Breast Cancer
Conditions
Keywords
stage IA breast cancer, stage IB breast cancer, stage II breast cancer, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, ductal breast carcinoma in situ
Brief summary
RATIONALE: It is not yet know whether higher per daily radiation therapy is equally as effective as standard per daily radiation therapy in treating breast cancer. PURPOSE: This randomized phase III trial studies how well an accelerated course of higher per daily radiation therapy with concomitant boost works compared to standard per daily radiation therapy with a sequential boost in treating patients with early-stage breast cancer that was removed by surgery.
Detailed description
OBJECTIVES: Primary * To determine whether an accelerated course of hypofractionated whole-breast irradiation (WBI) including a concomitant boost to the tumor bed in 15 fractions following lumpectomy will prove to be non-inferior in local control to a regimen of standard WBI with a sequential boost following lumpectomy for early-stage breast cancer patients. Secondary * To determine whether breast-related symptoms and cosmesis from accelerated WBI that is hypofractionated (in only 3 weeks) with a concomitant boost is non-inferior to standard WBI with sequential boost. * To determine whether the risk of late cardiac toxicity in patients with left-sided breast cancer treated with hypofractionation will be non-inferior to conventional fractionated radiation therapy (RT) based upon analysis of radiation dosimetry from CT-based treatment planning and normal tissue complication probability (NTCP) calculations. * To determine whether CT-based conformal methods intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) for WBI are feasible in a multi-institutional setting following lumpectomy in early-stage breast cancer patients and whether dose-volume analyses can be established to assess treatment adequacy and likelihood of toxicity. * To determine that cosmetic results and breast-related symptoms 3 years after hypofractionated breast radiation with concomitant boost will not be inferior to that obtained 3 years after WBI with sequential boost. * To determine whether future correlative studies can identify individual gene expressions and biological host factors associated with toxicity and/or local recurrence from standard and hypofractionated WBI. * If shown to be non-inferior, to then determine if accelerated course of hypofractionated WBI including a concomitant boost to the tumor bed in 15 fractions following lumpectomy will prove to be superior in local control to a regimen of standard WBI with a sequential boost following lumpectomy for early-stage breast cancer patients. * To determine whether treatment costs for hypofractionated WBI with concomitant boost are not higher than WBI with sequential boost. OUTLINE: This is a multicenter study. Patients are stratified according to age (\< 50 vs. ≥ 50 years), prior chemotherapy (yes vs. no), estrogen-receptor status (+ vs. -), and histology grade (1-2 vs. 3). Patients are randomized to 1 of 2 treatment arms. Treatment begins within 9 weeks of last surgery or chemotherapy delivery. After completion of study therapy, patients are followed at 1 month, at 6 months, and then yearly.
Interventions
RADIATIONStandard 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.
RADIATIONHypofractionated 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.
RADIATIONConcurrent 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.
RADIATIONSequential 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.
