Randomized Trial of Hypofractionated Whole Breast Irradiation Versus Conventionally Fractionated Whole Breast Irradiation for Ductal Carcinoma In Situ and Early Invasive Breast Cancer
Phase: PHASE2
Conditions: Ductal Breast Carcinoma In Situ, Invasive Breast Carcinoma, Stage I Breast Cancer AJCC v6, Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage II Breast Cancer AJCC v6 and v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7
Sponsor: M.D. Anderson Cancer Center

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Randomized Trial of Hypofractionated Whole Breast Irradiation Versus 
Conventionally Fractionated Whole Breast Irradiation for Ductal Carcinoma in Situ 
and Early Invasive Breast Cancer 
 
1.0 Background 
 
1.1 
Background and epidemiology 
Ductal carcinoma in situ (DCIS) is a premalignant disease of the breast that, if left untreated, carries a high propensity for 
transformation to invasive carcinoma. Approximately 68,000 women are diagnosed with ductal carcinoma in situ of the breast on a 
yearly basis in the United States.1 Current treatment for localized DCIS consists of either breast conserving surgery (BCS) alone, BCS 
followed by whole breast irradiation (BCS+WBI) or mastectomy.2 Approximately 70% of women with DCIS in the United States are 
treated with BCS. Of these, about half will be treated with radiation therapy following breast conserving surgery. 
Invasive breast cancer is the most common cancer diagnosed in women in the United States, with approximately 182,000 cases 
per year, and is the second most common cause of cancer death, with approximately 40,000 deaths per year.1 More than 100,000 
women per year in the United States are diagnosed with early invasive breast cancer, which herein is defined as pathologic stage T1-2 
N0-1. Accepted local-regional treatments for early invasive breast cancer consist of breast conserving surgery followed by WBI or 
mastectomy (typically without post-mastectomy radiation). Approximately 66% of women with early invasive breast cancer choose 
breast conserving surgery, and up to 90% will subsequently receive WBI.3,4 
 
1.2 
Radiation therapy for DCIS and early invasive breast cancer 
Four large, multi-center randomized clinical trials have demonstrated conclusively that BCS+WBI, as compared to BCS alone, 
lowers the subsequent risk of both invasive and in situ ipsilateral breast tumor recurrence (IBTR) for women with DCIS (Table 1).58 
Clinical trials and institutional series indicate that the risk of IBTR in patients with DCIS treated with BCS+WBI is approximately 1% per 
year.5-9 To date, all of the randomized studies to investigate the role of radiotherapy in the treatment of DCIS have used a conventional 
fractionation scheme which consists of 2 Gy delivered on a daily basis, five days per week, for approximately five weeks. Although not 
used in the randomized trials, many centers also routinely employ a five to eight fraction boost to the tumor bed for patients with  
DCIS.10  
For women with early invasive breast cancer, multiple randomized clinical trials and a large meta-analysis have demonstrated 
that BCS+WBI, as compared to BCS alone, lowers the relative risk of IBTR by approximately 60-70% and improves 15-year overall 
survival.11 The vast majority of the literature comparing BCS+WBI to BCS in early invasive breast cancer also used daily fractions of 2 
Gy or less to doses of approximately 45 – 50 Gy to the whole breast. A tumor bed boost of 10-16 Gy in 5 to 8 fractions is commonly 
utilized following CF-WBI based on 10-year results of a prospective randomized trial that included 5,318 patients and found that a tumor 
bed boost, when added to CF-WBI, significantly lowered the risk of IBTR.10 
Based on the randomized clinical trials, fractionation schemes characterized by a daily dose of 2 Gy or less, referred to herein as 
conventionally fractionated whole breast irradiation (CF-WBI), have represented the historical standard of care for radiation therapy to 
the whole breast in the United States for DCIS and early invasive breast cancer.12,13 Although CF-WBI has been demonstrated to be 
both safe and effective in the treatment of DCIS and early invasive breast cancer, it has certain shortcomings, principally the 
inconvenience to patients associated with receipt of daily treatment for up to seven weeks and the cost of treatment, both in terms of the 
actual health care expenditures and also costs to the patient and society due to time away from home and work.14 
 
1.3 
Hypofractionated whole breast irradiation (HF-WBI) for Early Invasive Breast Cancer 
Growing evidence from four recently published randomized clinical trials (Canadian,15-17 Royal Marsden Hospital/Gloucester 
Oncology Center (RMH/GOC),18,19 and Standardization of Breast Radiotherapy (START)  A and B,20,21) has demonstrated that 
hypofractionated whole breast irradiation (HF-WBI), in which the dose per fraction is increased while the total dose delivered to the 
breast is decreased, confers long-term toxicity, local control, and survival outcomes comparable to CF-WBI for early invasive breast 
cancer with up to 12 years median follow up (Table 2, Appendix D).15,17-21 At present, substantial controversy exists among radiation 
oncologists in the United States regarding the extent to which HF-WBI should be incorporated into routine clinical practice. For example, 
the American Society for Radiation Oncology (ASTRO) has recently completed an evidence-based guideline on fractionation for whole 
breast irradiation and concluded that the available evidence has demonstrated that HF-WBI has been proven equivalent to CF-WBI for 
patients who meet the following criteria: 50 years of age or older, disease stage pT1-2 pN0, not treated with chemotherapy, and treated 
with a radiation dose homogeneity within ±7% in the central axis plane.22 For patients not meeting these criteria, the authors of the 
ASTRO guideline refused to render a recommendation as to the appropriateness of HF-WBI due to substantial disagreements regarding 
interpretation of the published literature and wide variation in practice patterns among the authors. The ASTRO guideline specifically 
highlighted two areas of ongoing controversy regarding HF-WBI: 1) whether or not it is safe to add a tumor bed boost following HF-WBI, 
and 2) whether or not it is safe to use HF-WBI in patients receiving anthracycline- or taxane-based chemotherapy.22 The limited amount 
of data pertaining to use of HF-WBI in patients receiving a tumor bed boost and/or chemotherapy is a major obstacle to its widespread 
adoption in the United States, as approximately 85% of American radiation oncologists routinely use a tumor bed boost in their 
practice23 and chemotherapy is routinely used for patients with tumors greater than 1 cm or node-positive disease.24 
With regard to a tumor bed boost, none of the patients in the Canadian randomized trial received a tumor bed boost.17 Sixty-one 
percent of patients in the START A trial and 43% of those in the START B trial undergoing breast-conserving surgery received the 
optional tumor-bed boost of 10 Gy in 5 fractions.20,21 Entry into the START trials was stratified by intention to give a tumor-bed boost, but 
the outcomes for whether a boost was actually used have not yet been reported.20,21 The RMH/GOC trial included a substudy in which 
723 patients were randomized to receive no boost or a boost of 14 Gy in 7 fractions to the tumor bed.18,19 The rates of IBTR in relation to 
the use of a boost have not been reported. Patients allocated to receive a boost had a higher risk of breast induration and telangiectasia 
than those who received no boost, but there was no difference between these groups in breast appearance (assessed photographically 
by a blinded observer), proportion of fair or poor cosmetic results, or risks of breast shrinkage, breast distortion, breast edema, arm 
swelling, or shoulder stiffness. However, results were not further divided according to whether patients received HF-WBI or CF-WBI, so 

