A Phase III Trial of Hypofractionated Radiotherapy to the Whole Breast Alone After Breast Conserving Surgery
Phase: PHASE3
Conditions: Stage I Breast Cancer AJCC v7, Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage II Breast Cancer AJCC v6 and v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7, Stage IIIA Breast Cancer AJCC v7
Sponsor: Mayo Clinic

 
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Mayo Clinic Radiation Oncology 
 
A phase III trial of hypofractionated radiotherapy to the whole breast alone after breast conserving 
surgery 
 
 
Study Chair Arizona: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Co-Chair Minnesota: 
 
 
 
 
 
 
Study Co-Chair Surgery:     
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Co-Chair Health outcomes: 
 
 
 
 
 
 
 
 
Study Co-Investigators: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
 
 
 
                                      Physics Chair Arizona:       
  
                                   
       
 
 
                                       
 
Study contributor(s) not responsible for patient care. 

 
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12/5/18 
 
Document History 
 
(Effective Date) 
Active 
9/13/17 
Modification 1 
11/06/17  
Modification 2 
1/4/18 
Modification 3 
Modification 4 
Modification 5 
Modification 6 
Modification 7 
Modification 8 
2/21/18 
8/22/18 
12/5/18 
01/16/19 
4/22/19 
10/09/2019 
 
 
 
 
 
 
 

 
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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 
18.0 
Records and Data Collection Procedures 
19.0 
Study Finances 
20.0 
Publication Plan 
21.0 
References 
Appendix I - ECOG Performance Status 
Appendix II – Mayo Breast Patient Survey 
Appendix III - Mayo Patient Survey PRO-CTCAE Mayo 10 
Appendix IV – Mayo Patient Survey 
 
 
 
 
 
 
 
 

 
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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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pStage T0-T3N0-N1M0 or  
ypStage T0-3N0-N1micM0 and 
indications for whole breast irradiation 
without regional nodal irradiation, 
after breast conserving surgery. 
ARM 2: 5 Fraction 
Hypofractionation 
25 Gy (RBE) / Gy in 5 
daily fractions with 
optional concurrent boost 
to a total dose of 30 Gy 
(RBE) / Gy in 5 fractions 
(n=55) 
RANDOMIZE 
Treatment 
Observation 
(Section 4.0 Test Schedule) 
Cancer Recurrence 
Event Monitoring 
(Section 18.0 –5 years total 
follow-up) 
SCHEMA 
ARM 1: Conventional 
hypofractionation  
40 Gy (RBE) / Gy in 15 
daily fractions with 
optional 10 Gy (RBE) / 
Gy in 4 fractions 
sequential boost to a 
total dose of 50 Gy in 19 
fractions;  or a 
concomitant boost  to 
total dose of 48Gy in 15 
daily fractions.(n=55) 

 
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N=110 patients  
 
Study Design: This is an open label phase III randomized controlled trial to determine the safety of 5 
fraction vs 15 fraction pencil beam scanning proton radiotherapy to the whole breast alone after breast 
conserving surgery. 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 
Breast conserving therapy (BCT), consisting of partial mastectomy, followed by whole 
breast radiotherapy, is a widely accepted standard of care and the preferred local 
treatment approach for many women with breast cancer.  Women opting for breast 
conserving therapy have improved body image, quality of life, and sexual function1,2.  
 
Six randomized studies with long term follow up have established the equivalent overall 
survival of breast conserving therapy to mastectomy3-8 . The breast radiotherapy 
component of BCT has been shown to improve rates of local control, reduce distant 
recurrence, and improve survival 9,10.  Despite the strong evidence for breast conserving 
therapy, there is underutilization of both breast conserving surgery 11 and adjuvant 
radiotherapy12 .  While many factors likely contribute, convenience of therapy, access to 
treatment facilities13, cost, and perceived toxicity of therapy may all represent barriers to 
radiation therapy14.   
 
Survival rates for breast cancer are high, as most women diagnosed will not die of their 
disease15. As such, recent oncologic emphasis has highlighted survivorship, with 
strategies aimed to improve treatments, treatment-related adverse effects, and long term 
quality of life 16,17.  These improvement strategies aim to improve the therapeutic ratio, 
with enhanced benefits of therapy, reduced toxicity, or both.  
 
Careful study of photon breast radiotherapy techniques has highlighted potential long 
term toxicities and opportunities to enhance the therapeutic ratio. Data demonstrating late 
cardiovascular toxicity, particularly for women with left-sided tumors, and risk of 
secondary malignancy have garnered particular attention in recent years,18 and these 
toxicities have been shown to partially offset the cause-specific survival benefit of 
adjuvant radiotherapy9,19.   
 
Cardiovascular toxicity has been studied in great detail and appears to be primarily 
mediated by a vascular etiology, likely with macro- and microvascular contributions. 
Amongst women undergoing adjuvant radiotherapy for breast cancer, Correa and 
colleagues20 demonstrated a likelihood of left anterior descending artery (LAD) stenosis 
in excess of what would be expected, providing indirect evidence of radiation-mediated 
coronary artery disease. Darby and co-authors19 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.  Radiation related cardiovascular toxicity is likely multifactorial, and multiple 
dose-volume relationships are likely important  risk factors of subsequent cardiac disease, 
including dose to the LAD, heart (mean heart dose and volumetric parameters such as 
V25) and left ventricle21.  Efforts to minimize cardiac exposure to radiotherapy, while 
studying the potential dose relationships are of utmost importance, particularly in the 

 
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modern systemic therapy era, which now includes more agents with known cardiac 
effects, including anthracyclines and trastuzumab.  
 
Adjuvant radiotherapy for breast cancer has also been associated with an elevated risk of 
developing a secondary malignancy9. Specifically, radiotherapy is associated with 
increased risk of developing and dying from ipsilateral lung cancer9,22. Radiotherapy is 
also associated with increased risk of contralateral breast carcinoma9. This is a result of 
inadvertent and unnecessary dose delivered to normal organs adjacent to disease targets.  
 
Radiotherapy to the breast may also result in breast fibrosis, breast shrinkage, worsening 
of cosmesis, and arm and shoulder pain.23,24.25  There is evidence that these late effects 
are potentially dose dependent.   
 
In summary, breast conserving therapy is a standard of care and offers many advantages 
to women, and radiotherapy is necessary to achieve optimal oncologic outcomes.  
However, in the modern era of enhanced technology and improved emphasis on 
survivorship, there is strong rationale for the development and evaluation of novel 
strategies that reduce unnecessary radiation exposure to normal tissue, as well as novel 
dose and fractionation regimens which may improve the therapeutic ratio, while reducing 
costs and increasing convenience of delivery. We propose a prospective phase III trial 
that will evaluate the use of hypo-fractionation with either x-rays or proton therapy 
 
1.2 
Rationale for Proton Therapy in Breast Cancer 
 
Enhanced radiotherapy delivery techniques may enable better treatment delivery with 
reduced toxicity.   Proton therapy, in particular, may reduce treatment toxicity, as there is 
less non-target tissue exposed to radiation therapy.  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, target tissues may be 
covered with a similar or better dose distributions as with photons, with reduced 
unintended dose to other tissues, including reduced integral dose 26,27.  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 potential to reduce toxicity.  
 
Clinical experience with proton beam radiotherapy (PBT) in the treatment of breast 
cancer patients remains limited, though increased institutional experiences are reported, 
and a multi-center randomized study in node positive patients has been initiated (CITE 
PCORI). A recent review examined published experience with PBT for breast cancer28. 
This report highlights the limited published clinical experience with proton beam for 
breast cancer, in particular demonstrating very little data for whole breast radiotherapy 
without regional nodal treatment.  The two such cited studies were retrospectively 
planned proton versus plan comparisons, rather than clinical experience, yet each 
supported a dosimetric advantage to PBT for left sided breast cancer patients undergoing 
BCT, with a reduction in mean heart dose, coronary artery dose, and ipsilateral lung 
dose29,30.   
 
