Study of Radiation Fractionation on Patient Outcomes After Breast REConstruction (FABREC) for Invasive Breast Carcinoma
Phase: NA
Conditions: Breast Cancer
Sponsor: Dana-Farber Cancer Institute

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 / May 4, 2021 
 
 
 
 
 
 
 
 
Page 1 
This is a multi-site clinical trial.  The lead site, coordinating center, and regulatory sponsor 
for this study is Dana-Farber/Harvard Cancer Center (DF/HCC).  The DF/HCC Protocol 
Number is #16-304. 
 
 
TITLE Study of Radiation Fractionation on Patient Outcomes After Breast REConstruction 
(FABREC) for Invasive Breast Carcinoma 
 
 
Coordinating Center/Lead Site: 
 
Dana-Farber Cancer Institute 
 
450 Brookline Avenue, 
 
Boston, MA 02215 
 
Study Co-Chairs: 
Rinaa Punglia, MD, MPH 
FABREC Co-Chair 
Dana-Farber Cancer Institute/  
Brigham and Women’s Hospital 
rpunglia@partners.org 
617-632-3591 
Julia Wong, MD 
FABREC Co-Chair 
Dana-Farber Cancer Institute/ 
Brigham and Women’s Hospital 
jwong@partners.org 
617-632-3591 
 
Lead Statistician: 
 
Central Study Coordinator*:  
 
Hajime Uno, PhD 
Dana-Farber Cancer Institute  
 
Dana-Farber Cancer Institute 
450 Brookline Ave, MA 02215 
 
Hajime_uno@dfci.harvard.edu 
FABREC_Study@dfci.harvard.edu 
 
617-632-6893 
617-582-8484 
*PRIMARY CONTACT WITH ANY 
QUESTIONS 
 
 
 
Data and Safety Monitoring: 
 
 
 
 
Dana-Farber Office of Data Quality (ODQ) 
 
20 Overland Street, 2nd Floor Boston, MA 02115  
 
Phone: (617) 632-2114  
 
Fax: (617) 632-2295  
 
Email: ODQDataSafety@dfci.harvard.edu 
 
 
This study does not involve any INDs (investigational new drugs or devices).   
 
This study is funded by PCORI (Patient-Centered Outcomes Research Institute). 
 
The EDC (electronic data capture) application being used for Case Report Forms (CRFs)/data 
submission is InForm. 
 
This study is posted on www.ClinicalTrials.gov (NCT03422003). 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 2 
Contents 
 
SCHEMA .........................................................................................................................................4 
1. 
INTRODUCTION ...............................................................................................................5 
1.1 
Study Overview .......................................................................................................5 
1.2 
Rationale ..................................................................................................................8 
2. 
OBJECTIVES ......................................................................................................................9 
2.1 
Study Design ............................................................................................................9 
2.2 
Objectives ................................................................................................................9 
3. 
PARTICIPANT SELECTION ...........................................................................................10 
3.1 
Inclusion Criteria ...................................................................................................10 
3.2 
Exclusion Criteria ..................................................................................................10 
3.3 
Inclusion of Women and Minorities ......................................................................11 
4. 
PRETREATMENT EVALUATIONS/MANAGEMENT .................................................11 
5. 
REGISTRATION AND RANDOMIZATION PROCEDURES .......................................11 
5.1 
Registration Process for all sites ............................................................................11 
5.2 
Study Enrollment Timing ......................................................................................12 
5.3 
Stratification Factors and Treatment Assignment..................................................13 
6. 
RADIATION THERAPY ..................................................................................................13 
6.1 
Radiation therapy schedule ....................................................................................13 
6.2 
Radiation technical factors .....................................................................................14 
6.3 
Radiation simulation ..............................................................................................14 
6.4 
Treatment planning ................................................................................................14 
6.5 
Treatment verification ............................................................................................14 
6.6 
Compliance criteria ................................................................................................15 
6.7 
Radiation quality assurance review .......................................................................15 
6.8 
Radiation adverse events and reporting .................................................................15 
6.9  
RT Modifications ...................................................................................................15 
6.10  Supportive Care .....................................................................................................15 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................16 
7.1 
Routine Solicited Adverse Events .........................................................................16 
7.2 
Expedited Serious Adverse Events ........................................................................16 
7.3 
Submission of SAEs to IRB(s) ..............................................................................17 
7.4 
AE Data Collection and Definitions ......................................................................17 
7.5 
Expected Adverse Reactions ..................................................................................18 
8. 
SCHEDULE OF ASSESSMENTS ....................................................................................18 
8.1 
Administration of Patient Questionnaires ..............................................................21 
9. 
DATA COLLECTION AND SUBMISSION ...................................................................21 
9.1 
Summary of data collection and submission .........................................................22 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 3 
10. 
STATISTICAL CONSIDERATIONS...............................................................................24 
11. 
REGULATORY CONSIDERATIONS .............................................................................29 
11.1 
Data Safety Monitoring ..........................................................................................29 
11.2 
Multicenter Guidelines ...........................................................................................30 
12. 
PUBLICATION PLAN .....................................................................................................30 
13. 
BUDGET ...........................................................................................................................31 
13.1 
Funding ..................................................................................................................31 
13.2 
Start-up Payment ....................................................................................................31 
13.3 
Per Case Payment ..................................................................................................31 
13.4 
Other costs .............................................................................................................31 
14. 
REFERENCES ..................................................................................................................32 
15. 
APPENDICES ...................................................................................................................36 
APPENDIX A:  DATA SAFETY MONITORING PLAN ...........................................................37 
APPENDIX B:  RADIATION THERAPY TREATMENT GUIDELINES .................................48 
APPENDIX C:  PHOTOGRAPHIC GUIDELINES .....................................................................50 
APPENDIX D:  PATIENT-FACING MATERIALS ....................................................................55 
 
 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 4 
Mastectomy patients 
with immediate 
expander or implant 
placement 
200 
participants 
Radiation therapy 
(RT) recommended 
and doses in protocol 
medically appropriate 
SCHEMA 
 
 
 
 
 
 
 
Randomization 
Arm 2 
Conventional (RT for 25 
treatments) 
Arm 1 
Hypofractionation (RT 
for 16 treatments) 
400 participants 
200 
participants 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 5 
1. INTRODUCTION 
 
1.1 
Study Overview 
Almost 100,000 mastectomies are performed in the US to treat breast cancer each year.1 Breast 
reconstruction represents a major advance in the care of breast cancer patients undergoing 
mastectomy and the use of immediate implant‐based reconstruction is increasing.2 However, 
many women with mastectomy are recommended to undergo radiation therapy to improve cancer 
outcomes.3 Radiation therapy currently entails over five weeks of daily treatment and can 
compromise outcomes of breast reconstruction. An alternative three‐week short‐course radiation 
regimen (hypofractionation) may improve reconstruction outcomes and be equally effective. The 
decision regarding conventional versus short‐course radiation therapy after mastectomy and 
immediate reconstruction is relevant to approximately 20,000 women annually. Currently no 
information exists to help inform the treatment choice between conventional (long‐course) 
versus hypofractionation (short‐course) radiation therapy in women with mastectomy and 
immediate reconstruction. 
 
Impact of radiation therapy after mastectomy on health of individuals and populations:  
Mastectomy, or removal of the entire breast, is a common treatment strategy for breast cancer. In 
2015, an estimated 231,840 new cases of invasive breast cancer were expected to be diagnosed 
in women in the US, including 60,290 new cases of non‐invasive (in situ) cancer.4 Of these cases, 
almost 40 percent are treated with mastectomy.5 Patients with multicentric (involving more than 
one quadrant of the breast) cancers, cancers not easily encompassed by limited surgery such that 
an unacceptable cosmetic outcome would result, or patients at elevated risk for a new or 
recurrent breast cancer typically opt for mastectomy. In recent years, there has been an increase 
in the frequency of mastectomy perhaps due in part to patient preference and the wish to 
minimize new future breast cancer risk.1 Radiation therapy is indicated for almost one‐third of 
patients who receive mastectomy.3 After mastectomy, radiation is used to reduce the risk of 
breast cancer recurrence in the chest wall or regional lymph nodes. Radiation therapy has been 
established as standard treatment for patients with four or more positive (involved) axillary 
nodes, and there is increasing evidence that radiation improves outcomes in patients with one to 
three positive nodes. An update of the large meta‐analysis of randomized trials showed a clear 
benefit to the use of post‐mastectomy radiation therapy in patients with one to three positive 
axillary nodes, with respect to reducing local regional recurrence (recurrence in the breast area 
and nearby lymph nodes), overall recurrence, and deaths from breast cancer.6 After mastectomy, 
the main areas at risk for local-regional recurrence (and therefore, targeted in the planned 
radiation) are the nodal basins (axillary, supraclavicular, internal mammary) depending on 
anatomy, pathology, and extent of axillary surgery. Radiation techniques have continued to 
evolve to minimize long‐term side effects.  
 
Breast reconstruction and radiation therapy after mastectomy: 
The option to receive breast reconstruction is a major advance for women undergoing 
mastectomy. Breast reconstruction has been shown to improve emotional, psychological, and 
physical well‐being of women treated with mastectomy.7, 8 Patient satisfaction after breast 
reconstructive surgery has been shown to be improved as well.9 Awareness of reconstruction as a 
routine issue to be addressed in the management of patients who require mastectomy 10, 11 and the 
use of implant‐based reconstruction after mastectomy are increasing.2 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 6 
 
Women who undergo mastectomy can receive immediate or delayed reconstruction. Breast 
reconstruction can begin at the time of mastectomy (“immediate”) as opposed to a separate, later 
operation (“delayed”). The psychological benefit of immediate reconstruction is established, 
clearly favoring immediate over delayed.12 Immediate reconstruction also affords the plastic 
surgeon the opportunity to utilize more original breast skin, which may improve the ultimate 
cosmetic outcome. Delayed reconstruction may be preferable in settings where there is high‐risk 
disease that requires an uncomplicated postoperative course in order to plan post‐mastectomy 
radiation therapy, or if the technique and dose aspects of radiation are optimized by the absence 
of a reconstruction. The two main types of breast reconstruction are implant‐based or autologous 
(patient tissue‐based). Implant‐based reconstruction typically consists of a tissue expander, 
which is a temporary, inflatable device placed under the pectoralis major muscle, that has a port 
or opening that permits the plastic surgeon to sequentially (over weeks to months) instill saline 
solution to create a breast mound. This process allows the body and skin to gradually adjust to 
the size of an implant. The tissue expander is eventually replaced with a permanent implant. 
Alternatively, in selected cases where the anatomy permits, a permanent implant may be placed 
directly under muscle and skin at the time of mastectomy. Implants are not expected to last a 
lifetime and may need to be replaced every 10‐15 years.  
 
Autologous tissue reconstruction utilizes a muscle‐skin combination from another site (e.g., 
abdomen, back, buttock) or in some settings, can be performed without compromising muscle 
(using abdominal tissue anterior to the muscle). If post-mastectomy radiation therapy is delivered 
to an unreconstructed chest wall, delayed implant reconstruction usually is not possible or 
advisable given the long‐term effects of radiation (tightness, scar tissue) on the chest wall and the 
accompanying inability to place a tissue expander or permanent implant under the irradiated 
pectoralis muscle and chest wall skin. There has been an increase in immediate implant‐based 
reconstruction in recent years, particularly in patients who may require post‐mastectomy 
radiation therapy. This trend is likely due in part to the ease of planning this type of surgery 
(shorter operative time, shorter recovery time). Moreover, immediate reconstruction allows for 
an implant option if radiation therapy will be delivered, as implant‐based reconstruction is 
typically only possible prior to radiation—when the tissues of the chest wall are still pliable.  
 
The combination of post‐mastectomy radiation therapy and reconstruction is challenging. 
Radiation therapy can compromise the cosmetic outcome of the reconstruction and increase 
complications.13,14,15 Radiation is associated with an increased likelihood of forming scar tissue 
around the implant, resulting in long‐term problems with increased hardness, suboptimal 
positioning (the implant can migrate on the chest wall), and the need to remove or replace the 
implant. There is also an increased risk of complications such as delayed healing and infection 
(sometimes requiring permanent removal of the implant). Women have reported less satisfaction 
with reconstruction in the setting of radiation therapy (versus no radiation).16 
 
Patient and treatment characteristics have been evaluated in attempts to discern which may 
contribute to higher risk of complications or poor cosmetic outcomes. Factors described as being 
associated with poorer outcomes include age, medical conditions (e.g., smoking, high blood 
pressure, diabetes, body mass index), weight of breast specimen, and scar location.17‐19 There is 
no agreement upon whether it is preferable to irradiate a tissue expander or a permanent implant. 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 7 
Cordeiro et al. recently reported that six‐year reconstruction failure rates were higher for 
irradiated tissue expanders compared to permanent implants, but initial tissue expander 
placement was associated with a higher proportion of good‐to‐excellent cosmetic results 
compared to an initial permanent implant.20  
 
Modification of the conventional radiation schedule may yield improved outcomes: 
Hypofractionation, or short-course radiation therapy, reduces the number of radiation treatments 
and the overall treatment length, increasing patient convenience. This regimen has been shown in 
randomized trials (e.g., the START‐B trial), largely in the breast-conservation setting, to reduce 
acute radiation therapy side‐effects, decrease fatigue at six months and improve cosmetic 
results.21,22 A large randomized study from Canada showed a hypofractionated regimen to be safe 
and effective in early‐stage breast cancer.23 Despite these results, adoption of hypofractionation 
was initially sluggish in the breast‐conserving therapy setting 24,25 likely due to a preference for 
the familiarity and experience with conventional long‐course radiation therapy. Of note, patients 
receiving care in community practice are less likely to receive hypofractionation26 perhaps due to 
increased financial incentives to treat with longer-course radiation therapy. The majority of 
patients in the START‐B trial, and all of the patients in the Canadian trial, were treated solely to 
the whole breast, without a separate radiation field to treat lymph nodes. In the post‐mastectomy 
setting, patients routinely have lymph node radiation. Some of the radiation side effects 
associated with this separate lymph node field include lymphedema (potentially related to the 
extent of surgery), and, much less likely, radiation pneumonitis (inflammation of the lung due to 
radiation—typically temporary and treatable), and, extremely rarely, brachial plexopathy (injury 
to the nerves that supply the arm). Long term data following hypofractionation to the lymph 
nodes have not revealed an increased risk of brachial plexopathy.27 While hypofractionation is 
used commonly in the UK in the post‐mastectomy setting, there are no randomized studies 
specifically studying outcomes following its use in women who undergo breast reconstruction. 
Therefore, there is an even greater barrier to the use of hypofractionation in this setting in the 
US. With improved cosmetic results found with hypofractionation in the breast conservation 
setting, this shorter regimen may have the potential to improve reconstruction success rates 
(which are modest overall) for patients who require post‐mastectomy radiation. In addition, 
given the financial repercussions of a reduced number of radiation treatments, high‐quality, 
Level I randomized evidence is needed in this population to change practice patterns regarding 
the radiation regimen. 
 
