A Randomized Trial of 15 Fraction vs 25 Fraction Pencil Beam Scanning Proton Radiotherapy After Mastectomy in Patients Requiring Regional Nodal Irradiation
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Mayo Clinic

 
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Mayo Clinic Radiation Oncology 
 
A randomized trial of 15 fraction vs 25 fraction pencil beam scanning proton radiotherapy after 
mastectomy in patients requiring regional nodal irradiation 
 
 
Protocol ID:  MC1631 
 
 
Study Chair: 
 
 
 
 
 
 
 
 
Co-investigator: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
 
 
                                            Physics Rochester:     
 
 
                                      
 Physics Arizona:       
 
 
                Medical Oncology/Health Outcomes:      
                                         
 
                                       
 
    Cardiology:      
 
 
                                                          Pathology:      
 
 
Study contributor(s) not responsible for patient care. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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DRAFT 4/8/2016 
Document History 
(Effective Date) 
Modification 1 
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Modification 5 
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Modification 10 
Modification 11 
Modification 12 
Modification 13 
 06/15/2016 
 09/06/2016 
10/10/2016 
01/19/2017 
04/04/2017 
05/03/2017 
08/22/2017 
01/04/2018 
05/10/2018 
09/27/2018 
12/27/2018 
09/12/2019 
06/05/2024 
 
 
 
 
 
Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
protocol document, consent form, 
regulatory issues, 
forms completion and submission 
Rad Onc Study Coordinator 
 

 
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Index 
Schema 
  1.0 
Background   
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors 
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Radiotherapy Dose Modifications Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation  
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Study Finances 
20.0 
Publication Plan 
21.0 
References 
Appendix 1 - ECOG Performance Status 
Appendix 2 – Cosmesis Score Sheet 
Appendix 3 – Breast-Q Reconstruction Module (Post-Operative) 2.0 
Appendix 4 – Breast-Q Mastectomy Module (Post-Operative ) 2.0 
 
 
 
 
 
 
 
 

 
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List of Abbreviations 
3DCRT 
3-D Conformal Radiation Therapy 
AE 
Adverse Event/Adverse Experience 
CBCT 
Cone Bean CT 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTV 
Clinical Target Volume 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IBTR 
Ipsilateral breast tumor recurrence 
IMRT 
Intensity Modulated Radiation Therapy 
IRB 
Institutional Review Board 
MRI 
Magnetic Resonance Imaging 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PTV 
Planning Target Volume 
QOL 
Quality of Life  
RBE 
Relative biologic effectiveness 
RT 
Radiation Therapy 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
XRT 
X-ray Radiation Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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ARM 1: Conventional 
Fractionation  
50.0 Gy (RBE) in 25 
daily fractions 
pStage T1-T4N0-N3M0 or  
ypStage T0-4N0-N3M0 and 
indications for chest wall and regional 
nodal irradiation after mastectomy with 
or without reconstruction 
ARM 2: 
Hypofractionation 
40 Gy (RBE) in 15 daily 
fractions 
RANDOMIZE 
Treatment 
Observation 
(Section 4.0 Test Schedule) 
Refusal 
Or End of Active Monitoring Phase 
Off-Study  
Cancer Recurrence 
Event Monitoring 
(Section 18.0 –5 years total 
follow-up) 
Patient Selection 
SCHEMA 

 
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Study Design: This is an open label phase II randomized controlled trial to determine the safety of 15 
fraction vs 25 fraction pencil beam scanning proton radiotherapy after mastectomy in patients requiring 
regional nodal irradiation. Proton therapy is recognized as a standard option for the delivery of 
radiotherapy for breast cancer.  
 
1.0 
Background 
 
1.1 
Benefits and Risks of Adjuvant Radiotherapy 
Postmastectomy radiotherapy to the chest wall and regional lymph nodes after 
mastectomy have been shown to result in improvement in rates of recurrence and survival 
for women with early stage and locally-advanced breast cancer[1].  Despite the oncologic 
benefits of radiotherapy, however, concerns have been raised regarding the attending 
toxicity of photon radiotherapy.  Data demonstrating late cardiovascular toxicity, 
particularly for women with left-sided tumors, and risk of secondary malignancy have 
garnered particular attention in recent years,[2] and these toxicities have been shown to 
partially offset the cause-specific survival benefit of adjuvant radiotherapy[1, 3].   
 
Cardiovascular toxicity has been studied in great detail and appears to be primarily 
mediated by a vascular etiology, likely with macro- and microvascular contributions. 
Correa and colleagues[4] demonstrated a likelihood of left anterior descending artery 
(LAD) stenosis for women treated with adjuvant radiotherapy for breast cancer in excess 
of what would be expected for the general population, providing indirect evidence of 
radiation-mediated coronary artery disease. Darby and co-authors[3] found that the risk 
of major coronary events (myocardial infarction, coronary revascularization, or death 
from ischemic heart disease) was related to the mean heart dose and not the LAD, 
suggesting a microvascular etiology. Notably in that study the increase in cardiac toxicity 
began within the first 5 years after radiotherapy. Cardiovascular toxicity is likely 
multifactorial, and multiple dose-volume relationships are important in determining risk 
of subsequent cardiac disease, including dose to the LAD, heart (mean heart dose and 
volumetric parameters such as V25) and left ventricle[5].  
 
Adjuvant radiotherapy for breast cancer has also been associated with an elevated risk of 
developing a secondary malignancy[1]. Specifically, radiotherapy is associated with 
increased risk of developing and dying from ipsilateral lung cancer[1, 6]. Radiotherapy is 
also associated with increased risk of developing esophageal and contralateral breast 
carcinoma[1]. This is a result of inadvertent and unnecessary dose delivered to normal 
organs adjacent to disease targets. Radiotherapy to the axillary and supraclavicular lymph 
nodes increases the risk of lymphedema following axillary surgery.[7] Radiotherapy to 
the breast and chest wall is also associated with breast fibrosis, breast shrinkage, 
worsening of cosmesis, and arm and shoulder pain.[8, 9] In patients who undergo 
mastectomy with implant based reconstruction, postmastectomy radiotherapy is 
associated with higher rates of complication including capsular contracture, unplanned 
re-operation, and reconstruction failure.[10]  
 
In summary, although adjuvant radiotherapy for breast cancer improves locoregional 
control and survival, there is strong rationale for the evaluation of novel techniques that 
reduce unnecessary exposure to normal tissue and novel dose and fractionation regimens 
which may improve the therapeutic ratio.  
 
1.2 
Rationale for Proton Therapy in Breast Cancer 

 
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Relative to photons, protons have fundamental physical advantages in the treatment of 
tumors adjacent to radiosensitive normal structures.  By exploiting the Bragg peak of 
proton beams, clinicians are able to achieve a dose distribution to target tissues similar or 
better to that accomplished with photons, while reducing unintended dose to nearby 
normal structures[11, 12].  Thus, interest in the possible benefits of breast cancer 
radiotherapy with protons is emerging, with hopes of being able to maintain or improve 
the locoregional control and cause-specific survival with the addition of photon radiation, 
while reducing toxicity.  
 
MacDonald et al [13] recently published early outcomes for a small cohort of 12 patients 
treated with proton radiotherapy following mastectomy.  All patients received chest wall 
irradiation and eleven received radiotherapy to the supraclavicular, level 3, and internal 
mammary lymph node chains. Five of the 12 women had permanent implants at the time 
of radiotherapy. Nine patients had grade 2 skin toxicity and 3 patients had grade 1 skin 
toxicity. There was no ≥ grade 3 skin toxicity reported. During treatment 6 patients 
experienced grade 1 fatigue, 5 patients experienced grade 2 fatigue, and there was one 
incident of grade 3 fatigue. By 4 weeks follow-up fatigue had completed resolved in all 
but 1 patient who continued to have grade 1 fatigue. There were no reported cases of 
pneumonitis. The average mean dose to the heart was 0.44 Gy and the average mean V20 
of the lung was 12.7%.   Cuaron et al. recently reported the results of treatment of the 
largest cohort of patients treated with proton therapy for breast cancer.[14] Four patients 
were treated after lumpectomy, 24 after mastectomy (including 14 patients with implant 
reconstruction and 1 patient with autologous reconstruction) and 2 patients received 
proton therapy after wide local excision of a chest wall recurrence. Grade 2 dermatitis 
occurred in 20 patients (71.4%), 8 of whom (28.6%) also experienced moist 
desquamation. Grade 2 esophagitis was observed in 8 patients (28.6%). There was 1 
grade 3 reconstructive complication. The median mean heart dose was 0.88Gy and the 
median V20 of the ipsilateral lung was 16.5%. This early data suggests that post-
mastectomy proton therapy is feasible and associated with reduced dose to the heart and 
lung, warranting further study.   
 
The work of MacDonald and colleagues was performed using passively scattered protons. 
A concern with this technique is the high entrance skin dose which may be associated 
with higher skin toxicity.[15] Scanning beam proton therapy, the technique proposed in 
this study, offers potential advantages over passively scattered protons including 
increased conformality with less unintended dose to normal tissues, including the 
skin.[16] However, this technique is also potentially more sensitive to uncertainties 
including interfractional as well as intrafractional motion which must be taken into 
account in treatment delivery. Rigorous clinical studies of scanning beam proton therapy 
are needed to determine the disease control and toxicity outcomes with this technique and 
to determine whether the physical dose advantages of proton therapy translate to 
substantial and lasting improvements in patient outcome. 
 