Clinical experience in the node positive setting is published.  MacDonald et al 31 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 

 
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node chains. 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.32 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. Grad 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 and 
post-lumpectomy proton therapy is feasible and well tolerated with reduced dose to the 
heart and lung, warranting further study.  
 
In addition to the clinical experience in the locally advanced setting, several institutions 
have examined PBT for partial breast radiotherapy.  One such initial report showed high 
rates of acute skin toxicity, pigmentation changes, and worse physician reported cosmesis 
33.  However, the planning techniques reported therein, including passive scatter and a 
single beam treated per day for many, possibly contributed to these outcomes.  A larger 
series from Loma Linda with 60 month follow up and 100 patients reported good to 
excellent cosmetic outcome in >90% throughout 5 years of follow up34. No patient had 
acute grade 3 or higher skin toxicity.   Ispilateral tumor recurrence rates at 5 years were 
3%.  In addition to differences in dose and technique, once daily treatments were used.     
 
Much of the published PBT experience is with passively scattered protons. A concern 
with this technique is the high entrance skin dose which may be associated with higher 
skin toxicity and adverse cosmesis.33 This higher skin dose may be of particular concern 
in patients who undergo breast conserving surgery. Scanning beam proton therapy, the 
technique proposed in this study, offers potential advantages over passively scattered 
protons including increased conformality with even less unintended dose to normal 
tissues, including the skin.35 However, this technique is also potentially more sensitive to 
uncertainties including inter-fractional as well as intra-fractional 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. 
 
In summary, there is strong interest in prospectively designing and understanding proton 
therapy in breast cancer.  Data for proton therapy in breast cancer are limited, particularly 
in the intact breast setting, yet there is compelling rationale for study of proton beam 
therapy for breast cancer to reduce radiation dose to non-target tissue and potentially 
improve outcomes for breast cancer survivors. In view of the need to gain experience, a 
clinical study is supported.  
 
 
 
1.3 
Rationale for Hypofractionation in Breast Cancer 

 
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            Hypofractionated, or shorter course, radiotherapy presents an opportunity to enhance 
access to care, increase convenience and acceptability of therapy, while reducing cost and 
potentially improving toxicity.  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.  While 
proton therapy is 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. 36-38 An important driver of cost of both photon and proton radiotherapy is 
the number of treatments delivered to individual patients, with shorter courses resulting 
in lower expenditures39. Studies are needed to evaluate whether equivalent or improved 
outcomes can be achieved with shorter courses of therapy. 
 
Furthermore, the optimal dose and fractionation regimen for whole breast irradiation, 
whole breast and regional nodal irradiation, and postmastectomy radiotherapy remains 
unknown.  While there is widespread clinical experience with standard fractionation, 
newer preclinical and clinical data support a shorter course of radiotherapy.  
 
For fraction sizes up to approximately 8 Gy, The linear-quadratic formula model is 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.40 In it, the biologically effective dose (BED) of 
a given fractionation regimen is related to the α/β ratio in the following equation, 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.41   
 
Emerging evidence 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.42,43 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).24 
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 

 
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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 supporting hypofractionated regimens 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.24,44. 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 that differences in 
overall treatment time of a course of radiation therapy may be more important than 
originally thought, potentially allowing further dose reduction when fractionation 
regimens are shortened, as we propose here.45,46. 
 
Other moderate hypofractionated radiotherapy treatments support excellent local control 
and comparable toxicity outcomes. Ahlawat el al, reported on 83 women treated after 
breast conserving surgery 36.63 Gy in 11 fractions of 3.33 Gy per day, with a 4 fraction 
boost of an addition 3.33 Gy47.  Three year local recurrence free survival was 95.9%, and 
breast cosmesis was good or excellent in 94% of evaluable patients.  
 
In the FAST trial, 915 women aged ≥ 50 years with node negative early breast cancer 
after wide local excision were randomly assigned to receive 50 Gy in 25 fractions of 2.0 
Gy over 5 weeks versus 28.5 Gy or 30Gy in 5 fractions once weekly fractions of 5.7 Gy 
or 6.0 Gy. Three-year rates of physician-assessed moderate/marked adverse effects in the 
breast were 17.3% (13.3-22.3%, p<0.001) for 30Gy and 11.1% (7.9-15.6%, p=0.18) for 
28.5Gy compared with 9.5% (6.5-13.7%) after 50Gy.48 Further follow-up is needed to 
determine local control of these three regimens but promisingly at a median follow-up of 
37.3 months in survivors, only 2 ipsilateral breast recurrences were noted. 
 
 
Rovea, et al reported outcomes with 5 fractions of 6 to 6.5 Gy delivered once weekly for 
291 elderly patients49. 5 year Local control was excellent at 98%.  Late skin fibrosis was 
Grade 2 in 4.2% and grade 3 in 1.4%. Breast edema was low, at 7%, 4.2%, and 1.4% for 
Grade 1, 2, and 3, respectively.  Good to excellent cosmetic outcome was reported in 
86.4%.   Similarly, favorable acute toxicity results were reported among 42 women with 
early stage breast cancer, treated to the whole breast with 30 Gy in 5 weekly fractions, 
with or without a boost, despite the majority of women having an obese BMI50.    
 
Min reported a modern cohort of patients treated according to an older French trial51.  82 
patients were treated to 23 Gy over 4 fractions, delivered on days 1 and 3 and 15 and 17.  

 
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Five year local control was 99%, with low rates of acute toxicity.  63 of 74 (86%) 
reported good or excellent cosmesis at last follow up.  An included cost analysis 
supported substantial cost savings, compared with both standard fractionated and 
moderate hypofractionated schemes52.  
 
 
Despite strong interest and rationale for study of hypofractionated radiotherapy in breast 
cancer, there are no data available presently on the role of hypofractionation for breast 
cancer with scanning beam proton therapy.31 
 
The overlying hypothesis of this study is that the low α/β of breast cancer can be 
exploited with carefully designed hypofractionated proton therapy regimens to further 
optimize the therapeutic ratio, improve patient convenience, and reduce cost. The goal of 
this phase III randomized controlled trial is to determine whether the hypofractionated 
proton regimens proposed are non-inferior compared with standard fractionated proton 
radiotherapy and therefore worthy of further investigation.  
 
1.4 
Rationale for Doses Selected 
As described above, a linear 
quadratic model can be used 
to define the alpha-beta of 
the normal structures and 
tumor as well biologic 
effective doses. Plausible 
population averaged 
radiobiologic parameters for 
breast cancer (95% 
confidence level) are α/β = 
2.88 (0.75–5.01) Gy; a = 0.08 ± 0.02 Gy_1; potential doubling time Td = 14.4 ± 7.8 
day.43 The fractionation regimens in table 1 (modified from Qi et al.)43 is based on the 
fitting of clinical data including the hypofractionated randomized trials mentioned above 
and justifies the five fraction regimen proposed for arm 2. The concurrent boost dose of 6 
Gy x 5 is also based in part on the work of Formenti et al. who recently reported the 5-
year results of a prospective trial of 3D-CRT APBI of 100 patients treated in the prone 
position to a total dose of 30Gy in 6Gy fractions. At a median follow-up of 64 months, 
there has been just one local recurrence and one contralateral recurrence and cosmesis 
was rated as good/excellent in 89% of patients with at least 36 months follow-up.53 Livi 
et al has also shown excellent 5-year toxicity, cosmetic outcome and local failure results 
employing a dose of 30Gy in 5 treatments.54The control arm for this study will be 15 
fractions based on the favorable long term follow-up of the UK START B55. More 
recently the initial toxicity results of the fast forward trial have been published.  Very low 
rates of grade 3 toxicity were seen using either the 40 Gy over 3 weeks, or 26 Gy or 27 
Gy over one week.56  It is possible that the spot proton RBE may be different than 1.1 for 
hypo-fractionated treatments. Trials like the currently proposed would be critical to 
define differences in RBE with spot scanned hypofractionated radiation as well as the 
cancer and normal tissue alpha/beta.   
 
