentage of participants Interval 94.4 to 96.9	95.1 percentage of participants Interval 93.8 to 96.4

SECONDARY outcome

Population: Eligible population

Disease-free survival (DFS) time is defined as time from randomization to local-regional disease recurrence, distant metastases, second/new primary, death due to any cause or last known follow-up (censored). DFS rates are estimated by the Kaplan-Meier method and distributions between the two arms are compared using the log-rank test. Five-year rates are provided here.

Outcome measures

Outcome measures
Measure	Whole Breast Irradiation + Sequential Boost (Arm 1) n=1124 Participants Standard fractionation whole breast irradiation (WBI) with sequential boost. Standard fractionation whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Sequential boost: 6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.	Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) n=1138 Participants Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost Hypofractionated whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Concurrent boost: 15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.
Percentage of Participants Alive Without Disease	90.2 percentage of participants Interval 88.5 to 92.0	88.5 percentage of participants Interval 86.7 to 90.4

SECONDARY outcome

Population: Eligible population

Distant disease-free survival (DDFS) time is defined as time from randomization to distant metastases, second/new primary, death due to any cause or last known follow-up (censored). DDFS rates are estimated by the Kaplan-Meier method and distributions between the two arms are compared using the log-rank test. Five-year rates are provided here.

Outcome measures

Outcome measures
Measure	Whole Breast Irradiation + Sequential Boost (Arm 1) n=1124 Participants Standard fractionation whole breast irradiation (WBI) with sequential boost. Standard fractionation whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Sequential boost: 6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.	Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) n=1138 Participants Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost Hypofractionated whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Concurrent boost: 15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.
Percentage of Participants Alive Without Distant Disease	91.5 percentage of participants Interval 89.9 to 93.2	90.2 percentage of participants Interval 88.4 to 91.9

SECONDARY outcome

Population: Adverse event population

Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data

Outcome measures

Outcome measures
Measure	Whole Breast Irradiation + Sequential Boost (Arm 1) n=1100 Participants Standard fractionation whole breast irradiation (WBI) with sequential boost. Standard fractionation whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Sequential boost: 6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.	Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) n=1123 Participants Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost Hypofractionated whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Concurrent boost: 15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.
Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment Grade 1	427 Participants	554 Participants
Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment Grade 2	379 Participants	290 Participants
Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment Grade 3	34 Participants	35 Participants
Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment Grade 4	2 Participants	4 Participants
Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment Grade 5	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline and 3 years

Population: Quality of life population, with data at baseline and 3 years.

The BCTOS cosmesis subscale score measures perceived aesthetic (e.g., breast shape) status . Patients rated each item using a four-point scale evaluating the differences between the treated and the untreated breast (1=no difference, 2=slight difference, 3=moderate difference, 4=large difference) with higher scores indicating a worse outcome. The score for each subscale is the mean of the ratings over all items belonging to that specific subscale. Change was calculated as the value at 3 years minus the value at baseline. A positive change reflects a decline at 3 years and a negative change reflects an improvement at 3 years.

Outcome measures

Outcome measures
Measure	Whole Breast Irradiation + Sequential Boost (Arm 1) n=254 Participants Standard fractionation whole breast irradiation (WBI) with sequential boost. Standard fractionation whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Sequential boost: 6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.	Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) n=274 Participants Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost Hypofractionated whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Concurrent boost: 15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.
Change in Breast Cancer Treatment Outcome Scale (BCTOS) Cosmesis Subscale Score From Baseline to 3 Years	0.16 score on a scale Interval 0.08 to 0.24	0.18 score on a scale Interval 0.11 to 0.25

SECONDARY outcome

Timeframe: 3 years

Population: Quality of life population, with data at 3 years.

Physicians rated cosmesis using a four point scale: * Excellent: When compared to the untreated breast or the original appearance of the breast, there is minimal/no difference in the size or shape of the treated breast. * Good: There is a slight difference in the size or shape of the treated breast as compared to the opposite breast or the original appearance of the treated breast. * Fair: Obvious differences in the size and shape of the treated breast. This change involves quarter or less of the breast. * Poor: Marked change in the appearance of the treated breast involving more than a quarter of the breast tissue.

Outcome measures

Outcome measures
Measure	Whole Breast Irradiation + Sequential Boost (Arm 1) n=199 Participants Standard fractionation whole breast irradiation (WBI) with sequential boost. Standard fractionation whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Sequential boost: 6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.	Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) n=216 Participants Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost Hypofractionated whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Concurrent boost: 15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.
Percentage of Participants With a Physician-reported Cosmetic Score of Excellent or Good at 3 Years	86 percentage of participants Interval 80.0 to 90.0	82 percentage of participants Interval 77.0 to 87.0

SECONDARY outcome

Timeframe: From randomization to end of follow-up.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From randomization to last follow-up.