1.3 
Rationale for Hypofractionation in Breast Cancer 
            The optimal dose and fractionation regimen for postmastectomy radiotherapy remains 
unknown. The linear-quadratic formula model has emerged as the preferred method of 
predicting the relationship between fraction size and tissue response of varying 
radiotherapy regimens. Its origins stem from what has been described as a two-
component survival curve for mammalian cells represented by the curvilinear dose-
response curve for the log of cell survival.[17] In it, the biologically effective dose (BED) 
of a given fractionation regimen is related to the α/β ratio in the following equation, 

 
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where α represents the loge of the cells killed per gray and β is the loge of the cells killed 
per gray squared: 
 
BED = nd(1 + d/α/β) 
d = dose per fraction 
n = # of identical fractions 
 
The ratio of α/β is the dose at which the linear and quadratic components of cell killing 
are the same. In general, early-responding tissues such as skin desquamation have a high 
ratio whereas late-responding tissues such as dermal contraction have a low ratio and are 
very sensitive to increases in fraction size.[18]  Therefore, patients treated by Macdonald 
and colleagues and Cuaron and colleagues generally received 50.4 Gy (relative biological 
effectiveness [RBE]) to the chest wall and 45-50.4 Gy (RBE) to the regional lymph nodes 
in 1.8 Gy (RBE) fractions using an RBE value of 1.1.[14, 19]  
 
Emerging evidence, however, suggests that the α/β ratio of breast cancer may be low and 
more in line with that of late responding tissues and therefore breast cancer patients may 
not benefit from prolonged fractionation regimens.[20, 21] Indeed, the most robust data 
to date suggesting this relationship has come from the UK Standardization of Breast 
Radiotherapy (START) trials, two modern breast cancer randomized controlled trials 
examining various fractionation regimens that have recently been reported with 10-year 
follow-up. In START-A, a regimen of 50Gy in 25 fractions to the whole breast over 5 
weeks was compared with 41.6Gy or 39 Gy in 13 fractions over 5 weeks. There was no 
significant difference in local-regional relapse between the 41.6Gy and 50Gy regimens 
(6.3% vs 7.4%, p=0.65) or the 39Gy and 50Gy regimens (8.8 vs 7.4%, p=0.41).[9] 
Moderate or marked breast induration, telangiectasia, and breast edema was less common 
in the 39Gy group compared with the 50Gy group, and rates of these toxicities were no 
different between the 41.6Gy and 50Gy groups. The treatments in each arm were given 
over the same time period, enabling an estimate of sensitivity of breast cancer to changes 
in fraction size that was not confounded by differences in treatment time. An α/β ratio for 
local-regional relapse of breast cancer was determined from a meta-analysis of START-A 
and the START pilot trial (349 events, 3646 women) as 3.5 Gy (95% CI 1.2-5.7).  The 
α/β ratio for normal tissue toxicity endpoints included 3.5Gy (95% CI 0.7-6.4) for breast 
shrinkage, 4Gy (2.3-5.6) for breast induration, 3.8Gy (1.8-5.7) for telangiectasia, and 4.7 
Gy (2.4-7.0) for breast edema, suggesting that normal tissue toxicity may not be reduced 
and may even be increased when breast cancer radiotherapy fractionation regimens are 
prolonged with small daily fractions. 
 
Further evidence suggesting hypofractionated regimens may be attractive for breast 
cancer came from the START-B clinical trial, in which 50Gy in 25 fractions over 5 
weeks was compared with 40Gy in 15 fractions over 3 weeks. There was no difference in 
local-regional relapse at 10 years between 40Gy and 50Gy groups, (4.3% vs 5.5%, p=0.2) 
but breast shrinkage, telangiectasia, and breast edema were significantly less common 
with the shorter fractionation regimen. These data are consistent with the results of the 
Canadian hypofractionation trial which compared 42.5Gy in 16 fractions in 3.2 weeks to 
50Gy in 25 fractions over 5 weeks, and suggest that the use of smaller fractions is of no 
benefit in terms of tumor control or reduction in toxicity, at least in the doses used in 
these studies, and may potentially be deleterious.[9, 22]. Interestingly, if one applies an 
α/β ratio for both normal tissue toxicity and tumor control of 3.5 from START-A, the 
40Gy regimen from START-B is equivalent to 44.9Gy in 2 Gy fractions. This may imply 

 
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that differences in overall treatment time of a course of radiation therapy may be more 
important than originally thought.[23, 24]. 
 
Only a small minority of patients treated on the START-A and START-B clinical trials 
had undergone mastectomy or received regional nodal irradiation and none underwent 
immediate reconstruction. Therefore in North America, 1.8-2 Gy fraction size remains 
the “preferred” dose in these settings.(NCCN 2014)  More data is needed to determine 
whether patients treated to the chest wall and regional nodes  might also benefit from 
hypofractionated approaches. Moreover, it will be critical to understand whether 
hypofractionated radiotherapy is feasible in the setting of immediate implant based 
reconstruction. Finally, there is no data available presently on the role of 
hypofractionation for breast cancer with scanning beam proton therapy.[13] 
 
Although the use of proton therapy for breast cancer is still in early development, 
concerns regarding proton therapy have primarily been related to costs, rather than 
technical feasibility in the clinic. Proton therapy departments are more expensive to build 
as they require huge accelerators to deliver the beam.  Although protons are considered 
more expensive than conventional forms of radiation, cost-benefit studies have suggested 
cost-effectiveness in the long term due to decreased long term toxicity.[25, 26] An 
important driver of cost of both photon and proton radiotherapy is the number of 
treatments delivered to individual patients. Studies are needed to evaluate whether 
equivalent or improved outcomes can be achieved with shorter courses of therapy. 
 
The overlying hypothesis of this study is that the low α/β of breast cancer can be 
exploited with a carefully designed hypofractionated proton therapy regimen in the post-
mastectomy setting to further optimize the therapeutic ratio, improve patient 
convenience, and reduce cost.  
 
2.0 
Goals  
 
2.1 
Primary 
 
2.1.2 
To determine whether the 24 month complication rate (defined as grade 3 or 
greater late adverse events; and unplanned surgical intervention in patients who 
undergo mastectomy with reconstruction) of 15 fraction chest wall and regional 
node pencil beam scanning proton radiotherapy is acceptable relative to 25 
fraction chest wall and regional nodal pencil beam scanning  proton radiotherapy 
and worthy of further investigation. 
 
2.2 
Secondary 
 
2.21 
To evaluate acute and late toxicity 
 
2.22 
To evaluate the rate of reconstruction failure (defined as loss of the tissue 
expander or implant with the inability to replace it resulting in no final 
reconstruction or conversion to autologous reconstruction or unplanned revision 
with the addition of autologous reconstruction).[27, 28] 
 
2.23 
To determine the 5-year locoregional control, disease free survival and overall  
 
 
survival 
 

 
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2.24  
To evaluate fatigue, arm function, and other patient reported outcomes 
 
2.25  
To evaluate clinical features, treatment technique, dose-volume parameters, 
histologic and genetic variants associated with fair and poor cosmetic outcome or 
unplanned surgical intervention.  
 
2.26  
To compare echocardiographic changes, including left ventricular strain pattern, 
between fractionation regimens  
 
3.0 
Patient Eligibility    
 
 
3.1 
Inclusion Criteria  
 
3.12 
Age ≥ 18 years 
 
3.13 
Histologic confirmation of breast cancer resected by mastectomy with or without 
immediate reconstruction and chest wall and regional nodal irradiation planned. 
 
3.14 
pStage T1-T4N0-N3M0 or ypStage T0-4N0-N3M0 
 
 
Note: The axilla must be staged by sentinel node biopsy alone, sentinel node  
 
 
biopsy followed by axillary node dissection, or axillary lymph node dissection  
 
 
alone 
 
3.15 
ECOG Performance Status (PS) 0 to 2. (Appendix I). 
 
 
3.17 
Radiotherapy must begin within 12 weeks of last surgery (breast or axilla) or last 
chemotherapy. 
 
 
Note: Breast implants and expanders allowed 
 
3.18 
Able to and provides IRB approved study specific written informed consent 
 
3.19a 
Ability to complete questionnaire (s) by themselves or with assistance 
 
 
3.19b 
Able to complete all mandatory tests listed in section 4.0 
 
3.19c 
Willing to return to enrolling institution for follow-up (during the active 
monitoring phase of the study) 
 
3.19d 
Willing to provide tissue and blood samples for correlative research purposes. 
 
3.19e 
Rochester and Arizona patients: Willing to sign consent onto the Mayo Clinic 
Radiotherapy Patient Outcomes Registry and Biobanking study, IRB number 15-
000136 
 
3.30 
Rochester patients: Willing to sign consent onto Evaluation of cardiac function in 
patients undergoing proton beam or photon radiotherapy, IRB number 15-007443 
 
 

 
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3.2 
Exclusion Criteria  
 
3.21 
Medical contraindication to receipt of radiotherapy. 
3.22 
Severe active co-morbid systemic illnesses or other severe concurrent disease 
which, in the judgment of the investigator, would make the patient inappropriate 
for entry into this study or interfere significantly with the proper assessment of 
safety and toxicity of the prescribed regimens. 
 
3.23 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements or providing informed consent. 
3.24 
Active systemic lupus or scleroderma.  
 
3.25 
Pregnancy or women of childbearing potential who are sexually active and not 
willing/able to use medically acceptable forms of contraception 
 
3.26 
Prior receipt of ipsilateral breast or chest wall radiation that would result in 
significant overlap of radiation therapy fields. Prior contralateral radiotherapy for 
breast cancer is allowed.  
 
3.27 
Positive margins after definitive surgery 
 
3.28 
History of non-breast malignancies (except for in situ cancers treated only by 
local excision and basal cell and squamous cell carcinomas of the skin) within 5 
years prior study entry 
 
3.29 
Inflammatory breast cancer 
 
3.29a 
Recurrent Breast Cancer 
 
3.29b 
Boosts to the chest wall after mastectomy. Nodal boosts are allowed. 