Gaps in Evidence:  
Mastectomy, immediate implant‐based reconstruction, and radiation therapy constitute a 
common treatment paradigm. There are conflicting data on the treatment outcomes with respect 
to quality of life (QoL), cosmetic results, and complications. Variability in treatment technique 
(surgery and radiation) contributes to the uncertainty, and in the absence of prospective data with 
specified treatment protocols and rigorous evaluation of outcomes, this uncertainty is likely to 
continue. Hypofractionated radiation has been studied well in breast‐conserving therapy, with 
equivalent efficacy in preventing cancer recurrence, and a possible benefit in cosmetic outcome, 
when compared to conventional, longer‐ course radiation. There are limited data on its use in the 
post‐mastectomy setting and with nodal irradiation.  
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 8 
1.2 
Rationale 
Over 180,000 diagnoses of invasive breast cancer are made in the US each year. Over one‐third 
of women with early stage and over half with late‐stage breast cancer are treated with 
mastectomy (removal of the entire breast) due to tumor size, multiple cancers within the breast, 
genetic cancer predisposition, and/or patient preference. Following treatment with mastectomy, 
women who receive breast reconstructive surgery may experience better quality of life as they do 
not have to leave surgery with a bare chest wall. However, large randomized trials of post-
mastectomy radiation therapy reveal a survival benefit with the addition of radiation after 
mastectomy in women who have cancer present in the axillary lymph nodes.6 The delivery of 
radiation therapy in the presence of a breast reconstruction is challenging and often leads to 
undesirable consequences including reconstruction loss, need for major surgical revision, or poor 
cosmetic outcomes. Therefore, oncologists and patients are forced to decide between the 
potential for improved oncologic outcomes with radiation therapy versus increased likelihood of 
complications and suboptimal cosmetic results. Because of this, some patients may be foregoing 
reconstruction if radiation therapy after mastectomy is needed; or foregoing radiation therapy if 
they have had breast reconstructive surgery.28  
 
Hypofractionation enhances patient convenience and decreases treatment burden. This regimen 
has been shown in randomized trials largely in the breast‐conservation setting to reduce acute 
radiation therapy side‐effects, decrease fatigue at six months and improve cosmetic results.21, 22 
Despite these results, adoption of hypofractionation has been slow among women with breast 
cancer treated with breast‐conserving surgery24, 25 likely due to familiarity and experience of 
conventional long‐course radiation therapy. While hypofractionation is used commonly in the 
UK for patients with mastectomy, there are no randomized studies particularly studying 
outcomes following shorter course radiation therapy in women who undergo mastectomy with 
breast reconstruction. Therefore, there is an even greater barrier to the use of hypofractionation 
in this setting in the US. With improved cosmetic results found with hypofractionation, this 
shorter regimen may have the potential to improve reconstruction success rates which are 
unfortunately modest overall, for patients who require post-mastectomy radiation. Especially in 
contrast to financial disincentives to reduce number of radiation treatments, Level I randomized 
evidence is needed in this population to change practice patterns regarding radiation regimen. 
 
Patient‐centeredness:  
Our study of radiation fractionation regimens has the potential to increase use of 
hypofractionation among women treated with mastectomy, thereby decreasing treatment burden. 
Our team of patient stakeholders ensures that our outcomes measures encompass all domains of 
survivorship after breast cancer (physical and mental health as well as satisfaction with the 
decision‐making process). Despite the large numbers of breast cancer survivors who undergo 
mastectomy, reconstruction and radiation therapy, little is known about which domains of quality 
of life are affected and their importance to these patients. This study uses previously validated 
tools for measuring patient outcomes, and have added questions for areas which are important to 
patients that may not have been captured adequately by previous tools. In concert with the 
increasing awareness of the importance of survivorship care to cancer care, identifying a 
comprehensive set of outcomes measurement tools following treatment with radiation therapy, 
mastectomy, and reconstruction is an important asset for future treatment evaluation in these 
women. In summary, the proposed pragmatic trial is highly significant because: 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 9 
1. A critical knowledge gap exists for a common medical condition in a well‐defined 
population 
2. Patients and/or their physicians may be foregoing radiation to preserve the cosmetic 
results of reconstruction 
3. Clinicians are unsure whether to adopt hypofractionation or continue with the familiar but 
problematic conventional treatment 
4. Hypofractionation has the potential to improve outcomes following breast reconstruction 
5. Hypofractionation decreases treatment burden for patients with fewer radiation 
treatments 
6. There are no randomized studies specifically evaluating hypofractionation after 
mastectomy and reconstruction 
7. The trial is being conducted in diverse settings including community oncology practices 
8. Engaged patient partners will help disseminate findings 
9. The trial will examine outcomes that matter to patients including the QoL and cosmetic 
results 
10. The trial will have long‐term implications for improving and measuring the QoL of breast 
cancer survivors and will enhance the increasingly important field of survivorship 
research. 
 
 
2. OBJECTIVES 
 
2.1 
Study Design 
The FABREC study is a pragmatic randomized trial of hypofractionation versus conventional 
radiation therapy in women who have undergone mastectomy and immediate breast 
reconstruction.  
 
The trial will be conducted at academic and community practice sites to ensure a diverse and 
representative patient population. Study participants will be randomized 1:1 to conventional 
fractionation or hypofractionation after mastectomy and breast reconstruction with a tissue 
expander or implant.  
 
All participants will be assessed for cosmetic and reconstruction outcomes, lymphedema and 
cancer status through month 18. During the 10-year follow-up period, participants will be 
assessed for oncologic outcomes (local recurrence, distant disease, and survival) and side effects. 
Surveys will be used to ask participants to report pain, appearance, mobility, and self-image.  
 
2.2 
Objectives 
 
Objective 1: Compare the effect of short-course versus long-course post-mastectomy 
radiation therapy on highly-relevant patient-reported outcomes (PROs) and outcomes 
prioritized by individual trial participants.  
Our primary outcome is the Physical Well Being (PWB) domain of the FACT-B 
instrument. PRO assessment will be further patient-focused, as we will also ask each 
subject to choose the FACT-B subdomain most relevant to their experience and separately 
correlate this domain to that patient’s radiation schedule.  We will thereby create a more 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 10 
patient-centered outcome by comparing short- versus long-course radiation according to 
the subscale selected to be most important to the individual patient. In addition, we will 
assess pain, arm mobility, lymphedema, self-image, satisfaction with decision to undergo 
reconstruction, sexual well-being, functional well-being, and treatment burden in all 
patients using standard instruments.  
Hypothesis: Short-course radiation therapy will improve patient quality of life in 
multiple domains. 
 
Objective 2: Compare clinical outcomes for patients receiving short-course versus long-
course radiation.  
These include complications and clinically-assessed cosmetic results. We will also create 
an infrastructure to monitor long term oncologic outcomes such as recurrence and breast-
cancer specific survival, and rare radiation side effects (secondary malignancy and 
brachial plexopathy).   
Hypothesis: Short-course radiation therapy will decrease complications, improve 
clinician-quantified cosmetic results, and will have no increased risk of local or 
regional recurrence or side-effects. 
 
 
3. PARTICIPANT SELECTION 
 
3.1 
Inclusion Criteria  
 
1. Diagnosed with clinical or pathologic stage 0‐III invasive breast cancer with Tis, TX, or 
T1‐T3 tumor 
2. Has been treated with mastectomy 
3. Has undergone immediate reconstructive surgery with placement of a tissue expander or 
permanent implant at time of mastectomy  
4. Is a candidate for unilateral post‐mastectomy radiation therapy as per local, institutional 
practice (post‐mastectomy radiation therapy is indicated for most patients with positive 
lymph nodes at time of surgery and infrequently for selected node‐negative patients) 
5. Use of bolus is permitted, but not required  
6. Age ≥18  
 
3.2 
Exclusion Criteria 
 
1. T4 cancer 
2. History of prior ipsilateral breast radiation therapy 
3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, and/or mental health 
illness that the consenting investigator feels would affect patient’s ability to participate in 
this study 
4. Pregnant or nursing 
5. History of a different malignancy except for the following circumstances: 
o Either disease‐free for at least five years OR deemed by the investigator to be at low 
risk for recurrence of that malignancy. 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 11 
o Cervical cancer in situ and basal cell or squamous cell carcinoma of the skin 
6. Breast cancer requiring bilateral breast/chest wall radiation therapy. 
 
Notes about eligibility:  
• If your site can accommodate consenting and orally administering questionnaires via 
translator to patients in languages other than English, then non-English speaking patients 
are eligible.  
• Participants enrolled to the FABREC Trial may be enrolled to other treatment and/or 
non-treatment trials if the consenting investigator deems that there are no 
contraindications. 
• Concurrent systemic therapy will be considered on a case-by-case basis.  Please ask the 
study co-chairs about whether any systemic therapy may be administered concurrently 
with PMRT. 
• A pregnancy test is not required per FABREC protocol. 
• Microscopically positive surgical margins are permitted. 
• Patients should only be enrolled in this study if the treating physician feels it is medically 
appropriate for the patient to receive the radiation therapy outlined in this protocol. 
• Reconstruction will be considered immediate if it occurred: 
o At the time of mastectomy 
OR 
o Up to one month after mastectomy and before radiation treatment planning 
• Patients who have stage 0 disease (ductal carcinoma in situ) may undergo radiation 
therapy after mastectomy to reduce the risk of recurrence, especially in the setting of 
positive/close margins and/or extensive involvement of the breast.  As our purpose is to 
evaluate patient outcomes after mastectomy and immediate reconstruction, we seek to 
include patients with stage 0 disease who are receiving radiation in this setting. 
 
3.3 
Inclusion of Women and Minorities 
Women of any race/ethnicity are eligible for this trial. Women who are pregnant or nursing are 
excluded from this trial.  
 
4. PRETREATMENT EVALUATIONS/MANAGEMENT 
It is necessary to delay enrollment until after mastectomy and reconstruction because a large 
percentage of patients will not meet the criteria for radiation therapy (and, therefore, for the 
study) once the pathology results from the mastectomy become available.  
 
5. REGISTRATION AND RANDOMIZATION PROCEDURES 
 
5.1 
Registration Process for all sites 
This section applies to DF/HCC Institutions (Dana-Farber/Harvard Cancer Center) and all other 
investigative sites. 
 
To register a participant on the FABREC Trial, please follow these steps: 
• Each participating site should identify eligible participants at their site. 
• The consenting investigator should approach the patient and hold an informed consent 
discussion. 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 12 
• If the potential participant agrees to participate, the consenting investigator and the 
patient should both sign the Informed Consent document. 
• The study staff should then send the following documents to the Central Study 
Coordinator (CSC) via secure email to FABREC_Study@dfci.harvard.edu or via fax to 
617-582-7450 (be sure to write ATTENTION: FABREC Central Study Coordinator on 
your fax cover sheet). 
1. Signed Informed Consent Form (all pages) 
2. Signed HIPAA authorization form (if applicable: At some sites the HIPAA 
authorization form and the informed consent document are two separate 
documents.  At other sites, the HIPAA authorization form is contained within 
the informed consent document, so only the informed consent document need 
be submitted) 
3. Completed Eligibility Checklist 
• The CSC will review the eligibility checklist to ensure that all fields are complete and 
that all values are within the acceptable range allowed by the protocol. If any information 
is missing, the CSC will contact the site.   
• Next the CSC will work with the Dana-Farber Office of Data Quality (ODQ) to register 
and randomize the participant. 
• Within 24 business hours*, the CSC will email the following information to the site: 
1. Confirmation that the participant has been successfully registered 
2. The participant’s unique study ID number 
3. The arm to which the participant was randomized  
 
*Business hours for this study are defined as: Monday through Friday from 8:00 AM to 5:00 PM 
Eastern Time, not including holidays.  
 
If you need expedited assistance during normal business hours (Eastern Standard Time), please 
contact the FABREC Central Study Coordinator at 617-582-8484 or 
FABREC_Study@dfci.harvard.edu. 
 
5.2 
Study Enrollment Timing 
 
REGISTRATION: Participant must be registered and randomized before protocol treatment 
(PMRT) begins. 
 
BASELINE PATIENT QUESTIONNAIRE: The baseline questionnaire can be administered 
to the patient immediately following signed consent (recommended).  The baseline 
questionnaire must be completed by the participant after she signs informed consent but before 
PMRT begins. 
 
TREATMENT: Protocol treatment (PMRT) must begin <=4-months after randomization.  
Issues that would cause treatment delays should be discussed with the Study Chairs.  Permission 
to deviate from DF/HCC SOP REGIST-101A has been approved and is documented in OnCore.   
 