Population: The protocol did not provide sufficient detail to meet current National Cancer Institute requirements for release of specimens from the NRG Oncology tissue bank for the protocol-specified analysis, therefore no assays were performed, and no data were collected for this outcome measure. Specimen use will require federal approval and funding separate from this trial.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From randomization to end of treatment.

Outcome measures

Outcome data not reported

Adverse Events

Whole Breast Irradiation + Sequential Boost

Serious events: 18 serious events

Other events: 866 other events

Deaths: 87 deaths

Hypofractionated Whole Breast Irradiation + Concurrent Boost

Serious events: 20 serious events

Other events: 910 other events

Deaths: 86 deaths

Serious adverse events

Other adverse events

Additional Information

Wendy Seiferheld

NRG Oncology

Phone: 215-574-3208

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.
Publication restrictions are in place

Restriction type: OTHER

Measure	Whole Breast Irradiation + Sequential Boost n=1100 participants at risk Standard fractionation whole breast irradiation (WBI) with sequential boost. Standard fractionation whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 25 fractions of 2.0 Gy for a total dose of 50.0 Gy or 16 fractions of 2.67 Gy for a total dose of 42.7 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Sequential boost: 6 fractions of 2.0 Gy per fraction for a total dose of 12 Gy or 7 fractions of 2.0 Gy for a total dose of 14 Gy to the lumpectomy cavity. May be given by either electron beam or photon beams using either 3D-CRT or IMRT. Begins without a treatment break after completion of the treatment to the entire breast.	Hypofractionated Whole Breast Irradiation + Concurrent Boost n=1123 participants at risk Hypofractionated whole breast (H-WBI) irradiation with a concurrent boost Hypofractionated whole breast irradiation: Target-based radiation using three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) to deliver 15 fractions of 2.67 Gy for a total dose of 40.0 Gy. Must begin within 9 weeks of last surgery or chemotherapy delivery. Concurrent boost: 15 fractions of 3.2 Gy for a total dose of 48 Gy to the lumpectomy cavity. Given concurrently with treatment to the entire breast. May be given by either electron beam or photon beams using either 3D-CRT or IMRT.
Gastrointestinal disorders Nausea	5.5% 60/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	5.0% 56/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
General disorders Fatigue	39.5% 435/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	38.0% 427/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
General disorders Localized edema	11.2% 123/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	10.3% 116/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
General disorders Pain	14.5% 160/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	12.8% 144/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Injury, poisoning and procedural complications Dermatitis radiation	36.3% 399/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	34.2% 384/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Musculoskeletal and connective tissue disorders Arthralgia	10.5% 116/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	11.0% 124/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Musculoskeletal and connective tissue disorders Fibrosis deep connective tissue	5.3% 58/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	6.1% 69/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Other, specify	6.1% 67/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	7.3% 82/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Musculoskeletal and connective tissue disorders Pain in extremity	6.3% 69/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	5.5% 62/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Musculoskeletal and connective tissue disorders Superficial soft tissue fibrosis	11.2% 123/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	9.3% 105/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Nervous system disorders Headache	4.0% 44/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	5.2% 58/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Nervous system disorders Peripheral sensory neuropathy	6.5% 72/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	7.6% 85/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Psychiatric disorders Depression	3.9% 43/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	5.1% 57/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Psychiatric disorders Insomnia	5.3% 58/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	6.9% 77/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Reproductive system and breast disorders Breast atrophy	5.7% 63/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	5.7% 64/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Reproductive system and breast disorders Breast pain	29.5% 325/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	28.5% 320/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Reproductive system and breast disorders Reproductive system and breast disorders - Other, specify	8.1% 89/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	9.7% 109/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Skin and subcutaneous tissue disorders Dry skin	4.5% 49/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	6.2% 70/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Skin and subcutaneous tissue disorders Erythema multiforme	7.5% 83/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	7.0% 79/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Skin and subcutaneous tissue disorders Pruritus	11.4% 125/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	7.7% 86/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - Other, specify	17.4% 191/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	15.3% 172/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	42.2% 464/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	40.8% 458/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Skin and subcutaneous tissue disorders Skin induration	8.4% 92/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	8.6% 97/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Vascular disorders Hot flashes	18.5% 204/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	16.9% 190/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Vascular disorders Hypertension	7.6% 84/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	6.0% 67/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.
Vascular disorders Lymphedema	7.2% 79/1100 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.	7.5% 84/1123 • Weekly during radiation therapy (RT), last day of RT, 1, 6, and 12 months after RT completion, then annually. Maximum follow-up at time of analysis was 10.1 years. All-cause mortality was assessed in the eligible population. Adverse events were assessed in the adverse event population.