 
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4.0 
Test Schedule 
 
Assessments, tests and 
procedures 
Treatment 
Observation7 
 
Baseline2 
Last day of 
treatment (+/-2 
days) 
 
12 weeks (+/-  8 
weeks) post-
radiation 
12 months (+/- 3 month) post 
completion of radiotherapy, 24 months 
(+/- 3 months), 36 months (+/- 3 
months), and at 5 years (+/- 3 months)   
 
History and Physical exam 
(including breast assessment/exam)1 
X 
X 
              X 
X 
 
Mammogram 
 
X10 
 
 
X11 
Cosmesis ,QOL Outcome 
Assessment and Breast-Q16 (see 
section 11.3 and Appendix) 
 
X13 
 
X 
X 
 
X 
 
 
Digital Photograph 
 
X 
 
X 
X 
X 
 
Review of surgical specimen(s) to 
confirm eligibility  
 
 
X3 
 
 
Echocardiography 9, 14 
 
X13 
 
 
 
 
 
X8 
Radiation toxicity assessment (see 
section 10.4) 
 
X 
X 
X 
X 
Serum pregnancy test 
X4 
 
 
 
 
Blood specimen5, 17, R 
 
X15 
X 
X 
X12  
Surgical tumor specimen6, 18, R 
 
X 
 
 
 
 
1. A general history & physical must be done ≤ 8 weeks prior to registration. This should include  an assessment of ECOG 
performance status (see Appendix I). 

 
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2. Following definitive surgical resection and adjuvant chemotherapy if indicated, prior to the start of radiation.  
 
3. Outside pathology must be reviewed at the treating institution.  
4. For women of childbearing potential only, must be within 7 days of radiotherapy 
5. See section 14 for collection time and preparation of samples 
6. See section 17 for collection time and preparation of samples    
7. Patients that cannot come back to Mayo Rochester within the time constraints of the follow-up schedule; efforts to obtain outside 
records and send QOL’s to be completed will occur, however the required items may not be captured. 
8. Ideally 6-12 months post radiotherapy in HER2 positive patients treated with HER2 directed therapy and in patients treated with 
anthracycline as part of routine clinical care. Only followed for Echos 1 year post therapy. 
9. Co-enrollment on IRB 15-007443 (echo protocol) is required in Rochester while open 
10. Completed ≤ 12 months prior to study entry 
11. As clinically indicated 
12. At 12 months post-treatment visit only to coincide with echocardiography. 
13. Should be ≥ 14 days since last chemotherapy 
14. After closure of IRB 15-007443 (echo protocol) echocardiography tests will be performed only in left sided patients previously 
treated with anthracycline and/or HER2 directed systemic therapy. This correlative component will occur at Rochester Mayo only.  
15. Baseline blood collection will be drawn through co-enrollment on IRB 15-000136 (Radiation Oncology Outcomes Registry and 
Biobanking Study).  
16. Breast-Q forms to be completed by patient at Observation timepoints.  
17. Post radiation blood specimen submission for Rochester site only. 
18. Surgical tumor specimen for Rochester site only.  
R. Research funded 
 
 

 
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5.0 
Randomization Factors  
5.1 
Assignment of treatments will be balanced with respect to the presence of immediate 
reconstruction  (mastectomy/immediate reconstruction vs mastectomy/no immediate 
reconstruction) using a biased-coin minimization algorithm.[29]  
  
6.0  
Registration 
4.1 
Registration will entail confirming patient eligibility and signing the informed consent 
4.2 
Pretreatment tests/procedures (see section 4.0) will be completed within the guidelines 
specified on the assessment schedule. 
4.3 
All required baseline symptoms (see section 10.0) must be documented and graded. 
7.0 
Protocol Treatment 
 
Doses throughout will be prescribed in Gy (RBE). One Gy will be the equivalent of one Gy 
(RBE) for proton therapy for the purposes of the descriptions below. Radiation therapy must 
begin within 12 weeks of the last breast cancer surgery or the last dose of adjuvant chemotherapy 
and no sooner than 14 days since the last chemotherapy. The dose, schedule, and timing 
(neoadjuvant vs adjuvant) of chemotherapy and endocrine therapy are at the discretion of the 
treating oncologists. Concurrent cytotoxic chemotherapy with radiotherapy is not allowed. Use of 
anti-HER2 therapy during radiotherapy is permitted. 
 
7.1 
Radiation Therapy Arm 1 
Patients who are randomized to arm 1 will receive conventionally fractionated  
radiotherapy in daily fractions to the chest wall plus regional nodal area CTV (with setup 
uncertainty analyses of 3-5mm perturbations along each translation axis and 3% beam 
range uncertainty).  Boosts to the chest wall after mastectomy are not permitted but nodal 
boosts to sites of initial gross disease are allowed. 
 
7.2 
Radiation Therapy Arm 2 
Patients who had a lumpectomy or mastectomy and are randomized to arm 2 will receive 
hypofractionated radiotherapy in daily fractions to the chest wall plus regional nodal area 
CTV (with setup uncertainty analyses of 3-5mm perturbations along each translation axis 
and 3% beam range uncertainty). Boosts to the chest wall after mastectomy are not 
permitted but nodal boosts to sites of initial gross disease are allowed.  
 
7.3 
Dose Specifications 
7.31 
Arm 1 post-mastectomy plus regional nodal irradiation 
7.311 Chest wall and regional nodes: 50 Gy (RBE) in 25 fractions of 2 Gy 
(RBE) 
7.32 
Arm 2 post-mastectomy plus regional nodal irradiation 
7.321 Chest wall and regional nodes: 40.05 Gy (RBE) in 15 fractions of 2.67 
Gy (RBE) 
 
7.4 
Treatment Technique 

 
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7.41 
Radiation will be delivered using available scanning beam proton equipment at 
the treating institution. 
 
7.5 
Localization, Simulation, Immobilization 
7.51 
Simulation should be performed with the patient in the supine position 
7.52 
Patients should be optimally positioned with an immobilization device such as an 
alpha cradle cast, breast board or other customized immobilization device at the 
discretion of the treating physician. 
7.53 
Arm position may be up or down. 
7.54 
For patients who have an expander in place for reconstruction, the expander 
should be fully expanded or fully collapsed in order to optimize reproducibility. 
The expander should remain in the same condition from the time of CT 
simulation until the completion of radiotherapy.  
7.55 
The CT should extend cephalad to at least the level of the mandible to include 
both elbows and extend caudally to encompass the entire lung volume. The CT 
scan thickness should be ≤5mm. 
7.56 
External skin markers, which may include permanent tattoos, are recommended 
for daily set-up. 
7.57 
KV image guidance will be performed daily. Other imaging modalities, such as 
CBCT and jVision RT, should be performed based on institutional guidelines.  
7.58 
Volumetric imaging may be performed with re-planning at the physician’s 
discretion. 
 
7.6 
Treatment Planning 
7.61 
For proton planning, 1 en face or 2 oblique fields are generally recommended. 
7.62 
The use of skin bolus is not allowed 
 
7.7 
Target Volumes 
The definitions for the CTV and normal structures for this protocol will generally follow the 
RTOG (Radiation Therapy Oncologic Group)-endorsed consensus guidelines for delineation 
for breast cancer 
with 
exceptions described below. 
 
7.71 
Post-mastectomy chest wall and regional node target volumes (Arms 1 and 2) 
Post-mastectomy chest wall and regional node CTV: Includes the chest wall, along with 
all 3 levels of the axilla, supraclavicular lymph nodes, and internal mammary lymph 
nodes. The chest wall contour is based on anatomical borders of the chest wall from the 
RTOG Breast Cancer Atlas but not extending deeper than the anterior surface of the ribs 
and intercostal muscles except in the vicinity of the internal mammary lymph nodes. The 
chest wall is also limited anteriorly to exclude the first 3 mm of tissue under the skin. In 
general, the chest wall CTV should include the mastectomy scar but not cross midline. 
Expanders, implants, or autologous tissue present for reconstruction is allowed and at 
least the most peripheral 1 cm should be included in the post-mastectomy chest wall and 
regional node CTV. In patients with subpectoral implants the implant may be excluded 
only with permission from the principal investigator or representative. The 3 levels of the 
axilla should generally follow the RTOG-endorsed consensus guidelines, although the 
superior border of level II of the axilla should extend to the most cranial CT-slice of the 
axillary vessels and [30] both the medial and lateral supraclavicular lymph nodes should 

 
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be included (Brown et al IJROBP 2015), as described by Dijkema and colleagues.[30]  In 
addition, the internal mammary lymph nodes will be defined as the region of the internal 
mammary vessels plus an approximate 5 mm medial and 5 mm lateral margin, limited 
medially by the sternum and posteriorly by the lung and heart. The internal mammary 
lymph nodes should extend from the cranial CT-slice of the 4th rib to the cranial CT-slice 
of the jugulo-subclavian junction.[30]. The internal mammary lymph node structure 
should be incorporated into the CTV but it will also have its own separate individual 
constraints. 
 
 
7.8 
Critical Structures 
 
 
7.81 
Chest wall skin: Will be defined as the first 3 mm of tissue under the body  
 
 
surface anterior to the CTV and limited superiorly by the slice where the CTV is  
 
 
>5mm from the skin; this is generally at or below the inferior border of the  
 
 
clavicular head). 
 
 
7.82  
Supraclavicular skin (after lumpectomy or mastectomy): Will be defined as the  
 
 
first 3 mm of tissue under the body surface anterior to the Breast/chest wall CTV  
 
 
limited inferiorly by the last slice of “breast skin” and superiorly by the most  
 
 
superior slice of the CTV. 
 