The rationale for allowing <=4 months between randomization and start of PMRT is that there 
are a lot of treatment-related activities that must occur between Arm Assignment and PMRT 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 13 
Initiation including: chemotherapy must be completed (as/if applicable); sequential inflations of 
the tissue expander need to be completed (as/if applicable); simulation must be performed locally 
at the treating site; the physics plan must be generated and approved locally at the treating site; 
and treatment verification films need to be approved locally at the treating site.   
Note: the sponsor does not need to pre-approve your PMRT plan. 
 
Information about PMRT treatment planning will be collected via Medical Record Review 
CRFs.  The PMRT Treatment Plan for a patient does not need to be submitted prior to initiation 
of PMRT; this will reduce study burden on sites and clinicians. 
Note: Concurrent systemic therapy will be considered on a case-by-case basis.  Please ask the 
study co-chairs about whether any systemic therapy may be administered concurrently with 
PMRT. 
 
5.3 
Stratification Factors and Treatment Assignment 
 
400 patients will be randomized 1:1 into either Arm 1 (short-course PMRT) or Arm 2 (long-
course PMRT). 
 
Randomization will be stratified by treatment center and age of the patient (<45 vs. ≥45). 
 
 
6. RADIATION THERAPY  
 
6.1 
Radiation therapy schedule 
Radiation therapy will be delivered to all intended fields, once daily, excluding holidays, 
weekends, and unavoidable factors limiting machine or patient availability.   
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 14 
Conventional fractionation: 25 fractions of radiation therapy (daily, Monday through 
Friday) to the chest wall with or without internal mammary nodes, and 23‐25 fractions to 
the supraclavicular (with or without axillary) lymph nodes. Each fraction will consist of 
200 cGy per day. Total dose = 5000 cGy to the chest wall and 4600‐5000 cGy to the lymph 
nodes. 
 
Hypofractionation: 16 fractions of radiation therapy (daily, Monday through Friday) to 
the chest wall with or without internal mammary nodes, and 15 fractions to the 
supraclavicular (with or without axillary) lymph nodes. Each fraction consists of 266 cGy 
per day. Total dose = 4256 cGy to the chest wall and 3990 cGy to the lymph nodes. 
 
6.2 
Radiation technical factors 
• Radiation will be delivered with megavoltage (MV) equipment at energies of 6MV or 
higher.   
• Protons are not permitted. 
• Bolus to the mastectomy scar or chest wall will be prescribed at the discretion of the 
treating physician. 
• No boost dose to the scar or other areas of the reconstructed chest wall is permitted. 
• No deflation or expansion of tissue expander(s) should occur between simulation and 
radiation treatment completion. 
 
6.3 
Radiation simulation 
Simulation will be CT-based. Patients will be positioned supine on the planning table in a 
customized immobilization device as per institutional protocol.  Techniques to limit radiation 
dose to the heart, such as deep inspiration breath hold (DIBH) or gating are encouraged. 
 
6.4 
Treatment planning 
The target volume will be the chest wall, tissue expander (or implant), and any associated nodal 
stations as per physician discretion.  Delineation of these volumes will be as per institutional 
protocol.  Per FABREC Trial protocol, microscopically positive margins are permitted.  Per 
FABREC Trial protocol, giving PMRT solely for margins and not to treat nodes is permitted. 
 
Lung and heart volumes will be limited as per institutional protocol.  Maximum separation will 
be recorded.  Location of mastectomy incision will be recorded. 
 
Inhomogeneity will be limited to 110% in the chest wall, recording volume above 107%.  Efforts 
will be made to strive for a maximum of 107% in hypofractionated cases (110% permitted).  
Inhomogeneity in the supraclavicular (+/-axillary) field will be limited to 110%. 3D-conformal 
RT or IMRT are permitted.  There is no specified maximum dose on the composite plan. The 
composite plan may exceed 110%.  Individual plans for the chest wall or lymph nodes must not 
exceed 110% inhomogeneity.   
 
6.5 
Treatment verification 
For 3D-CRT and IMRT, quality assurance filming should be done per local, institutional 
protocol and does not need to be submitted to the sponsor.  Dose distribution images and 
treatment planning fields should be kept by the treating institution for review by the sponsor, if 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 15 
needed. 
 
6.6 
Compliance criteria 
If inhomogeneity constraints are not attainable in the hypofractionated setting, the patient will be 
treated with standard fractionation as per protocol. Switching arms in this case is permitted, and 
these participants who switch arms will still be asked to complete all patient questionnaires and 
will be followed for 10 years.  If the site plans to have a participant switch arms, the site must 
submit the Change in Study Status CRF via InForm 2 business days prior to the switch which 
will give the Study Chairs time to pre-approve the switch.  Sites will be notified via email if 
approved. 
 
6.7 
Radiation quality assurance review 
The Study Chairs will oversee quality assurance reviews for all participants treated on protocol.  
RT quality assurance review will be ongoing and performed remotely.  RT quality assurance 
reviews will be facilitated by the study chairs and the study staff. The CSC will obtain the 
radiation therapy data from the Inform database for the Study Chairs to review and assess. 
 
6.8 
Radiation adverse events and reporting 
All participants will be seen weekly, according to their treatment plan, by an attending radiation 
oncologist while undergoing treatment. Side effects will be recorded and managed using clinical 
discretion. For information about adverse events, see Adverse Event Reporting section of 
protocol.  Details on the adverse event reporting can be found in the AE section of the protocol. 
 
6.9  
RT Modifications 
Treatment breaks should be kept to a minimum but do not constitute protocol violations. 
 
Changes in RT dose will constitute major protocol violations. 
 
6.10  Supportive Care 
Supportive care is permitted and is at the discretion of the treating investigator.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 16 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.   
 
7.1 
Routine Adverse Events  
 
Routine Adverse Events will not be collected for the FABREC Trial.  Only events outlined in 
Section 7.2 should be reported via InForm.  
 
 
7.2 
Reportable Serious Adverse Events  
 
Reportable Serious Adverse Events that occur at any time between initiation of PMRT and 3-
years after the initiation of PMRT must be reported using the FABREC Serious Adverse Event 
CRF.  In general, the CRF should be submitted via InForm within 5 calendar days of the AE 
date.  When an adverse event occurs at an institution outside the enrolling site, there may be a 
delay between when an adverse event occurs and when the study team is alerted to the event. In 
these instances, it is acceptable for the study team to submit those adverse events in InForm 
within 5 calendar days of being notified about the event and will not incur a violation.  
 
Only “reportable SAEs” require reporting.  For the FABREC trial, a reportable SAE is defined 
as:  
• Grade 1, 2, or 3 brachial plexopathy (per NCI CTCAE v 4.03, this AE does not have 
grade 4 or 5) 
• Grade 3 chest wall pain (per NCI CTCAE v 4.03, this AE does not have grade 4 or 5) 
• Grade 3 lymphedema (per NCI CTCAE v 4.03, this AE does not have grade 4 or 5) 
• Grade 3, 4, or 5 myocardial infarction 
• Grade 1, 2, 3, 4, or 5 pneumonitis 
 
Summary of how to collect and report adverse events (AEs) for the FABREC trial: 
 
1. Standard Care All patients will be seen per their treatment plan by an attending 
radiation oncologist while undergoing treatment. All adverse events should be 
recorded in the patient’s medical record per standard practice at your site and managed 
using clinical discretion.  On the Medical Record Review CRFs for the FABREC 
Study, Clinical Research Professionals (CRPs) will be asked to report AEs as 
documented in the patients’ charts; these medical record reviews will be done at pre-
specified timepoints.  
 
2. Routine Solicited Adverse Events will not be collected for the FABREC Trial. 
 
3. Reportable Serious Adverse Events should be reported using the FABREC Serious 
Adverse Event CRF each time a reportable SAE occurs.  These CRFs should be 
submitted using InForm.  For a list of reportable SAEs, see below. 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 17 
• Grade 3, 4, or 5 treatment related secondary malignancy 
• Grade 3, 4, or 5 wound infection 
• Unexpected grade 3 or 4 with a possible, probable or definite attribution to PMRT  
• Grade 5 (death); all deaths on study require expedited reporting regardless of attribution 
or causality.  
• Local/regional recurrence (not in NCI CTCAE v4) 
o Note: We are only interested in following participants who experience 
local/regional recurrences. When participants experience distant recurrences, they 
should be withdrawn from the study and all follow-up should be discontinued as 
these patients may not be monitored for local/regional recurrences due to distant 
disease.  
 
NCI CTCAE v4 can be downloaded from 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
Only the events listed above need to be reported in InForm.  Events that fall outside the list 
above do not need to be reported in InForm. 
 
7.3 
Submission of SAEs to IRB(s) 
 
The Study chairs will submit all applicable SAEs from both Dana-Farber/Harvard Cancer Center 
sites and outside institutions to the Dana-Farber Cancer Institute IRB per the DFCI IRB Adverse 
Event Reporting Policy.  
 
Other investigative sites will report AEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events.  
 
7.4 
AE Data Collection and Definitions 
 
AE, date of event, grade, attribution, and relation to an underlying disease or condition will be 
collected for each AE and SAE. 
 
Grade: 
• Grade 1 - Mild AE  
• Grade 2 - Moderate AE  
• Grade 3 - Severe AE  
• Grade 4 - Life-threatening or disabling AE  
• Grade 5 - Death related to AE 
 
Attribution: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated – The AE is clearly NOT related to the study treatment. 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 18 
Study treatment = PMRT 
 
 
7.5 
Expected Adverse Reactions  
 
Radiation is associated with an increased likelihood of: 
 Forming scar tissue around the implant, resulting in long‐term problems with increased 
hardness 
 Suboptimal positioning (the implant can migrate on the chest wall) with a need to remove 
or replace the implant 
 Increased risk delayed healing and infection (sometimes requiring removal of the 
implant)  
 Reddening or tanning of the skin 
 Desquamation in the treatment field  
 Mild pain 
 Thickening of the skin 
 
Some radiation side effects associated with lymph node radiation include: 
 Lymphedema (potentially related to the extent of surgery)  
 
8. SCHEDULE OF ASSESSMENTS 
 
 
Prior to 
Enrollment 
(Screening) 
Baseline 
(After 
participant 
signs 
informed 
consent) 
 
During 
Radiation 
Therapy 
(both 
arms) 
30 Days 
after RT 
completion 
6 mos. 
+/- 4 
weeks 
after RT 
initiation 
12 mos. 
+/- 4 
weeks 
after RT 
initiation 
18 mos. 
+/- 4 
weeks 
after RT 
initiation 
Every 
year for 
10 years 
after RT 
initiation 
Medical chart 
review  
X 
X 
 
X 
 
X 
 
X 
SAE 
Reporting 
 
 
Reportable SAEs that occur at any time between initiation of PMRT and 
3-years after the initiation of PMRT must be submitted via InForm (see 
AE section). 
Radiation 
Treatment 
Information 
 
 
 
X 
 
 
 
 
Photo 
Evaluation 
 
X 
 
 
X 
X 
X 
 
Participant 
Questionnaires 
 
X 
 
 
X 
X 
X 
 
Annual 
Follow-Up 
 
 
 
 
 
 
 
X 
 
Medical Chart Review. Medical Record Review CRFs will collect data on sociodemographic 
information, social history, cancer diagnoses, co-morbidities, treatment details, radiation 
treatment, surgical history and follow up, toxicities, medical history and follow up, disease 
recurrence, significant clinical events, and mortality.  
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 19 
Study Visits.  Because this is a pragmatic trial, there are no protocol mandated study visits.  All 
clinic visits are per standard of care.   
 
Solicited AEs and Expedited SAE Reporting. See Adverse Event Reporting section of 
protocol for full details. 
 
Radiation Treatment Information. Sites will enter specific information related to the radiation 
treatment received. This information will be collected by reviewing participants’ medical charts 
at the end of treatment. 
 
Photo evaluation. In order to assess reconstruction, de-identified photos of participant 
reconstruction will be submitted for evaluation by the Study Chairs or delegate.  The participant 
may take and submit the reconstruction photographs herself (see appendix for patient-facing 
instructions on how to take and submit reconstruction photographs), or any clinician (nurse, 
doctor, etc.) who has been trained on the FABREC protocol may take reconstruction 
photographs. 
 
In extremely rare cases where submission of photographs is not possible, the study chairs will 
work with the site investigator to complete the Cosmetic Outcome CRFs. 
 
Participant Questionnaires. The following contain items from the following instruments:  
• FACT‐B version 4 - Quality of Life - includes modules for assessing physical well‐being, 
emotional well-being, social well‐being, functional well‐being and a 2‐item question 
characterizing a breast cancer patient’s relationship with her physician. Descriptive statistics 
for FACT‐B have been well characterized.33,34 
• BREAST-Q post‐operative, reconstruction module - Satisfaction with Breast Surgery 
Outcome - tool was developed at Memorial Sloan Kettering Cancer Center and includes 
questions regarding changes on the appearance and feel of the reconstruction after radiation 
therapy.35, 36 Domains covered by the reconstruction module include satisfaction with breast, 
satisfaction with outcome, psychosocial well‐being, sexual well‐being, and chest and upper 
body physical well‐being.   
• Lymph‐ICF - Questions regarding lymphedema, selected from the Lymphedema 
Functioning, Disability and Health Questionnaire.42, 43  
• Measures of treatment burden - These questions have been adapted from Kent et al. and 
the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) caregiver 
survey.44, 45, 46 The measures of treatment burden will only be administered at the 6-month 
time-point.  
• Sociodemographics and social/medical history. 
 
Change in Study Status.  Whenever there is a change in a participant’s status on the study 
including the development of a distant recurrence or metastatic disease, the Change in Study 
Status CRF should be completed and submitted via InForm within 5 business days of the change.  
 