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it is not possible to determine whether one regimen was preferable when a boost was used. Further, the risk of a fair or poor cosmetic 
outcome in this trial was high (58-74% at 10 years), raising concern that the overall treatment plan did not result in optimal cosmesis, 
irrespective of assigned dose and use of a boost. One randomized trial including 1,024 women with invasive breast cancer 3 cm or 
smaller and negative surgical margins treated with HF-WBI (50 Gy in 20 fractions of 2.5 Gy) compared a tumor-bed boost of 10 Gy in 4 
fractions or no boost.25 With a median follow-up duration of 3.3 years, receipt of a tumor-bed boost was associated with a lower risk of 
IBTR, a higher risk of telangiectasia, and no difference in patient-reported cosmetic outcome. However, the relatively short length of 
follow-up in this trial precluded firm conclusions as to the long-term toxicity profile of a tumor-bed boost in patients receiving HF-WBI. In 
addition, the effective biologic dose of the HF-WBI regimen used in this trial was higher than that of the HF-WBI arms of the Canadian 
and START trials.15,16,21  
With regard to chemotherapy, anthracycline-containing and taxane-containing regimens were used in 25% and 1%, respectively, 
of patients in the START A trial and in 13% and 0.4%, respectively, of patients in the START B trial.20,21 The fraction of patients receiving 
anthracyclines or taxanes in the Canadian and RMH/GOC trials was not reported, although it is likely that anthracyclines and taxanes 
were used very infrequently during the era in which those trials were conducted.15,17-19  
Given the currently available data, the majority of experts comprising the ASTRO fractionation guideline task force reported that 
they routinely consider using HF-WBI in patients with early invasive breast cancer who have received chemotherapy or require a tumor 
bed boost, but a minority voiced concern that the currently published randomized data does not rule out an increased risk of normal 
tissue toxicity when HF-WBI is used sequentially with chemotherapy or a tumor bed boost. As a result, the ASTRO evidence-based 
guideline called for further investigation of HF-WBI for early invasive breast cancer in these two common clinical situations.  
With regard to other clinical and pathologic selection criteria for use of HF-WBI, risk of IBTR after breast-conserving surgery 
followed by adjuvant WBI decreases as age increases, and is particularly high for younger women ages 40 and under.26 The reasons for 
this discrepancy are not fully understood, but one possibility is that the sensitivity of breast cancer to radiation therapy may vary with 
age. Thus, it may be necessary to consider younger and older women as two distinct patient populations when evaluating the 
appropriateness of HF-WBI. Approximately 21% to 30% of patients enrolled in clinical trials comparing HF-WBI with CF-WBI were age 
50 years or younger at diagnosis.15-21 The effect of age on outcome has only been reported for the Canadian trial, which stratified entry 
by age (younger than 50 years versus 50 years or older).15,17 A preplanned analysis found that HF-WBI was equivalent to CF-WBI in 
both groups.15-17 However, the Canadian trial included only 305 women under 50, and no further division of results by age was 
performed within this group (e.g., age 40 years or younger versus age 41 to 49 years). Authors of the ASTRO whole breast fractionation 
guideline could not reach agreement on the appropriateness of HF-WBI for women under the age of 50 years; although the majority 
reported using HF-WBI for women under the age of 50 years, a minority felt that further data was needed.22 Given this lingering 
uncertainty, for our trial we plan to exclude the youngest patients with the highest risk of recurrence (those under the age of 40 years) 
but include patients ages 40 years and older. 
With regard to nodal status, radiation therapy to the supraclavicular fossa is generally indicated for patients with pathologic stage 
N2 or N3 breast cancer. Radiation therapy to the supraclavicular fossa is used on occasion for patients with N1 breast cancer who have 
additional risk factors for supraclavicular failure. To date, there is relatively little data regarding the safety of hypofractionated radiation 
to the supraclavicular fossa, and there is concern that such treatment could lead to a higher risk of late radiation-induced brachial 
plexopathy. However, for patients with N1 breast cancer for whom supraclavicular radiation is not planned, the ASTRO guideline 
indicates that “the majority of task force members thought that HF-WBI could be used”, although few patients with these characteristics 
were included in the randomized trials. Accordingly, we plan to study patients with N0 or N1 breast cancer who will be receiving whole 
breast radiation alone without addition of a third field to treat the supraclavicular lymph nodes. 
 
1.4 
HF-WBI for DCIS 
None of the prospective randomized trials comparing CF-WBI to HF-WBI included women with DCIS.15,17-21 To the best of our 
knowledge, only one phase II study has examined the efficacy and safety of HF-WBI in the treatment of DCIS.27 This study enrolled 59 
patients who have been followed for a median of 3 years and no ipsilateral breast tumor recurrences were reported. A total of 91% of 
patients experienced good or excellent cosmetic outcome based on physician report, but patient reported cosmetic outcomes were not 
included in this study.  
Theoretically, it is expected that the documented equivalence of HF-WBI to CF-WBI for invasive breast cancer should also 
extend to DCIS. Nevertheless, given the fact that patients with DCIS have been excluded from the randomized trials comparing CF-WBI 
to HF-WBI, many radiation oncologists continue to be reluctant to recommend HF-WBI for patients with DCIS and the ASTRO 
fractionation guideline concluded that “that data were insufficient to allow an evidence-based recommendation for or against HF-WBI for 
women with DCIS”.22  
 
1.5 
Cosmetic outcome of WBI 
In studying the side effect profile of WBI, a key outcome is the cosmetic result of the treated breast, which reflects not only the 
goal of breast conserving therapy (preservation of the breast with acceptable cosmesis) but also the extent to which normal tissue is 
damaged by radiation therapy. To date, however, none of the randomized trials to compare HF-WBI to CF-WBI have used a validated 
instrument to assess patient-reported cosmetic outcome.15,17-21 The Canadian trial assessed cosmetic outcome using photographic 
assessment evaluated by a trained research nurse who was not blinded to the randomization arm.15,17 In contrast, the START A and B 
trials did incorporate patient-reported cosmetic outcomes, but rather than developing a validated instrument these trials simply asked 
patients about overall change in breast appearance using a four-point scale.20,21 Another limitation of currently available randomized 
trials comparing HF-WBI to CF-WBI is that they were conducted in Canada and the United Kingdom, and it is not known whether 
cosmetic standards may differ between these countries and the United States.28  
To our knowledge, the best instrument available to assess patient-reported cosmetic outcome following BCS+WBI is the Breast 
Cancer Treatment Outcomes Scale (BCTOS), which was derived from a series of 185 women treated with BCS+WBI for DCIS or early 
invasive breast cancer.29 This questionnaire consists of 22 items from which internally consistent subscales regarding cosmetic 
outcome, functional status, and breast pain were developed (Appendix K). Each item is rated on a scale of 1 to 4, with 1 indicating no 
difference between the treated and untreated breast and area, 2 indicating slight difference between treated and untreated breast and 
area, 3 indicating moderate difference between treated and untreated breast and area, and 4 indicating large difference between treated 
and untreated breast and area. Each subscale is calculated by computing the arithmetic mean of the answers for each of the items 
relevant to the given subscale. Thus, the score for each subscale is a continuous variable ranging from 1 to 4. In the original publication, 
the mean BCTOS cosmetic score was 2.24 with a standard deviation of 0.77 and a range of 1 to 4. Currently the BCTOS is being used 
in the pivotal phase III intergroup trial comparing WBI to accelerated partial breast irradiation (NSABP B-39/RTOG 0413).  

