A Phase II Study of Accelerated 3 Fraction Photon and Proton Partial Breast External Beam Radiotherapy and Partial Breast Brachytherapy for Early Invasive and Noninvasive Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Mayo Clinic

MC1532 
 
 
 
 
Mayo Clinic Radiation Oncology 
 
MC1532, A Phase II Study of Accelerated 3 Fraction Photon and Proton Partial Breast External 
Beam Radiotherapy and Partial Breast Brachytherapy for Early Invasive and Noninvasive Breast 
Cancer  
 
 
 
 
Study Chair: 
  
 
 
 
 
 
 
 
Surgical Co-chair: 
 
 
 
 
 
Radiation Oncology Co-chairs: 
 
 
 
 
 
 
 
 
 
Radiation Physics Co-chairs: 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
 
 
 
 
 
 
 
  
 
 
√Study contributor(s) not responsible for patient care. 
 
 
Document History 
(Effective Date) 
Active 
5/8/15 
Modification 1 
6/22/15 
Modification 2 
Modification 3 
Modification 4 
Modification 5 
Modification 6 
Modification 7 
8/10/15 
11/02/15 
11/23/15 
5/2/16 
8/5/16 
1/04/17 

 
2  
 
 
 
 
 
 
 
 
 

 
3  
 
Index 
Schema 
  1.0 
Background  
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors  
  6.0 
Randomization /Registration Procedures 
  7.0 
Clinical Protocol Treatment 
  8.0 
Radiotherapy Dose Modifications Based on Adverse Events 
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring 
11.0 
Treatment Evaluation  
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient 
14.0 
Body Fluid Biospecimens 
15.0  
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Study Finances 
20.0 
Publication Plan 
21.0 
References 
 
Appendix I: ECOG Performance Status 
Appendix II: Radiation Therapy Quality Control Guidelines 
 
 
 
 
 
 
 
 
 
 
 

 
4  
 
 
List of Abbreviations 
3DCRT 
3-D Conformal Radiation Therapy 
AE 
Adverse Event/Adverse Experience 
ALI 
Angiolympatic Invasion 
APBI 
Accelerated Partial Breast Irradiation 
BCT 
Breast Conserving Therapy 
BED 
Biological Effective Dose 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTV 
Clinical Target Volume 
DCIS 
Ductal Carcinoma In Situ 
DSMP 
Data and Safety Monitoring Plan 
EBRT 
External Beam Radiation Therapy 
EIC  
Extensive Intraductal Component 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDR 
High Dose Rate 
HIPAA 
Health Insurance Portability and Accountability Act 
IBTR 
Ipsilateral Breast Tumor Recurrence 
IORT 
Intraoperative Radiation Therapy 
IRB 
Institutional Review Board 
LDR 
Low Dose Rate 
MIB 
Multicatheter interstitial Brachytherapy 
NSABP 
National Surgical Adjuvant Breast and Bowel Project 
PI 
Principal Investigator 
PHI 
Protected Health Information 
PTV 
Planning Target Volume 
QOL 
Quality of Life 
RTOG 
Radiation Therapy Oncologic Group 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
WBI 
Whole Breast Irradiation 
 
 
 

5 
 
Summary 
 
This is an open label phase II study to determine the safety and efficacy of a novel 3 fraction daily dosing 
regimen for accelerated partial breast irradiation (APBI) for early invasive and noninvasive breast cancer. 
The three techniques utilized are recognized as standard options for the delivery of APBI, and there is no 
evidence that either technique is superior or inferior to any other. The APBI technique utilized will be at 
the physician’s discretion and will be based on technical considerations, availability at the treating 
radiation facility, insurance coverage, as well as patient preference.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

6 
 
Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.0 
 Background 
Elect catheter-based Brachytherapy 
APBI 
Patient Eligibility for APBI Considered 
Observation (See section 4.0) 
 
Elect Proton APBI 
Day 1: Lumpectomy, 
Brachytherapy Device 
Placed  
Day 2-4: Brachytherapy 
Treatment Planning 
Final Pathology and 
Eligibility Confirmed  
Brachytherapy APBI 7Gy x 3  
Lumpectomy  
Final Pathology and Eligibility 
Confirmed/ Consent Obtained for 
Proton APBI if not Done 
Preoperatively 
Proton APBI 7.3Gy x 3 (begins 
2-10 weeks after surgery) 
 Proton APBI Treatment Planning 
Cancer Recurrence 
Refusal 
Or End of Active Monitoring Phase 
Event Monitoring (up to 5 
years after registration, once 
complete, off study) 
If APBI Candidate, Brachytherapy, 3DCRT, and Proton APBI Techniques 
Considered by Physician(s) and Patient 
Patient and Physician Elect APBI Technique and Informed Consent Obtained 
Elect 3D-CRT APBI 
Lumpectomy  
Final Pathology and Eligibility 
Confirmed/ Consent Obtained for 
3DCRT APBI if not Done 
Preoperatively 
3DCRT APBI 7.3Gy x 3 (begins 
2-10 weeks after surgery) 
 3DCRT APBI Treatment Planning 