Reasons a participant might have a change in study status include:  
• ACTIVE PARTICIPANT WITHDRAWAL: Study participant actively withdrew 
consent for one or more components of the study, including:  

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 20 
a. protocol treatment (PMRT), and/or  
b. participant contact for questionnaires and follow up, and/or  
c. access to his/her medical record for Medical Record Abstraction.  
 
HOW TO PROCEED: Unless the participant explicitly (in writing) withdraws 
consent to access his/her medical record, site study staff SHOULD complete all 
Medical Record Abstraction CRFs and all Follow-up CRFs through the end of the 10-
year follow up period.  
 
• CLINICIAN WITHDRAWAL: Clinician took participant off protocol treatment 
(PMRT). Please note that after taking a subject off protocol treatment, study 
questionnaires and follow-up CONTINUE through the 10-year follow up period. Site 
study staff should complete all Medical Record Abstraction CRFs and Follow-up CRFs. 
 
• DEATH: If a study participant dies, the site staff should complete all Medical Record 
Abstraction CRFs through death.  After all data has been collected through death, sites 
may take participant off study by submitting the Off-Study CRF via InForm. 
 
• FOUND TO BE INELIGIBLE: Participant was enrolled on the trial but was later found 
to be ineligible. Select one:  
a. Yes, protocol treatment (PMRT) will continue [treating physician and study chairs 
agree there are no safety concerns if the patient continues protocol treatment].  
b. No, protocol treatment will not continue [in this case, study questionnaires and 
follow up should continue through the 10 year follow up period. Site study staff 
should complete all Medical Record Abstraction CRFs no matter how long the 
subject actually received protocol treatment].  
 
• SWITCHED ARMS: If inhomogeneity constraints are not attainable in the 
hypofractionated setting, the patient will be treated with standard fractionation as per 
protocol. Switching arms in this case is permitted, and these participants who switch arms 
will still be asked to complete all patient questionnaires and will be followed for 10 years 
 
• OTHER: Please specify.  
o Note: If a participant experiences a distant recurrence, they should be withdrawn 
from the study by selecting this option in InForm. Once participants are 
withdrawn from the study due to distant recurrence, all follow-up should be 
discontinued.   
 
Annual Follow-Up Form/Event Monitoring. Participants will be followed for 10-years for 
long-term outcomes including recurrence, new malignancy, and survival.  “Annual follow up 1 
of 10” is defined as 1-year after the date on which the participant initiated PMRT.  “Annual 
follow up 2 of 10” is defined as 2-years after the date on which the participant initiated PMRT, 
and so on through “Annual follow up 10 of 10”.  For each annual follow up, if the site has lost 
track of the participant, then the CSC may send participants the Annual Follow-up Questions 
sheet (see Appendix D) about recent infections, surgeries, and cancer-related issues.  Once the 
CSC receives the completed question sheet, s/he may call participants to follow up on recurrence 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 21 
and new malignancies.  A script for these calls can also be found in Appendix D.  
 
8.1 
Administration of Patient Questionnaires 
Each participant can choose to complete each questionnaire in writing or orally.  Each participant 
can choose to return his/her questionnaire responses in-person, via postal mail, by phone, 
scanning and emailing, faxing, or texting (participants may text photographs of the completed 
questionnaire pages).   
 
The enrolling site staff will be responsible for administering the Baseline Questionnaire to 
the participant.  The Baseline Questionnaire must be administered after the participant has signed 
informed consent but before protocol treatment begins.  It is operationally easiest to administer 
the Baseline Questionnaire immediately after the participant signs informed consent.   
 
The Central Study Coordinator will administer the Follow-up Questionnaires to 
participants.  In the consent form that patients sign, it is clearly stated that the patient’s contact 
information will be shared with the Central Study Coordinator who sits at Dana-Farber Cancer 
Institute in Boston, MA for the purposes of questionnaire administration and gift card 
distribution.  A participant will be contacted by the Central Study Coordinator up to five times 
per timepoint in an attempt to complete each patient study questionnaire.  The CSC may contact 
the participant via email, text message (texts will only be used if participant explicitly responds 
on their baseline questionnaire that we may contact them via text message), in-person, phone, or 
postal mail, as appropriate.  The participant may return their survey via email, in-person, phone, 
orally, written, fax, or text message, based on patient preference.  If a participant does not 
respond after five attempts, then the Central Study Coordinator will ask the enrolling site’s staff 
to attempt contact before the survey deadline.  If the enrolling site’s staff is unable to make 
contact after three attempts, then the questionnaire will be marked as missing and the participant 
will not be contacted regarding that questionnaire again.   
 
9. DATA COLLECTION AND SUBMISSION 
 
No research biospecimens will be collected as part of this study.  
 
Data will be collected via medical record reviews, CRFs, patient surveys, and photographs of 
reconstruction taken by the clinician or by the participants themselves.  
 
The EDC (electronic data capture) application being used for this study is InForm.  To get 
access to InForm, please contact the Central Study Coordinator at 
FABREC_Study@dfci.harvard.edu.  The CSC will assist you in getting an InForm weblink, a 
username & password, and will provide training on how to enter data for this study. 
 
 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 22 
9.1 
Summary of data collection and submission 
Acronyms used in following table: 
CRP = Clinical Research Professional (at enrolling site) 
CSC = Central Study Coordinator (sits at lead site, Dana-Farber) 
Timepoint 
Data to be 
collected 
Who’s responsible? 
How to Collect & Submit data? 
Enrollment 
(after participant 
signs informed 
consent but 
before protocol 
treatment begins) 
 Eligibility 
checklist 
Site CRP should: 
 Fax or securely email the eligibility checklist, all pages of the signed informed 
consent form, and the HIPAA authorization form (if it is a separate document from 
the ICF) to the CSC. 
CSC will:  
 Email site with participant’s unique study ID and treatment arm randomization within 
24 business hours. 
 Enter Eligibility Checklist data into InForm 
 Baseline Patient 
Questionnaire 
Site CRP should: 
 Administer questionnaire to patient  
 Submit patient responses via InForm  
 Keep paper original at your site 
CSC will:  
 Send participant $50 gift card upon receipt 
Baseline 
(after enrollment 
but before 
protocol 
treatment begins) 
 Baseline 
Medical Record 
Review CRF 
Site CRP should:  
 Submit electronically via InForm  
 
 Reconstruction 
photographs  
Patient or Clinician should: 
 Take reconstruction photographs 
Patient or Clinician or Site CRP should: 
 Send photographs to CSC electronically via secure file transfer protocol (FTP).  
Contact the CSC for detailed FTP instructions. 
 Cosmetic 
Outcomes CRF 
Study Chair (or delegate) will: 
 Evaluate photos 
 Submit the Cosmetic Outcomes CRF via InForm 
<= 30-days after 
PMRT ends 
 Off Treatment 
CRF 
Site CRP should:  
 Submit electronically via InForm  
Ongoing from 
initiation of 
PMRT through 
3-years after date 
of PMRT 
initiation 
 Serious 
Adverse Event 
(SAE) 
Reporting CRF 
Site CRP should: 
 Enter SAE into InForm ONLY when a reportable event occurs 
 Submit within 5 calendar days of start of SAE 
 For a list of “reportable SAEs,” see the AE section of protocol. 
6-months  
(defined as 6-
months after 
initiation of 
PMRT) 
 6-month Patient 
Questionnaire 
CSC should: 
 Administer patient questionnaire 
 Enter patient responses into InForm 
 Send participant $50 gift card 
 Reconstruction 
photographs 
Patient or Clinician should: 
 Take reconstruction photographs 
Patient or Clinician or Site CRP should: 
 Send photographs to CSC electronically via secure file transfer protocol (FTP).  
Contact the CSC for detailed FTP instructions. 
 Cosmetic 
Outcomes CRF 
Study Chair (or delegate) will: 
 Evaluate photos 
 Submit the Cosmetic Outcomes CRF via InForm 
Table continued on next page. 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 23 
Acronyms used in following table: 
CRP = Clinical Research Professional (at enrolling site) 
CSC = Central Study Coordinator (sits at lead site, Dana-Farber) 
Timepoint 
Data to be collected 
Who’s responsible? 
How to Collect & Submit data? 
12-months^  
(defined as 12-months after 
initiation of PMRT) 
 12-month Patient 
Questionnaire 
CSC should: 
 Administer patient questionnaire 
 Enter patient responses into InForm 
 Send participant $50 gift card 
 Reconstruction 
photographs 
Patient or Clinician should: 
 Take reconstruction photographs 
Patient or Clinician or Site CRP should: 
 Send photographs to CSC electronically via secure file transfer 
protocol (FTP).  Contact the CSC for detailed FTP instructions. 
 Cosmetic Outcomes CRF 
Study Chair (or delegate) will: 
 Evaluate photos 
 Submit the Cosmetic Outcomes CRF via InForm 
18-months  
(defined as 18-months after 
initiation of PMRT) 
 18-month Patient 
Questionnaire 
CSC should: 
 Administer patient questionnaire 
 Enter patient responses into InForm 
 Send participant $50 gift card 
 Reconstruction 
photographs 
Patient or Clinician should: 
 Take reconstruction photographs 
Patient or Clinician or Site CRP should: 
 Send photographs to CSC electronically via secure file transfer 
protocol (FTP).  Contact the CSC for detailed FTP instructions. 
 Cosmetic Outcomes CRF 
Study Chair (or delegate) will: 
 Evaluate photos 
 Submit the Cosmetic Outcomes CRF via InForm 
Annual Follow up 1 of 10^ 
(defined as 1-year after 
initiation of PMRT) 
 Follow-up Medical 
Record Review CRF 
Site CRP should:  
 Submit electronically via InForm 
If no follow up data available in medical record, CSC may mail 
patient brief set of questions and/or call patient for follow up. 
Annual Follow up 2 of 10 
(defined as 2-years after 
initiation of PMRT) 
 Follow-up Medical 
Record Review CRF 
Site CRP should:  
 Submit electronically via InForm 
If no follow up data available in medical record, CSC may mail 
patient brief set of questions and/or call patient for follow up. 
At EACH: Annual Follow 
up 3, 4, 5, 6, 7, 8, 9, and 10 
of 10 
 Follow-up Medical 
Record Review CRF 
Site CRP should:  
 Submit electronically via InForm 
If no follow up data available in medical record, CSC may mail 
patient brief set of questions and/or call patient for follow up. 
After “Annual Follow up 
10 of 10” 
 Off-study CRF 
Site CRP or CSC should:  
 Submit electronically via InForm 
As needed, at any time from 
baseline through end of 10-
year follow up period 
 Change in Status CRF 
Site CRP or CSC should:  
 Submit electronically via InForm 
^ The “12-months” timepoint (defined as 12-months after initiation of PMRT) and the “Annual Follow up 1 of 10” 
timepoint (defined as 1-year after initiation of PMRT) overlap, meaning that they both occur on the same date. 
 
 
 
 
 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 24 
Note about missing forms:  
• If any of the following forms are missing for a participant, then this would constitute a 
major protocol violation:  
o Eligibility checklist 
o Baseline Medical Record Review CRF 
o Solicited Adverse Event CRF 
o Cosmetic Outcomes CRF 
o Off Treatment CRF 
o Expedited Serious Adverse Event (SAE) Reporting CRF 
o Follow-up Medical Record Review CRF  
o Change in Status CRF 
 
• The following questionnaires are required; however, if any of the following are missing 
for a participant despite best efforts by Central Study Coordinator and Site Staff to collect 
from participant, then this does not constitute a major or minor protocol violation:  
o Baseline Patient Questionnaire 
o 6-month Patient Questionnaire 
o 12-month Patient Questionnaire 
o 18-month Patient Questionnaire 
o Reconstruction photographs (at baseline, 6, 12, and 18 months)  
 
 
 
10. STATISTICAL CONSIDERATIONS 
 
10a. Accrual: Based on previous years’ treatment records, we anticipate that there will be about 
40-50 eligible patients per month across the multiple participating academic and community 
centers. The accrual rate of this study is expected to be about 22 patients per month. We expect 
conservatively (based on survey data) that 75% of the eligible patients (after confirmation of the 
need for radiation therapy) are willing to be randomized to either the long-course or short-course 
treatment. The accrual will be open until 400 patients are enrolled. Randomization will be 
stratified by treatment center and age of the patient (<45 vs. ≥45). We expect the proportion of 
patients in the younger cohort of the study sample to be 40%. The anticipated length of the 
accrual period is 21-27 months.  
 
10b. Statistical analysis plan for patient-reported quality of life outcomes and power 
considerations 
 
Quality of life (QoL) measurement and the primary endpoint: We will use an array of 
instruments to rigorously assess quality of life among study participants, such as the FACT-B 
scores, satisfaction with breast surgery outcomes (BREAST-Q), Lymph-ICF, and financial 
burden. We will record and report all reasons for dropout and which outcomes were not reported, 
and include this data in our final reports.  FACT-B (version 4) specifically measures quality of 
life in breast cancer patients and includes modules for assessing physical well-being, emotional 
well-being, social well-being, functional well-being and a 2-item question characterizing a breast 
cancer patient’s relationship with her physician. QoL will be assessed at baseline, 6 months, 12 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 25 
months and 18 months. This data will allow peer reviewers and readers of our publications to 
assess the validity of our study.  
 
To determine the primary endpoint among those measurement scales, we surveyed patients who 
had undergone radiation therapy after mastectomy and immediate reconstruction and found that 
the majority of chose the Physical Well-Being (PWB) subscale of the FACT-B (version 4) to 
be the most important element of their quality of life, regardless of age (data not shown, 
manuscript in preparation). Based on this result, we selected the FACT-B PWB score as the 
primary endpoint of this study. To adjust for QoL at baseline, we will compare change in PWB 
score (relative to each patient’s pre-radiation score) between the short and long-course treatment 
groups, instead of comparing PWB scores between the two groups. 
 