Sponsors
Radiation Therapy Oncology Group
National Cancer Institute (NCI)
NRG Oncology
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
1. Pathologically proven diagnosis of breast cancer resected by lumpectomy and whole breast irradiation with boost without regional nodal irradiation planned 2. The patient must be female 3. The patient must meet at least one of the three following criteria: * A. Pathological stage I, II Breast Cancer AND at least one of the following: * Age \< 50 years or * Positive axillary nodes or * Lymphovascular space invasion or * 2 or more close resection margins (\> 0 mm to ≤ 2 mm) or * 1 close resection margin and extensive intraductal component (EIC) \[Per College of American Pathologist (CAP) Recommendation\] or * Focally positive resection margins or * Non-hormone sensitive breast cancer (estrogen receptor (ER)- and progesterone receptor(PR)-negative) or * Grade III histology or * Oncotype recurrence score \> 25 or * B. Pathological stage 0 breast cancer with nuclear grade 3 ductal carcinoma in situ (DCIS) and patient age \<50 years or * C. Post-neoadjuvant pathological 0, I, II breast cancer resected by lumpectomy after neoadjuvant systemic therapy 4. Study entry must be within 50 days from whichever comes later: last surgery (breast or axilla) or last chemotherapy. The day of surgery is Day "0". 5. If multifocal breast cancer, then it must have been resected through a single lumpectomy incision with negative margins 6. Breast-conserving surgery with margins defined as follows: (also see 3.1.3 for eligibility) * Negative margins defined as no tumor at the resected specimen edge. * Close resection margins \> 0 mm to ≤ 2 mm. as follows: * One close resection margin and EIC (per College of American Pathologist (CAP) Recommendation) * 2 or more close resection margins. * A focally positive resection margin 7. For invasive breast cancer the axilla must be staged by one of the following: * Sentinel node biopsy alone, if sentinel node is negative, i.e. any of the following: * pN0: no regional lymph node metastasis identified histologically, * pN0(i-): pN0 and immunohistochemical (IHC) negative, or * pN0(i+): pN0 and IHc positive; * Sentinel node biopsy alone, OR followed by axillary node dissection per investigator discretion, for clinically node negative patients as described below: * microscopic sentinel node positive (pN1mic) * one or two sentinel nodes positive (pN1) without extracapsular extension * negative sentinel node biopsy after neoadjuvant chemotherapy * Axillary node dissection is required following sentinel node (SN) biopsy with a minimum total of 6 axillary nodes if any of the following exist: * for \> 2 positive SN * any positive SN biopsy after neoadjuvant chemotherapy * for clinically (by either imaging or examination) T3 disease * for extracapsular extension * Axillary dissection alone (with a minimum of 6 axillary nodes) 8. Age ≥ 18 9. CT-imaging of the ipsilateral breast within 28 days prior to study entry for the radiation treatment planning. Must be able to delineate on CT scan the extent of the target lumpectomy cavity for boost 10. Appropriate stage for protocol entry, including no clinical evidence for distant metastases, based upon the following minimum diagnostic workup: * History/physical examination, including breast exam (inspection and palpation of the breasts) and documentation of weight and Zubrod Performance Status of 0-2 within 28 days prior to study entry; * Right and left mammography within 90 days of diagnostic biopsy establishing diagnosis 11. Patients must have had ER analysis performed on the primary breast tumor prior to study entry according to current American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) Guideline Recommendations for hormone receptor testing. If negative for ER, assessment of PR must also be performed according to current ASCO/CAP Guideline Recommendations for hormone receptor testing (http://www.asco.org) 12. Complete blood count (CBC)/differential obtained within 14 days prior to study entry, with adequate bone marrow function defined as follows: * Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3 * Platelets ≥ 75,000 cells/mm3 * Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.) 13. Women of childbearing potential must have a negative urine or serum pregnancy test within 14 days of study entry 14. Women of childbearing potential must be non-pregnant and non-lactating and willing to use medically acceptable form of contraception during radiation therapy 15. Patient must provide study specific informed consent prior to study entry 16. Breast implants allowed
Exclusion criteria