7 
 
 
1.1 
Rationale for Accelerated Partial Breast Irradiation 
 
The combination of breast conserving surgery and radiotherapy has been confirmed to 
provide equivalent disease-free and overall survival in multiple prospective randomized 
controlled trials with follow-up periods of over 20 years in early stage breast cancer.1-3 
Despite the cosmetic and potential emotional advantages of BCT (breast conserving 
therapy), many patients may choose mastectomy or decline radiation following 
lumpectomy due to the protracted nature of a conventional course of whole breast 
irradiation (WBI), which is delivered to the whole breast and frequently followed by a 
boost to the tumor bed, usually over 3-6.5 weeks.   
 
The optimal volume of breast irradiation remains an area of ongoing study.4  Several 
lines of evidence suggest that WBI is unnecessary in a substantial number of patients 
with appropriately defined histological and clinical characteristics. For example, in a 
review of 217 mastectomy specimens, treated in Nijmegen, the Netherlands, residual 
disease was rarely identified more than 2 cm beyond the edge of the primary tumor 
unless an extensive intraductal component (EIC) was present.5 A pathologic analysis of 
reexcision specimens at William Beaumont Hospital demonstrated that in 90% of 134 
patients with negative initial lumpectomy margins, any residual disease present was 
limited to <10mm from the edge of the original lumpectomy margin.6 Clinical validation 
of these histologic findings comes from analyses of patterns of failure after BCT which 
have shown that a majority of local recurrences in the first 5-10 years after BCT occur in 
close proximity of the original tumor, and the rate of recurrences outside of this area in 
the treated ipsilateral breast are similar to the rate of contralateral breast failures.7-10 With 
increasing follow-up, a larger proportion of recurrences are seen in other quadrants of the 
breast.7  Similar findings have also been seen in patients treated with lumpectomy 
without radiation, implying that an “in breast recurrence” may be due to growth of 
residual tumor cells left following the initial therapy (the target of adjuvant radiation), or 
the development of new primary tumors without relation to the initial breast cancer 
diagnosis.11,12 The impact of WBI in reducing local recurrence therefore appears to be 
primarily related to irradiation of the lumpectomy cavity and the immediately 
surrounding breast tissue.  
 
In response to this clinical data, the patient inconvenience of protracted conventional 
WBI, and the possibility that unnecessary prophylactic treatment of uninvolved breast 
tissue may place the patient at greater risk of acute and chronic toxicity, accelerated 
partial breast irradiation (APBI) has been studied as a viable alternative to WBI. In 
general, APBI involves treating the surgical cavity with a 1-2cm margin. This substantial 
reduction in the volume of exposed breast tissue has enabled much shorter treatment 
schemes than WBI, making treatment more convenient for patients, and potentially 
decreasing the overall cost of treatment substantially.13 The results of multiple large, 
multicenter randomized controlled studies, including the National Surgical Adjuvant 
Breast and Bowel Project B 39 & Radiation Therapy Oncology Group 0413, are 
underway comparing ABPI to WBI and will be reported in the years ahead. To date, a 
small number of phase III and multiple phase I-II studies of various APBI techniques and 
fractionation schemes have been published. The sum of this data suggests that local 
recurrence rates with APBI are low in properly selected, low-risk women. However, the 
optimal technique, dose and length of treatment to be used for APBI remains undefined.  
The rationale for the proposed dose and fractionation of 7.3Gy x 3 is delineated in section 
1.3.2. 