7.83 
Heart: To be contoured on all cases. The contour should begin just inferior to the 
level in which the pulmonary trunk branches into the left and right pulmonary 
arteries (PA) and should extend to its most inferior extent near the diaphragm. 
The esophagus, ascending and descending aorta and inferior vena cava should be 
excluded from the heart contour. The pericardium should be included but not the 
anterior pericardial fat, if present. 
 
7.84 
Left anterior descending (LAD) interventricular branch: To be contoured on left 
sided cases. “Originates from the left coronary artery and runs in the 
interventricular groove between the right and left ventricles. If it is difficult to 
see, raising the level and lowering the window may help (e.g. level 50, window 
150)”.[31]  
 
7.85 
Right coronary artery (RCA). To be contoured on all right sided cases. 
“Originates from the right side of the ascending aorta. Due to the native heart 
position in the chest, on axilla CT, it appears to start inferior to the left coronary 
artery. It moves significantly with cardiac motion, so often the location can seem 
noncontiguous from axial CT slice to slice, as the position of the AV groove 
changes.”[31] 
 
7.86 
Ipsilateral lung: To be contoured on all cases, auto-segmentation with manual 
verification is permitted 
 
7.87 
Contralateral lung: To be contoured on all cases, auto-segmentation with manual 
verification is permitted 
 

 
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7.88 
Total lung: To be contoured on all cases, auto-segmentation with manual 
verification is permitted 
 
7.89 
Esophagus: Should be contoured from its most superior extent at the lower 
border of the cricoid cartilage to the bifurcation of the trachea. 
 
7.810 Internal mammary lymph nodes: Defined as the internal mammary vessels plus 
an approximate 3 mm medial and 3 mm lateral margin to include the adjacent 
soft tissues/fat pad, and limited medially by the sternum and posteriorly by the 
lung and heart. Should extend from the cranial CT-slice of the 4th rib to the 
cranial CT-slice of the jugulo-subclavian junction.[30]. Should be incorporated 
into the CTV but it will also have its own separate individual constraints. 
 
 
 
 
 
 
 
 
 
 
7.811 Contralateral breast: Dose to the contralateral breast will not be constrained in 
treatment planning and therefore contouring of the contralateral breast is not 
required in this protocol. However, efforts should be made to limit inadvertent 
dosing of the contralateral breast. 
 
7.812 Ipsilateral Brachial Plexus: Should be contoured when present in the CTV in 
addition to 3 slices above the CTV as described by Hall and colleagues.[32] 
 
 
 
7.9 
Prescription and Normal Tissue Constraints 
 
7.91 For treatment planning, setup uncertainty analyses of 3-5mm perturbations along 
each translation axis and 3% beam range uncertainty will be performed on the CTV and 
organs at risk. All CTV target volume parameters must be met under each setup 
uncertainty analysis. Acceptability of the level of robustness achieved of normal tissue 
constraints with proton planning will be left to the discretion of the treating physician, 
provided that all criteria below are met on the planning CT, but will be reported. 
 
 
 
7.92 Normal Structures (Note: “of prescription” refers to the non-boost prescription) 
 
Arms 1 and 2 
Chest wall and Regional Node CTV 
• 
Per protocol ≥ 95% will receive ≥95% of prescription; Variation 
Acceptable ≥ 90% receives ≥ 90% of prescription 
• 
Per protocol D.01cc ≤110%; Variation Acceptable D.01cc 
≤115% 
 
 
 
Normal Structures (Note: “of prescription” refers to the non-boost prescription) 
Chest wall skin 
• 
Per protocol D1cc ≤ 96% of prescription; Variation acceptable 
D1cc ≤ 105% of prescription 
Supraclavicular skin 
• 
Per protocol D1cc ≤ 80% of prescription; Variation acceptable 
D1cc ≤ 90% of prescription 
Internal mammary nodes 

 
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• 
Per protocol 95% receives 90% of prescription; Variation 
Acceptable 90% receives 85% of prescription. 
Heart (for left-sided cases only) 
• 
Per protocol mean heart dose ≤  1.5% of prescription and; 
Variation acceptable  ≤ 3%  of prescription 
Heart (for right-sided cases only) 
• 
Per protocol mean heart dose ≤  1.5% of prescription; Variation 
acceptable ≤ 2%  of prescription 
LAD (for left-sided cases only) 
• 
Per protocol D0.01cc ≤ 6 % of prescription; Variation acceptable 
D0.01cc ≤ 30% of prescription.  
RCA (for right-sided cases only) 
• 
Per protocol D0.01cc ≤ 6% of prescription; Variation acceptable 
D0.01cc ≤ 30% of prescription.  
Ipsilateral lung 
• 
Per protocol V40 % ≤ 15% (≤ 15% of the ipsilateral lung can 
receive ≥ 40% of prescription); Variation acceptable V40 % ≤ 
20% 
• 
Ipsilateral lung mean dose, V20%, V60%, V80%, and V100% 
should be recorded 
Contralateral lung 
• 
Per protocol V10 % ≤ 10% (≤ 10% of the contralateral lung 
receives ≥ 10% of prescription); Variation acceptable V10% ≤ 
15% 
 Total lung 
• 
Record total lung V20%, V20Gy, and mean dose 
 Esophagus 
• 
Per protocol proton D1cc ≤ 72% of prescription; Variation 
acceptable D1cc ≤ 90% of prescription 
Cord 
• 
Per protocol D0.01cc ≤ 80 % 
  
 Brachial Plexus 
• 
Per protocol D0.01cc ≤ 102 % 
Variation acceptable ≤ 108% 
 
7.10 
Quality Assurance Documentation 
 
7.10.1At a minimum, the first treatment plan per physician will be centrally reviewed by 
the principal investigator or designee prior to the start of treatment. 
 
 
8.0 
Radiotherapy Dose Modifications Based on Adverse Events  
 
This study has no pre-specified interruptions due to adverse events. Treatment interruptions are 
discouraged. If radiation needs to be interrupted for > 2 days, this should be approved by the 
principal investigator or representative and documented. 
 
9.0 
Ancillary Treatment/Supportive Care 

 
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Skin changes are common complications of breast cancer radiation therapy. Usual care will be 
provided as per the treating institution’s standard of practice. Mepitel film is allowed. If the skin 
becomes erythematous and/or there is pruritis, topical steroid cream may be prescribed. The 
addition of antihistamines may be used for severe pruritis. Patients experiencing pain will be 
prescribed pain medication. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Definitions 
Adverse Event- An untoward or undesirable experience associated with the use of a 
medical product (i.e. drug, device, biologic) in a patient or research subject. 
Serious Adverse Event - Adverse events are classified as serious or non-serious.  Serious 
problems/events can be well defined and include; 
• 
death 
• 
life threatening adverse experience 
• 
hospitalization 
• 
inpatient, new, or prolonged; disability/incapacity 
• 
persistent or significant birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-
investigator may have adversely affected the rights, safety, or welfare of the subjects or 
others, or substantially compromised the research data. All adverse events that do not 
meet any of the criteria for serious, should be regarded as non-serious adverse events.  
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO)- Any 
unanticipated problem or adverse event that meets the following three criteria:  
Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, DSMB reports, interim findings, product labeling change) that in the opinion 
of the local investigator may adversely affect the rights, safety, or welfare of the subjects 
or others, or substantially compromise the research data, AND 
Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
Preexisting Condition- A preexisting condition is one that is present at the start of the 
study.  A preexisting condition should be recorded as an adverse event if the frequency, 
intensity, or the character of the condition worsens during the study period. At screening, 
any clinically significant abnormality should be recorded as a preexisting condition.  At 

 
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the end of the study, any new clinically significant findings/abnormalities that meet the 
definition of an adverse event must also be recorded and documented as an adverse event.  
 
 
10.2 
Recording Adverse Events 
 
 
 
CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting unless as otherwise stated in the 
table below. 
 
All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site: 
) 
 
10.21 Adverse event monitoring and reporting is a routine part of every clinical 
trial. First, identify and grade the severity of the event using the CTCAE 
version 4.0. Next, determine whether the event is expected or unexpected 
and if the adverse event is related to the medical treatment or procedure. With 
this information, determine whether the event must be reported as an expedited 
report (see Section 10.3). 
 
 
 
10.22 Assessment of Attribution 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event. 
 
 
 
10.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event 
Worksheet and log.  The sponsor-investigator will evaluate the event and determine the 
necessary follow-up and reporting required. 
 
a. Serious Adverse Events will be reported as part of regular adverse event 
reporting mechanisms via the data capture system and logged for review 
reporting. 
 
10.31 Investigator Reporting: Notifying the Mayo IRB: 
 
The IRB requirements reflect the guidance documents released by the Office of 
Human Research Protections (OHRP), and the Food and Drug Administration 
(FDA) in early 2007 and are respectively entitled “Guidance on Reviewing and 

 
21  
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Reporting Unanticipated Problems Involving Risks to Subjects or Others and 
Adverse Events” and “Guidance for Clinical Investigators, Sponsors, and IRBs: 
Adverse Event Reporting – Improving Human Subject Protection.” 
 
10.311 
According to Mayo IRB Policy any serious adverse event (SAE) 
which the Principal Investigator has determined to be a 
UPIRTSO must be reported to the Mayo IRB as soon as possible 
but no later than 5 working days after the investigator first learns 
of the problem/event. 
10.312 
Non-UPIRTSO – the investigator reports problems or events that 
do NOT meet criteria of an UPIRTSO in summary format at the 
time of the next continuing review. The investigator monitors the 
severity and frequency of subsequent non-UPIRTSOs. 
 