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Physician-reported cosmetic outcomes have been historically reported as a single four-level variable in RTOG trials: excellent, 
good, fair, and poor.30 This scoring system derives from a scoring system developed at Harvard and is widely used in current literature  
(Appendix G).31 
1.6 Radiogenomic Predictors of Radiation Toxicity 
In the past decade, interest has grown in identifying genomic polymorphisms that correlate with risk of radiation toxicity, under 
the premise that certain genetic polymorphisms correlate with an individual’s baseline normal tissue radiosensitivity.32-36 If such 
polymorphisms can be reliably identified and rigorously validated, their presence could be determined prospectively in patients, thereby 
impacting the decision to offer radiation therapy or selection of an appropriate radiation dose, allowing treatment to be tailored to an 
individual patient’s genomic profile. To date, polymorphisms affecting DNA-repair pathways and the fibrotic response to tissue injury 
have been implicated as potentially associated with risk of radiation toxicity.32-42 However, many of these studies investigated multiple 
polymorphisms with multiple putative outcomes, and thus risk of a false positive result was high due to the problem of multiple 
comparisons. Accordingly, confirmatory studies are essential to establish any one putative polymorphism as clinically relevant. One 
such polymorphism that has been identified in early studies is the C-509T variant allele in the transforming growth factor-beta (TGF-b) 
gene, with a study in 167 breast cancer patients reporting a statistically significant three-fold increased risk of radiation-induced fibrosis 
among patients who were heterozygous or homozygous for the variant allele, in comparison to wild type patients. This study used the 
Subjective, Objective, Medical Management, Analytic (SOMA) scale to assess late radiation-induced fibrosis.43 Our collaborators in the 
Department of Epidemiology have already established their experience in measuring this allele and correlating its impact on risk of 
radiation pneumonitis in patients with lung cancer.44 
1.7 Rationale for Study Design 
Currently, both HF-WBI and CF-WBI are accepted treatment regimens used commonly in the community setting in North 
America and are endorsed by the ASTRO guideline on fractionation for whole breast irradiation. Nevertheless, there remains some 
uncertainty regarding whether there may be any clinically meaningful differences in these two standards of care, To gain further 
information regarding the safety and efficacy of HF-WBI in the treatment of DCIS and early invasive breast cancer, we plan to initiate a 
prospective randomized trial to compare HF-WBI to CF-WBI following conservative surgery for breast cancer. All patients will receive a  
tumor bed boost with a final dose dependant on final margin status. We will stratify patients according to chemotherapy (yes/no), 
margin status (< 2 mm vs > 2 mm), breast size (D cup or higher versus C cup or lower), post-lumpectomy/pre-radiation physician-
assessed cosmetic outcome, and treatment location (Houston area facilities vs. Banner MD Anderson vs MD Anderson Orlando). The 
primary objective of this study is to compare patient-reported cosmetic outcome at 3 years using the BCTOS for patients assigned to 
HF-WBI versus CF-WBI. Specifically, we will compare the 2 treatment arms with respect to the percent of women with adverse cosmetic 
scores at 3 years after completion of breast conserving surgery, as determined by the patient-reported BCTOS. A BCTOS cosmesis 
score of 2.5 or higher has been chosen a priori to indicate an adverse cosmetic outcome. Secondary aims will include comparing 
physicianassessed cosmetic outcome and risk of IBTR for patients treated with HF-WBI versus CF-WBI.  
This study will address current concerns in the United States regarding adoption of HF-WBI by including a validated 
patientreported cosmesis scale as the primary outcome measure and by including patients treated with a tumor bed boost with or 
without chemotherapy. In addition, investigating this question in women with DCIS will provide important data on the efficacy of HF-WBI 
in this sizeable patient cohort who were excluded from randomized trials of HF-WBI.  
If HF-WBI is shown to confer cosmetic and tumor control outcomes comparable to CF-WBI, such a finding could help to promote 
its adoption in the United States, leading to major public health benefits, as HF-WBI is both more convenient and less expensive than 
CF-WBI.14 In addition, improvements in the convenience of radiation therapy for DCIS could potentially increase utilization of radiation 
therapy following BCS for DCIS which is currently only approximately 50%.45 In contrast, if this study demonstrates unacceptable 
cosmetic outcomes of HF-WBI in this cohort in the United States, such a finding would provide important evidence to suggest that HF- 
WBI should be studied carefully and cautiously prior to widespread adoption of HF-WBI for both DCIS and invasive breast cancer in the 
United States. 
Thus, a study to evaluate patient-reported cosmetic outcomes for patients in the United States treated with HF-WBI followed by 
a tumor bed boost as compared to CF-WBI followed by a tumor bed boost should provide a meaningful addition to the literature that will 
help to guide radiation oncologists in the United States as they consider adopting HF-WBI.  
As a secondary aim, we will conduct an optional, translational study to determine whether the C-509T variant allele of TGF-b is 
associated with an increased risk of late radiation-induced fibrosis. This study will help to confirm or refute the putative association of 
this allele with radiation toxicity, thereby bringing this finding either closer to clinical application or providing evidence that it should not 
be further explored. 

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2.0 Objectives 
2.1 Primary 
2.1.1  
To compare patient-reported cosmetic outcome at 3 years using the BCTOS for patients assigned to HF-WBI versus 
CFWBI. Specifically, we will compare the 2 treatment arms with respect to the percent of women with adverse cosmetic scores at 3 
years after completion of breast conserving surgery, as determined by the patient-reported BCTOS. A score of 2.5 or more indicates 
an adverse cosmetic outcome. 
2.2 Secondary 
 
2.2.1  
To determine patient-reported cosmetic outcome using the BCTOS at 6 months, 1, 2, 4, and 5 years. 
2.2.2  
To determine physician-rated cosmetic outcome at 6 months, 1, 2, 3, 4, and 5 years using the Radiation Therapy and 
Oncology Group (RTOG) scale for physician assessment.30 Physician outcome will be determined using photographic assessment 
and scored by a panel of three attending physicians specializing in breast cancer who will be blinded to the patient randomization 
arm. 
2.2.3  
To determine the level of agreement between patient-rated cosmetic outcome and physician-rated cosmetic outcome at 
the various timepoints assessed.  

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2.2.4  
To determine the 5-year and risk of pathologically-confirmed invasive and/or in situ ipsilateral breast tumor recurrence 
(IBTR) for patients with DCIS and early invasive breast cancer. 
2.2.5  
To determine patient-reported functional status and breast pain using the BCTOS at 6 months, 1, 2, 3, 4, and 5 years 
after treatment. 
2.2.6  
To determine maximal acute (within 6 weeks of treatment) and late (more than 6 weeks after treatment) skin and soft 
tissue toxicities using the NCI CTCAE v4.0 scale. 
2.2.7  
To determine the relationship between the volume of breast tissue receiving excessive dose (defined as greater than 
105% of the prescription dose) and the risk of adverse cosmesis. 
 
2.2.8  
To determine the relationship between bra cup size and the risk of adverse cosmesis. 
2.2.9  
To determine whether there is a statistical interaction between breast volume and volume of tissue receiving greater 
than 105% of the prescription dose in predicting adverse cosmesis. 
2.2.10  
To determine in an exploratory analysis whether any other demographic, clinical, and pathologic factors correlate with 
risk of adverse cosmesis, quality of life, body image, image investment, and risk of IBTR. 
2.2.11  
To determine if the C-509T variant allele of TGF-b is associated with an increased risk of grade 2 or higher fibrosis (as 
determined by the SOMA scale) three years after completion of radiation. 
 
2.2.12  
To compare the cost of radiation for the two treatment arms. 
2.2.13 
To compare patient quality of life, body image, and appearance investment for the two treatment arms using the FACT-
B, Appearance Schemas Inventory-Revised (ASI-R), and Body Image Scale, respectively. 
2.2.14  To contribute additional blood samples to protocol LAB02-086 which is a case-control study investigating DNA repair 
phenotypes and genotypes in breast cancer. 
2.2.15 
To assess the psychometric profile of the FACT-B version 4 in collaboration with investigators from the Department of 
Medical Social Science, Northwestern University Feinberg School of Medicine. 
2.2.16  To determine the influence of oncoplastic lumpectomy on the following outcomes: 
physician and patient reported cosmetic outcomes, other patient reported health-realted quality of life outcomes, and  
photographic measurements of brease cosmetic outcome.  
3.0 Patient Eligibility 
3.1 Conditions for patient eligibility 
3.1.1  
Pathologically confirmed ductal carcinoma in situ of the breast or early invasive breast cancer defined as pathologic 
stage Tis, T1, or T2, N0, N1mic, or N1a  (pathologic staging of the axilla is required for all patients with invasive disease but is not 
required for patients with DCIS only).  (Upfront pathologic stage cannot be assigned to patients treated with neoadjuvant 
chemotherapy. For such patients, the criteria for pathologic stage shall be applied to the initial clinical stage). 
 
3.1.2  
Treatment with breast conserving surgery. 
3.1.3  
Final surgical margins must be negative, defined as no evidence for ductal carcinoma in situ or invasive breast 
cancer touching the inked surgical margin. If the invasive or in situ breast cancer approaches within less than 1 mm of the final 
surgical margin, then a re-excision is strongly encouraged. Lobular carcinoma in situ at the final surgical margin will be 
disregarded. 3.1.4  Age 40 years or older.  This age cutoff is justified because breast cancers in women under the age of 40 are 
known to have a significantly higher risk of IBTR presumably due to underlying biologic differences.10,22 
 
3.1.5  
Female sex. 
3.1.6 
Attending radiation oncologist declares intention to treat the whole breast only and that a third radiation field to treat 
regional lymph nodes is not planned (radiation of the undissected level I/II axilla with high tangents is allowed).  
3.1.7 
If the patient has a history of a prior non-breast cancer, all treatment for this cancer must have been completed prior to 
study registration and the patient must have no evidence of disease for this prior non-breast cancer. 
3.1.8 
Patients must be enrolled on the trial within 12 weeks of the later of two dates: the final breast conserving surgical 
procedure or administration of the last cycle of cytotoxic chemotherapy.  
 