Statistical analysis of the primary endpoint and power: As per the intention-to treat principle, 
the primary analysis population will be all women who are randomly assigned to receive either 
short-course or long-course (conventional) radiation therapy. The secondary analysis population 
will be the per-protocol cohort.  We hypothesize that the short-course radiation therapy will lead 
to improved PWB scores compared to the conventional long-course treatment. To confirm this 
hypothesis, we will use Analysis of Covariance (ANCOVA) models. Change in the FACT-B 
PWB subscale (7 items) score at 6 months relative to baseline will be the response variable, 
and the intervention group indicator (long-course versus short-course radiation therapy) and age 
group (below 45 vs. 45 or above) will be included in the ANCOVA model as independent 
variables.  Using change in the PWB score relative to baseline will give us a more normal 
distribution of outcomes, versus using the score itself.  The age threshold of 45 years was 
selected by our patient advocates.  
 
Based on our patient survey data, we anticipate that the mean post-conventional (long-course) 
PWB score to be 19.0 for the younger patient group and 24.0 for the older group, and that the 
standard deviation (SD) is 6.0 for each. We also expect the correlation coefficient between the 
baseline and 6-month value to be 0.65-0.7, thus the SD of change from baseline to 6 months will 
be 3.6 to 4.2. “Table: Expected PWB subscale scores at 6 months by treatment arm” shows 
the expected treatment effect in each age group, based on our preliminary data and studies of 
short-course therapy in other breast cancer settings.  The effect of short-course radiation on 
quality of life outcomes in these other breast cancer settings (breast-conserving surgery or 
mastectomy without reconstruction) are likely underestimates for our study given the relatively 
poor outcomes of long-course radiation after mastectomy with reconstruction, rendering our 
treatment effect expectation to be conservative. The PWB subscale of FACT-B has been 
documented to have sensitivity to change in quality of life measurement,37 and change in PWB 
has been used to study other breast cancer interventions.47,48 A change in PWB score of greater 
than or equal to 2 has been defined as clinically meaningful in a multicenter radiation technique 
study in lung cancer patients.49  In a study of 41 patients with gynecologic cancer, radiation 
therapy led to a mean decline of 3.1 points in PWB score, and was associated with radiation 
treatment technique.50 With expected data from a total of 400 patients (200 for each arm), the 
study will have sufficient power, at a two-sided 0.05 alpha level, to detect a marginal treatment 
difference of 2.8 in PWB scores. If the SD of change from baseline to 6 months is 4.0, the 
study’s power will be 93%. We will also perform the test for interaction between age group and 
intervention group on the outcome to investigate the heterogeneity of treatment effect (section 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 26 
10e).  
Table: Expected PWB subscale scores at 6 months by treatment arm 
 
Younger patients 
(under 45) 
Older patients  
(45 and above) 
Marginal score 
Short-course (hypofractionation) 
treatment 
23.0 
26.0 
24.8 
Long-course (conventional) treatment 
19.0 
24.0 
22.0 
Difference in differences from baseline 
score 
4.0 
2.0 
2.8 
 
Under the same setting as shown described above, “Table: N=400 randomized patients, 
α=0.05” reveals the power to detect an age interaction will be 59%-89%. These are conservative 
estimates for the 6-month change in PWB, given that patients in our survey were interviewed 
between 6 and 24 months (data not shown, manuscript in preparation), and there may be some 
recovery in physical symptoms with time.   
 
Table: N=400 randomized patients, α=0.05. 
PWB score ∆ 
SD of ∆ 
Power 
Younger patients 
Older patients 
 
Main analysis 
Interaction 
4.0 
2.0 
3.5 
>0.99 
0.80 
4.0 
2.0 
4.0 
>0.99 
0.69 
4.0 
2.0 
4.5 
>0.99 
0.59 
 
Strategy for handling missing data: Given the patient incentives, short time required to 
complete surveys, and enthusiasm voiced by the patients we surveyed, we expect that the 
dropout fraction from the study at 6 months will be at most 5% and that the dropout mechanism 
would be mostly random. In a primary analysis, we will exclude those who dropout from the 
study or who do not have data at 6 months. However, because a random missing mechanism 
assumption is not verifiable empirically, we will use several methods to handle missing 
observations to confirm the stability of the findings from the primary analysis.  Specifically, we 
will perform the following: (1) last observation carried forward (LOCF), (2) mean value 
imputation, (3) worst-case and (4) best-case imputation. We will also conduct (5) multiple 
imputation51. For multiple imputation, we will create 10 complete datasets, imputing the missing 
values using chained equations. We will perform the analysis with the 10 complete datasets and 
integrate the results with Rubin’s method of imputation.51 For another approach, we will analyze 
this data according to (6) the methods described in Schluchter and in Schluchter, Greene and 
Beck.52,53 These methods take into account the possibility of informative “missingness” by 
jointly modeling the longitudinal responses (here, QoL scores) and the time to dropout.  
 
Other QoL analysis: In secondary analyses, we will use generalized estimating equation (i.e., 
marginal modeling) and random-effects models to analyze longitudinal data54 (i.e., baseline, 6 
months, 12 months and 18 months) for the FACT-B total score (37 items) and each subscale as 
well as the primary endpoint (FACT-B PWB subscale).  
 
We hypothesize that patients randomized to short-course radiation will have increased 
satisfaction with their reconstruction as measured by the BREAST-Q reconstruction survey. We 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 27 
will use a two-sample t-test for the BREAST-Q satisfaction score, and a chi-square test for 2x2 
tables for post-decision regret. We consider a difference of 10 points in the BREAST-Q 
satisfaction score to be clinically meaningful. With the given total sample size of 400 (200 per 
arm), we will be able to detect this difference with 80% or higher power at a two-sided 0.05 
significance level, if the standard deviation of the score is equal to or smaller than 35.6.  
 
Strategy for handling missing data in other QoL analysis: To assess the robustness of our 
results, we will perform several sensitivity analyses as well as complete case analysis. For 
example, we will perform worst-case or best-case imputation or generalized linear modeling in 
combination with multiple imputation51 methodology.  
 
Patient-centered outcomes analysis: Furthermore, we will also consider a new outcome that 
integrates tailored patient-prioritized quality of life measurement. As seen in our patient survey, 
the relative importance of QoL domains vary from patient to patient. At the baseline visit, we 
will ask each patient to give a weight to each FACT-B subscale based on its importance for her. 
We will then calculate a “weighted” total score of FACT-B (37 items) for each individual, using 
these weights. The weights will be standardized for each patient, so that the range of the 
weighted score can match with that of the FACT-B total score.  We will perform the same 
analyses described above to assess the impact of the intervention on this exploratory new 
outcome that may enhance the measurement of patient-centered outcomes. 
 
10c. Statistical analysis plan for clinical and oncologic outcomes and power consideration 
 
The primary analysis and power: We 
hypothesize that hypofractionated (short-
course) radiation therapy has a higher 
reconstruction success rate, compared to 
the conventional fractionation (long-
course) radiation at 18-months. We will 
use Chi-square test for 2x2 table to test 
this superiority hypothesis. We will also 
construct a two-sided 95% confidence interval for the difference in the composite outcome of 
reconstruction success likelihood (defined as no major complications, presence of reconstruction, 
and good or excellent cosmetic outcome). Recent estimates of reconstruction success after 
implant reconstruction and conventional radiation reveal a 71% likelihood at the 2-year time 
period.46  “Table: Effect size and power for superiority tests” shows the available power with 
various reconstruction success probabilities for hypofractionation (short-course treatment), given 
the sample size of 400 patients.  Variables that may affect outcomes such as chemotherapy 
regimen, endocrine therapy and patient age will be assessed for impact to ensure balance 
between both treatment arms.    
 
Data monitoring of local/regional recurrence event:  
We will also follow oncologic outcomes to exclude any unexpected increase in the risk of 
recurrence with hypofractionation (short-course) radiation therapy, although a detectable 
increase in recurrence rates is unlikely given data from prior experiences of hypofractionation.  
The cumulative incidence of local or regional recurrence in a recent series of post-mastectomy 
Table: Effect size and power for superiority 
tests  
Reconstruction Success Likelihood (%) 
Power 
(%) 
Long-course radiation 
Short-course radiation 
71.0 
82.8 
80 
71.0 
84.4 
90 
N=400 randomized patients and α(two-sided)=0.05 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 28 
radiation therapy is about 2% at 18 months.3 Therefore, in the case where the recurrence rate is  
 
suggested to be statistically significantly greater than 2%, the study will be suspended to allow 
for investigation.  
 
Local/regional recurrence event rate monitoring will 
occur at the first meeting of the DF/HCC Data and 
Safety Monitoring Board (DSMB) and continue until 
the last patient has completed radiation. Data 
analysis will be performed every 6 months (see 
Section 11).  Specifically, the event rate and 
corresponding 0.95 exact binomial confidence 
interval will be calculated, where the numerator is 
the number of the local/regional recurrence events 
and the denominator is the number of patients who 
have completed short-course treatment at time of 
analysis. The results will be reviewed by the 
DSMB. If the lower boundary of the 0.95 
confidence interval is greater than 2%, accrual of 
the study will be suspended and a decision will be 
made as to whether accrual can be resumed or if the 
study should be closed by the study team in 
consultation with the DSMB, IRB and study 
advisory board. The boundary for this criterion is shown in “Figure: Stopping boundary for 
local/regional recurrence-event monitoring”. With the sample size of 200 in the short-course 
radiation arm, the probability that the interim data meet the stopping criteria (see figure) in the 
course of the trial is 72% if the true local or regional recurrence rate were 5%. It would be 98% if 
the true recurrence rate is 8% at 18-months.  
 
There has been no suggestion of increased rare radiation side-effects or mortality with 
hypofractionation (short-course) radiation therapy with long term follow up in the studies using 
hypofractionation.23,24,31  Therefore, we do not expect any increased risk of side-effects in our 
short-course arm.  Nevertheless, to be extra cautious, we will follow these outcomes in our 
patients.  We recognize that our study is too short to detect differences in long-term distant 
recurrence, cardiac mortality and overall mortality.  Therefore, we will create an infrastructure 
with which monitor these outcomes and apply for additional funding for longer follow up.   
 
10e. Heterogeneity in treatment (HTE) outcomes 
In addition to age stratification (see 10a and 10b), heterogeneity or variation in outcomes will be 
examined based on pre-specified patient, cancer and treatment-related attributes (“Table: Pre-
specified attributes to examine heterogeneity/patient subgroups”).  These factors are 
included because they may have an independent association with the outcomes examined. 
As shown in the power considerations for Objective 1, with our sample size we will have a 
sufficient power to detect heterogeneity of treatment effect. We will not adjust for the 
multiplicity of the statistical testing, because the goal of the HTE analyses is not to confirm a 
specific treatment heterogeneity hypothesis, but to generate hypotheses of potential treatment 
Figure: Stopping boundary for local/regional recurrence-
event monitoring 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 29 
heterogeneity. Towards this end, we will focus more on describing the estimated treatment 
differences in each of pre-specified subgroups than testing.  
We have also planned analyses to identify subgroups of patients in which the treatment effect 
(benefit of short-course therapy) is potentially more pronounced than the average treatment 
effect, using a multivariable scoring approach.55  Specifically, we will derive a multivariable 
model that predicts the treatment difference for each patient.  Based on the predicted treatment 
difference scores, we will be able to define subgroups or clusters of patients who benefit more 
from short-course radiation therapy than the average patient on the study. For example, we will 
make two subgroups: one which consists of patients only with positive predicted treatment 
differences, and the other which consists of the remaining patients with negative predicted 
treatment difference. We will estimate the average treatment difference in each of the two 
subgroups and also perform a test for interaction. 
 
Table: Pre-specified attributes to examine heterogeneity/patient subgroups 
Patient attributes: 
 
Age (younger than 45, 45 and above) 
Smoking status 
Body mass index 
Comorbidity (hypertension, diabetes) 
Mastectomy specimen weight 
Cancer attributes: 
 
Tumor type (ductal, lobular, mixed histology) 
Tumor size 
Receptor status 
Tumor grade 
Treatment attributes: 
 
Number of nodes removed 
Expander versus permanent implant  
Volume of implant/expander fill 
Chemotherapy (yes/no) and regimen and timing of chemo 
Hormonal therapy  
Radiation therapy fields 
Bolus regimen 
Use of acelluar dermal matrix 
Mastectomy scar location 
Use of biologic therapy 
 
10f. AE Monitoring 
We will analyze adverse events toxicities experienced by all patients on the study. Adverse event 
rates will be summarized by types of adverse event (serious/non-serious, grade, and attribution) 
for each treatment arm, and they will be compared between the arms by using Fisher’s exact test. 
Toxicity data will be monitored by the DSMB every 6 months to assure safety of the participants 
(see Section 11).  
 
 
11. REGULATORY CONSIDERATIONS 
 
11.1 
Data Safety Monitoring 
The DF/HCC Data and Safety Monitoring Board (DSMB) reviews and monitors study progress, 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 30 
toxicity, safety and other data from this study. The board is chaired by a medical oncologist from 
outside of DF/HCC and has external and internal representation. Information that raises any 
questions about participant safety or protocol performance is addressed by the Study Chairs, 
statistician and study team. Should any major concerns arise; the DSMB will offer 
recommendations regarding whether or not to suspend the study. 
 
The DSMB will meet every 6 months to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; local/regional recurrence event rate, adverse events and serious 
adverse events reported by category; summary of any deaths on study; audit results; and a 
summary provided by the study team. Other information (e.g., scans, laboratory values) can be 
provided upon request.  
 
11.2 
Multicenter Guidelines 
This protocol adheres to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan. The specific responsibilities of the Study Chairs, Coordinating Center, 
and Participating Institutions and the procedures for auditing are presented in Appendix A, Data 
and Safety Monitoring Plan. 
 