Consider the following information to collect when developing any forms for 
documentation of adverse events. 
Example 
Information collected on the adverse event worksheet (and entered in the 
research database):  
• 
Subject’s name:  
• 
Medical record number:  
• 
Disease/histology (if applicable):  
• 
The date the adverse event occurred:  
• 
Description of the adverse event:  
• 
Relationship of the adverse event to the research (drug, procedure, or 
intervention):  
• 
If the adverse event was expected:  
• 
The severity of the adverse event: (use a table to define severity scale 1-
5) 
• 
If any intervention was necessary:  
• 
Resolution: (was the incident resolved spontaneously, or after 
discontinuing treatment) 
• 
Date of Resolution:  
 
The investigator will review all adverse event reports to determine if specific 
reports need to be made to the IRB and FDA.  The investigator will sign and date 
the adverse event report when it is reviewed.  For this protocol, only directly 
related SAEs/UPIRTSOs will be reported to the IRB. 
 
10.4 
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
 
System 
Organ 
Class 
(SOC)  
 
Adverse 
event/Symptoms 
 
Baseline 
Each  
evaluation 
Grading scale 
(if not CTCAE) 
Skin and Subcutaneous 
tissue disorders 
Dermatitis Radiation 
X 
X 
CTCAE 
Telangiectasia 
X 
X 
See 10.41 

 
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Breast 
Edema 
= 
CTCAE 
Vascular 
Lymphedema 
X 
X 
CTCAE, 
BCTOS1 
Superficial soft tissue 
Fibrosis 
X 
X 
CTCAE 
Seroma Formation 
X 
X 
CTCAE 
Skin 
hyperpigmentation 
X 
X 
CTCAE 
Skin 
hypopigmentation 
X 
X 
CTCAE 
Gastrointestinal Disorders 
Esophagitis 
X 
X 
 
Infections and infestations Breast infection 
X 
X 
CTCAE 
Respiratory, thoracic and 
mediastinal disorders 
 
Pneumonitis 
X 
X 
CTCAE 
General 
disorders 
and 
administration 
site 
conditions 
Non-cardiac 
chest 
pain 
X 
X 
CTCAE 
1. BCTOS = Breast Cancer Treatment Outcomes Scale 
10.41 Grading Scale for other toxicities 
Telangiectasia: Grade 0 – None; Grade 1 – 1cm2; Grade 2 – 2-4cm2; Grade 3 - >4cm2 
 
 
10.5 
Submit via appropriate reporting mechanisms the following AEs experienced by a patient 
and not specified in Section 10.4: 
 
 
 
 
10.52 
Grade 3 and 4 AEs regardless of attribution to the study 
treatment or procedure. 
 
10.53  
Grade 5 AEs (Death) 
 
 
10.531 
Any death within 30 days of the patient’s last 
study treatment or procedure regardless of 
attribution to the study treatment or procedure 
 
10.532 
Any death more than 30 days after the patients 
last study treatment or procedure that is felt to be 
at least possibly treatment related must also be 
submitted as a Grade 5 AE, with a CTCAE type 
and attribution assigned. 
 
10.6 
Monitoring and Auditing  
 

 
23  
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The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
the sponsor, and government regulatory agencies, of all study related documents (e.g. 
source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices 
 
10.61 Medical Monitoring  
It is the responsibility of the Principal Investigator to oversee the safety of the 
study at his/her site.  This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above, as well as the 
construction and implementation of a site data and safety-monitoring plan (see 
section 10.5  “Monitoring and Auditing”).  Medical monitoring will include a 
regular assessment of the number and type of serious adverse events.  Any 
serious adverse events will be followed up by the sentinel event reporting 
procedure. 
 
 
10.62 Internal Data and Safety Monitoring Board  
 
The trial will be reviewed by the Radiation Oncology Research Executive Board 
on a yearly basis to assess accrual, adverse events, and any endpoint problems. 
Any safety issues requiring protocol changes will be communicated through 
protocol amendments. The Mayo Clinic Cancer Center (MCCC) Data Safety and 
Monitoring Board (DSMB) is responsible for reviewing the accrual and safety 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office..  
 
11.0 
Treatment Evaluation  
 
11.1 
Patients will be evaluated at baseline, then according to the Assessment Schedule 
(Section 4.0)  
 
11.2 
At the time of reevaluation, patients will be classified in the following manner: 
 
11.2.1 No evidence of disease (NED). 
 
11.2.2 Recurrence of disease (REC). Recurrence must be confirmed by biopsy. 
 
11.2.3 The site of recurrence (or failure) will also be collected and classified as local vs. 
regional vs. distant recurrence.  The specific site of failure will also be collected 
as well. 
 
11.2.4 Secondary Treatment. The date of the first retreatment and extent of retreatment 
post-recurrence (i.e. secondary resection or re-irradiation for primary disease), 
will be collected. Pathology, if available, and operative reports are required to be 
submitted per Section 18.0. 
 
11.3 
Cosmesis evaluation and Patient Reported Outcomes 
 

 
24  
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11.3.1 Digital photographs should be performed according to the schedule outlined in 
section 4.0 and should include three poses: from the front with hands on hips, 
both oblique and lateral views with hands behind the back. Recommended 
framing should go from the sternal notch to the umbilicus. If possible, patients 
should be photographed against a solid colored background such as a white sheet. 
 
11.3.2 The Breast Cancer Treatment Outcome Scale (BCTOS) is a self-report 
instrument that has high reliability and validity and will be used for evaluating 
patient-rated cosmesis according to the schedule outlined in section 4.0. 
 
11.3.3 The 4 point (excellent, good, fair, poor) adaptation of the Harvard Cosmesis 
Scale will be used by nursing staff to grade cosmesis in women who undergo 
reconstruction.  
 
11.4 
Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse 
 
Events (PRO-CTCAE) will be used for patient self-reporting of toxicities in the CTCAE. 
 
Other Patient Reported Outcome questions (fatigue, pain, arm function etc.)  
 
Unplanned surgical intervention and Reconstruction Failure will be adjudicated by a 
plastic surgeon and a general surgeon. 
 
 
*Note the Outcomes assessments will be collected through clinical mechanisms by 
the Mayo Clinic Radiotherapy Patient Outcomes Registry and Biobanking study 
These will then be correlated with analysis from this study. 
 
11.5 
Cardiopulmonary function testing  
 
11.5.1 Echocardiography is a noninvasive tool that enables the detection of 
cardiovascular disease as a result of radiotherapy. Echocardiography can detect 
pericardial disease, left ventricular systolic and diastolic dysfunction , coronary 
artery disease suggested by resting or stress-induced regional wall motion 
abnormalities, and valvular heart disease.[33] Furthermore, echocardiographic 
strain rate imaging, a measure of regional myocardial function, has previously 
been reported to detect subclinical decline in cardiac function in the anterior wall 
of patients treated with radiotherapy for left-sided breast cancer.[34] 
Echocardiography will be used to detect clinical or subclinical cardiovascular 
disease as a result of radiotherapy. 
 
12.0 
Descriptive Factors  
 
• 
Breast Quadrant: upper inner, upper outer, lower inner, lower outer 
• 
AJCC Stage 
• 
Tumor Size 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
Follow-up data will be collected and entered after the observation phase outlined in section 4.0. If 
the patient is still alive after 5 years have elapsed from the on-study date, no further follow-up is 
required by this protocol. 

 
25  
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13.1 
Patients who have a recurrence while receiving therapy or during observation will go to 
the event-monitoring phase and be followed  
13.2 
Patients who discontinue treatment or observation for reasons other than recurrence will 
go to the event-monitoring phase and be followed  
 
13.3 
Patients who will not receive any radiation treatment or who will receive radiation 
treatment elsewhere will move to event monitoring phase.  
 
13.4      A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
 
If the patient received treatment, all data up until the point of confirmation of ineligibility 
must be submitted.  Event monitoring will be required per Section 18.0 of the protocol.  
 
11.5 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 
 
14.0 
Body Fluid Biospecimens   
 
14.1 
Summary Table of Research Blood and Body Fluid Specimens to be Collected for 
this Protocol 
 
Collection Tube 
Volume to Collect 
per Tube (Number of 
Tubes to Collect) 
Timepoint: 
 
Last day of treatment 
(+/- 2 days)  
Timepoint: 
 
12 weeks post-
radiation 
(+/- 2 days) 
Timepoint: 
 
12 months post-
treatment visit  
(+/- 3 months) 
EDTA tubes  
10 mL (1) 
 
 
X 
 
 
X 
 
 
X 
No additive tubes 
(for Serum) 
10 mL (1) 
 
 
X 
 
 
X 
 
 
X 
 
The baseline sample will be obtained through co-enrollment in Radiation Oncology 
Patient Outcomes Registry and Biobanking Study, IRB#15-00136.  All other samples will 
be drawn according to the test schedule and summary table above. Collect and process last 
day of treatment, 12 weeks post-radiation, and 12 months post-treatment, blood/blood 
products according to table 14.1. Label specimen tube(s) with protocol number, study 
patient ID number, and time and date blood is drawn. 
 