 
 
2.0 
Goals  
Table 1 

 
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2.1 
Primary Objectives 
 
2.1.1 
To determine the 24-month complication rate of 5 fraction whole radiotherapy 
+/- concurrent boost as compared to 15 fraction radiotherapy +/- sequential 
boost.  Complications will be defined as one or more of the following events:  1) 
grade 3 or higher late adverse event, 2) deterioration of cosmesis from 
excellent/good to fair/poor or from fair to poor. 
 
2.2 
Secondary Objectives  
 
2.21 
To evaluate acute and late toxicity  
2.22 
To estimate the 5-year locoregional control, invasive disease-free survival and 
overall  survival. 
 
 
2.3 
Correlative and Exploratory  
 
2.31  
To evaluate fatigue, and other patient-reported outcomes. 
 
2.32  
To evaluate clinical features, treatment technique, dose-volume parameters, 
histologic and genetic variants associated with fair and poor cosmetic outcomes 
or unplanned surgical intervention.  
 
2.32 
To evaluate the costs and comparative effectiveness of treatment 
 
2.33 
Compare the use of photon therapy with spot scanning proton therapy in two 
different hypo-fractionated whole breast schemas. 
 
 
 
3.0 
Patient Eligibility    
 
3.1 Inclusion Criteria   
 
3.12 
Age ≥ 18 years. 
 
3.13  
Histological confirmation of breast cancer.  
 
3.14 
Pathologic Stage T0-T3N0-N1M0. (8th edition) 
 
 
3.15 
ECOG Performance Status (PS) 0 to 2. (Appendix I). 
 
3.16 
Able to and provides IRB approved study specific written informed consent. 
 
3.17a 
Study entry (randomization) must be within 12 weeks of last surgery (breast or 
axilla) or last chemotherapy (if applicable). 
 
 
 
 
 

 
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3.17b 
Willing to return to enrolling institution for follow-up (during the active 
monitoring phase of the study). 
 
3.18 
Fair, good or excellent cosmesis, as determined by trained nurse assessment 
using the Harvard Cosmetic Scale. 
 
3.19 
Radiotherapy must begin within 12 weeks of the last breast cancer surgery or the 
last dose of adjuvant chemotherapy. 
 
3.20 
Breast conserving surgery and indications for whole breast radiotherapy. 
 
 
 
 
 
 
3.3 
Exclusion Criteria  
 
3.31 
Medical contraindication to receipt of radiotherapy. 
3.32 
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. 
 
3.33 
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. 
3.34 
Active systemic lupus or scleroderma.  
 
3.35 
Women of childbearing potential who are sexually active and not willing/able to 
use medically acceptable forms of contraception. 
 
3.36 
Prior receipt of ipsilateral breast or chest wall radiation.  
 
3.37 
Positive margins on ink after definitive surgery either for DCIS or invasive 
cancer. 
 
3.38 
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. 
 
3.39 
Recurrent breast cancer. 
 
3.40  
Indications for comprehensive regional nodal irradiation. 
 
3.41 
Male subjects. 
 
3.42 
Patient requires bilateral breast radiation treatment. 
 
 
 
       

 
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4.0 
Test Schedule  
 
 
 
 
1. A general history & physical exam should include height and weight (optional at Rochester 
site)  
2. Review of pathology at failure if obtained clinically 
3. Photographs can be done at any time before or after treatment at the discretion of the 
physician 
4. Last day of treatment +/-2 days per discretion of treating physician 
5. Outside pathology must be reviewed at treating institution to confirm eligibility within 365 
days. 
6. Blood pregnancy test to be completed prior to start of treatment on day 1 (for women of 
childbearing potential only). 
7. PET Scan at failure optional 
8. Per discretion of treating physician for Arm 2 (5 days) 
 
9.  These tests can be done before or up 3 days into treatment  
 
10. Limited physical exam to include ECOG; weight (optional for Rochester site) 
11.  As collected clinically 
12.  Patients that cannot come back to Mayo within the time constraints of the follow-up 
schedule; efforts to obtain outside records and  
complete QOL’s will occur, however the 
required items may not be captured.  
13. If follow up visit occurred at an outside institution, Cosmetic Assessment will not be 
required.  
 
 
*Failure defined as recurrent disease5.0 
Stratification Factors  
5.1  
Treatment modality:  Photons vs. spot scanned proton therapy. 
 
Of the total 110 patients in this study, fifty-five would be treated in each arm. We will 
 
Baseline 
Pre-treatment 
EOT 
 
Observation 12 
 
≤120 days 
prior to start of 
treatment 
≤45 days prior 
to start of 
treatment6 
Last day of 
Treatment (+/- 
5 days) 
12 weeks 
(+/- 4 weeks) 
post-
treatment  
6 months 
(+/- 2 
months) 
12 months (+/- 3 months), 24 months 
(+/- 6 months), 36 months (+/- 6 
months), 48 months (+/- 6 months) and 
5 years (+/- 6 months) post completion 
of treatment 
Failure* 
 
 
 
 
 
 
 
Consent  
X 
 
 
 
 
 
 
cal exam1 
X 
 
 
 
 
 
 
exam/ECOG 
us (see Appendix 
X 
 
X8 
X 
 
X 
X 
ment (see Section 
 
X9 
X8 
X 
 
X13 
X 
hs3 
 
X 
X 
X 
 
X 
 
dices 2,3,4)11 
 
X9 
X 
X 
X 
X 
X 
valuation (see 
 
X9 
X 
X 
 
X 
X 
nts  
 
 
 
 
 
 
 
al specimen  
X5  
 
 
 
 
 
X2 
 
 
 
 
 
 
X7 

 
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allow a maximum of 28 patients per arm per treatment modality (photons/x-ray or 
protons). 
  
  
6.0  
Registration / Randomization Procedures 
6.1 
Registration Procedures 
6.1 Patient will be registered to the study when they have consented, met eligibility 
criteria, and have been logged into Research Participant Tracking (Ptrax). 
6.2 Screening tests/procedures (see section 4.0) will be completed within the guidelines 
specified on the assessment schedule.  
 
6.2 
Randomization Procedures 
 
6.21 
The factors defined in Section 5.0, together with the registering membership, will be used 
as stratification factors. 
 
6.22  
After the patient has been registered into the study, the values of the stratification factors 
will be recorded, and the patient will be assigned to one of the following treatment groups 
using the Pocock and Simon dynamic allocation procedure which balances the marginal 
distributions of the stratification factors between the treatment groups. 57 
 
 
7.0 
Protocol Treatment 
 
Doses throughout will be prescribed in Gy (RBE) / Gy or Gy. One Gy will be the equivalent of 
one Gy (RBE) / Gy 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. 
 
The treatment technique (photon/x-ray vs. proton) utilized will be at the physician’s discretion 
and will be based on technical considerations, availability at the radiation oncology facility, 
insurance coverage considerations, and patient preference. See section 7.4. 
 