12. 
PUBLICATION PLAN 
Final project results are expected to be reported in a publicly accessible manner within 1 year of 
the end of the final year of funding, or, after the outcome data are sufficiently mature for 
analysis, as defined in the section on Sample Size, Accrual Rate and Study Duration. Photos 
could be used in a publication but will be presented in a way that the participant cannot be 
identified. If a report is planned to be published in a peer-reviewed journal, then that initial 
release may be an abstract that meets the requirements of the International Committee of Medical 
Journal Editors.  
 
To the utmost level permitted, we will comply with all policies on data sharing in a timely, 
transparent and thorough manner. 
 
The primary methods of data sharing we plan to utilize for this study are: 
• Publishing trial results in a peer‐reviewed scientific journal 
• Submitting study reports to publicly accessible registries dedicated to the dissemination 
of clinical trial information (including clinicaltrials.gov) 
• Releasing de‐identified data to interested investigators per Dana‐Farber/Harvard Cancer 
Center Office of Data Quality (DF/HCC ODQ) data sharing policy: DF/HCC ODQ may 
provide individual‐level de‐identified datasets that would be sufficient to reproduce 
results provided in a publication (i.e., published manuscript) containing the main study 
analysis. Participant contact information cannot be shared under any circumstance. 
Participant survey data stripped of identifiers may be shared. Source documentation will 
not be released. 
• Providing access to study measurement materials and coding instructions upon request 
• 
Allowing participants to choose if they would like to receive any published study 
information once it becomes available. A link to clinicaltrials.gov results will be sent to 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 31 
participants who opt-in (clinicaltrials.gov requires that results be publicly posted on the 
website within 1 year of completing data collection for the pre-specified primary 
outcomes of the study). Participants who opt-in will be contacted by lead study 
coordination site (Dana-Farber) using the contact information they have on file for the 
purposes of conducting the study questionnaires; the same location/storage/privacy 
protections will be in place for return of research results. 
 
Site PIs of sites that reach their accrual goal will be included as co-authors on the final 
manuscript. 
 
 
13. BUDGET 
 
13.1 
Funding 
This trial is supported through a Patient-Centered Outcomes Research Institute (PCORI) Award.  
 
13.2 
Start-up Payment 
A one-time start-up payment will be made to external sites for their unique IRB approval memos 
at the end of year 1 if the site meets their year 1 accrual goal. 
 
13.3 
Per Case Payment 
$1,500 per case payment will be made to sites for each participant enrolled to FABREC.  In 
order to receive payment, each site must have a fully executed subcontract in place with the lead 
site, Dana-Farber Cancer Institute.   
 
13.4 
Other costs 
This study will not provide any additional payment/funding for any additional costs.  All care, 
including PMRT (either arm) should be billed to the patient's insurance company or the patient 
as your site does for any other standard clinical care/treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 32 
14. REFERENCES 
 
1. Katipamula R, Degnim AC, Hoskin T, et al. Trends in mastectomy rates at the Mayo Clinic 
Rochester: effect of surgical year and preoperative magnetic resonance imaging. Journal of 
clinical oncology: official journal of the American Society of Clinical Oncology. 2009; 
27(25):4082‐4088. 
2. Cemal Y, Albornoz CR, Disa JJ, et al. A paradigm shift in U.S. breast reconstruction: Part 2. 
The influence of changing mastectomy patterns on reconstructive rate and method. Plastic 
and reconstructive surgery. 2013; 131(3):320e‐326e. 
3. Tseng YD, Uno H, Hughes ME, et al. Biological Subtype Predicts Risk of Locoregional 
Recurrence AfterMastectomy and Impact of Postmastectomy Radiation in a Large National 
Database. International journal of radiation oncology, biology, physics. 2015; 93(3):622‐
630. 
4. Breastcancer.org. 2015; http://www.breastcancer.org/symptoms/understand_bc/statistics. 
5. Greenberg CC, Lipsitz SR, Hughes ME, et al. Institutional variation in the surgical treatment 
of breast cancer: a study of the NCCN. Annals of surgery. 2011; 254(2):339‐345. 
6. Ebctcg, McGale P, Taylor C, et al. Effect of radiotherapy after mastectomy and axillary 
surgery on 10‐yearrecurrence and 20‐year breast cancer mortality: meta‐analysis of 
individual patient data for 8135 women in 22 randomised trials. Lancet. 2014; 
383(9935):2127‐2135. 
7. Rowland JH, Desmond KA, Meyerowitz BE, Belin TR, Wyatt GE, Ganz PA. Role of breast 
reconstructive surgery in physical and emotional outcomes among breast cancer survivors. 
Journal of the National Cancer Institute. 2000; 92(17):1422‐1429. 
8. Dean C, Chetty U, Forrest AP. Effects of immediate breast reconstruction on psychosocial 
morbidity after mastectomy. Lancet. 1983; 1(8322):459‐462. 
9. Alderman AK, Kuhn LE, Lowery JC, Wilkins EG. Does patient satisfaction with breast 
reconstruction change over time? Two‐year results of the Michigan Breast Reconstruction 
Outcomes Study. Journal of the American College of Surgeons. 2007; 204(1):7‐12. 
10. Joslyn SA. Patterns of care for immediate and early delayed breast reconstruction following 
mastectomy. Plastic and reconstructive surgery. 2005; 115(5):1289‐1296. 
11. Alderman AK, McMahon L, Jr., Wilkins EG. The national utilization of immediate and early 
delayed breast reconstruction and the effect of sociodemographic factors. Plastic and 
reconstructive surgery. 2003; 111(2):695‐ 703; discussion 704‐695. 
12. Al‐Ghazal SK, Sully L, Fallowfield L, Blamey RW. The psychological impact of immediate 
rather than delayed breast reconstruction. European journal of surgical oncology: the journal 
of the European Society of Surgical Oncology and the British Association of Surgical 
Oncology. 2000; 26(1):17‐19. 
13. Tallet AV, Salem N, Moutardier V, et al. Radiotherapy and immediate two‐stage breast 
reconstruction with a tissue expander and implant: complications and esthetic results. 
International journal of radiation oncology, biology, physics. 2003; 57(1):136‐142. 
14. Ascherman JA, Hanasono MM, Newman MI, Hughes DB. Implant reconstruction in breast 
cancer patients treated with radiation therapy. Plastic and reconstructive surgery. 2006; 
117(2):359‐365. 
15. Ho AL, Bovill ES, Macadam SA, Tyldesley S, Giang J, Lennox PA. Postmastectomy 
radiation therapy afterimmediate two‐stage tissue expander/implant breast reconstruction: a 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 33 
University of British Columbia perspective. Plastic and reconstructive surgery. 2014; 
134(1):1e‐10e. 
16. Albornoz CR, Matros E, McCarthy CM, et al. Implant breast reconstruction and radiation: a 
multicenter analysis of long‐term health‐related quality of life and satisfaction. Annals of 
surgical oncology. 2014; 21(7):2159‐2164. 
17. Kern P, Zarth F, Kimmig R, Rezai M. Impact of Age, Obesity and Smoking on Patient 
Satisfaction with Breast Implant Surgery ‐ A Unicentric Analysis of 318 Implant 
Reconstructions after Mastectomy. Geburtshilfe und Frauenheilkunde. 2015; 75(6):597‐604. 
18. Munhoz AM, Aldrighi CM, Montag E, et al. Clinical outcomes following nipple‐areola‐
sparing mastectomy with immediate implant‐based breast reconstruction: a 12‐year 
experience with an analysis of patient and breast related factors for complications. Breast 
cancer research and treatment. 2013; 140(3):545‐555. 
19. Fowble B, Park C, Wang F, et al. Rates of Reconstruction Failure in Patients Undergoing 
Immediate 
Reconstruction with Tissue Expanders and/or Implants and Postmastectomy Radiation 
Therapy. International journal of radiation oncology, biology, physics. 2015; 92(3):634‐641. 
20. Cordeiro PG, Albornoz CR, McCormick B, et al. What Is the Optimum Timing of 
Postmastectomy Radiotherapy in Two‐Stage Prosthetic Reconstruction: Radiation to the 
Tissue Expander or Permanent Implant? Plastic and reconstructive surgery. 2015; 
135(6):1509‐1517. 
21. Haviland JS, Owen JR, Dewar JA, et al. The UK Standardisation of Breast Radiotherapy 
(START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10‐
year follow‐up results of two randomised controlled trials. The Lancet. Oncology. 2013; 
14(11):1086‐1094. 
22. Shaitelman SF, Schlembach PJ, Arzu I, et al. Acute and Short‐term Toxic Effects of 
Conventionally Fractionated vs Hypofractionated Whole‐Breast Irradiation: A Randomized 
Clinical Trial. JAMA oncology. 2015; 1(7):931‐941. 
23. Whelan TJ, Pignol JP, Levine MN, et al. Long‐term results of hypofractionated radiation 
therapy for breast cancer. The New England journal of medicine. 2010; 362(6):513‐520. 
24. Bekelman JE, Sylwestrzak G, Barron J, et al. Uptake and costs of hypofractionated vs 
conventional whole breast irradiation after breast conserving surgery in the United States, 
2008‐2013. Jama. 2014; 312(23):2542‐2550. 
25. Jagsi R, Falchook AD, Hendrix LH, Curry H, Chen RC. Adoption of hypofractionated 
radiation therapy for breast cancer after publication of randomized trials. International 
journal of radiation oncology, biology, physics. 2014; 90(5):1001‐1009. 
26. Rajagopalan MS, Flickinger JC, Heron DE, Beriwal S. Changing practice patterns for breast 
cancer radiation therapy with clinical pathways: An analysis of hypofractionation in a large, 
integrated cancer center network. Practical radiation oncology. 2015; 5(2):63‐69. 
27. Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node‐positive 
premenopausal women with breast cancer. The New England journal of medicine. 1997; 
337(14):956‐962. 
28. Duxbury PJ, Gandhi A, Kirwan CC, Jain Y, Harvey JR. Current attitudes to breast 
reconstructive surgery for women at risk of post‐mastectomy radiotherapy: A survey of UK 
breast surgeons. Breast. 2015; 24(4):502‐512. 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 34 
29. Recht A, Edge SB, Solin LJ, et al. Postmastectomy radiotherapy: clinical practice guidelines 
of the American Society of Clinical Oncology. J Clin Oncol. 2001; 19(5):1539‐1569. 
30. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high‐risk 
premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish 
Breast Cancer Cooperative Group 82b Trial. N Engl J Med. 1997; 337(14):949‐955. 
31. Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high‐risk 
postmenopausal breastcancer patients given adjuvant tamoxifen: Danish Breast Cancer 
Cooperative Group DBCG 82c randomised trial. Lancet. 1999; 353(9165):1641‐1648. 
32. Wong JS, et al., 2015 American Society of Therapeutic Radiation Oncology Annual Meeting, 
International Journal of Radiation Oncology Biology Physics, 93(3): E11. 
33. Brady MJ, Cella DF, Mo F, et al. Reliability and validity of the Functional Assessment of 
Cancer Therapy‐Breast quality‐of‐life instrument. Journal of clinical oncology: official 
journal of the American Society of Clinical Oncology. 1997; 15(3):974‐986. 
34. Nguyen J, Popovic M, Chow E, et al. EORTC QLQ‐BR23 and FACT‐B for the assessment of 
quality of life in patients with breast cancer: a literature review. Journal of comparative 
effectiveness research. 2015; 4(2):157‐166. 
35. Eltahir Y, Werners LL, Dreise MM, et al. Quality‐of‐life outcomes between mastectomy 
alone and breastreconstruction: comparison of patient‐reported BREAST‐Q and other health‐
related quality‐of‐life measures. Plastic and reconstructive surgery. 2013; 132(2):201e‐209e. 
36. Pusic AL, Klassen AF, Scott AM, Klok JA, Cordeiro PG, Cano SJ. Development of a new 
patient‐reported outcome measure for breast surgery: the BREAST‐Q. Plastic and 
reconstructive surgery. 2009; 124(2):345‐353. 
37. Horowitz M, Wilner N, Alvarez W. Impact of Event Scale: a measure of subjective stress. 
Psychosomatic medicine. 1979; 41(3):209‐218. 
38. Hyer K, Brown LM. The Impact of Event Scale‐‐Revised: a quick measure of a patient's 
response to trauma. Am J Nurs. 2008; 108(11):60‐68; quiz 68‐69. 
39. Sheehan J, Sherman KA, Lam T, Boyages J. Association of information satisfaction, 
psychological distress and monitoring coping style with post‐decision regret following breast 
reconstruction. Psycho‐oncology. 2007; 16(4):342‐351. 
40. Zhong T, Hu J, Bagher S, et al. Decision regret following breast reconstruction: the role of 
self‐efficacy and satisfaction with information in the preoperative period. Plastic and 
reconstructive surgery. 2013; 132(5):724e‐ 734e. 
41. Korus LJ, Cypel T, Zhong T, Wu AW. Patient‐reported outcome measures in reconstructive 
breast surgery: is there a role for generic measures? Plastic and reconstructive surgery. 2015; 
135(3):479e‐490e. 
42. Devoogdt N, Van Kampen M, Geraerts I, Coremans T, Christiaens MR. Lymphoedema 
Functioning, Disability and Health questionnaire (Lymph‐ICF): reliability and validity. 
Physical therapy. 2011; 91(6):944‐957. 
43. Hopwood P, Fletcher I, Lee A, Al Ghazal S. A body image scale for use with cancer patients. 
European journal of cancer. 2001; 37(2):189‐197. 
44. de Souza, J. A., Yap, B. J., Hlubocky, F. J., Wroblewski, K., Ratain, M. J., Cella, D. and 
Daugherty, C. K. (2014), The development of a financial toxicity patient-reported outcome in 
cancer: The COST measure. Cancer, 120: 3245–3253. doi:10.1002/cncr.28814 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 35 
45. Kent, E. E., Forsythe, L. P., Yabroff, K. R., Weaver, K. E., de Moor, J. S., Rodriguez, J. L. 
and Rowland, J. H. (2013), Are survivors who report cancer-related financial problems more 
likely to forgo or delay medical care?. Cancer, 119: 3710–3717. doi:10.1002/cncr.28262 
46. Van Ryn M, Sanders S, Kahn K, et al. Objective burden, resources, and other stressors 
among informal cancer caregivers: a hidden quality issue? Psycho-oncology. 2011;20(1):44-
52. doi:10.1002/pon.1703. 
47. Freidlin B, Korn EL, George SL, Gray R. Randomized clinical trial design for assessing 
noninferiority when superiority is expected. J Clin Oncol. 2007; 25(31):5019‐5023. 
48. D'Agostino RB, Jr. Propensity score methods for bias reduction in the comparison of a 
treatment to a nonrandomized control group. Statistics in medicine. 1998; 17(19):2265‐2281. 
49. Schafer JL. Multiple imputation: a primer. Stat Methods Med Res. 1999; 8(1):3‐15. 
50. Schluchter MD, Greene T, Beck GJ. Analysis of change in the presence of informative 
censoring: application to a longitudinal clinical trial of progressive renal disease. Stat Med. 
2001; 20(7):989‐1007. 
51. Schluchter MD. Methods for the analysis of informatively censored longitudinal data. Stat 
Med. 1992; 11(14‐15):1861‐1870. 
52. Li J, Zhao L, Tian L et al, 2014: A Predictive Enrichment Procedure to Identify Potential 
Responders to a New Therapy for Randomized, Comparative, Controlled Clinical Studies; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 36 
15. 
APPENDICES 
 