8 
 
 
1.2 
 Clinical Studies of Partial Breast Irradiation 
 
Few randomized trials have been published to date with long-term outcomes comparing 
APBI to WBI. The first was conducted from 1982 to 1987 in Manchester, England, and 
randomized 708 evaluable patients with breast carcinoma 4cm or less in diameter to 
receive radiotherapy to the tumor bed only (40-42.5Gy in 8 fractions delivered over 10 
days, typically using 10MeV electrons to an average field size of 8 x 6cm, prescribed to 
the 100% isodose line) or to the whole breast and regional lymph nodes (40 Gy in 15 
fractions over 21 days, delivered with a 4-MV linear accelerator without the use of 
wedges). There was no axillary dissection or systemic therapy used and most patients did 
not have pre or postoperative mammographic evaluation. Moreover, there was no 
microscopic assessment of specimen margins and no CT planning for radiation so dose 
delivered to the target is uncertain. The 7-year actuarial breast recurrence rate (first event) 
for patients with infiltrating ductal carcinoma was 15% and 11% for the tumor bed only 
and whole breast/regional nodes arms, respectively. For patients with infiltrating lobular 
tumors, the respective recurrence rates were 34% and 8%.14  
 
The Hungarian National Institute of Oncology trial randomized 258 patients with T1 N0-
1mi, grade 1-2, nonlobular breast cancer without the presence of an EIC and resected 
with negative margins to lumpectomy followed by WBI (50Gy in 25 fractions, n=130) or 
APBI using either a high-dose-rate (HDR) multicatheter interstitial brachytherapy (MIB) 
technique (7 x 5.2Gy, n=88) or limited-field external-beam APBI with electrons (50Gy in 
25 fractions, using 6-15MeV en face electron fields to the tumor bed extended with a 
margin of 2cm, n=40). The 5-year actuarial rate of local recurrence was 4.7% in the WBI 
and 3.4% in the APBI arms, respectively (p=0.50), and there was no significant 
difference in overall survival, cancer-specific survival, and disease-free survival. The rate 
of good to excellent cosmesis was significantly better in the APBI arm: It was 77.6% 
with APBI (81.2% after HDR brachytherapy, 70.% after electron APBI) and 62.9% 
following WBI (52.2% in patients treated with cobalt, 65.6% after 6-9MV photons), 
p=0.009.15 
 
Multiple non-randomized phase I-II trials using various techniques to deliver APBI have 
been reported. Overall, these data suggest that with proper patient selection APBI appears 
to result in outcomes similar to those seen with WBI. The William Beaumont Hospital 
reported the largest American series of 199 patients treated with the MIB technique.  
Most patients had tumors smaller than 3cm in size, negative margins (≥2mm), were over 
the age of 40, and had negative lymph nodes. A total of 120 patients (60%) were treated 
with a low-dose-rate (LDR) implant of 50Gy over 96 hours, and seventy-nine patients 
(40%) were treated with a HDR implant of either 32Gy in 8 fractions or 34Gy in 10 
fractions, separated by 6 hours. With a median follow-up of 60 months, the cumulative 
incidence of local recurrence was 1%, and was not different than WBI patients on 
matched-pair analysis.16   
 
The Radiation Therapy Oncology Group (RTOG) performed a multi-institutional phase I-
II trial of MIB APBI based on the favorable results at William Beaumont and other 
institutions.  Eligibility for RTOG 9517 included tumors <3cm, unifocal disease, negative 
margins, and three or fewer lymph nodes without the presence of extra-capsular 
extension, and no EIC.  Patients were treated with either LDR (45Gy in 3.5-5days) or 
HDR (34Gy in 10 twice-daily fractions within 5 days) APBI. The target volume was 
defined as 2 cm beyond the lumpectomy cavity peripherally and 1 cm superficially and 

9 
 
deeply.17  With a median follow-up of 7years, the estimated 5-year in-breast failure rate 
for the 99 eligible patients was 4%. Of the 6 patients that failed within the treated breast, 
just two had failure outside of the treated volume.18 Five patients experienced grade 3 or 
4 acute adverse effects. The most common toxicities during follow-up were skin 
thickening and fibrosis, and late grade 3 toxicities were lower in patients treated with 
HDR compared with the LDR group (6% versus 18%).17   
 
MIB requires a considerable amount of physician technical expertise and the majority of 
radiation oncologists who treat breast cancer routinely do not have training to perform 
these procedures. The MammoSite® (Hologic Inc., Marlbourough, MA) breast 
brachytherapy applicator was designed to treat a similar volume of tissue around the 
lumpectomy cavity as MIB but with a single skin entry point, greater simplicity and less 
user-dependence.19  The American Society of Breast Surgeons (ASBS) MammoSite 
Breast Brachytherapy Registry Trial reported the outcomes of 1440 patients treated with 
this technique between 2002 and 2004 at 97 institutions. With a median follow-up for 
surviving patients of 53.7 months, the 5-year actuarial rate of ipsilateral breast tumor 
recurrence (IBTR) was 3.8% (3.86% for the 1249 patients with invasive breast cancer, 
3.39% for the 194 patients with DCIS). In patients with invasive breast cancer, the 5-year 
actuarial rate of regional nodal failure was 0.84%. Negative estrogen receptor status was 
the only variable significantly associated with ipsilateral breast tumor recurrence (IBTR) 
and was limited to the development of breast failures several centimeters from the 
primary site and believed to be a new primary cancer. 90.6% of patients had a good or 
excellent cosmetic result at 5 years, and the only factor significantly associated with 
favorable cosmesis was increasing balloon-to-skin distance.20 
 