1. American Joint Committee on Cancer (AJCC) pathologic T4, N2 or N3, M1 pathologic stages III or IV breast cancer 2. Treatment plan that includes regional node irradiation 3. Prior invasive non-breast malignancy (except non-melanomatous skin cancer, carcinoma in situ of the cervix) unless disease free for a minimum of 5 years prior to study entry 4. Prior invasive or in-situ carcinoma of the breast \[-prior lobular carcinoma in situ (LCIS) is eligible\] 5. Two or more breast cancers not resectable through a single lumpectomy incision 6. Bilateral breast cancer 7. DCIS only (without an invasive component) and age ≥ 50 years 8. DCIS nuclear grade 1 or 2 only (without an invasive component) and age \< 50 years 9. Invasive breast cancer and low risk for 5-year in breast recurrence after lumpectomy with negative margins that does not meet one of the eligibility factors in 3.1.3. 10. Unable to delineate on CT scan the extent of the target lumpectomy cavity for boost (Placement of surgical clips to assist in treatment planning of the boost is strongly recommended, see Section 6.4.2 for details) 11. Suspicious unresected microcalcification, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign 12. Non-epithelial breast malignancies such as sarcoma or lymphoma 13. Paget's disease of the nipple 14. Male breast cancer 15. Prior radiotherapy to the breast or prior radiation to the region of the ipsilateral breast that would result in overlap of radiation therapy fields 16. Intention to administer concurrent chemotherapy for current breast cancer. 17. Severe, active co-morbidity, defined as follows: * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months * Transmural myocardial infarction within the last 6 months * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; * Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration; * Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol * Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive 18. Pregnancy or women of childbearing potential who are sexually active and not willing/able to use medically acceptable forms of contraception 19. Active systemic lupus, erythematosus, or any history of scleroderma, dermatomyositis with active rash 20. Medical, psychiatric or other condition that would prevent the patient from receiving the protocol therapy or providing informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With In-breast Recurrence (Local Failure) | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Alive | 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 provided here. | 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. |
| Percentage of Participants Alive Without Disease | 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 provided here. | 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. |
| Percentage of Participants Alive Without Distant Disease | 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 provided here. | 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. |
| Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment | 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. | 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 |
| Change in Breast Cancer Treatment Outcome Scale (BCTOS) Cosmesis Subscale Score From Baseline to 3 Years | 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. |
| Percentage of Participants With a Physician-reported Cosmetic Score of Excellent or Good at 3 Years | 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. |
| Correlation Between Dose-volume Data and Both Adverse Events and Efficacy | From randomization to end of follow-up. | — |
| Translational Research of Single Nucleotide Polymorphisms (SNPs) in Transforming Growth Factor Beta 1 (TGFB1) and Ataxia-Telangiesctasia Mutated (ATM) Genes | From randomization to last follow-up. | — |
| Treatment Cost | From randomization to end of treatment. | — |
Countries
Canada, Hong Kong, Israel, Japan, Singapore, South Korea, Switzerland, United States
Contacts
PRINCIPAL_INVESTIGATORFrank A. Vicini, MD, FACR
St. Joseph Mercy Oakland
STUDY_CHAIRGary M. Freedman, MD
University of Pennsylvania
STUDY_CHAIRJulia R. White, MD
Ohio State University
STUDY_CHAIRDouglas W. Arthur, MD
Virginia Commonwealth University
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 1,124 |
| 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. | 1,138 |
| Total | 2,262 |
Baseline characteristics
| Characteristic | Whole Breast Irradiation + Sequential Boost | Hypofractionated Whole Breast Irradiation + Concurrent Boost | Total |
|---|---|---|---|
| Age, Continuous | 55 years | 55 years | 55 years |
| Age, Customized < 50 years | 403 Participants | 400 Participants | 803 Participants |
| Age, Customized ≥ 50 years | 721 Participants | 738 Participants | 1459 Participants |
| Axillary Staging Method Axillary dissection alone (with a minimum 6 axillary nodes) | 30 Participants | 22 Participants | 52 Participants |
| Axillary Staging Method None: non-invasive breast cancer | 15 Participants | 8 Participants | 23 Participants |
| Axillary Staging Method Sentinel node biopsy alone | 883 Participants | 934 Participants | 1817 Participants |