3.2. 
Conditions for patient ineligibility 
 
3.2.1  
Pathologic or clinical evidence for a stage T3 or T4 breast cancer. 
3.2.2  
Pathologic evidence for involvement of 4 or more axillary lymph nodes, or imaging evidence of involvement of 
infraclavicular, supraclavicular, or internal mammary lymph nodes. 
 
3.2.3  
Clinical or pathologic evidence for distant metastases. 

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3.2.4  
Any prior diagnosis of invasive or ductal carcinoma in situ breast cancer in either breast. 
 
3.2.5  
Current diagnosis of bilateral breast cancer. 
3.2.6 
History of therapeutic irradiation to the breast, lower neck, mediastinum or other area in which there could potentially be 
overlap with the affected breast. 
 
3.2.7  
Patients not fluent in English or Spanish. (The BCTOS will be available in these two languages) 
 
3.2.8  
Patient is pregnant.  
4.0 Additional Pretreatment Information 
4.1   The treating physician must document his/her intent to use whole breast irradiation without addition of a third field to treat 
regional lymph nodes (use of high tangent fields to treat the level I/II axilla is allowed; use of an electron field matched to the 
tangents fields to ensure adequate coverage of the in breast tumor bed is also allowed). 
4.2   For patients with invasive cancer, the patient must have either completed chemotherapy, refused chemotherapy, or been 
evaluated by a medical oncologist who specified that chemotherapy was not recommended at this time. 
5.0 Registration Procedure 
5.1    
Patients will be registered by the research nurse in the Breast Radiation Oncology Clinic at the University of Texas MD 
Anderson Cancer Center or by the staff within the Clinical Research Support Center for patients enrolled through the Regional Care 
Centers.  
5.2  Authority will be delegated to an individual(s) at MD Anderson Orlando, MD Anderson Albuquerque, and Banner MD Anderson 
to register patients in CORe (or patients from these institutions may be registered in aCORe according to section 5.1 if requested by 
these institutions).  
6.0 Radiation Therapy 
6.1 Treatment/Dose Specifications 
 
6.1.1  
External beam radiation therapy will be used exclusively in this study. Brachytherapy is not allowed. 
6.1.2  
Radiation therapy must begin within 12 weeks of the later of these two dates: the date of final breast conserving surgery 
or the date of the last infusion of cytotoxic chemotherapy. 
6.1.3  
The prescription dose for patients assigned to the HF-WBI arm will be 42.56 Gy in 16 fractions delivered to the whole 
breast on consecutive treatment days. A treatment day is defined as a normal business day, typically Monday – Friday excluding 
institutional holidays. The prescription dose for the tumor bed boost for patients assigned to HF-WBI will be 10 Gy in 4 fractions 
delivered on consecutive treatment days for patients with negative margins (> 2 mm from DCIS or invasive carcinoma and closest 
inked surgical margin) and 12.5 Gy in 5 fractions delivered on consecutive treatment days for patients with close surgical margins (< 
2 mm from DCIS or invasive carcinoma and closest inked surgical margin). The boost will begin on the treatment day following 
completion of whole breast irradiation. 
6.1.4  
The prescription dose for patients assigned to the CF-WBI arm will be 50 Gy in 25 fractions delivered to the whole 
breast on consecutive treatment days. The prescription dose for the tumor bed boost for patients assigned to CF-WBI will be 10 Gy 
in 5 fractions delivered on consecutive treatment days for patients with negative margins (> 2 mm from DCIS or invasive carcinoma 
and closest inked surgical margin) and 14 Gy in 7 fractions delivered on consecutive treatment days for patients with close surgical 
margins (< 2 mm from DCIS or invasive carcinoma and closest inked surgical margin). The boost will begin on the treatment day 
following completion of whole breast irradiation. 
6.1.5 
In the event of severe acute toxicity during the course of radiotherapy (as determined by the treating physician), whole 
breast irradiation may be placed on hold for up to 3 treatment days and be replaced with the tumor bed boost to allow acute toxicity 
to subside. In this case, whole breast irradiation must resume upon discontinuation of the boost, and the total doses contributed 
from whole breast irradiation and the tumor bed boost will remain as stipulated in section 6.1.3 for patients in the HF-WBI arm and 
section 6.1.4 for patients in the CF-WBI arm. 
6.1.6 
The prescription points for whole breast irradiation and the tumor bed boost will be selected at the discretion of the 
treating radiation oncologist to balance target coverage versus dose homogeneity. 
 
6.1.7  
Inhomogeneity corrections will be used in dose calculations. 
6.2 Technical Factors 
 
6.2.1  
Radiation will be delivered using a linear accelerator with a nominal energy > 6 MV. 
6.2.2  
Three-dimensional dose compensation will be used when needed to minimize dose inhomogeneity throughout the target 
volume using multileaf collimators and/or wedges. 
6.2.3  
Prone positioning may be utilized to improve normal tissue sparing when thought to be indicated by the treating radiation 
oncologist. 
6.2.4 
Respiratory gating with the deep inspiration breath hold technique may be utilized to minimize exposure of the heart to 
radiation when thought to be indicated by the treating radiation oncologist. 

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6.3 Localization, Simulation, and Immobilization 
6.3.1  
The tumor bed will be located on the basis of the treatment planning computed tomography scan supplemented by 
preoperative imaging data when available. 
 
6.3.2  
Patients will undergo computed tomography-based simulation with an axial slice thickness no greater than 5 mm. 
6.3.3  
Patients will be immobilized using a breast board and vacuum-lock bag or other institution-specific immobilization 
techniques in standard use at the discretion of their treating physician. 
 
6.4  
Treatment Planning/Target Volumes 
6.4.1  
Whole breast irradiation will be planned and delivered with traditional tangent fields, with the superior border set at 
approximately the inferior margin of the ipsilateral clavicular head, the medial border set at midline on the skin between the two 
breasts, the inferior border set 1-2 cm below in inframammary fold, and the lateral border set at approximately the mid-axillary line to 
ensure all palpable breast tissue is included within the fields. The posterior (deep) border of the medial and lateral tangent borders 
will be aligned to ensure that neither tangent field diverges into critical structures. A cardiac block may be utilized by the treating 
physician if it does not compromise coverage of the whole breast. Every effort should be made to minimize cardiac exposure.  
6.4.2  
Treatment of the level I/II axillary lymph nodes with high tangent fields is allowed. In such cases, the level I/II axillary 
lymph nodes should be contoured using the treatment planning CT images to assist with field delineation. 
6.4.3  
The clinical target volume will be defined as the seroma cavity and tumor bed clips (when present) as visualized on the 
treatment planning computed tomography scan. The clinical target volume will be trimmed such that it does not approach within 5 
mm of the skin surface. 
6.4.4  
The tumor bed boost will be delivered with electrons or photons at the discretion of the treating radiation oncologist. The 
tumor bed boost will be delivered to the clinical target volume plus a radial margin of 1.5-2.0 cm at the discretion of the treating 
radiation oncologist. A second treatment planning computed tomography scan, with compression of the tumor bed or repositioning 
of the patient, may be obtained to assist in planning the tumor bed boost. 
6.4.5  
The treating physician should strive to minimize dose inhomogeneity within the breast. Any technique including the use 
of a wedge, three-dimensional dose compensation with a multi-left collimator, and/or intensity modulated radiation therapy is  
permitted.  In treating the whole breast, use of an electron field matched to the tangent fields is allowed if needed to ensure 
adequate coverage of the tumor bed in the whole breast. 
6.5 Critical Structures 
6.5.1  
With respect to the lung, no more than 3 cm of lung shall be included in the tangent field as measured from the rib-lung 
interface to the deepest aspect of the tangent field. 
6.5.2  
The heart shall be excluded or the cardiac volume minimized from the tangent fields. This can be achieved through use 
of a cardiac block, deep inspiration breath hold, or other geometric means.  
6.6 Compliance Criteria 
6.6.1  
Plans will be considered acceptable if they adhere to the field borders as described in 6.4.1 and the clinical target 
volume is completely encompassed within the geometric projection of the tangent fields. 
6.6.2  
The treating physician shall treat the patient with CF-WBI, regardless of randomization arm, if either of the following 
occur: (1) in the judgment of the treating physician, the heart cannot be excluded from the fields without compromising tumor 
coverage; or (2) > 1 cubic centimeter of breast tissue is expected to receive > 108% of the prescription dose despite all efforts to 
optimize homogeneity.  
 