14.2 
BAP will process and store specimens per standard operating procedures. 
14.3 
Bloods will be collected prospectively and stored until funding sources have been 

 
26  
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secured to investigate exploratory analyses described in section 16.64 
 
 15.0 
Drug Information 
 
 
 
Not Applicable 
 
16.0  
Statistical Considerations and Methodology  
This is an open label phase II randomized controlled trial to determine the safety of 15 fraction vs 
25 fraction scanning beam proton radiotherapy after mastectomy in patients requiring regional 
nodal irradiation.  
16.1 
Primary Endpoint: 
 
 
 
16.1.2 Primary endpoint: 24 month complicate rate, defined as the percentage of women 
randomized who develop one or more of the following events: 
1) grade 3 or higher late adverse events 
2) unplanned surgical intervention (not including planned serial fat grafting) in 
patients who undergo mastectomy with reconstruction. 
16.2      Secondary Study Endpoints: The secondary aims of this study are to characterize acute 
and late adverse events including grade ≥ 2 pneumonitis and reconstruction failure rate, assess 
patient self-reported cosmesis, evaluate fatigue, breast pain, arm function and other patient 
reported outcomes, compare the locoregional control, disease free, overall survival. Blood will be 
collected for future studies exploring dose volume and genomic predictors of adverse cosmesis 
and biomarkers of cardiotoxicity. 
The following definitions are used for the secondary endpoints of interest: 
• 
Acute adverse events (up to 90 days post-RT): any adverse event, 
regardless of attribution, that occurs in the first  90 days post-RT. 
• 
Late adverse events (up to 5 years post XRT): any adverse event that 
occurred after the first  90 days post-RT and up to 5 years post-RT. 
• 
Reconstruction failure (up to 5 years post XRT): loss of the tissue 
expander or implant with the inability to replace it resulting in no final 
reconstruction or conversion to autologous reconstruction or revised with 
the addition of autologous reconstruction.[27, 28] 
• 
Patient Reported Outcomes/Quality of life: Elements of the Patient-
Reported Outcomes Version of the Common Terminology Criteria for 
Adverse Events (PRO-CTCAE) will be used for patient self-reporting of 
toxicities. The Breast Cancer Treatment Outcomes Scale (BCTOS) will 
be used to measure patient reported functional status (pain, mobility). 
Other measures of fatigue, pain, and arm function are listed in the 
appendix.  
• 
Patient self-reported cosmetic outcomes: the patient self-reported 
outcome will be assessed using a modified Harvard Cosmesis Scale and 
a modified BCTOS at baseline, 2 years, and 5 years.   
• 
Panel assessed cosmetic outcome: in addition to patient self-reported and 
physician reported outcomes, cosmesis will be assessed by a panel of 
breast cancer medical providers using digital photographs from baseline 
and at 2 years.  The Panel will be blinded to treatment allocation. 

 
27  
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• 
IBTR: this is defined as local recurrence from trial registration as a first 
event at 5 years. IBTR is defined as both invasive and non-invasive 
breast cancer involving the same breast parenchyma as the original 
tumor.  
• 
Regional recurrence: invasive breast cancer in the axilla, regional lymph 
nodes, chest wall, and skin of the ipsilateral breast at 5 years. 
• 
Distant recurrence: metastatic cancer that has either been biopsy 
confirmed or clinically diagnosed as recurrent invasive breast cancer at 5 
years. 
• 
Invasive disease free survival: this is defined as the time from study 
registration until the occurrence of one of the events in a composite 
endpoint. This endpoint includes invasive IBTR, regional invasive breast 
cancer recurrence, distant breast cancer recurrence, death due to any 
cause, contralateral invasive breast cancer, and second primary non-
breast invasive disease. 
• 
Overall survival: is defined as the time from registration to death due to 
any cause. 
16.4 
Sample Size Determination 
The proposed trial design is a randomized phase II trial with a 1:1 randomization ratio with the 
stratification variable noted in section 5.1. The primary endpoint for this trial is the 24-month 
complication rate, as defined above. The study will plan to enroll a total of 72 evaluable patients.  An 
evaluable patient is defined as a patient who receives any dose of the protocol-defined radiotherapy.  In this 
trial, we will accrue and randomize up to 96 patients over 3 years to account for ineligibility, cancellations 
(withdrawals prior to protocol therapy), major treatment violations, or other reasons, and treat a total of 82 
patients in order to ensure 72 evaluable patients at 24 months.  
This study is designed as a non-inferiority/superiority “hybrid” design using the approach of 
Freidlin et al.[36] It is estimated that approximately 2/3 of the patients will undergo 
reconstruction. For patients who undergo mastectomy with immediate reconstruction, the rate of 
unplanned surgical complications at the Mayo Clinic is ~15% (personal communications with Dr. 
Jacobson and Dr. Lemaine 6/2014), comparable to what has been reported in the literature in the 
modern era.[27]. The rate of grade 3 or greater late toxicity in this population is expected to be ≤1 
% (Whelan ASCO 2011). For the purpose of designing this trial, we will assume a 10% 
complication rate in the control arm. We consider that a 10% increase of this rate in the 
experimental arm would be acceptable (i.e. a non-inferiority margin of 10%). Based on the results 
of the START-B clinical trial[9],  it is also plausible that toxicities in the experimental arm may 
even be reduced with the shortened fractionation schedule. Therefore, a marginal decrease in 
complication rate in the experimental arm to 5% (i.e. marginal benefit margin of 5%) may be 
reasonably expected.  Denote p0 and p1 as the 24-month complication rate in the control arm and 
experimental arm, respectively. The null hypothesis is that the complication rate in the 
experimental arm is inferior to the control rate of 10% by more than 10% (i.e. H0: p1-p0 > 10%). 
The alternative hypothesis is that the complication rate in the experimental arm is non-inferior to 
the control rate of 10% (i.e. HA: p1-p0 < 10%). 
The primary analysis will occur after a minimum of 2-years following the enrollment of the last 
evaluable patient. The 24-month complication rate for each treatment arm will be estimated using 
exact binomial method along with a 1-sided 95% confidence limit. The approach of Freidlin et al. 
allows sequentially testing the hypotheses of non-inferiority and superiority in the same trial. 
Specifically, we will first test the non-inferiority hypothesis based on non-inferiority (NI) margin 
of 10%. If the upper bound of the 1-sided 95% confidence limit for (p1 – p0) is larger than 10%, 

 
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then inferiority (of the experimental arm) cannot be ruled out. Otherwise, if the null hypothesis is 
rejected in favor of non-inferiority, then a test of superiority will be performed. Specifically, if the 
upper bound of the 1-sided 95% confidence limit for (p1 – p0) is smaller than 0%, then superiority 
of the experimental arm is concluded; otherwise, if the upper bound of the 1-sided 95% 
confidence limit for (p1 – p0) exceeds 0% but does not exceed 10%, non-inferiority without 
superiority will be concluded. No multiple-comparison adjustment is required for the two 
hypotheses tests.[36] 
 
The operating characteristics of the proposed design are evaluated by carrying out 5,000 
simulations. Using a one-sided type I error rate of 0.05 (corresponding equivalently to 
constructing a 1-sided 95% confidence limit), a study of 72 evaluable patients will have 80% 
power to reject the null hypothesis that the 24-month complication rate in the experimental arm is 
higher than that of the control arm by more than 10% (i.e. rule out inferiority) under the 
alternative hypothesis that the complication rate in the experimental arm is 5% less than that of 
the control arm (i.e. superiority). However, the design will have only 41% power when the two 
treatment arms are equivalent (i.e. the complication rate is 10% for both arms). 
 
16.6  
Analysis Plan 
 
The primary analysis will occur after a minimum of 2-years following the enrollment of 
the last evaluable patient.  
 
16.61 Primary Analysis: The primary analysis will be to estimate the difference 
in the complication rate (grade 3+ toxicities, and unplanned surgical 
interventions) between the experimental arm and the control arm, which 
is defined as 24-month complication rate in experimental arm minus that 
in the control arm. All patients meeting the eligibility criteria who have 
signed a consent form and started treatment will be in the primary 
analysis. The complication rate will be estimated using a binomial 
estimator in both experimental arm and control arm, and a one-sided 
90% confidence interval of the difference will be computed with normal 
approximation.  
 
16.62 Secondary Analyses 
 
16.621 Acute adverse events (up to 90 days post-RT): All patients who were 
registered to the study and started treatment will be included in the acute 
adverse event analysis. An acute adverse event is an AE, regardless of 
attribution, that occurs up to 90 days post-RT. The maximum grade for 
each type of acute AE will be recorded for each patient. Data will be 
summarized as frequencies and relative frequencies by treatment arm. 
Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration.   
 
16.622 Late adverse events and reconstruction failure: All patients who were 
registered to the study and started treatment will be included in the late 
adverse event and reconstruction failure analysis. A late adverse event is 
an AE, regardless of attribution, that occurs at least 90 days  post-RT and 
up to 5 years post-RT. The maximum grade for each type of late AE will 
be recorded for each patient. Data will be summarized as frequencies and 

 
29  
MC1631 
 
 
 
 
relative frequencies by treatment arm. Additionally, the relationship of 
the adverse event(s) to the study treatment will be taken into 
consideration.   
 
16.623 Quality of life: The subscales of the BCTOS, elements from CTCAE-
PRO, and other patient reported measures such as fatigue, breast pain, 
breast shape, and arm related morbidity outlined in the appendix will be 
summarized as the mean ± SD and median (minimum value, maximum 
value). Changes in the QOL measurements from baseline will be 
determined at each follow-up visit and measured by treatment arm. The 
comparison of the changes at each time point between the two treatment 
arms within each cohort will be done with a paired t-test or Wilcoxon 
signed rank test, whichever is appropriate. 
 
16.624 Cosmesis: The values of the cosmesis instruments (patient self-reported 
and panel-assessed) will be summarized with the frequencies and 
confidence intervals of fair or poor cosmesis events at baseline, 2 years, 
and 5 years by treatment arm.  
 
16.625 IBTR incidence: The IBTR cumulative incidence will be estimated using 
a competing risks method (Gooley et al.) by treatment arm. The 
competing risks will be regional/distant breast cancer recurrence and 
death. 
 
16.626 Regional recurrence incidence: The regional breast cancer recurrence 
cumulative incidence will be estimated using a competing risks method 
(Gooley et al.) by treatment arm. The competing risks will be 
local/distant breast cancer recurrence and death. 
 