| Axillary Staging Method Sentinel node biopsy alone or followed by axillary node dissection | 183 Participants | 163 Participants | 346 Participants |
| Axillary Staging Method Sentinel node biopsy followed by axillary dissection/minimum 6 axillary nodes | 13 Participants | 11 Participants | 24 Participants |
| Estrogen receptor (ER) Status Negative | 335 Participants | 350 Participants | 685 Participants |
| Estrogen receptor (ER) Status Positive | 789 Participants | 788 Participants | 1577 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 57 Participants | 72 Participants | 129 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1046 Participants | 1051 Participants | 2097 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 21 Participants | 15 Participants | 36 Participants |
| Histologic Grade 1-2 | 535 Participants | 545 Participants | 1080 Participants |
| Histologic Grade 3 | 589 Participants | 593 Participants | 1182 Participants |
| Oncotype recurrence score > 25 No | 1030 Participants | 1014 Participants | 2044 Participants |
| Oncotype recurrence score > 25 Yes | 94 Participants | 124 Participants | 218 Participants |
| Pathologic Stage Stage 0 (Tis, N0, M0) | 36 Participants | 34 Participants | 70 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 | 0 Participants | 2 Participants |
| Pathologic Stage Stage II (T0/T1/T1mi, N1, M0 or T2, N0, M0 or T2, N1, M0 or T3, N0, M0) | 399 Participants | 376 Participants | 775 Participants |
| Pathologic Stage Stage I (T1/T1mi, N0, M0 or T0/T1/T1mi, N1mi, M0) | 683 Participants | 727 Participants | 1410 Participants |
| Pathologic Stage Stage IV (Any T, Any N, M1) | 4 Participants | 1 Participants | 5 Participants |
| Pathologic stage 0 breast cancer wtih nuclear grade 3 DCIS and patient age <50 years No | 1092 Participants | 1107 Participants | 2199 Participants |
| Pathologic stage 0 breast cancer wtih nuclear grade 3 DCIS and patient age <50 years Yes | 32 Participants | 31 Participants | 63 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 8 Participants | 8 Participants | 16 Participants |
| Race (NIH/OMB) Asian | 65 Participants | 62 Participants | 127 Participants |
| Race (NIH/OMB) Black or African American | 135 Participants | 131 Participants | 266 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 7 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 24 Participants | 19 Participants | 43 Participants |
| Race (NIH/OMB) White | 887 Participants | 909 Participants | 1796 Participants |
| Radiation Therapy Technique (plan at randomization) 3D-CRT | 887 Participants | 888 Participants | 1775 Participants |
| Radiation Therapy Technique (plan at randomization) IMRT | 237 Participants | 250 Participants | 487 Participants |
| Received Chemotherapy No | 446 Participants | 441 Participants | 887 Participants |
| Received Chemotherapy Yes | 678 Participants | 697 Participants | 1375 Participants |
| Resection Margin Status Close resection margins (>0mm to ≤2mm / Focally positive resection margin) | 182 Participants | 196 Participants | 378 Participants |
| Resection Margin Status Negative margins (no tumor at the resected specimen edge) | 942 Participants | 942 Participants | 1884 Participants |
| Sex: Female, Male Female | 1124 Participants | 1138 Participants | 2262 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Zubrod Performance Status 0 | 896 Participants | 943 Participants | 1839 Participants |
| Zubrod Performance Status 1 | 222 Participants | 190 Participants | 412 Participants |
| Zubrod Performance Status 2 | 6 Participants | 5 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 87 / 1,124 | 86 / 1,138 |
| other Total, other adverse events | 866 / 1,100 | 910 / 1,123 |
| serious Total, serious adverse events | 18 / 1,100 | 20 / 1,123 |
Outcome results
Primary
Percentage of Participants With In-breast Recurrence (Local Failure)
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.
Time frame: 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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Whole Breast Irradiation + Sequential Boost (Arm 1) | Percentage of Participants With In-breast Recurrence (Local Failure) | 2.0 percentage of participants |
| Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) | Percentage of Participants With In-breast Recurrence (Local Failure) | 1.9 percentage of participants |
Comparison: Assuming Arm 1 5-year IBR of 1.59%, for hypothesized upper bound hazard ratio (HR) of 2.12 (Arm 2 5-year IBR of 3.33%), 46 IBR events provide \>80% power to conclude non-inferiority with one-sided significance level = 0.05. Null hypothesis: HR ≥ 2.12 (inferior). Alternative hypothesis: HR \< 2.12 (non-inferior). See Limitations and Caveats section.p-value: 0.03990% CI: [0.84, 2.05]Regression, Cox
Secondary
Change in Breast Cancer Treatment Outcome Scale (BCTOS) Cosmesis Subscale Score From Baseline to 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.