Multi-lumen balloon catheter devices (Mammosite® ML and Contura® [SenoRx, Irvine, 
CA]) and non-balloon bundled-catheter device (SAVI® [Strut Adjusted Volume 
Implant], Cianna Medical, Aliso, Viejo, CA]) were developed to provide greater 
conformality to the lumpectomy cavity while enabling better tailoring of dose around 
normal tissue structures like the skin, chest wall, and heart compared with single-lumen 
applicators. Fisher et al. reported their results of treatment of 117 patients with APBI 
brachytherapy between 2004 and 2010.21 Seventy-seven were treated with single-lumen 
balloon catheter Mammosite® and 40 with the SAVI® applicator, all to total doses of 
34Gy in 10 fractions. Of the 40 patients treated with the SAVI® device, 12 had tumor 
bed-to-skin spacing of less than 7mm. None of these patients required device 
explantation, compared to 57% of patients treated with Mammosite when distances were 
<7mm. All 12 SAVI patients with minimal skin spacing had good or excellent cosmesis 
at short interval follow-up of 13 months thus far.21    
 
Three-dimensional (3D) conformal external-beam photon radiotherapy (3D-CRT) APBI 
is attractive because it is non-invasive, is widely available, and provides a more 
homogeneous radiation dose.  The RTOG 0319 was a phase I-II trial designed to 
determine the feasibility and reproducibility of 3D-CRT APBI in a multi-institutional 
setting. 58 patients with stage 1 or 2 invasive ductal carcinoma with tumors ≤3cm and 
negative surgical margins were enrolled. A total dose of 38.5Gy was administered in 10 
fractions over 5 days. The clinical target volume (CTV) included the lumpectomy cavity 
plus a 10-15mm margin. The Planning target volume (PTV) included the CTV plus a 10-
mm margin. The primary endpoint of reproducibility was met, as only 4 cases had major 
protocol violations.22 With a median follow-up of 4.5 years, a total of three ipsilateral 
breast failures were noted on RTOG 0319, with a four-year actuarial estimate of 6%. The 

10 
 
3DCRT technique was therefore included on the phase III NSABP B-39/RTOG 0413 
clinical trial and has been the most utilized APBI approach on that study. 
 
Formenti et al. 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 
delivered over 10 days with port film verification at each treatment. 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.23 
  
Proton beam APBI is a particularly promising alternative to other forms of APBI. Like 
3D-CRT APBI delivered with photons, it is noninvasive and has less dosimetric 
inhomogeneity compared with brachytherapy delivery methods.24 Due to unique physical 
properties of protons including their characteristic Bragg Peak, protons can be directed to 
treat deep-seated tumors while significantly sparing surrounding normal tissue, resulting 
in improved dose conformity. The Massachusetts General Hospital group recently 
reported long-term outcomes of their initial clinical experience with proton APBI on a 
phase 1 dose-escalation trial.25 Patients with unifocal, T1 tumors with tumor-free margins 
of ≥2mm and pathologically negative axillary nodes were eligible. The dose was 32Gy in 
8 fractions given twice daily and could be delivered with either protons, photons, or 
mixed photons and electrons. At 7 years, the local failure rate for all 98 evaluable patients 
was 6%. Physician rated cosmesis was good or excellent in 94% of photon patients, 
compared with 62% among the 19 patients treated with protons (p=0.03). Similarly, skin 
toxicity was more common in the proton group. The higher than expected level of skin 
toxicity is likely a result of suboptimal dose, beam arrangement and number of beams.24 
For example, a single field was used each fraction in the proton arm in order to minimize 
machine time. In contrast, Bush et al. from Loma Linda recently reported very favorable 
cosmetic and toxicity outcomes in 100 patients treated on a phase II study of proton 
APBI.26 Eligibility included non-lobular carcinoma of the breast, pathologically negative 
margins by at least 2mm, and primary tumors ≤3cm. In this study, 40Gy was delivered in 
10 daily fractions over 2 weeks and multiple fields were treated each day. With a median 
follow-up of 5 years, good or excellent cosmesis was noted in 90% of patients by both 
physician and patient reports. There was no acute or late grade 3 skin toxicity. Grade 1 
telangiectasias were seen in just 7% of patients. The 5 year  ipsilateral breast tumor 
recurrence-free survival was 97%.  
 