16.627 Distant recurrence incidence: The distant breast cancer recurrence 
cumulative incidence will be estimated using a competing risks method 
(Gooley et al.) by treatment arm. The competing risks will be 
local/regional breast cancer recurrence and death. 
 
16.628 Disease-free survival: DFS is defined as the time from registration until 
the time of disease recurrence or death due to any cause. The DFS will 
be estimated with a Kaplan-Meier estimator and curve by treatment arm. 
Estimates will be given for specific time points along with 95% CIs. 
 
16.629 Overall survival: The OS will be estimated with a Kaplan-Meier 
estimator and curve by treatment arm. Estimates will be given for 
specific time points along with 95% CIs. 
 
16.63 Exploratory Analyses: 2D and 3D strain parameters will be analyzed after 
radiotherapy compared to baseline and will be cmopared between patients 
undergoing conventional versus hypoofractionated radiotherapy. Continuous 
variable will be compared using unpaired t tests and nonimal variables will be 
compared using contingency tables and Chi square analyses.   
 
16.64 Correlative Analyses:  
 

 
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16.641 Cardiac toxicity 
 
Cardiac toxicity remains an important late effect of radiotherapy for breast 
cancer.[3, 34, 37, 38] Echocardiography is a noninvasive tool that enables the 
detection of cardiovascular disease as a result of radiotherapy. Echocardiography 
can detect pericardial disease, left ventricular systolic and diastolic dysfunction , 
coronary artery disease suggested by resting or stress-induced regional wall 
motion abnormalities, and valvular heart disease.[33] Ideally, cardiac toxicity 
could be predicted prior to the onset of clinical symptoms to enable an earlier 
opportunity for risk stratification, surveillance, and preventative interventions 
that reduce risk. Echocardiographic strain rate imaging, a measure of regional 
myocardial function, has previously been reported to detect subclinical decline in 
cardiac function in the anterior wall of patients treated with radiotherapy for left-
sided breast cancer.[34]  
 
Patients requiring regional nodal irradiation, including treatment of the internal 
mammary lymph nodes, are at highest risk of developing radiation induced late 
cardiac complications such as coronary artery disease and myocardial 
infarction.[39] This is a result of a higher mean dose to the heart when dose the 
internal mammary lymph nodes are targeted.[3] Furthermore, many high risk 
patients are exposed to anthracyclines and HER2 directed therapies such as 
trastuzumab and pertuzumab which are also associated with cardiovascular 
toxicities [40]. Therefore, assessment of therapy-induced cardiac toxicity will be 
performed as outlined in section 4.0. 
 
Cardiac imaging modalities have limitations such as cost and operator-
dependency. In contrast, serum biomarkers are operator- independent and are a 
potentially lower cost, non-invasive means of predicting cardiac toxicity. In one 
prospective study of women undergoing adjuvant radiotherapy for breast cancer, 
mean cardiac troponin I (TnI) levels, a highly sensitive marker or cardiac 
damage, were significantly elevated after photon radiotherapy in left-sided 
patients compared to baseline, but not in right-sided patients.[34] However, other 
studies have not shown cardiac troponins to consistently be of clinical utility in 
this setting.[41, 42]. The natriuretic peptide N-terminal pro-B-type naturetic 
peptide (NT-proBNP) has also been shown to be elevated in left-sided breast 
cancer patients after photon radiotherapy for breast cancer.[42] Similar to the 
case of cardiac troponins, results have been mixed and inconsistent.[41]  There is 
no information available regarding the effects of scanning beam proton 
radiotherapy for breast cancer on these cardiac biomarkers. Blood will be drawn 
according to the schedule in section 4.0 to assess cardiac troponins and 
natriuretic peptides. Changes across time will be evaluated. 
In addition, blood will be stored for future testing of emerging biomarkers of 
radiation induced cardiac toxicity.  
 
16.643 Molecular and Genomic Predictors of Fibrosis and Reconstruction 
 
Toxicity 
 
Predictors of fibrosis and reconstruction failure are poorly understood. If a subset 
of patients at high risk of complications could be identified, their treatment could 
be personalized. Factors previously associated with worsened cosmesis after 
breast conserving therapy include inferior tumor location, large excision volume, 

 
31  
MC1631 
 
 
 
 
the presence of postoperative breast complications, higher dose (including 
radiotherapy boost), inhomogeneity, and use of concurrent chemotherapy.[43-45] 
We will analyze clinical and dose volume parameters correlated with increased 
risk of fibrosis and reconstruction failure following proton radiotherapy. However, 
clinical and dose-volume factors alone are not sufficient to explain the patient to 
patient variation in late toxicity following a course of radiation therapy.[46, 47]  
Indeed, patient specific molecular and genomic features may also be of significant 
importance in determing variation in normal tissue radiation response following 
breast cancer radiotherapy. 
 
Cytokines and growth factors are involved in the radiation response and tissue 
remodelling and may serve as predictive factors for normal tissue damage. For 
example, levels of transforming growth factor β1 (TGF- β1) vary substantially 
between individuals and has previously been associated with radiation fibrosis in 
early-stage breast cancer patients.[48] TGF- β1 is a multi-functional cytokine that 
attracts fibroblasts and stimulates collagen production.[49] Although basal levels 
may be important, expression levels of this protein are induced within an hour or 
less after exposure to ionizing radiation and therefore TGF- β1 induction 
following radiation may be a better functional marker of an elevated fibrotic 
response.[50, 51]  Therefore, blood will be drawn pre-treatment and on the last 
day of radiotherapy 1 hour following the final fraction. The pre and post 
radiotherapy levels of TGF- β1 and other proteins in the fibrotic response will be 
compared and correlated with toxicity.   
 
Mounting evidence also suggests that genetic variation may play an important role 
in determining susceptibility to radiation toxicity.[52] Radiogenomics is an 
emerging field aimed at studying genetic differences associated with variability in 
the effectiveness and toxicity of radiation.[47] We plan to use a candidate gene 
approach[47] to investigate the association of single nucleotide polymorphisms 
(SNPs), previously correlated with normal tissue toxicity, fibrosis, and 
reconstruction failure. For example, in addition to TGF- β1, SNPs in the XRCC1 
(codon 241) and XRCC1 (codon 399) genes, the protein products of which 
function in the DNA repair pathways of base excision repair and homologous 
recombination, respectively,  have been correlated with increased risk of 
subcutaneous fibrosis following breast cancer radiotherapy. 
 
laboratory at the Mayo Clinic has used a genome-wide association approach in 
human lymphoblastoid cell lines to identify radiation response biomarkers. 
C13orf34, MAD2L1, PLK4, TPD52, and DEPDC1B were identified and 
functionally validated as modifiers of radiation response. These promising 
findings, however, require further clinical validation, potentially as part of a meta-
analysis of patients treated with breast cancer radiotherapy.[47, 53]  
 
BRCA1 and BRCA2 (BRCA1/2) germline mutations are responsible for the 
majority of hereditary breast cancer. The protein products encoded by BRCA1/2 
are essential members of the homologous recombination (HR) DNA repair 
pathway.  PALB2, ATM, CHEK2, and NBN are other breast cancer predisposition 
genes that play important roles in HR. Emerging evidence suggests that HR-
deficient cells are hypersensitive to protons.[54] Compared to x-rays, DNA repair 
is delayed following proton irradiation in HR-deficient, but not in wild-type 
cells.[55] Protons result in more clustered DNA DSBs, complex chromosomal 
aberrations, and an increased frequency of sister chromatid exchanges than x-

 
32  
MC1631 
 
 
 
 
rays.[56, 57] These results suggest that the quality of DNA damage caused by 
protons has a greater requirement for DNA repair by HR. We will use emerging 
sequencing assays of known breast and ovarian cancer predisposition genes to 
develop preliminary data on whether patients with germline HR gene alterations 
are at increased risk of toxicity from proton therapy.[58] Flash frozen and paraffin 
embedded tumor and adjacent normal tissue will also be available through the 
breast spore to determine the impact of field effect cancerization toxicity 
outcomes.[59, 60]  DNA will be extracted and HR gene sequencing analyses will 
be performed on tumor and adjacent normal tissue. Although event rates will 
likely be too low for definitive conclusions to be drawn, the impact of HR 
deficiency on disease control outcomes will also be assessed, potentially as part of 
a pooled analysis of breast, prostate, and pancreatic tumors treated with x-ray and 
particle therapy from multiple institutions. The final design of these future studies 
will depend on the event rates observed, cost and state of technology at the time.  
 
16.7            Data & Safety Monitoring 
 
16.71  Data and Safety Monitoring Plans: The Mayo Clinic Cancer Center (MCCC) 
Data Safety and Monitoring Board (DSMB) is responsible for reviewing the 
accrual and safety for this trial at least twice a year, based on reports provided by 
the MCCC Statistical Office.. 
 
16.72 Adverse Event Stopping Rules: The stopping rules specified below are based on  
knowledge available at study development.  We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in consideration of 
newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation.  The study team may choose to suspend accrual 
because of unexpected adverse event profiles that have not crossed the specified 
rule below.  The following rule will be evaluated for each arm separately. 
 
Accrual will be temporarily suspended if at any time we observe events 
considered at least possibly related to study treatment (i.e. an adverse event with 
attribute specified as  “possible,” “probable,” or “definite”) that satisfy one of the 
following:  
• 
If 3 or more patients in the first 15 treated patients experience a grade 3 
or higher adverse event, besides acute dermatitis, that is at least possibly 
related to treatment within 90 days post treatment. 
• 
After the first 15 patients have been treated: if ≥ 20% of all patients 
experience a grade 3 or higher adverse event, besides acute dermatitis, 
that is at least possibly related to treatment within 90 days post treatment. 
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
 
16.9 
Inclusion of Women and Minorities 
 
16.91  This study will be available to all eligible patients, regardless of race,  or ethnic 
origin. 

 
33  
MC1631 
 
 
 
 
 
16.92  There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, or ethnicity, and there is no reason to expect 
such differences to exist..Although the planned analysis will, as always, look for 
differences in treatment effect based on racial groupings, the sample size is not 
increased in order to provide additional power for subset analyses. 
 