Time frame: Baseline and 3 years
Population: Quality of life population, with data at baseline and 3 years.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whole Breast Irradiation + Sequential Boost (Arm 1) | Change in Breast Cancer Treatment Outcome Scale (BCTOS) Cosmesis Subscale Score From Baseline to 3 Years | 0.16 score on a scale |
| Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) | Change in Breast Cancer Treatment Outcome Scale (BCTOS) Cosmesis Subscale Score From Baseline to 3 Years | 0.18 score on a scale |
p-value: <0.000195% CI: [-0.08, 0.13]t-test, 1 sided
Secondary
Correlation Between Dose-volume Data and Both Adverse Events and Efficacy
Time frame: From randomization to end of follow-up.
Secondary
Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment
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
Time frame: 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.
Population: Adverse event population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Whole Breast Irradiation + Sequential Boost (Arm 1) | Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment | Grade 2 | 379 Participants |
| Whole Breast Irradiation + Sequential Boost (Arm 1) | Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment | Grade 4 | 2 Participants |
| Whole Breast Irradiation + Sequential Boost (Arm 1) | Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment | Grade 3 | 34 Participants |
| Whole Breast Irradiation + Sequential Boost (Arm 1) | Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment | Grade 5 | 0 Participants |
| Whole Breast Irradiation + Sequential Boost (Arm 1) | Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment | Grade 1 | 427 Participants |
| Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) | Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment | Grade 5 | 0 Participants |
| Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) | Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment | Grade 1 | 554 Participants |
| Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) | Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment | Grade 2 | 290 Participants |
| Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) | Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment | Grade 3 | 35 Participants |
| Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) | Number of Participants by Highest Grade Adverse Event Reported as Definitely, Probably, or Possibly Related to Protocol Treatment | Grade 4 | 4 Participants |
Secondary
Percentage of Participants Alive
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.
Time frame: 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 provided here.
Population: Eligible population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Whole Breast Irradiation + Sequential Boost (Arm 1) | Percentage of Participants Alive | 95.7 percentage of participants |
| Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) | Percentage of Participants Alive | 95.1 percentage of participants |
p-value: 0.96Log Rank
Secondary
Percentage of Participants Alive Without Disease
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.
Time frame: 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 provided here.
Population: Eligible population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Whole Breast Irradiation + Sequential Boost (Arm 1) | Percentage of Participants Alive Without Disease | 90.2 percentage of participants |
| Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) | Percentage of Participants Alive Without Disease | 88.5 percentage of participants |
p-value: 0.14Log Rank
Secondary
Percentage of Participants Alive Without Distant Disease
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.
Time frame: 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 provided here.
Population: Eligible population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Whole Breast Irradiation + Sequential Boost (Arm 1) | Percentage of Participants Alive Without Distant Disease | 91.5 percentage of participants |
| Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) | Percentage of Participants Alive Without Distant Disease | 90.2 percentage of participants |
p-value: 0.34Log Rank
Secondary
Percentage of Participants With a Physician-reported Cosmetic Score of Excellent or Good 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.
Time frame: 3 years
Population: Quality of life population, with data at 3 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Whole Breast Irradiation + Sequential Boost (Arm 1) | Percentage of Participants With a Physician-reported Cosmetic Score of Excellent or Good at 3 Years | 86 percentage of participants |
| Hypofractionated Whole Breast Irradiation + Concurrent Boost (Arm 2) | Percentage of Participants With a Physician-reported Cosmetic Score of Excellent or Good at 3 Years | 82 percentage of participants |
Secondary
Translational Research of Single Nucleotide Polymorphisms (SNPs) in Transforming Growth Factor Beta 1 (TGFB1) and Ataxia-Telangiesctasia Mutated (ATM) Genes
Time frame: 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.
Secondary
Treatment Cost
Time frame: From randomization to end of treatment.