7.1       Radiation Therapy, Arm 1  
 
Patients who had breast conserving surgery and are randomized to arm 1 (standard 
fractionation) will receive whole breast radiotherapy delivered to the breast CTV with or 
without a sequential boost to the lumpectomy cavity CTV. Boost indications will be left 
to physician discretion. Potential risk factors suggesting increased absolute benefit from a 
boost include but are not limited to age < 40, close margins, extensive DCIS adjacent to 
the invasive tumor.58,59 
 
7.2 
Radiation Therapy, Arm 2 

 
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Patients who had breast conserving surgery and are randomized to arm 2 (5 fraction 
hypofractionation) will receive whole breast radiotherapy in 5 daily fractions delivered to 
the breast CTV with or without a concurrent boost to the lumpectomy cavity CTV.   
Boost indications will be left to physician discretion. Potential risk factors suggesting 
increased absolute benefit from a boost include but are not limited to age < 40, close 
margins, extensive DCIS adjacent to the invasive tumor.58,59  
 
7.3 
Dose Specifications 
7.31 
Arm 1 Post-lumpectomy whole breast irradiation +/- sequential boost 
7.311 Breast: 40.05Gy (RBE) / Gy/Gy in 15 fractions of 2.67 Gy (RBE) / 
Gy/Gy 
7.312 Lumpectomy cavity (optional): Sequential boost dose will be 10 Gy 
(RBE) / Gy in 2.5 Gy (RBE) / Gy fractions for a total dose of 50.05Gy 
(RBE) / Gy / Gy. Simultaneously integrated boost is allowed to a total 
dose of 48Gy (RBE) / Gy over 15 fractions.   
7.32 
Arm 2 Post-lumpectomy whole breast irradiation +/- concurrent boost 
7.321 Breast: 25 Gy (RBE) / Gy in 5 fractions of 5 Gy (RBE) / Gy  
7.322 Lumpectomy cavity (optional): Dose to the lumpectomy cavity 
(concurrent boost dose) will be 30 Gy (RBE) / Gy in 5 fractions  of 6 Gy 
(RBE) / Gy 
 
7.4 
Treatment Technique 
7.41 
Radiation will be delivered using available photon (x-ray) or scanning beam 
proton equipment at the treating institution. 
7.42 
Only one breast will be treated on the protocol. 
7.43 
While planning the scanning target volumes, care must be taken to not put Bragg 
Peaks either in the Chest Wall or in the first 5 mm from the external surface of 
the body. 
 
7.5 
Localization, Simulation, Immobilization 
7.51 
Simulation should be performed with the patient in the supine or prone position 
7.52 
Patients should be optimally positioned with a custom immobilization device at 
the discretion of the treating physician. 
7.53 
Arm position may be up or down. 
7.54 
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 will be 2mm. 
7.55 
External skin markers, which may include permanent tattoos, are recommended 
for daily set-up. 
7.56 
KV image guidance will be performed daily. Other imaging modalities, such as 
CBCT and Vision RT, real time tracking or others should be performed based on 
institutional guidelines.  
7.57 
Volumetric imaging may be performed with re-planning at the physician’s 
discretion. 
 
7.6 
Treatment Planning 
7.61 
For proton planning, 1 or more en face or oblique fields are recommended. 
 

 
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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-lumpectomy breast target volumes (Arms 1 and 2) 
7.711 High tangents volume:  Alternatively, breast target volume can be 
defined by traditionally treated volume. All palpable breast tissue and all 
tissue encompassed by a standard tangent fields would be considered 
breast tissue.  A medial tangent would be placed at the costo-condral 
junction and a lateral tangent would be placed at the mid axillary line or 
more posterior as necessary to cover all breast tissue laterally. The caudal 
border would be 1 cm below all breast tissue. The superior border would 
be placed at the second intercostal space. Position would be verified on 
CT and in general it should not be closer than 1.5 cm from the inferior 
border of the humeral head and no more than 2 cm distally.  
7.712 Low tangents volume: would be defined in the same manner; with the 
exception that the superior border should be between 2-4 cm from the 
inferior border of the humeral head. 
7.713 Manual modifications: alternatively, volumes can be defined using the 
RTOG breast atlas as above. However, for uniformity of the posterior 
margin the breast volume would include muscle tissue as needed to 
maintain a uniform distal edge. Please see breast CTV (section 7.7.1.4.2). 
7.714 Lumpectomy Cavity: Contour using the excision cavity volume, 
architectural distortion, lumpectomy scar, seroma and/or extent of 
surgical clips (clips and/or fiducials are strongly recommended). 
7.7.1.4.1 
Lumpectomy Cavity CTV:  Lumpectomy Cavity + 5mm 3 
D expansion. Limit the CTV 5 mm from skin.   
7.7.1.4.2 
Breast CTV: the breast would be the same as the CTV high 
tangents or low tangents without further expansions. The 
lumpectomy CTV is also included. The breast CTV volume 
is limited 5mm from the skin.  The breast CTV posteriorly, 
would be limited 5mm from the lung excluding the chest 
wall. 
7.715 Photon therapy 
7.7.1.5.1 
PTV-eval (PTV evaluation): PTV evaluation would be used 
for photon patients. PTV eval would equal to the breast CTV 
as defined above. The breast CTV as defined above matches 
the definition of the RTOG 1005 “This Breast PTV Eval is 
limited anteriorly to exclude the part outside the patient and 
the first 5 mm of tissue under the skin (in order to remove 
most of the buildup region for the DVH analysis) and 
posteriorly is limited no deeper to the anterior surface of the 
ribs (excludes boney thorax and lung).” 
 
7.8 
 
Critical Structures 
7.81 
Breast skin eval: Will be defined as the first 3 mm of tissue under the body 
surface anterior to the Breast CTV.   

 
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7.82 
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.  
 
7.83 
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)”.60  
 
7.84 
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.”60 
 
7.85 
Ipsilateral lung: To be contoured on all cases, auto-segmentation with manual 
verification is permitted 
 
7.86 
Contralateral lung: To be contoured on all cases, auto-segmentation with 
manual verification is permitted 
 
7.87 
Total lung: To be contoured on all cases, auto-segmentation with manual 
verification is permitted 
 
7.88 
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. 
 
7.89 
Chest wall: from patient’s midline, at the mid plane of the sternum, to the 
patient’s posterior axillary line. The thickness would be defined by measuring the 
distance from the lung-chest wall interface to the posterior edge of the pectoralis 
muscle and creating virtual structure. It can be manually modified to exclude the 
pectoralis muscle at the discretion of the treating physician. No breast tissue 
should be included in this structure. The CTV should not be included in this 
structure plus 2mm. 
  
7.9 
 
Prescription and Normal Tissue Constraints 
 
7.91 
Arms 1 and 2 (protons and photons/x-rays) 
7.911 Breast CTV:  

 
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7.9.1.1.1 
Per protocol ≥ D95% will receive ≥95% of prescription; 
Variation acceptable ≥ D90%  receives ≥ 90% of 
prescription 
7.912 Tumor  CTV 
7.9.1.2.1 
Per protocol   D95% receives ≥95% of dose; variation 
acceptable  D90% receives ≥90% of the boost dose 
7.913 Robustness analysis for Protons 
7.9.1.3.1 
Breast CTV coverage would be evaluated for 5mm 
movements or 3% range changes. Per protocol Breast CTV  
V90% receives ≥95% of the prescription dose; variation 
acceptable ≥ V90% receives ≥90% of the prescription dose. 
7.9.1.3.2 
Under the same robustness evaluation criteria, plans will be 
evaluated for D max.  Variation acceptable D0.01cc  % 
≤120% 
 
 
 
 
 
 
 
 
 
Protons DVH summary table 
 
 
 
Goal 
Major violation1 
Breast CTV 
 
≥ V95% will receive 
≥95% of 
prescription 
V90% <90% of 
prescription 
 
 
Dmax <107% 
Dmax >115% 
Tumor Bed CTV 
 
≥ V95% will receive 
≥95% of 
prescription 
V90% <90% of 
prescription 
 
 
Dmax <107% 
Dmax >115% 
Breast CTV 
robustness 
 
V90% >90% of 
prescription 
V90% <90% of 
prescription 
 
 
 
 
Heart 
Max dose 
≤25% of 
prescription 
>33% of 
prescription 
 
Mean 
<0.1Gy 
>1Gy 
Breast Skin 
Max dose 
≤105% of 
prescription 
>110% of 
prescription 
 
 
 
 
Lung Ipsilateral 
V50% of prescription 
≤10%  
>15% 
 
V20 
record 
 
Lung contralateral 
V50% 
≤7%  
 
>10% 
Lung Total 
Mean dose 
record 
 
 
V20Gy 
record 
 
 
V50% 
record 
 
LAD (optional) 
Mean dose 
record 
 
 
Max dose 
record 
 
RCA (optional) 
Mean dose 
record 
 
 
Max dose 
record 
 

 
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1. Major violations do not exclude patients from the protocol as it is an intent to treat analysis 
 