6.6.3  
A treatment break of up to 3 treatment days is acceptable. A break of 4 or more days will be considered a variation.  
6.6.4  
If the patient receives less than 95% of the intended whole breast radiation dose this will be considered a minor 
violation. If the patient receives less than 90% of the intended whole breast radiation dose this will be a major violation. 
6.6.5  
If, at the time of treatment planning, the treating physician feels that delivery of a tumor bed boost may be unsafe due to 
the clinical size of the seroma cavity, then the tumor bed boost may be omitted at the discretion of the treating radiation oncologist. 
This will be considered a variation, and patients not receiving a boost will be reported separately in outcomes analyses. 
6.7 Radiation Therapy Quality Assurance Reviews 
All cases will be presented for peer review in accordance with the policy of the Department of Radiation Oncology at The 
University of Texas MD Anderson Cancer Center or participating institution. To improve radiation therapy quality assurance 
processes, we will collaborate with the MD Anderson Cancer Center Radiation Oncology Medical Physicists to develop and evaluate 
new treatment planning techniques, first in a retrospective manner by utilizing “test” cases of participants who have already 
completed radiation therapy. Participants enrolled on this trial (2010-0559) may have their radiation treatment plans/ images or other 
study-related information collected under the 2010-0559 protocol such as toxicities, oncologic history, demographics, etc reviewed 
retrospectively under MD Anderson IRB- approved protocols RCR03-400 and/ or PA16-0379. 

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6.8 Radiation Adverse Events 
Events that may occur include fatigue, skin erythema, dry or moist desquamation, hyperpigmentation, alopecia, tenderness, and 
swelling. Uncommon side effects include breast cellulitis or abscess and severe breast pain. In the long term, breast changes may 
occur including fibrosis, hyper- or hypo-pigmentation, telangiectasia, shrinkage/breast asymmetry, poor cosmesis, and edema. 
Uncommon side effects that may occur after completion of radiation include upper extremity lymphedema, rib fracture, pneumonitis, 
pulmonary fibrosis, pericarditis, ischemic heart disease, and heart failure. 
 
6.9  
Adverse Events and Serious Adverse Events Reporting Requirements 
We will follow institutional guidelines at the University of Texas M. D. Anderson Cancer Center. 
7.0 Drug Therapy 
Not applicable to this study. 
8.0 Surgery 
All patients in this study will undergo breast conserving surgery, either with or without “oncoplastic” techniques including reduction 
mammoplasty. Placement of radio-opaque clips to define the extent of the lumpectomy cavity is encouraged but not required. 
9.0 Other Therapy 
9.1 Permitted Supportive Therapy 
All supportive therapy indicated for optimal medical therapy during the course of radiation will be permitted for this study.  
Supportive therapy will be documented as concomitant medication. Supportive therapy may include, but is not limited to, the following: 
• Radiodermatitis creams or ointments 
• Topical steroids 
• Oral antipruritics 
• Oral analgesics to include non-narcotic and narcotic medications 
• Antibiotic therapy as indicated for breast infection 
• Nutritional supplementation 
10.0 Tissue/Specimen Submission 
10.1  
Blood procurement. One-time 4-cc blood samples will be drawn into heparinized green-top tubes for each of the eligible 
subjects who grant consent. Blood drawn at the Main Campus may be hand delivered to Dr. Liao's laboratory. Blood drawn at 
regional care centers will be sent via courier to the Diagnostic Center at the Main Campus, where it will or picked up by a Radiation 
Oncology Research staff and delivered to Dr. Liao's lab. Preprinted labels with study identification numbers will be placed on each 
blood tube. A transmittal slip (multiple-copy form) will accompany each blood sample, and a copy will be retained in the Study 
Coordinator’s office. All samples will be logged in TissueStation as per institutional requirements.  Blood drawn at participating 
institutions outside of the greater Houston area will be sent via overnight carrier to Tanisha Davis, RN Research Nurse, Division of 
Radiation Oncology, UT MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1210 Houston, TX 77030, Phone: 713-563-8698 
(Office). 
10.2  
The genotype of the C-509T, G915C, and T869C alleles of the TGF-b gene will be determined by Dr. Liao's laboratory 
using polymerase chain reaction restriction fragment length polymorphism assessment according to their previously published 
methods.44 
10.3  
The Molecular Diagnostic Laboratory (MDL) at MD Anderson will use the collected DNA samples to develop and 
optimize a new assay for the detection of the C－509T (rs1800469) variant allele of TGFB1 (GenBank NC_000019.10). Up to 120 
DNA samples will be required for evaluate performance characteristics determined by the MDL at MD Anderson Cancer Center. As 
this test will be used for clinical purposes, the MDL is certified under the Clinical Laboratory Improvement Act (CLIA) of 1988 to 
perform high complexity clinical laboratory testing. 
To accomplish this, a real-time polymerase chain reaction assay will be applied to DNA samples to genotype rrs1800469 (dbSNP) of the 
TGFB1 gene using the QuantStudio 7 Flex Fast Sequence Detection System (PE Applied Biosystems). M13-tagged primers will be 
designed to confirm ASO-PCR findings using traditional Sanger sequencing. Concordance between the two methods, reproducibility, and 
limit of detection will be tested and established. 
11.0 Patient Assessments 
 
11.1  
Study Parameters: 
See Appendix C. 
 
11.2  
Evaluation During Study:  
11.2.1  
Patients will undergo weekly evaluations during radiation therapy, history and physical exam approximately 6 months 
(+/2 months) after completing radiation therapy, and yearly (+/-3 months) history and physical exam for the 5 years following 
radiation therapy. Patients may be followed more frequently at the discretion of the treating radiation oncologist. After completing 
five years of follow up, patients will be off study and may be discharged to either the Institution’s Cancer Survivors Clinic or to their 
primary medical doctor.  
11.2.2  
 The schedule for surveillance mammography is as follows: at the six month follow up visit, at the one year follow up 
visit, and yearly thereafter while on study. However, the routine standard of care for mammographic follow up in the community in 
which the patient is treated is also acceptable. The routine standard of care in the community is typically mammographic follow up 

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approximately once per year. Skin thickness on post-treatment mammograms may also be measured as a surrogate for skin toxicity 
from radiation. 
11.2.3  
Abnormal findings on mammography or clinical exam will be further investigated with additional imaging modalities such 
as ultrasound. Findings that remain suspicious after additional imaging should be biopsied to determine the presence or absence of 
ipsilateral breast tumor recurrence. 
 
11.3  
Patient-Rated Evaluations 
11.3.1  
The Breast Cancer Treatment Outcomes Scale will be used to score cosmetic outcome from 1 to 4, with a score of 2.5 
or higher indicating adverse cosmetic outcome (Appendix K). 
11.3.2  
The Breast Cancer Treatment Outcomes Scale will also be used to assess the domains of functional status and breast 
pain on a scale of 1 to 4, with a score of 2.5 or higher indicating adverse outcome (Appendix K). 
11.3.3 
The FACT-B is a validated instrument used to assess quality of life for women with breast cancer and will be used to 
assess general quality of life and will be scored according to standard guidelines that accompany the instrument. 
11.3.4 
The Body Image Scale (BIS) is a validated instrument that will be used to assess body image and will be scored 
according to standard guidelines for this instrument. This is not required for Spanish-only speakers because the questionnaire is 
only available in English. 
11.3.5 
The Appearance Schemas Inventory-Revised (ASI-R) is a validated instrument to assess appearance investment and 
will be scored according to standard guidelines for this instrument. This is not required for Spanish-only speakers because the 
questionnaire is only available in English. 
11.3.6  
The BCTOS, FACT-B, BIS, and ASI-R will be administered within 14 days prior to start of radiation treatment and at the 
following timepoints measured from the date of completion of radiation therapy: 6 months (+/- 2 months), 1, 2, 3, 4, and 5 years (+/- 
3 months annually). These questionnaires may be mailed to non-returning patients by regular mail (with provision of a selfaddressed 
stamped envelope for return mail) or encrypted email. Patients may also be contacted by telephone. If the patient loses a breast 
during the follow up interval, the BCTOS will no longer be required. 
 