16.93   The geographical region served by the Mayo Clinic, has a population which 
includes approximately 5% minorities.  We expect about 5% of patients will be 
classified as minorities by race and about 100% of patients will be women.

 
34  
MC1631 
 
 
 
 
 
 
17.0  
Pathology Considerations/Tissue Biospecimens   
 
17.1  
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
 
 
Mandatory or Optional 
Type of 
Tissue to 
Collect 
Block, 
Slides, 
Core, etc. 
(# of each 
to submit) 
Process at 
Site? (Yes 
or No) 
 
Diagnostic 
 
Mandatory (as available 
through the breast 
SPORE registry) 
 
Formalin 
Fixed and 
Flash Frozen 
tumor and 
adjacent 
normal 
TBD 
 
Yes 
 
Mastectomy 
 
Mandatory (as available 
through the breast 
SPORE registry) 
Formalin 
Fixed and 
Flash Frozen 
tumor and 
adjacent 
normal 
TBD 
 
Yes 
*If no tissue available from mastectomy surgery, obtain diagnostic slides 
 
17.2 
Patients will be consented to have tissue collected through the Breast SPORE registry 
available for future research studies associated with this protocol. No tissue will be collected 
or altered in any way under this IRB . 
 
18.0 
Records and Data Collection Procedures   
 
18.1 
Submission Timetable 
Initial Material(s) -  
CRF 
Treatment 
(Compliance with Test Schedule Section 4.0) 
 
Institutional Contacts 
 
 
 
2 weeks after registration  
 
 
 
 
 
 
 
*6 months after accrual 
Patient Eligibility 
Demographics 
On-Study 
On Study: Neoadjuvant Chemotherapy 
Surgery 
Pathology of Ipsilateral Breast 
Breast Reconstruction 
Adjuvant Therapy 
Adverse Events- Baseline 
Specimen Submission: Blood (Baseline) 
Specimen Submission: Tissue (Baseline)* 

 
35  
MC1631 
 
 
 
 
 
 
CRF 
Treatment 
(Compliance with Test Schedule Section 4.0) 
 
Patient Status: Baseline 
 
 
Patient Assessment 
Off Treatment 
Submit 2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
 
 
Test Schedule Material(s) 
CRF 
 
End of Treatment 
12 weeks 
post/Observation 
Phase4  
Event Monitoring5 
Radiation Therapy 
X 
 
 
Post Mastectomy Therapy: Chest Wall 
X 
 
 
Radiation Therapy: Regional Nodes 
X 
 
 
Patient Assessment 
X 
X 
 
Specimen Submission: Blood (post rad tx) 
X 
 
 
Adverse Events Solicited 
X 
X 
 
Adverse Events: Other 
X2 
X2 
 
Off Treatment 
X2 
X2 
 
Patient Status Form 
X 
X 
X 
Specimen Submission: Tissue 
(Recurrence) 
 
X2 
 
Consent Withdrawal  
X2 
X2 
 
Lost to Follow-up 
X2 
X2 
 
Breast/Chest Wall Radiotherapy 
Questionnaire3 
X 
X 
 
1. Complete at each evaluation during Active Treatment (see Section 4.0). 
2. When applicable 
3. Survey will need to be entered manually if has not alternately been  scanned or entered electronically 
4. Active monitoring observation phase, post radiation (+/-2 days), 12 weeks (+/- 4 weeks), 12 months 
(+/- 30 days), annually for 4 years (+/-3 months, total 5 years follow-up). If patient progresses within 
observation, they will move to the event monitoring phase where they will be followed until 5 years 
of follow-up information has been completed from the end of treatment timepoint 
5. If patient has a recurrence prior to being off radiation therapy for 5 years, continue to follow yearly. 
 
 
18.3 
Data Handling and Record Keeping 
 
18.31 Confidentiality 

 
36  
MC1631 
 
 
 
 
 
 
Information about study subjects will be kept confidential and managed according 
to the requirements of the Health Insurance Portability and Accountability Act of 
1996 (HIPAA).  Those regulations require a signed subject authorization informing 
the subject of the following:  
• What protected health information (PHI) will be collected from subjects in 
this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of 
their PHI.  
(This information is contained within the Mayo IRB Informed Consent Template 
Section 14) 
In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected 
prior to the revocation of subject authorization.  For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (long term survival status that the subject is alive) at 
the end of their scheduled study period. 
 
18.32 Source Documents 
Source data is all information, original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial.  Source data are contained in source documents.  
Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical trial. 
Source documents are kept in a secure location that is locked and requires 
approved access.  
 
18.33 Case Report Forms  
The study case report form (CRF) is the primary data collection instrument for 
the study.  All data requested on the CRF must be recorded.  All missing data 
must be explained.  If a space on the CRF is left blank because the procedure was 
not done or the question was not asked, write “N/D”.  If the item is not applicable 
to the individual case, write “N/A”.  All entries should be printed legibly in black 
ink.  If any entry error has been made, to correct such an error, draw a single 
straight line through the incorrect entry and enter the correct data above it.  All 
such changes must be initialed and dated.  Do not erase or use “white-out” for 
errors.  For clarification of illegible or uncertain entries, print the clarification 
above the item, then initial and date it.  If the reason for the correction is not clear 
or needs additional explanation, neatly include the details to justify the 
correction. 
 
 
 
18.37 Records Retention 
 

 
37  
MC1631 
 
 
 
 
 
 
The investigator will maintain records and essential documents related to the 
conduct of the study.  These will include subject case histories and regulatory 
documents. 
 
The investigator will retain the specified records and reports for; 
1. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and 
Access to Research Data Policy” 
   
 
 
19.0  
Study Finances 
 
 
19.1 
Costs charged to patient:  routine clinical care 
 
 
19.2 
Tests to be research funded: Venipuncture, additional echocardiography 
 
 19.3 
Other budget concerns: The Mayo Clinic Radiation Oncology Unit is funding the study 
 
and will cover costs related to running the study 
 
20.0 
Publication Plan 
The principal investigators hold primary responsibility for publication of the results of this study 
and approval from the principal investigators must be obtained before any information can be 
used or passed on to a third party.   
 
 
21.0 
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35. 
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for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer 
registries. The Lancet. Oncology, 2005. 6(8): p. 557-65. 
38. 
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40. 
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Lung cancer, 2008. 62(3): p. 351-5. 
42. 
D'Errico, M.P., et al., N-terminal pro-B-type natriuretic peptide plasma levels as a potential 
biomarker for cardiac damage after radiotherapy in patients with left-sided breast cancer. 
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Appendix I 
 
ECOG PERFORMANCE STATUS 
 
Grade 
0  
Fully active, able to carry on all pre-disease activities without restriction 
(Karnofsky 90-100). 
 
1  
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work (Karnofsky 
70-80). 
 
2  
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50 percent of waking hours   (Karnofsky 50-
60). 
 
3  
Capable of only limited self-care, confined to bed or chair 50 percent or more of 
waking hours (Karnofsky 30-40). 
 
4  
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair (Karnofsky 10-20). 
 
5  
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 2 
 
 
 
 
 
 
MC#:  _____________    Scoring Nurse: _______________    Date: __________ 
 
 
Right Breast 
 
 
 
 
     Left Breast 
 
Overall Score: 
 3  Excellent 
 
 
Overall Score:  3  Excellent 
 
 
 2  Good  
 
 
 
 2  Good 
 
 
 1  Fair  
 
 
 
 
 1  Fair 
 
 
 0  Poor  
 
 
 
 0  Poor 
 
________________________________________________________________________ 
 
A= Asymmetry  
 
 
A= Asymmetry 
 
 
3  Excellent 
 
 
 
 
3  Excellent 
 
 
2  Good  
 
 
 
2  Good 
 
 
1  Fair  
 
 
 
 
1  Fair 
 
 
0  Poor  
 
 
 
 
0  Poor 
 
B= Breast Shape  
 
 
B= Breast Shape 
 
 
3  Excellent 
 
 
 
 
3  Excellent 
 
 
2  Good  
 
 
 
2  Good 
 
 
1  Fair  
 
 
 
 
1  Fair 
 
 
0  Poor  
 
 
 
 
0  Poor 
 
N= Nipple deformation 
 
 
N= Nipple deformation 
 
 
3  Excellent 
 
 
 
 
3  Excellent 
 
 
2  Good  
 
 
 
2  Good 
 
 
1  Fair  
 
 
 
 
1  Fair 
 
 
0  Poor  
 
 
 
 
0  Poor 
 
S= Skin condition 
 
 
 
S= Skin condition 
 
 
3  Excellent 
 
 
 
 
3  Excellent 
 
 
2  Good  
 
 
 
2  Good 
 
 
1  Fair  
 
 
 
 
1  Fair 
 
 
0  Poor  
 
 
 
 
0  Poor 
 
W= Wound scar  
 
 
W= Wound scar 
 
 
3  Excellent 
 
 
 
 
3  Excellent 
 
 
2  Good  
 
 
 
2  Good 
 
 
1  Fair  
 
 
 
 
1  Fair 
 
 
0  Poor  
 
 
 
 
0  Poor 
 
 
 
 
 
 
Total score = ________ 
 
 
Total score = ________ 
 
 
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Appendix 3 
 
 

 
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Appendix 4 
 

 
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