Photons (x-rays)  DVH summary table 
 
 
 
Goal 
Major violation 
PTV Eval 
 
≥ V95% will receive 
≥95% of 
prescription 
V90% <90% of 
prescription 
 
 
Dmax <107% 
Dmax >115% 
Tumor Bed CTV 
 
≥ V95% will receive 
≥95% of 
prescription 
V90% <90% of 
prescription 
 
 
Dmax <107% 
Dmax >115% 
Breast CTV 
robustness 
 
V90% >90% of 
prescription 
V90% <90% of 
prescription 
 
 
 
 
Heart 
Max dose 
≤33% of 
prescription 
>50% of 
prescription 
 
Mean 
<1Gy 
>2Gy 
Breast Skin 
Max dose 
≤107% of 
prescription 
>115% of 
prescription 
 
 
 
 
Lung Ipsilateral 
V50% of prescription 
≤10%  
>15% 
 
V20 
record 
 
Lung contralateral 
V50% 
≤7%  
 
>10% 
Lung Total 
Mean dose 
record 
 
 
V20Gy 
record 
 
 
V50% 
record 
 
LAD (optional) 
Mean dose 
record 
 
 
Max dose 
record 
 
RCA (optional) 
Mean dose 
record 
 
 
Max dose 
record 
 
1. 
Major violations do not exclude patients from the protocol as it is an intent to treat 
analysis 
 
Quality Assurance Documentation 
7.92 
At a minimum, the initial 2treatment plans per institution 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. No dose modifications should be done for treatment interruptions. 
 
9.0 
Ancillary Treatment/Supportive Care 
 
Skin changes are common complications of breast cancer radiation therapy. Usual care will be 

 
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provided as per the treating institution’s standard of practice. If the skin becomes erythematous 
and/or there is pruritus, topical steroid cream may be prescribed. The addition of antihistamines 
may be used for severe pruritus. 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 – Any grade 4 or 5 adverse event as defined by CTC AE v4.0. 
Adverse events are classified as serious or non-serious.  Serious problems/events can be 
well defined and include in general: 
 
Death 
 
Life threatening adverse experience where emergent lifesaving treatment is 
necessary. 
 
 
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 
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. 

 
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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: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
 
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 
Only G4 or G5 adverse events will require an attribution. Any change in the 
grade of an adverse event within the list of monitored AEs will be recorded and 
considered to be related to treatment. Any new adverse not listed occurring 
within the Radiated area or in close proximity will be graded and attribution 
defined by the study PI. 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the treatment 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 
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 

 
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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 v5.0 grading unless otherwise stated in the table 
below. Version 4 is allowed if v5 is not available, however, AEs will have to be updated 
to V5 once is available: 
 
 
System 
Organ 
Class 
(SOC)  
 
Adverse 
event/Symptoms 
 
Baseline 
Each  
evaluation 
Grading scale 
(if not CTCAE) 
General 
Pain 
X 
X 
CTCAE 
Skin and subcutaneous 
tissue disorders 
 
Dermatitis Radiation 
X 
X 
CTCAE 
Skin 
hyperpigmentation 
X 
X 
CTCAE 
Skin 
hypopigmentation 
X 
X 
CTCAE 
Superficial 
Soft 
Tissue Fibrosis 
X 
X 
CTCAE 
Breast 
edema 
(lymphedema) 
X 
X 
CTCAE 

 
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Vascular 
Lymphedema -arms 
X 
X 
CTCAE 
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis  
X 
X 
CTCAE 
 
 
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, 4, and 5 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. 
 
 
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). Consider biopsy of the site and PET scan.  
 
11.2.3 The site of recurrence (or failure) will also be collected and classified as local vs. 
regional vs. distant recurrence.   
 
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 
 
11.3.1 The Harvard/NSABP/RTOG Cosmesis Scale will be used to score cosmesis by 
trained nurses for the primary endpoint according to the schedule outlined in 
section 4.0. 
 

 
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Excellent: Treated breast nearly identical to untreated breast 
 
 
Good: Treated breast slightly different than untreated (minimal but 
identifiable effects of the treated breast). Mild reddening or darkening of 
the breast may be present. Thickening or scar tissue causes only a mild 
change in the shape or size. 
 
 
Fair: Obvious difference in the size and shape of the treated breast. The 
change involves one-quarter or less of the breast.  Severe thickening 
or scarring can be present.   
 
 
Poor:  Marked change in appearance or shape involving more than  
one-quarter or less of the breast. Treated breast seriously distorted 
(severe sequelae of breast tissue)  
 
11.3.2 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. 
 
 
11.3.3 The Quality of Life (QOL) questionnaires are adapted from the Breast Cancer 
Treatment Outcome Scale (BCTOS). PRO-CTCAE will also be used for QOL 
questionnaires. 
 
11.4 
Quality of life questionnaires are being done as part of the standard of care for all 
patients. We will correlate results of this standard of care questionnaires with clinical 
outcomes.  
 
11.4.1 The Quality of Life (QOL) questionnaires are adapted from the Breast Cancer 
Treatment Outcome Scale (BCTOS). PRO-CTCAE will also be used for QOL 
questionnaires. 
 
 
Unplanned surgical intervention will be adjudicated by a plastic surgeon and a general 
surgeon. 
 
 
 
12.0 
Descriptive Factors  
 
 
Breast: left vs. right 
 
AJCC Stage: 0 vs IA vs IB vs IIA vs IIB vs IIIA 
 
Tumor Size: 0-2cm vs  > 2-5cm vs > 5cm  
 
Lymph Nodes: N0 vs N1  
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 

 
27  
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Follow-up data will 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. 
 
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.  
 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted.  No further data submission is 
necessary. 
 
13.5 
A patient is deemed withdrawn if 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 Bio-specimens   
 
14.1 N/A 
 
 15.0 
Drug Information 
 
 
 
Not Applicable 
 
 
16.0  
Statistical Considerations and Methodology  
16.1  
Overview:  This is an open label phase III randomized controlled trial to determine the 
safety of 5 fraction vs 15 fraction radiotherapy after breast conserving surgery.  The goal 
is to determine whether the difference in 24-month complication rates between the 
experimental arm and the control arm is acceptable. Of interest is whether the 
experimental arm results in an unacceptable increase in the 24-month complication rate. 
If it does not, then the experimental arm will be recommended for further study. If the 24-
month complication rate is found to be unacceptable, then the recommendation would be 
to do no further studies of the experimental arm. 
 
16.2 
Primary and Secondary Endpoints 
 

 
28  
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16.21 Primary Endpoint:  The 24-month complication rate, defined as the percentage of 
women evaluable at 24 months who develop one or more of the following events: 
 
1) grade 3 or higher late adverse event  OR 
 
2) deterioration of cosmesis from excellent/good to fair/poor or from fair to 
poor at the 24-month evaluation (using the Harvard/NSABP/RTOG 
Cosmesis Scale)  
 
16.22 
Secondary Endpoints:  
16.221 Acute and late adverse events including grade ≥2 pneumonitis.  
16.223  Locoregional control, invasive disease-free, distant recurrence, disease- 
free survival, cause-specific survival, overall survival.  
The following definitions are used for the secondary endpoints of interest: 
 
Acute adverse events: any adverse event, regardless of attribution, that 
occurs in the first 90 days post-RT. 
 
Late adverse events (up to 5 years post RT): any adverse event that 
occurred after the first 90 days post-RT and up to 5 years post-RT. 
 
Ipsilateral breast tumor recurrence (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.  
 