11.3.7 
Patients will be given the opportunity to watch an informational video about the protocol. 
 
11.4  
Physician-Rated Evaluations:  
11.4.1 
Baseline physician-rated cosmesis will be scored by the treating radiation oncologist within 14 days prior to start of 
radiation treatment using RTOG criteria. Patients will be stratified for randomization according to whether their treating physician 
rates their cosmetic outcome as excellent or good versus fair or poor (Appendix G). For documentation, photographs will be taken 
prior to radiation therapy as well. Photographs will be framed to include the low neck down to the upper abdomen and will be taken 
with arms at the side and patients will be asked to remove all jewelry prior to photography. Five views will be obtained: right lateral, 
right anterior oblique, anteroposterior, left anterior oblique, and left lateral. When possible, photographs will be obtained in the 
Department of Plastic Surgery three-dimensional photography suite, thereby enabling quantitation of breast size and position. All 
photographic data will be stored the Radiation Oncology Access to Data Systems (ROADS) (https://roads.mdanderson.org) 
database for this study. Access to the photos will be limited only to those study personnel with a need to view photos and will be 
logged using ROADs. Photographs may also be stored on a password-protected institutional drive with access limited only to those 
study personnel with a need to view and upload photographs. Photographs obtained in the three-dimensional photography suite will 
be de-identified through removing the patient’s head and, afterwards, such de-identified photographs may be securely transferred to 
the University of Texas at Austin where one of the study collaborators (Dr. Mia Markey) is located and/or to the University of 
Houston where another study collaborator (Dr. Fatima Merchant) is located. Dr. Markey’s lab and/or Dr. Merchant’s lab will be able 
to use sophisticated image processing algorithms to quantitate metrics related to breast size and position. This data will be stored in 
a secured database system supported by UT Austin Information Technology Services or the University of Houston Information 
Technology Services. Research personnel at UT Austin and University of Houston will undergo training on research with human 
participants and on the university's information technology security policies. All data sent to UT-Austin and University of Houston will 
be deidentified and coded by patient registration number only. 
11.4.2 
For follow up evaluations, photographs as described above will be obtained at 6 months (+/- 2 months), 1, 2, 3, 4, and 5 
years (+/- 3 months annually) from the date of completion of radiation therapy. A group of at least three attending physicians with 
expertise in breast cancer (physician specialty may include radiation oncology, surgical oncology, or plastic surgery), blinded to the 
randomization arm, will score the photographs using RTOG criteria and will attempt to reach consensus for each patient and 
timepoint. In the absence of consensus, scores from each physician will be averaged. A mean physician-reported cosmetic score 
higher than 2.5 will be considered excellent/good cosmesis and a score less than or equal to 2.5 will be considered fair/poor 
cosmesis. Patients not returning for a protocol-specific follow-up visit may have their photographs taken by their local physician or by 
a family member and sent to Dr. Smith.  Patients will be encouraged to return to their treating radiation oncologist for the 3-year 
follow-up visit as the primary objective is cosmesis at 3 years post treatment. If the patient loses the treated breast during the follow 
up interval, photographs will no longer be required. Selected, representative baseline and follow up photographs without identifying 
features (i.e. without tatooes or other identifying markings) may be included as representative images in the decision aid developed 
under protocol 2016-0878. 
11.4.3 
For completion of the Follow-Up Form (Appendix O), for patients not returning to their treating physician for a 
protocolspecific follow-up visit, the local physician may be requested to complete this form and return to research staff in a provided 
selfaddressed stamped return envelope. 
 
11.5  
Treatment planning parameters 
11.5.1 
The volume of breast tissue receiving excessive dose > 105% of the prescription dose will be determined using 
treatment planning software.  

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11.5.2 Breast volume will be determined using the total volume of irradiated tissue receiving at least 90% of the prescription dose.  
 
11.5.3  
The maximal point dose within the breast will also be recorded. 
 
11.5.4  
The volume of the clinical target volume in cubic centimeters will be recorded. 
 
11.5.5  
The separation at the central axis will be recorded. 
 
11.6 
Summary of all study forms and data collected 
 
11.6.1 
Acute Toxicity Form (Appendix H) 
Purpose – This form captures information regarding physician-reported toxicities that occur during radiation therapy treatment. The 
form should be filled out and signed weekly by the treating physician at the time of the weekly treatment visit. Toxicities are graded by 
number using the NCI CTCAE v4.0 scale as per the protocol. This form should also be used to document any toxicities that are 
documented during unscheduled follow up visits that occur within six weeks of completing radiation therapy. Any adverse events noted 
must also be reported to the IRB and Protocol Principal Investigator in accordance with Section 5.0 herein. This form is not for IRB 
submission, but for recording the toxicities in the research database. 
Timeline for completion – Filled out and signed by an attending physician at the time of each weekly treatment visit. The protocol does 
not require the patient to be evaluated by a physician within six (6) weeks of completing radiation. However, if such an encounter takes 
place, and the patient is experiencing any toxicity with a grade higher than documented at the last treatment visit, this form should be filled 
out and signed by the attending physician.  
 
11.6.2 
FACT-B v.4 (Appendix I) 
Purpose – Documents health-related quality of life for breast cancer patients. This form is available in both English and Spanish and 
patients should be allowed to use the language that they prefer.  
Timeline for completion – Completed at time of registration and during each scheduled follow up visit (at 6 months, 1 year, 2 years, 3 
years, 4 years, and 5 years after the end of radiation treatment).  
 
11.6.3 
Body Image Scale (BIS) (Appendix I) 
Purpose – This form captures information regarding patient-reported body image. This form is only available in English. Patients fluent 
only in Spanish are not required to fill it out.   
Timeline for completion – Completed at time of registration and during each scheduled follow up visit (at 6 months, 1 year, 2 years, 3 
years, 4 years, and 5 years after the end of radiation treatment).  
 
11.6.4  Appearance Schemas Inventory-Revised (ASI-R) (Appendix I)   
Purpose – This form captures information regarding patient-reported image investment. This form is only available in English. Patients 
fluent only in Spanish are not required to fill it out.  
Timeline for completion – Completed at time of registration and during each scheduled follow up visit (at 6 months, 1 year, 2 years, 3 
years, 4 years, and 5 years after the end of radiation treatment).  
 
11.6.5  Dosimetry Form (Appendix J) 
Purpose – This form captures technical details regarding the radiation therapy plan. It should be filled out by a dosimetrist. Any 
questions can be referred directly to the study PI (bsmith3@mdanderson.org, 713-404-4182 pager, 713-563-2380 office).   
Timeline for completion – Filled out by a certified medical dosimetrist within four weeks of completing radiation.  
 
11.6.6 
Breast Cancer Treatment Outcomes Scale (BCTOS) (Appendix K and L) 
Purpose – Documents patient-reported cosmetic outcome, breast pain, and functional status by comparing the affected breast and area 
to the unaffected breast and area. This form is available in both English and Spanish and patients should be allowed to use the language 
that they prefer. 
Timeline for completion – Completed at time of registration and during each scheduled follow up visit (at 6 months, 1 year, 2 years, 3 
years, 4 years, and 5 years after the end of radiation treatment).  
 
11.6.7 
Baseline Data Collection Form (Appendix N) 
Purpose – Outlines protocol-specific baseline characteristics and includes the following:  
· Participant Demographics (Name, medical record number, age, race, origin). ·
 Baseline health characteristics (menopausal status, height, weight). 
 
· 
Tumor characteristics (stage, size, histology, ER/PR/Her2-neu status) 
 
· 
Treatment characteristics (date of surgery, receipt and type of chemotherapy) 
 Timeline for completion – At time of registration. 
 