A. Data Safety Monitoring Plan  
B. Radiation Therapy Treatment Guidelines 
C. How to Take Reconstruction Photographs 
D. List of Patient-Facing Study Materials 
E. Script for Annual Follow-up Calls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 37 
 
 
APPENDIX A:  DATA SAFETY MONITORING PLAN  
 
 
 
 
 
 
 
 
 
 
 
FABREC Trial 
DFCI IRB Protocol #: 16-304 
 
 
 
 
 
APPENDIX A 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
Lead Institution: 
• Dana-Farber Cancer Institute 
 
Sponsor: 
• Dana-Farber/Harvard Cancer Center (DF/HCC) Overall Investigator 
 
Study Co-Chairs: 
• Rinaa Punglia MD MPH 
• Julia Wong MD 
 
Coordinating Center: 
• Dana-Farber Cancer Institute, Boston, MA 
 
Central Study Coordinator: 
• FABREC_Study@dfci.harvard.edu 
 
 
 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 38 
INTRODUCTION 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC that 
will be participating in the research protocol. 
 
Purpose 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures.        
 
Multi-Center Data and Safety Monitoring Plan Definitions 
DF/HCC Multi-Center Protocol:  A research protocol in which one or more outside institutions 
are collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC investigator is the 
sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial 
Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-
Farber Cancer Institute (DFCI)) responsible for the coordination, development, submission, and 
approval of a protocol as well as its subsequent amendments per the DFCI IRB and applicable 
regulatory guidelines.  The Lead Institution is the home of the DF/HCC Sponsor. The Lead 
Institution also serves as the Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the DF/HCC Overall Principal Investigator, who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. The DF/HCC 
Sponsor has ultimate authority over the protocol and is responsible for the conduct of the study at 
DF/HCC and all Participating Institutions. The DF/HCC Sponsor is the same person as the 
DF/HCC Overall Principal Investigator. 
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC consortium 
that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  
The Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority 
and responsibility for the overall conduct of the study.    
 
Coordinating Center: The entity (Lead Institution, Dana-Farber Cancer Institute) that provides 
administrative support to the DF/HCC Sponsor in order that he/she may fulfill the 
responsibilities outlined in the protocol document and DSMP, and as specified in applicable 
regulatory guidelines. The Lead Institution is the Coordinating Center for the DF/HCC Multi-
Center Protocol.  
 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible for registering 
human subjects for trials, ensuring high-quality standards are used for data collection and the 
ongoing management of clinical trials, auditing, and data and safety monitoring. ODQ also 
coordinates quality assurance efforts related to multi-center clinical research. 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 39 
GENERAL ROLES AND RESPONSIBILITIES 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the 
Participating Institutions are expected to adhere to the following general responsibilities:  
 
DF/HCC Sponsor 
The Sponsor, DF/HCC Overall Principal Investigator, will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
• Oversee the coordination, development, submission, and approval of the protocol as well 
as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives adequate 
protocol training and/or a Site Initiation Visit prior to enrolling participants and 
throughout trial’s conduct as needed. 
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Ensure compliance with all requirements as set forth in the Code of Federal Regulations, 
applicable DF/HCC requirements, HIPAA requirements, and the approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior to 
extending the protocol to that site. 
• Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements.  
 
Coordinating Center  
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development.  
• Review registration materials for eligibility and register participants from Participating 
Institutions with DF/HCC ODQ. 
• Distribute protocol and informed consent document updates to Participating Institutions 
as needed. 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the DF/HCC 
Sponsor for timely review.   
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the 
DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide Participating Institutions with information regarding DF/HCC requirements that 
they will be expected to comply with. 
 
• Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring.  

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 40 
• Maintain Regulatory documents of all Participating Institutions which includes but is not 
limited to the following: local IRB approvals/notifications from all Participating 
Institutions, confirmation of Federalwide Assurances (FWAs) for all sites, all SAE 
submissions, Screening Logs for all sites, IRB approved consents for all sites 
• Conduct regular communications with all Participating Institutions (conference calls, 
emails, etc.) and maintain documentation all relevant communications. 
 
Participating Institution 
Each Participating Institution is expected to comply with all applicable federal regulations and 
DF/HCC requirements, the protocol and HIPAA requirements.  
 
The general responsibilities for each Participating Institution may include but are not limited to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as 
requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial as 
required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research related 
activities.  
• Submit Serious Adverse Event (SAE) reports to local IRB per local requirements and to 
the Coordinating Center, in accordance with DF/HCC and protocol requirements.  
• Submit protocol deviations and violations to local IRB per local requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at the 
conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring queries or 
audit findings. 
 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol.  
 
Protocol Distribution 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
Protocol Revisions and Closures 
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its 
IRB of these revisions. 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 41 
Non-life-threatening revisions: Participating Institutions will receive written notification of 
protocol revisions regarding non life-threatening events from the Coordinating Center. Non-life-
threatening protocol revisions must be IRB approved and implemented within 90 days from 
receipt of the notification. 
 
Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to protect lives 
with follow-up by fax, mail, e-mail, etc.  Life-threatening protocol revisions will be implemented 
immediately followed by IRB request for approval. 
 
Protocol closures and temporary holds: Participating Institutions will receive notification of 
protocol closures and temporary holds from the Coordinating Center. Closures and holds will be 
effective immediately.  In addition, the Coordinating Center, will update the Participating 
Institutions on an ongoing basis about protocol accrual data so that they will be aware of 
imminent protocol closures. 
 
Informed Consent Requirements 
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow the 
consent template as closely as possible and should adhere to specifications outlined in the 
DF/HCC Guidance Document on Model Consent Language for PI-Initiated Multi-Center 
Protocols.  This document will be provided separately to each Participating Institution. 
 
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior 
to submission to their local IRB. The approved consent form must also be submitted to the 
Coordinating Center after approval by the local IRB for all consent versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the sub-investigator 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that only 
attending physicians obtain informed consent and re-consent to interventional trials (i.e. drug 
and/or device trials).   
 
IRB Documentation 
The following must be on file with the Coordinating Center: 
Initial approval letter of the Participating Institution's IRB.  
Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB.  
Participating Institution’s IRB approval for all amendments. 
Annual approval letters by the Participating Institution's IRB. 
 
IRB Re-Approval 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received from 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 42 
the Participating Institution on or before the anniversary of the previous approval date.   
 
Participant Confidentiality and Authorization Statement 
In 1996, Congress passed the first federal law covering the privacy of health information known 
as the Health Insurance Portability and Accountability Act (HIPAA). Any information, related to 
the physical or mental health of an individual is called Protected Health Information (PHI). 
HIPAA outlines how and under what circumstances PHI can be used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the course of a 
study, the study participant must sign an authorization statement.  This authorization statement 
may or may not be separate from the informed consent document.  The Coordinating Center, 
with the approval from the DFCI IRB, will provide a consent template, with information 
regarding authorization for the disclosure of protected health information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its 
trials. However, because of the nature of these trials, certain protected health information must 
be collected. DF/HCC has chosen to use authorizations, signed by the participant in the trial, 
rather than limited data sets with data use agreements. 
 
DF/HCC Multi-Center Protocol Confidentiality 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should be 
de-identified. It is recommended that the assigned DF/HCC ODQ case number (as described 
below) be used for all participant specific documents. Participant initials may be included or 
retained for cross verification of identification.  
 
DF/HCC Multi-Center Protocol Registration Policy 
 
Participant Registration and Randomization  
Protocol treatment may not begin without confirmation from the Coordinating Center 
that the participant has been registered and randomized.  
 
Sites may fax or securely email registration paperwork (eligibility checklist, all pages of signed 
ICF, and HIPAA authorization form, if separate from ICF) to the lead site at any time, 24 hours a 
day/7 days a week.   
 
The lead site will process the registration paperwork and send a registration/randomization 
confirmation email to the site within 24 business hours.  Business hours for this study are defined 
as: Monday through Friday from 8:00 AM to 5:00 PM Eastern Time, not including holidays. 
 
Initiation of Therapy 
Participants must be registered with the DF/HCC ODQ before receiving treatment.  Treatment 
may not be initiated until the Participating Institution receives confirmation of the participant’s 
registration from the Coordinating Center. The DF/HCC Sponsor and DFCI IRB must be notified 
of any violations to this policy. 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 43 
 
Eligibility Exceptions 
The DF/HCC ODQ will make no exceptions to the eligibility requirements for a protocol without 
DFCI IRB approval. The DF/HCC ODQ requires each institution to fully comply with this 
requirement. 
 
DF/HCC Unique Study ID Number 
At the time of registration, ODQ requires identifiers for all subjects (including, name, date of 
birth, address, etc.; see eligibility checklist). Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique study ID number.  
Participating Institutions should submit all de-identified subsequent communication and 
documents to the Coordinating Center, using this study ID number to identify the subject.   
 
Protocol Deviations, Exceptions and Violations 
Federal Regulations require an IRB to review proposed changes in a research activity to ensure 
that researchers do not initiate changes in approved research without IRB review and approval, 
except when necessary to eliminate apparent immediate hazards to the participant. DF/HCC 
requires all departures from the defined procedures set forth in the IRB approved protocol to be 
reported to the DF/HCC Sponsor, who in turn is responsible for reporting to the DFCI IRB. 
 
 
For reporting purposes, DF/HCC uses the terms “violation,” “deviation,” and “exception” to 
describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy for 
reporting to their local IRB. 
 
Definitions 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
 
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB prior 
to its initiation or implementation.  
 
 
Reporting Procedures 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations and 
violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol 
violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI IRB. 
The Participating Institution must submit the deviation request to the Coordinating Center who 
will then submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation 
is submitted to the Participating Institution IRB, per institutional policy. A copy of the 
Participating Institution’s IRB report and determination will be forwarded to the Coordinating 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 44 
Center within 10 business days after the original submission.  
 
All protocol violations must be sent to the Coordinating Center in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for review. 
Subsequently, the Participating Institution’s IRB violation/deviation report will be submitted to 
the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will forward all violation 
reports to CTEP via an internal DF/HCC process, as applicable. 
 
Safety Assessments and Toxicity Monitoring 
The study teams at all participating institutions are responsible for protecting the safety, rights 
and well-being of study participants. Recording and reporting of adverse events that occur during 
the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated treatment will be 
evaluated for safety. The safety parameters include all laboratory tests and hematological 
abnormalities, physical examination findings, and spontaneous reports of adverse events reported 
by participants.  All toxicities encountered during the study will be evaluated according to the 
criteria specified in the protocol. Life-threatening toxicities must be reported immediately to the 
DF/HCC Sponsor via the Coordinating Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
Guidelines for Reporting Serious Adverse Events  
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are detailed 
in the Adverse Event Reporting section of the protocol.  
 
 
 
 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the Coordinating 
Center following the DFCI IRB Adverse Event Reporting Policy (see AE Reporting section of 
protocol).  
 
The Coordinating Center will maintain documentation of all Participating Institution Adverse 
Event reports and be responsible for communicating to all participating investigators, any 
observations reportable under the DFCI IRB Reporting Requirements.  Participating Institutions 
will review and submit to their IRB according to their institutional policies and procedures 
 
Data Management 
The DF/HCC ODQ develops case report forms (CRF/eCRFs), for use with the protocol.  These 
forms are designed to collect data for each study. The DF/HCC ODQ provides a web based 
training for eCRF users. 
   
Data Forms Review 
Data submissions are monitored for timeliness and completeness of submission. Participating 
Institutions are notified of their data submission delinquencies in accordance with the following: 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 45 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting institution will 
receive a written or electronic query from the DF/HCC ODQ Data Analyst, Coordinating Center 
or designee.  Responses to all queries should be completed and submitted within 14 calendar 
days.  Responses may be returned on the written query or on an amended paper case report form, 
or in the case of electronic queries, within the electronic data capture (eDC) system. In the case 
of a written query for data submitted on a paper case report form, the query must be attached to 
the specific data being re-submitted in response.   
 
Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will receive a Missing 
Form Report from the Coordinating Center noting the missing forms.  These reports are 
compiled by the DF/HCC ODQ and distributed on a monthly basis.  
 
MONITORING: QUALITY CONTROL 
The quality control process for a clinical trial requires verification of protocol compliance and 
data accuracy. The Coordinating Center, with the aid of the ODQ provides quality control 
oversight for the protocol. 
 