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 any IBTR, regional invasive breast cancer recurrence, 
distant breast cancer recurrence, death due to any cause,  
 
Cause specific survival:  is defined as the time from registration to death 
due to breast cancer. If the cause of death is unkonw or difficult to 
stablish patients with a distant failure at the time of death would be 
censored as dying from breast cancer 
 
Overall survival: is defined as the time from registration to death due to 
any cause. 
 
 
16.3  Exploratory endpoints:   

 
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16.31 Patient self-reported cosmesis evaluate fatigue, breast pain, arm function and 
other patient reported outcomes.  
The following definitions are used for the exploratory endpoints of interest: 
 
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 
the 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. 
 
16.4 
Sample Size Determination 
This study requires 100 evaluable women for the primary endpoint analysis (50 evaluable 
patients per arm). 
Ninety-two percent of expected patients completed a 3-year assessment of cosmesis in 
the randomized phase III study reported by Olivotto et al.61 Expected was defined as 
patients who were projected to have had their 3-year follow-up visit based on the date of 
random assignment and who did not experience recurrence, undergo mastectomy, or die. 
Therefore to be conservative we will anticipate enrolling 10 (5 per arm) additional 
patients to account for ineligibility, cancellation, major treatment violations, or other 
reasons. The maximum projected enrollment is therefore 110 women. 
 
In a large randomized controlled trial Whelan and colleagues compared cosmetic 
outcomes between conventional and hypofractionated whole breast radiotherapy after 
lumpectomy. At baseline, 84% of patients in the hypofractionated arm were rated as 
having good or excellent cosmesis by trained nursing assessment. At 3 years, the 
percentage was 77%, or an absolute change of 7%.62 In the study proposed here, a subset 
of patients may receive a boost to the lumpectomy cavity which has been associated with 
a slightly higher risk of fibrosis and adverse cosmesis.63,64 Therefore, the sample size 
proposed for arms 1-2 is based on an assumed value of a 10% complication rate in the 
control arm. The rate of grade 3 or higher late toxicity in this population is expected to be 
≤1 % (Whelan ASCO 2011).  Since the local failure rate and death rate at 2-years in the 
UK start B trial24 was less than 3% we assume that an additional 10% to account for 
patients lost to follow, failures, deaths and others should be adequate (Total enrollment of 
110 patients).  
16.5 
Study Decision Rule and Operating Characteristics 
 

 
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The primary endpoint for this trial is the 24-month complication rate. Complications will 
be defined as at least one of the following events:  1) grade 3 or higher late adverse event 
OR 2) deterioration of cosmesis from excellent/good to fair/poor or from fair to poor 
(using the Harvard/NSABP/RTOG Cosmesis Scale)  
 
The proposed analysis would be to compute the difference in the 24-month complication 
rate between the experimental arm and the control arm. A one-sided 90% confidence 
interval (with the upper bound of the interval) was computed by assuming a 10% 
complication rate in the control arm and a 15% “non-inferiority margin” of the difference 
(i.e. the maximum the difference can be between the experimental arm and control arm, 
the largest difference we’re willing to accept). The decision rule would be of the 
following: 
 
Upper bound of the one-sided confidence interval (CI) for the difference 
(experimental arm 24-month complication rate minus control arm 24-month 
complication rate) lies above 15% then recommend that the experimental arm is 
not investigated further. The 24-month complication rate of the experimental arm is 
unacceptably high. 
 
Upper bound of the one-sided confidence interval (CI) for the difference 
(experimental arm 24-month complication rate minus control arm 24-month 
complication rate) is less than 15% then recommend that the experimental arm 
undergo further investigation. The 24-month complication rate of the experimental 
arm is potentially acceptable. 
 
With 100 evaluable patients, this study has 80% power with a 1-sided alpha of 0.05 to 
test a null hypothesis that the control arm complication rate is10% and experimental arm 
control rate is 25% versus an alternate hypothesis that the complication rate in both arms 
is 10%.  Sample size was computed using PASS v.15 software. 
 
Other considerations:  Adverse events, quality/duration of response, and patterns of 
treatment failure observed in this study, as well as scientific discoveries or changes in 
standard care will be taken into account in any decision to terminate the study. 
 
16.6  
Analysis Plan 
 
 
The analysis for this trial will commence at the planned time points and at the time the 
 
patients have become evaluable for the primary endpoint.  
 
16.61 Primary Analysis: The primary analysis will be to estimate the difference 
in the complication rate (adverse cosmesis and grade 3+ toxicities) which 
is defined as the 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 include all women evaluable at 24 
months.  Those who have recurrent disease or die before 24 months will 
not be included in this calculation.  We expect that <3% of patients will 
not be found eligible based on failure or death.24 The complication rate 
will be estimated using a binomial estimator in both experimental arm 

 
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and control arm, and a one-sided 90% confidence interval of the 
difference will be computed with normal approximation. As mentioned 
above, the following decisions will be made based on the 90% CI: 
 
The upper bound of the 1-sided 90% CI of the difference lies below 
15%: The experimental arm regimen is acceptable. 
 
The upper bound of the 1-sided 90% CI of the difference lies above 
15%: The experimental arm regimen is unacceptable. 
 
16.62 Secondary Analyses 
 
16.621 Acute adverse events: 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. Rates will be compared between arms using chi-squared 
tests. 
   
16.622 Late adverse events: All patients who were registered to the study and 
started treatment will be included in the late adverse event analysis. A 
late adverse event is an AE, regardless of attribution, that appears or 
persists after 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 relative frequencies by treatment 
arm. Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration. Rates will be compared 
between arms using chi-squared tests. 
 
16.623 Locoregional control: The cumulative incidence of locoregional 
recurrence will be estimated using a competing risks method (Gooley et 
al.) by treatment arm. The competing risks will be distant breast cancer 
recurrence and death.  Comparison between arms will employ Fine-Gray 
regression. 
 
16.624 Invasive disease-free survival: i-DFS is defined as the time from 
registration until the time of invasive disease recurrence (not including 
DCIS) or death due to any cause. The i-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. Comparison between 
arms will employ a log-rank test. 
 
16.625  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. 
Comparison between arms will employ a log-rank test. 
 
16.626  Cause specific survival: The CSS will be estimated with a Kaplan-Meier 
estimator and curve by treatment arm. Estimates will be given for specific time 

 
32  
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points along with 95% CIs. Comparison between arms will employ a log-rank 
test. 
16.627 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. Comparison between arms will 
employ a log-rank test. 
 
 
16.631 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). Mixed models will be used to estimate changes at fixed time 
points as well as compare outcomes between arms. 
 
16.632 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.   Comparisons between arms will employ 
chi-squared tests. 
 
 
16.7            Data & Safety Monitoring 
 
16.71  The study chair(s) and the study statistician will review the study at least twice a 
year to identify accrual, adverse event, and any endpoint problems that might be 
developing. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring 
Board (DSMB) is responsible for reviewing accrual and safety data 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. 
 
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 4 or more patients in the first 10 treated patients (per treatment arm) 
experience a grade 3 or higher adverse event, besides acute dermatitis, at 
least possibly related to treatment at any time following completion of 
the protocol treatment within 90 days post-treatment.   
 
After the first 10 patients have been treated (per treatment arm): if ≥ 20% 
of all patients experience a grade 3 or higher adverse event, besides acute 

 
33  
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dermatitis,  at least possibly related to treatment at any time following 
the completion of protocol 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. 
 
16.8  
Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary Endpoints 
(i.e., “Outcome Measures”) along with other required information for this study will be 
reported on ClinicalTrials.gov. For purposes of timing of the Results Reporting, the 
initial estimated completion date for the Primary Endpoint of this study is 48 months after 
the study opens to accrual. The definition of “Primary Endpoint Completion Date” 
(PECD) for this study is at the time the last patient registered has been observed for 24 
months. 
 
 
16.9 
Inclusion of Women and Minorities 
 
16.91  This study will be available to all eligible patients, regardless of race,  or ethnic 
origin. 
 
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. 
 