11.6.8 
Follow Up Form (Appendix O) 
Purpose – Records the following information to report any patient encounter that occurs more than six (6) weeks after 
completing radiation:  
 
· 
Treatment with endocrine therapy 
 
· 
Any recurrences 
 
· 
Any surgical procedures on the treated or untreated breast 
 
· 
Toxicity data 

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Timeline for completion – Filled out and signed by the attending physician at each scheduled follow up visit (at 6 months, 1 
year, 2 years, 3 years, 4 years, and 5 years after the end of radiation treatment). This form should also be filled out and signed by 
the attending physician to document any unscheduled follow up visit that occurs more than 6 (six) weeks after completion of 
radiation therapy.  
 
11.6.9  Off Study Form (Appendix P) 
Purpose -The Off Study Form is submitted if the participant removes herself from the protocol prior to the five-year follow up 
visit or if the patient expires.  
Timeline for completion – Completed at the time of notification that the patient has removed herself from the protocol or at the 
time of notification of patient death.  
11.6.10 Randomization Form (Appendix Q) 
Purpose – documents stratification factors:  
 
· 
Bra cup size 
 
· 
Chemotherapy 
 
· 
Margin status 
 
· 
Baseline cosmesis 
Timeline for completion – At time of registration.  
11.6.11 Treatment Summary (Appendix R) 
Purpose – Records the following information related to the time the participant receives protocol treatment:  
 
· 
Treatment start and end dates  
 
· 
Total dose and number of fractions 
· This form will only be filled out by the participating institutions MD Anderson Orlando and Banner MD Anderson. The data will be 
imported directly from Mosaiq into ROADs for other sites. 
Timeline for completion – This note will be dictated into Clinic Station for all patients treated at MD Anderson Main Campus or  
Regional Care Centers within 30 days of completion of radiation therapy. There is no requirement for a copy of the Clinic Station 
Treatment Summary to be kept in the study file for patients treated at MD Anderson Orlando or the Main Campus, as salient 
information from the treatment summary will be important into the trial database directly from the Mosaiq radiation oncology 
treatment record. For patients treated at MD Anderson Orlando, a hard copy of the Treatment Summary will be submitted. 
11.6.12 Breast Photographs 
Purpose -To create a photographic record of the appearance of the patient’s breasts:  
· Includes five pictures (right lateral, right anterior oblique, anteroposterior, left anterior oblique, and left lateral). Pictures shall be taken 
as per instructions in section 11.4 of the protocol. 
Timeline for completion – Completed at time of registration and during each scheduled follow up visit (at 6 months, 1 year, 2 years, 3 
years, 4 years, and 5 years after the end of radiation treatment).  
11.7  
All data will be collected at The University of Texas MD Anderson Cancer Center and will be stored on 
HIPPAAcompliant institutional computer systems. The Radiation Oncology Access to Data Systems (ROADS)  
(https://roads.mdanderson.org) will be used to track all data. Forms may be filled out directly into the ROADS database for this 
trial, thereby obviating the need for paper forms.   
If a patient chooses to no longer follow-up with Radiation Oncology or Surgical Oncology but does not withdraw consent, we will 
continue to follow their chart for recurrence information.   
11.8 
It is expected that approximately 10 patients per year will be enrolled at MD Anderson Orlando and 10 patients per year 
at Banner MD Anderson. These institutions will be expected to comply with the Data and Quality Monitoring Plan as outlined in 
Appendix S. 
It is permissable for each center to accrue more or less patients that the expected accrual, provided that the total number of 
randomized and treated patients accrued to the protocol does not exceed 288. 
12.0 Data Collection 
All data will be collected at The University of Texas M. D. Anderson Cancer Center and will be stored on HIPPAA-compliant institutional 
computer systems. 
13.0 Statistical Considerations 
13.1  
Primary Endpoint: The primary endpoint for this study is the patient-reported cosmesis score on the BCTOS at 3 years 
after completing radiation therapy. Cosmesis scores range from 1 to 4, and scores of 2.5 or more indicate adverse cosmetic 
outcomes. Our objective is to show that the proportion of patients treated with HF-WBI with adverse cosmetic outcomes is not more 
than 10% greater than the proportion of patients treated with CF-WBI with adverse cosmetic outcomes.  
A cutoff point of 2.5 was chosen in defining adverse cosmetic outcome for several reasons. First, if  a patient scores 2.5 or higher, this 
means that, on average, they feel that their treated breast is at least moderately different from the untreated breast (ie they rated more 
domains as moderate or higher change rather than mild or less change). In the opinion of the clinical investigators on this trial, a 
patientreported moderate difference between the treated and untreated breast is clinically relevant. Second, in the initial study using the 
Breast Cancer Treatment Outcomes Scale (BCTOS), the mean BCTOS cosmetic score was 2.23 with a standard deviation of 0.77.  The 
BCTOS cosmetic score stratified at a cutoff of 2.5 was not reported. However, given the mean and standard deviation, we estimate that in 

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the initial study of the BCTOS the percent of women with a cosmetic score of 2.5 or higher was approximately 35-40%. Our study’s power 
calculation is based on the assumption that the adverse cosmetic score will be 35% in the HF-WBI arm and 40% in the CF-WBI arm. 
Accordingly, we believe that the cutoff we selected for defining adverse cosmesis will yield a risk of adverse cosmesis that is in concert with 
the assumptions built into our power calculation. 
As reported in the START A and START B trials,20,21 we expect the proportion of patients treated with CF-WBI experiencing an 
adverse cosmetic outcome at 3 years to be about 40%. For the current study, if we assume an alpha/beta ratio of 3.4 Gy for late 
normal tissue toxicity,22 the equivalent doses in 2 Gy per fraction to the tumor bed in the HF-WBI arm are 58.7 Gy for patients with 
widely negative margins and 61.4 Gy for patients with close margins, slightly less than the tumor bed doses of 60 Gy and 64 Gy, 
respectively, that will be used in the CF-WBI. Accordingly, we make the a priori assumption that the risk of adverse cosmetic 
outcome will be slightly lower in the HF-WBI arm than in the CF-WBI arm. 
Patients with early breast cancer are generally highly compliant with follow up care. For example, in the four main randomized trials 
comparing HF-WBI to CF-WBI (cited in the protocol), the number of patients lost to follow up ranged from 0% - 1.3%. We will analyze 
sociodemographic correlates of trial participation status and outcomes, including patient sociodemographic characteristics as well as 
geographic (neighborhood) characteristics. In addition, local failures requiring a mastectomy are rare in this population, typically less than 
3% at 3 years. As a result, we do not anticipate patient drop out being a major concern. Nevertheless, as a conservative measure we plan 
to conduct a sensitivity analysis in which patients who do drop out prior to 3 years will be considered to have an adverse cosmetic outcome. 
13.2  
Sample Size: If we assume that 35% of patients treated with HF-WBI will have adverse cosmetic scores and 40% of 
patients treated with CF-WBI will have adverse cosmetic scores, a sample size 
of 274 patients (137 randomized to each treatment arm) will yield 90% power 
with a 1-sided significance level of 0.10 for testing the following hypothesis: 
where PHF-WBI is the proportion of patients treated with HF-WBI who have 
adverse cosmetic outcomes at 3 years and PCFWBI is the proportion of patients treated with CF-WBI who have adverse cosmetic 
outcomes at 3 years. We also expect a loss rate of 5% due to death, loss to follow up, or local recurrence requiring mastectomy 
which will prevent assessment of cosmetic outcome, Accounting for this, our study will require a sample size of 288 patients (144 
on each arm).   
13.3 Randomization: Patients will be randomized to HF-WBI or CF-WBI using CORe. Randomization will be stratified by the post-
lumpectomy/pre-radiation physician-reported cosmetic score (excellent/good versus fair/poor), bra cup size (D or higher versus C or 
lower), receipt of chemotherapy (yes/no), margin status (< 2 mm vs > 2 mm), and treatment location (Houston area facilities vs 
Banner MD Anderson vs MD Anderson Orlando). 
13.4  
Interim Analysis: The accrual rate is expected to be 100 patients per year, and the primary outcome is measured at 3 
years. Therefore, it is impractical to conduct an interim analysis of non-inferiority or futility. 
 