Ongoing Monitoring of Protocol Compliance 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data quality, 
and participant safety. Monitoring will occur before the clinical phase of the protocol begins, 
continue during protocol performance and through study completion. Additional monitoring 
practices may include but are not limited to; source verification, review and analysis of the 
following: eligibility requirements of all participants, informed consent procedures, adverse 
events and all associated documentation, study treatment administration, regulatory files, 
protocol departures, response assessments, and data management.  
 
Participating institutions will receive monthly email updates highlighting overall protocol 
progress and important announcements. 
 
Remote Monitoring/Auditing 
The Participating Institutions will be required to submit participant source documents to the 
Coordinating Center for the 5th participant they enroll at their site for monitoring.   
If the monitoring results in the need for significant retraining, then the Participating Institution 
will be required to submit participant source documents to the Coordinating Center for the 10th 
participant they enroll. If the monitoring results in no retraining or minimal retraining, then the 
Participating Institution will not be required to submit participant source documents to the 
Coordinating Center for the 10th participant they enroll.   
All Participating Institutions will be required to submit participant source documents to the 
Coordinating Center for the 20th participant they enroll for monitoring.   
 
Source documents can be de-identified, but should be labeled with the participant’s unique study 
ID number. 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 46 
The Participating Institutions may be required to submit additional participant source documents 
to the Coordinating Center for monitoring.  
 
Monitoring Reports 
The DF/HCC Sponsor will review all monitoring reports for remote monitoring of Participating 
Institutions to ensure protocol compliance. The DF/HCC Sponsor may increase the monitoring 
activities at Participating Institutions that are unable to comply with the protocol, DF/HCC 
Sponsor requirements or federal and local regulations. Participating Institutions may also be 
subject to an audit as determined by the DF/HCC Sponsor. 
 
Accrual Monitoring 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each participating institution. Accrual will be monitored for each participating 
institution by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual 
expectations may be subject to termination. 
 
Accrual expectations for Participating Institutions: The Study Chairs will visit sites (either in-
person or via virtual site visit) who have enrolled fewer than 75% of anticipated participants 
within the previous 6 months during the enrollment period.  These assessments will be made 
every 6 months after enrollment has started until the end of the enrollment period.  During these 
visits, the Study Chairs will give presentations about the study to the breast oncology, and/or 
radiation oncology physician teams and meet with the site PI and research coordinators to 
determine the root-cause for low enrollment and discuss mechanisms to overcome these barriers.  
The Department of Radiation Therapy at Dana-Farber Cancer Institution has committed to 
providing the time and covering the expense for these site visits, should they be necessary. 
 
AUDITING: QUALITY ASSURANCE 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards and 
procedures were followed. Auditing is the systematic and independent examination of all trial 
related activities and documents.  Audits determine if evaluated activities were appropriately 
conducted and whether data was generated, recorded and analyzed, and accurately reported per 
the protocol, Standard Operating Procedures (SOPs), and the Code of Federal Regulations 
(CFR). 
 
Audit Plan: DF/HCC Sponsored Trials 
For this study, remote monitoring and auditing will be performed simultaneously.  For the 
monitoring/auditing schedule, please see section 4.1 of the DSMP above.  If violations which 
impact participant safety or the integrity of the study are found, more participant records may be 
audited.  
 
Audit Notification 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates and re-audit dates (if applicable), which involve this protocol. All 
institutions will forward a copy of final audit and/or re-audit reports and corrective action plans 
(if applicable) to the Coordinating Center, within 12 weeks after the audit date.  
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 47 
Audit Reports  
The DF/HCC Sponsor will review all final audit reports and corrective action plans if applicable. 
The Coordinating Center, must forward these reports to the DF/HCC ODQ per DF/HCC policy 
for review by the DF/HCC Audit Committee. Based upon the audit assessments the DF/HCC 
Audit Committee could accept or conditionally accept the audit rating and final report. 
Conditional approval could require the DF/HCC Sponsor to implement recommendations or 
require further follow-up.  For unacceptable audits, the DF/HCC Audit Committee would 
forward the final audit report and corrective action plan to the DFCI IRB as applicable. 
 
Participating Institution Performance 
The DF/HCC Sponsor and DFCI IRB are charged with considering the totality of an institution’s 
performance in considering institutional participation in the protocol. 
 
Corrective Actions 
Participating Institutions that fail to meet the performance goals of accrual, submission of timely 
and accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be recommended for a six-month probation period. Such institutions must 
respond with a corrective action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved performance measures. 
Participating Institutions that fail to demonstrate significant improvement will be considered by 
the DF/HCC Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI IRB 
may terminate a site’s participation if it is determined that a site is not fulfilling its 
responsibilities as described above. 
 
 
 
 
 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 48 
APPENDIX B:  RADIATION THERAPY TREATMENT GUIDELINES  
 
General. 
Radiation therapy will be delivered to all intended fields, as 5 daily treatments per calendar 
week, excluding holidays or unavoidable factors pertaining to machine or patient availability. 
Most patients will receive nodal radiation, but on occasion, a patient may receive solely chest 
wall radiation, without a separate nodal field. If postoperative chemotherapy is not given, then 
patients must begin radiation in no more than 4 months from mastectomy.  If postoperative 
chemotherapy is given, patients must begin radiation in no more than 4 months from the 
beginning of the last cycle of chemotherapy.  Note: Concurrent systemic therapy will be 
considered on a case-by-case basis.  Please ask the study co-chairs about whether any systemic 
therapy may be administered concurrently with PMRT. 
 
 
Dose/fractionation. 
1) Conventional fractionation cohort: 
a. Tangential fields: 5000 cGy in 25 fractions (200 cGy each) 
b. Supraclavicular (+/‐ axillary) field: 4600 – 5000 cGy in 23 – 25 fractions (200 cGy 
each) 
2) Hypofractionation cohort: 
a. Tangential fields: 4256 cGy in 16 fractions (266 cGy each) 
b. Supraclavicular (+/‐ axillary) field: 3990 cGy in 15 fractions (266 cGy each) 
 
Patient position and simulation. The patient will be positioned supine, in an immobilization 
device as per institutional protocol. Treatment planning must utilize CT simulation. Techniques 
to minimize radiation dose to the heart, such as deep inspiration breath hold (DIBH) or gating are 
encouraged. 
 
Target volumes and field arrangement. 
1) Chest wall/tissue expander or implant: tangential fields typically will include the planning 
target volume (mastectomy scar, skin, subcutaneous tissue, muscles of the chest wall, and ribs 
underlying the mastectomy site). Ipsilateral internal mammary lymph nodes (IMNs; 1st  2nd  or 
3rd  intercostal spaces) may be included at the discretion of the treating physician. A separate, 
anterior IMN field is not permitted. There will be no mastectomy scar boost. 
 
2) Supraclavicular (+/‐ axillary) nodes: Anterior‐posterior fields as required to achieve dose 
homogeneity (see “Treatment planning requirements” below). Typical medial and superior 
borders are the pedicle and top of first rib, respectively. The inferior border will be matched to 
the superior border of the tangential fields as per institutional protocol. The lateral border will be 
set by the treating physician. Blocks (e.g., spinal cord, humeral head) may be utilized. 
 
Treatment planning requirements. 
1) Megavoltage (6 MV or above) is required. CT simulation will permit generation of a 3D 
conformal or IMRT plan. 
2) Coverage of the planning target volumes by isodose curves will be as per the treating 
physician discretion. The only coverage stipulation is 95% coverage at the rib-lung interface. 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 49 
Other coverage decisions are at the discretion of the treating physician, to allow for clinical 
judgment to address different clinical scenarios, and to optimize the generalizability of the results 
of this pragmatic trial. 
3) The maximum dose inhomogeneity permitted is 110% for the lymph nodes and 110% (with 
less than 1 cc > 110%) for the chest wall. Lightly‐weighted oblique subfields are permitted. 
Note: There is no specified maximum dose on the composite plan.  The composite 
plan may exceed 110%.  Individual plans for the chest wall and lymph nodes must not 
exceed 110% inhomogeneity. 
4) Mean cardiac dose and V20 (volume of ipsilateral lung receiving 20 Gy) will be recorded. 
5) Inclusion of IMNs will be recorded. 
6) The metal port in the tissue expander should be accounted for in the planning process, and if 
possible, the correct density used. 
7) Bolus to the mastectomy scar or chest wall may be prescribed at the discretion of the treating 
physician (specifics will be recorded at the time of patient registration). 
 
Treatment verification and quality assurance. 
1) Machine verification films are required on or prior to the first treatment day, and at least once 
a week during treatment or as per institutional protocol. 
2) The radiation therapy “chart” will be reviewed by the physics staff as per institutional 
protocol, to evaluate for discrepancies in documentation, dose prescription and dose recording. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 50 
APPENDIX C:  PHOTOGRAPHIC GUIDELINES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX C BEGINS ON THE NEXT PAGE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 51 
PHOTOGRAPHIC GUIDELINES 
For Clinicians and/or Patients  
 
Thank you for your participation in this study. We greatly appreciate you taking the time to 
complete study activities and be part of our study. 
 
Instructions: 
• Although we encourage you to have your photos taken by a clinician, if you are unable to 
have your photos taken during your visit to the clinic, or if you will not be in clinic for 
future photographs, then we kindly request that you take your photographs yourself 
following the guidelines below. If it is difficult to take your own photographs, then you 
may have someone (caregiver, family member, friend, etc.) help you. 
 
• You may use a digital camera or cell phone camera to take your photographs. Make sure 
to remove all articles of clothing to show your surgical site in the photos. You should not 
have on a bra or shirt for any of these photos.  
 
• We will kindly ask you to retake any photos that do not meet the guidelines set below.  
This is to ensure the scientific quality of the photographs.  
 
When to take photos: 
• Before you receive any radiation treatment, please take and submit 5 photos. 
• 6 months after receiving radiation treatment, please take and submit 5 photos. 
• 12 months after receiving radiation treatment, please take and submit 5 photos. 
• 18 months after receiving radiation treatment, please take and submit 5 photos. 
 
How to submit your photos: 
• If your clinician takes your photos for you, the s/he will submit your photos on your 
behalf. 
• If you take your photos yourself, then please call or email the FABREC Central Study 
Coordinator at 617-582-8484 and/or FABREC_Study@dfci.harvard.edu.  She will 
provide you with a link to a secure webpage where you will be able to upload your 
photos from your computer or mobile phone. 
 
 
Why are these photos being collected for the FABREC Study? 
In this research study, we are comparing the effects of short-course radiation therapy 
(hypofractionation) with the effects of long course (conventional) radiation therapy on: 
• Quality of life (how much radiation therapy impacts well-being)  
• Cosmetic outcome (how reconstruction looks after receiving radiation therapy)* 
• Risks of radiation therapy 
This study will help us learn about which radiation schedule is better for women who 
have had breast reconstruction after mastectomy.  
 
*The way we will learn about the cosmetic outcomes is from these photos. 
Photo guidelines continued on the next page  

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 52 
How to take the photos: 
 
Guidelines 
• Please photograph your reconstructive surgery site (the chest area between your neck and 
just below your belly button; please include your shoulders in the photos). 
• Please do not include your face in the photographs. 
• Please minimize any extra materials in the background of your photos. You can minimize 
background issues by taking your photos while standing in front of a solid colored wall 
(preferably a white wall).  
• Please try to minimize shadows on your chest area by taking the photos in a well-lit 
location.  
 
Note: The model in these photos is wearing a sweater. You should not wear a bra or clothing in 
your photos in order to view the skin and other areas around your surgery site. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Photo 1 of 5, Frontal View:  
For this photo, please capture the 
reconstruction site in a frame 
which includes the top of your 
neck to the bottom of your 
bellybutton and both arms and 
shoulders. A little bit of a shadow 
can be seen in this photo, this is 
okay.  
 
Reminder:  
Photos should 
be unclothed. 
 
Photo guidelines continued on the next page  

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 53 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Photo 3 of 5, Right Oblique Angle 
View:  
Facing a right diagonal (at a 45-degree 
angle), please make sure your neck, 
shoulders, both arms and bottom of 
your bellybutton can be seen.  
 
Photo 2 of 5, Left Oblique Angle 
View:  
Facing a left diagonal (at a 45-
degree angle), please make sure 
that your neck, shoulders, both 
arms, and the bottom of your 
bellybutton can be seen.  
 
Reminder:  
Photos should 
be unclothed. 
 
Reminder:  
Photos should 
be unclothed. 
 
Photo guidelines continued on the next page  

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 54 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Photo 4 of 5, Left Lateral View:  
Facing left, please make sure your 
neck, shoulder, right arm, and the 
bottom of your bellybutton can be seen.  
 
Photo 5 of 5, Right Lateral View: 
Facing right, make sure your neck, 
shoulder, left arm, and the bottom 
of your bellybutton can be seen. 
 
Reminder:  
Photos should 
be unclothed. 
 
Reminder:  
Photos should 
be unclothed. 
 
End of photo guidelines. 

DF/HCC Protocol #: 16-304 
Protocol Version Date: 5 /  May 4, 2021 
 
 
Page 55 
APPENDIX D:  PATIENT-FACING MATERIALS 
 
The patient-facing materials are not enclosed with this protocol.  They are included in a separate 
packet of documents entitled “FABREC Patient-Facing Materials.”   
 
To obtain copies of the following materials, email FABREC_Study@dfci.harvard.edu. 
 
• Baseline Study Questionnaire 
• 6-month Study Questionnaire 
• 12-month Study Questionnaire 
• 18-month Study Questionnaire 
• Annual Follow-up Question Sheet 
• Phone Script for Annual Follow-up Questions 
• How to take Reconstruction Photographs (also found in Appendix C) 
In addition, sites should obtain a copy of the Model Informed Consent Form from the Lead Site 
by emailing FABREC_Study@dfci.harvard.edu.