 
Accrual Estimates by Gender/Ethnicity/Race 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
3 
0 
3 
 
 
 
 
Not Hispanic or Latino 
105 
0 
105 
Hispanic or Latino 
5 
0 
5 
Ethnic Category: Total of all subjects 
110 
0 
110 
 
American Indian or Alaskan Native 
1 
0 
1 
Asian 
1 
0 
1 
Black or African American 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 

 
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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
White (Hispanic and non-Hispanic) 
107 
0 
107 
Racial Category: Total of all subjects 
110 
0 
110 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 

 
35  
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17.0  
Pathology Considerations/Tissue Biospecimens   
 
17.1  
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
 
 
None 
 
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 
Adjuvant Therapy 
Adverse Events- Baseline 
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 
 
 
Radiation Lumpectomy Therapy 
X 
 
 
Patient Assessment 
X 
X 
 
Adverse Events Solicited 
X 
X 
 
Adverse Events: Other 
X2 
X2 
 
Off Treatment 
X2 
X2 
 
Patient Status Form 
X 
X 
X 

 
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CRF 
 
End of Treatment 
12 weeks 
post/Observation 
Phase4  
Event Monitoring5 
Specimen Submission: Pathology Report 
(Recurrence) 
 
X2 
 
Consent Withdrawal  
X2 
X2 
 
Lost to Follow-up 
X2 
X2 
 
Breast 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.  Refer to test schedule in section 4.0If 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 
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 

 
37  
MC1635 
 
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 
 
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 
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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34. 
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Withers HR. Biologic basis for altered fractionation schemes. Cancer 1985;55:2086-95. 
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Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 
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Qi XS, White J, Li XA. Is alpha/beta for breast cancer really low? Radiother Oncol 
2011;100:282-8. 
44. 
Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy 
for breast cancer. N Engl J Med 2010;362:513-20. 
45. 
Wyatt RM, Jones BJ, Dale RG. Radiotherapy treatment delays and their influence on tumour 
control achieved by various fractionation schedules. Br J Radiol 2008;81:549-63. 
46. 
Rosenstein BS, Lymberis SC, Formenti SC. Biologic comparison of partial breast irradiation 
protocols. Int J Radiat Oncol Biol Phys 2004;60:1393-404. 
47. 
Ahlawat S, Haffty BG, Goyal S, et al. Short-Course Hypofractionated Radiation Therapy With 
Boost in Women With Stages 0 to IIIa Breast Cancer: A Phase 2 Trial. Int J Radiat Oncol Biol Phys 
2016;94:118-25. 
48. 
Agrawal RK, Alhasso A, Barrett-Lee PJ, et al. First results of the randomised UK FAST Trial of 
radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015). Radiother Oncol 
2011;100:93-100. 
49. 
Rovea P, Fozza A, Franco P, et al. Once-Weekly Hypofractionated Whole-Breast Radiotherapy 
After Breast-Conserving Surgery in Older Patients: A Potential Alternative Treatment Schedule to Daily 
3-Week Hypofractionation. Clin Breast Cancer 2015;15:270-6. 
50. 
Dragun AE, Quillo AR, Riley EC, et al. A phase 2 trial of once-weekly hypofractionated breast 
irradiation: first report of acute toxicity, feasibility, and patient satisfaction. Int J Radiat Oncol Biol Phys 
2013;85:e123-8. 
51. 
Baillet F, Housset M, Maylin C, et al. The use of a specific hypofractionated radiation therapy 
regimen versus classical fractionation in the treatment of breast cancer: a randomized study of 230 
patients. Int J Radiat Oncol Biol Phys 1990;19:1131-3. 
52. 
Min C, Connolly E, Chen T, Jozsef G, Formenti SC. Hypofractionated radiation therapy for early 
stage breast cancer: outcomes, toxicities, and cost analysis. Breast J 2014;20:267-73. 
53. 
Formenti SC, Hsu H, Fenton-Kerimian M, et al. Prone accelerated partial breast irradiation after 
breast-conserving surgery: five-year results of 100 patients. Int J Radiat Oncol Biol Phys 2012;84:606-11. 
54. 
Livi L, Meattini I, Marrazzo L, et al. Accelerated partial breast irradiation using intensity-
modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised 
controlled trial. Eur J Cancer 2015;51:451-63. 
55. 
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. Lancet Oncol 2013;14:1086-94. 
56. 
Brunt AM, Wheatley D, Yarnold J, et al. Acute skin toxicity associated with a 1-week schedule of 
whole breast radiotherapy compared with a standard 3-week regimen delivered in the UK FAST-Forward 
Trial. Radiother Oncol 2016;120:114-8. 
57. 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the 
controlled clinical trial. Biometrics 1975;31:103-15. 
58. 
Werkhoven E, Hart G, Tinteren H, et al. Nomogram to predict ipsilateral breast relapse based on 
pathology review from the EORTC 22881-10882 boost versus no boost trial. Radiother Oncol 
2011;100:101-7. 
59. 
MacDonald S, Taghian AG. Prognostic factors for local control after breast conservation: does 
margin status still matter? J Clin Oncol 2009;27:4929-30. 
60. 
Feng M, Moran JM, Koelling T, et al. Development and validation of a heart atlas to study 
cardiac exposure to radiation following treatment for breast cancer. Int J Radiat Oncol Biol Phys 
2011;79:10-8. 

 
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61. 
Olivotto IA, Whelan TJ, Parpia S, et al. Interim cosmetic and toxicity results from RAPID: a 
randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam 
radiation therapy. J Clin Oncol 2013;31:4038-45. 
62. 
Whelan T, MacKenzie R, Julian J, et al. Randomized trial of breast irradiation schedules after 
lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 2002;94:1143-50. 
63. 
Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher radiation dose on local control 
and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost 
versus no boost EORTC 22881-10882 trial. J Clin Oncol 2007;25:3259-65. 
64. 
Harris JR, Levene MB, Svensson G, Hellman S. Analysis of cosmetic results following primary 
radiation therapy for stages I and II carcinoma of the breast. Int J Radiat Oncol Biol Phys 1979;5:257-61. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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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 II 
Mayo Breast Patient Survey 
 
Mayo Breast Patient Survey 
 
Survey Date (mm/dd/yyyy): 
 
DIRECTIONS: For each question below, please mark one response that describes how you would rate 
your symptoms DURING THE PAST DAY. 
 
1. 
How you would describe… 
 
 
Your overall quality of life? Response scale 1 to 10, with 1 = as bad as it could be; 10 = 
as good as it could be 
 
 
The severity of your pain, on average? Response scale 1 to 10, with 1 = no pain; 10 = 
Pain as bad as it could be 
 
Your level of fatigue, on average? Response scale 1 to 10, with 1 = no fatigue; 10 = 
fatigue as bad as it could be 
 
 
DIRECTIONS: For each question below, please mark one response that describes how you would rate 
your symptoms IN THE LAST 7 DAYS. 
 
2. 
In the last 7 days, how much did anxiety interfere with your usual or daily activities? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
3. 
In the last 7 days, how much did insomnia, including falling asleep, staying asleep, or  
 
waking up early INTERFERE with your usual or daily activities? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
4. 
In the last 7 days, what was the SEVERITY of your shortness of breath at its WORST? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
5. 
In the last 7 days, what was the SEVERITY of your cough at its WORST? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 

 
44  
MC1635 
 
 
6. 
In the last 7 days, how much did problems with concentration INTERFERE with your  
 
usual or daily activities? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
7. 
In the last 7 days, how much did sad or unhappy feelings INTERFERE with your usual  
 
or daily activities? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
8. 
In the last 7 days, what was the SEVERITY of your skin burns from radiation at their  
 
worst? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
9. 
In the last 7 days, what was the SEVERITY of your difficulty swallowing at its  
 
WORST? 
 