13.5 
Primary Analysis 
13.5.1 We will use descriptive statistics to summarize the demographic and clinical characteristics of the patients by treatment arm.  
13.5.2 
We will use a chi-square test, stratified by randomization strata with a 1-sided significance level of 0.10 to test the 
hypothesis stated above. We will also estimate the proportion of patients in each treatment group with an adverse cosmetic outcome 
at 3 years with a 95% confidence interval. 
 
13.6  
Secondary Analyses 
13.6.1  
For each treatment arm we will tabulate the scores on the BCTOS at 6 months, 1, 2, 3, 4, and 5 years. Adverse 
cosmetic outcome will be defined as scores of 2.5 or more. We will use McNemar’s test to assess changes in cosmetic outcome 
from 2 to 5 years and from 5 to 10 years within each treatment arm. We will use a chi-square test stratified by randomization strata 
to compare scores on the BCTOS for the two treatment arms at 2, 3, and 5 years. 
13.6.2  
For each treatment arm, we will tabulate the physician-rated cosmetic outcome using the Radiation Therapy and 
Oncology Group (RTOG) scale for physician assessment at 6 months, 1, 2, 3, 4, and 5 years. We will dichotomize the outcomes as 
excellent/good and fair/poor, and we will use McNemar’s test to assess changes in cosmetic outcome from 2 to 5 years within each 
treatment arm. We will use a chi-square test stratified by randomization strata to compare scores for the two treatment arms at 6  
months, 1, 2, 3, 4, and 5 years.  
13.6.3  
We will estimate with 95% confidence intervals the concordance between the BCTOS and the RTOG scale for physician 
assessment for classifying adverse cosmetic outcome at 6 months, 1, 2, 3, 4, and 5 years. 
13.6.4 
We will use the product-limit method of Kaplan and Meier to estimate with 95% confidence intervals the 5-year and 
10year probability of pathologically confirmed invasive and/or in situ ipsilateral breast tumor recurrence (IBTR) stratified by treatment 
arm and tumor type (DCIS or early invasive breast cancer). Patients will be censored at the time of death or distant recurrence.  

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13.6.5 
For each treatment arm we will tabulate the patient-reported functional status and breast pain as measured by the 
BCTOS at 6 months, 1, 2, 3, 4, and 5 years. Scores of 2.5 or more will indicate adverse outcomes, and we will estimate with 95% 
confidence intervals the proportions of patients in each treatment arm with adverse outcomes at each assessment time. 
13.6.7 
For each treatment arm we will tabulate the maximal acute (within 6 weeks of completing treatment) and late (more than 
6 weeks) skin and soft tissue toxicities using the NCI CTCAE v4.0 scale. In accordance with prior studies, we will also report the 
outcomes of fibrosis and telangiectasia using the SOMA scale.43 
13.6.8 
We will use logistic regression methods to model the logit of the probability of patient reported adverse cosmetic 
outcome at each assessment time and the volume of breast tissue receiving >105% of the prescription dose as a function of 
treatment arm, breast size, and other demographic and clinical factors. 
13.6.9 
The one-sided Fisher’s exact test will be used to test the association between the presence of at least one copy of the 
C509T variant allele and risk of grade 2 or higher fibrosis at three years as reported using the SOMA scale. This strategy will yield 
83% power to detect a 15% absolute difference in risk of grade 2 or higher fibrosis at a significance level of 0.05 assuming that 150 
patients participate in this component of the study, the baseline risk of fibrosis in the wild type group is 5%, and the frequency of the 
variant allele in the population is 0.33. For hypothesis generation, we will use the two-sided Fisher’s exact test to test the association 
between the C-509T, G915C and T869C variant alleles in TGF-b and early and late radiation-related toxicities captured using the 
CTCAE v4.0 and the risks of fibrosis and telangiectasia captured using the SOMA scale. 
 
13.6.10 
The cost of radiation for the two treatment arms will be compared using the Wilcoxon 2-sample test. 
13.6.11  
Data collected from the FACT-B, BIS, and ASI-R will be used to conduct exploratory analyses to identify putative 
cutpoints for these measures that could potentially discriminate between the two treatment arms. In addition, we will use 
longitudinal data analysis methods to describe how patient’s scores for these measures may change over time and if treatment arm 
impacts this change. 
13.6.12  DNA repair phenotypes and genotypes and their associations with baseline clinical-pathologic covariates will be assessed 
in accordance with the statistical methods outlined in protocol LAB02-086. 
13.6.13 Skin thickness on available post-treatment mammograms will be compared between the two treatment arms 
using the Wilcoxon two-sample test. 
13.6.14 
 To study the psychometric properties of the FACT-B v.4, we will provide a de-identified dataset to 
investigators at the Department of Medical Social Science, Northwestern University Feinberg School of Medicine. This 
dataset will include the following data collected at baseline: sociodemographic and clinicopathologic covariates,  
physician-reported cosmetic outcome, and item-level patient responses to the FACT-B v.4, Breast Cancer Treatment 
Outcomes Scale, Appearance Schemas Inventory-Revised, and Body Image Scale. The dataset will include the 
following data collected at  
6 and 12 months: physician-reported cosmetic outcome and item-level patient responses to the FACT-B v.4, Breast 
Cancer Treatment Outcomes Scale, Appearance Schemas Inventory-Revised, and Body Image Scale. Patient identifiers 
will be removed from the provided dataset, and randomization arm will not be provided. A flag variable will be created for 
each patient-reported outcome instrument to indicate whether the instrument was filled out using a paper form or an 
iPad. Internal consistency reliability will be estimated for each multi-item subscale with Cronbach’s coefficient alpha. 
Cronbach’s coefficient alpha is a measure of how closely correlated a set of items are with each other. A Cronbach’s 
coefficient alpha of 0.70 or greater is generally considered acceptable for group comparisons. Several types of validity 
will be evaluated, including (1) construct-related: convergent and divergent validity, known-groups validity, (2) 
criterionrelated: associations with criterion measures (valid measures of the same concept), (3) responsiveness: 
sensitivity to change, and (4) comparison of alternative methods of administration (paper vs. iPad).  Standard statistical 
tests for continuous and categorical data will be performed, e.g., t-tests, analysis of variance, chi-squared tests, 
correlation coefficients. Effect sizes will be estimated to evaluate minimally important differences. 
 
13.7  
Toxicity Monitoring 
Within each treatment arm we will monitor the rate of CTCAE v4.0 grade 3 or higher acute radiation-induced dermatitis 
developed within 6 weeks of completion of radiation therapy. If we have reason to believe that the rate of acute dermatitis is more 
than 20% in either treatment arm we will stop the trial. 
We will employ the following monitoring rule as a guide in assessing whether we are observing excess CTCAE v4.0 grade 3 or 
higher acute dermatitis. This rule is based on the method proposed by Thall et al.46  We assume a beta(0.4, 1.6) prior distribution for 
the rate of CTCAE grade 3 or higher acute dermatitis. T his distribution has a mean of 20% and a standard deviation of 23%.  
We will stop the trial if the Pr(CTCAE grade 3 or higher acute dermatitis > 20% | data) > 0.90 on either treatment arm. That is, if 
there is more than a 90% chance that the CTCAE grade 3 or higher acute dermatitis rate is more than 20% on either treatment arm 
we will stop the trial. We will monitor patients in cohorts of size 20 within each treatment arm. This monitoring rule gives us the 
following stopping boundaries. 
Stop the trial if, within either treatment arm, the 
[# patients with CTCAE grade 3+ acute dermatitis / # of patients evaluated] > 7/20, 12/40, 17/60, 22/80. 
The operating characteristics of this monitoring rule are summarized in the following table. From this table we see that if the rate 
of CTCAE v4.0 grade 3 or higher acute dermatitis within 6 weeks of radiation therapy is 30% we have an 81.3% probability of 
stopping the study early, with a median sample size of 40 patients on each treatment arm. Also, if the rate of CTCAE grade 3 or 
higher acute dermatitis within 6 weeks of radiation therapy is 15% we have only a 3.2% chance of stopping the study early. P25, P50, 
and P75 are the first quartile, median, and third quartile of the sample size for each treatment arm. 

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