Not at all 
 
A little bit 
 
Somewhat 
 
Quite a bit 
 
Very much 
 
10. 
In the last 7 days, how SEVERE have the following problems been (at their WORST)? 
 
Flaking or peeling of the treated breast or chest wall; response options 0 to 10, 0 = not at all, 10 = 
flaking as much as could be 
 
Bleeding of or leaking fluid from the treatment breast or chest wall; response options 0 to 10, 0 = not 
at all, 10 = bleeding as much as could be 
 
Blistering of the treated breast or chest wall; response options 0 to 10, 0 = not at all, 10 = blistering 
as much as could be 
 
Itching of the treated breast or chest wall; response options 0 to 10, 0 = not at all, 10 = as itchy as it 
could be 
 
Skin burns from radiation on your back; response options 0 to 10, 0 = not at all, 10 = as itchy as it 
could be 
 
11. 
If you had to do it all over again, would you have this RADIATION treatment again? 
 
Yes 
 
No 

 
45  
MC1635 
 
 
12. 
Have you been diagnosed with an infection at your breast cancer surgical site that 
required treatment with antibiotics or surgery? 
 
Yes 
 
No 
 
We are interested in your evaluation of your physical appearance and functioning. Please rate the 
following items from 0 to 10, according to how you feel AT THIS POINT IN TIME. 
 
Is the color of your treated breast/chest wall skin different than the other side (red, tan, or lighter)? 
response options 0 to 10, 0 = not at all, 10 = as different as it could be 
 
 
Do you have visible small blood vessels (spider veins) on your treated breast/chest wall? response 
options 0 to 10, 0 = not at all, 10 = as many as it could be 
 
Do you have pain with swallowing? response options 0 to 10, 0 = not at all, 10 = as painful as could 
be 
 
Do you have numbness or a tingling sensation in the arm on the side that was treated? response 
options 0 to 10, 0 = not at all, 10 = as much as it could be 
 
Do you have tightness, pulling, or stretching in the arm, breast, or chest area (in the side that was treated?) response 
options 0 to 10, 0 = not at all, 10 = as much as it could be 
 
Do you have tenderness or discomfort on the treated breast/chest wall? response options 0 to 10, 0 = 
not at all, 10 = as much as it could be 
 
Overall, how would you rate the cosmetic results of your breast treatment? 
 
Excellent  Good Fair Poor 
 
Please rate the following items according to your evaluation at this point in time: 
 
 
 
 
 
 
Breast/chest wall texture (hardening) 
 None 
 Slight 
Moderate 
Large 
Arm heaviness 
 None 
 Slight 
Moderate 
Large 
Shoulder movement 
 None 
 Slight 
Moderate 
Large 
Arm movement 
 None 
 Slight 
Moderate 
Large 
Breast/chest wall pain 
 None 
 Slight 
Moderate 
Large 
Ability to lift objects 
 None 
 Slight 
Moderate 
Large 
Fit of shirt sleeve 
 None 
 Slight 
Moderate 
Large 
Breast/chest wall tenderness 
 None 
 Slight 
Moderate 
Large 
Shoulder stiffness 
 None 
 Slight 
Moderate 
Large 
Scar tissue 
 None 
 Slight 
Moderate 
Large 
Shoulder pain 
 None 
 Slight 
Moderate 
Large 
Arm pain 
 None 
 Slight 
Moderate 
Large 
Arm swelling 
 None 
 Slight 
Moderate 
Large 
Breast/chest wall swelling 
 None 
 Slight 
Moderate 
Large 
Arm stiffness 
 None 
 Slight 
Moderate 
Large 
Breast/chest wall sensitivity 
 None 
 Slight 
Moderate 
Large 
Fit of clothing 
 None 
 Slight 
Moderate 
Large 
Axillary (arm pit) fullness or numbness 
 None 
 Slight 
Moderate 
Large 
 

 
46  
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Please complete the following questions if you had breast conserving therapy or mastectomy with 
reconstruction. 
 
Please rate the following items according to your evaluation at this point in time 
 
Breast size 
 None 
 Slight 
Moderate 
Large 
Nipple appearance 
 None 
 Slight 
Moderate 
Large 
Breast shape 
 None 
 Slight 
Moderate 
Large 
Breast elevation (how 
high the breast is) 
 None 
 Slight 
Moderate 
Large 
Fit of bra 
 None 
 Slight 
Moderate 
Large 
Breast heaviness 
 None 
 Slight 
Moderate 
Large 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix III 
Mayo Patient Survey PRO-CTCAE Mayo 10 
 
Survey Date (mm/dd/yyyy): 
 
Please answer the following questions about your symptoms. 
 
 
Not at 
all 
A little 
bit 
Somewhat 
Quite a bit 
Very much 
In the last 7 days, how much did anxiety 
INTERFERE with your usual or daily 
activities: 
 
 
 
 
 
In the last 7 days, how much did insomnia 
including difficulty falling asleep, staying 
asleep, or waking up early INTERFERE 
with your usual or daily activities: 
 
 
 
 
 
In the last 7 days, how much did decreased 
appetite INTERFERE with your usual or 
daily activities: 
 
 
 
 
 
 
Never 
Rarely 
Occasionally Frequently 
Almost 
Constantly 
In the last 7 days, how OFTEN did you 
have nausea: 
 
 
 
 
 
 
Not at 
all 
A little 
bit 
Somewhat 
Quite a bit 
Very much 
In the last 7 days, how much did shortness 
of breath INTERFERE with your usual or 
daily activities: 
 
 
 
 
 
In the last 7 days, how much did problems 
with concentration INTERFERE with your 
usual or daily activities: 
 
 
 
 
 
In the last 7 days, how much did sad or 
unhappy feelings INTERFERE with your 
usual or daily activities: 
 
 
 
 
 
 
None 
Mild 
Moderate 
Quite a bit 
Very severe 
In the last 7 days, what was the 
SEVERITY of your constipation at its 
WORST: 
 
 
 
 
 
 
Not at 
all 
A little 
bit 
Somewhat 
 Quite a 
bit 
Very much 
In the last 7 days, how much did numbness 
or tingling in your hands or feet 
INTERFERE with your usual or daily 
activities: 
 
 
 
 
 
 
Never 
Rarely 
Occasionally Frequently 
Almost 
Constantly 
In the last 7 days, how OFTEN did you 
have loose or watery stools (diarrhea): 
 
 
 
 
 
 
 
 
 

 
48  
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Appendix IV 
Mayo Patient Survey 
 
Survey Date (mm/dd/yyyy): 
 
Please respond to each item by choosing one number per row. 
 
 
Excellent 
Very 
Good 
Good 
Fair 
Poor 
In general, would you say your health is: 
 
5 
 
4 
 
3 
 
2 
 
1 
In general, would you say your quality of life 
is: 
 
5 
 
4 
 
3 
 
2 
 
1 
In general, how would you rate your physical 
health? 
 
5 
 
4 
 
3 
 
2 
 
1 
In general, how would you rate your mental 
health, including your mood and your ability 
to think? 
 
5 
 
4 
 
3 
 
2 
 
1 
In general, how would you rate your satisfaction 
with your social activities and relationships? 
 
5 
 
4 
 
3 
 
2 
 
1 
In general, please rate how well you carry out 
your usual social activities and roles (Includes 
activities at home, work, community, parenting, 
marriage, friends.) 
 
5 
 
4 
 
3 
 
2 
 
1 
 
Completely 
Mostly 
Moderately 
A 
little 
Not at 
all 
To what extent are you able to carry out your 
everyday physical activities such as walking, 
climbing stairs, carrying groceries, or moving 
a chair? 
 
5 
 
4 
 
3 
 
2 
 
1 
 
Never 
Rarely 
Sometimes 
Often 
Always 
In the past 7 days… 
How often have you been bothered by 
emotional problems such as feeling anxious, 
depressed, or irritable? 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
How would you rate your fatigue on average? 
 
 
 
 
 
 
 
How would you rate your fatigue on average? 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
 
Worst pain 
imaginable 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
No 
pain 
 
 
 
 
 
 
 
 
 
Worst pain 
imaginable