Electronic and intraoperative APBI devices have recently gained in popularity. Although 
the convenience of single fraction intraoperative radiation (IORT) is attractive, target and 
normal tissue dosimetery is limited and follow-up to date is short. TARGIT-A (targeted 
intraoperative radiation therapy), is a phase III prospective non-inferiority trial comparing 
whole breast EBRT to 20 Gy single fraction IORT delivered to the surface of the tumor 
bed with 50kV x-rays using spherical applicators.  Patients aged 45 or older with unifocal 
invasive ductal carcinoma and tumor sizes <3.5cm were eligible and enrolled between 
March 24, 2000 and June 25, 2012. If final pathology demonstrated pre-specified adverse 
features, EBRT was added to the TARGIT arm. The primary outcome was absolute 
difference in local recurrence in the conserved breast, with a prespecified non-inferiority 
margin of 2.5% at 5 years. For the whole cohort, the median follow up was 2 years and 5 
months. 1721 patients were randomized to TARGIT and 1730 patients to EBRT. 
Supplemental EBRT after TARGIT was given in 15.2% of patients treated with 
TARGIT. The 5-year risk for local recurrence were 3.3% (95% CI 2.1-5.1) and 1.3% 
(0.7-2.5, p=0.042) for the TARGIT and EBRT arms respectively, p=0.042, with an 

11 
 
absolute difference within the pre-specified non-inferiority margin.27  Significantly fewer 
non-breast cancer deaths were noted with TARGIT compared to EBRT (1.4% [0.8-2.5] 
vs 3.5% [2.3-5.2]; p=0.0086). 
 
In the Electron IntraOperative Therapy (ELIOT) phase III trial, patients aged 48-75 years 
with invasive tumors ≤2.5cm were randomized to 21Gy in 1 fractions to the tumor bed 
using 6-9MEV electrons prescribed to the 90% isodose line (n=651) or whole breast 
EBRT to 50Gy followed by a 10Gy boost.28  88.4% of patients on the study received 
endocrine therapy and 21.5% had chemotherapy. The study was designed with an 
assumed 5-year local recurrence rate of 3% in the EBRT group and equivalence of the 
two groups if the 5-year local recurrence rate in the ELIOT group did not exceed 7.5%. 
The 5-year event rate for IBTR was 4.4% (95% CI 2.7-6.1) in the ELIOT group, which 
was significantly higher compared to the 0.4% (0.0-1.0) rate in the conventional group, 
p=0.0001.  The hazard ratio for the development of IBTR was 9.3 [95% CI 3.3-26.3]. The 
rate of IBTR in the intraoperative radiotherapy group, however, was within the 
prespecified equivalence margin. The 5-year IBTR exceeded 10% in patients with tumors 
>2cm, patients with four or more positive lymph nodes, grade 3 tumors, ER negative 
tumors, and triple negative tumors. In multivariable analysis, tumor size greater than 2cm 
(HR 2.24, 95% CI 1.03-4.87), the presence of four or more positive lymph nodes (2.61, 
0.91-7.50), grade 3 (2.18, 1.00-4.79), and triple-negative subtype (2.40, 0.94-6.10) were 
associated with elevated risk of IBTR. The 5-year occurrence of IBTR was 1.5% in the 
452 women who did not have one of these unfavorable characteristics. The development 
of distant metastasis and overall survival at 5 years did not differ significantly between 
the two groups. There was significantly less erythema, dryness, hyperpigmentation, and 
pruritus in the ELIOT group, but a higher occurrence of fat necrosis. 
 
1.3 
 Rationale For the Current Study Design 
 
1.3.1 
Patient Selection 
 In order to limit the risk of local failure, only patients who have tumors that are limited in 
their spread beyond the index lesion, and unlikely to be at increased risk of chest wall, 
skin, or regional nodal recurrence if these sites are not fully irradiated should be offered 
APBI. Therefore, patients with positive axillary nodes, angiolymphatic invasion (ALI), 
large (>2.5 cm) or multicentric/multifocal tumors, those with lobular histology or an EIC, 
those with ER negative disease will be excluded.14,28,29 Patients with unifocal DCIS will 
be included based on multiple lines of evidence suggesting low rates of recurrence in 
properly selected patients with DCIS treated with APBI.30-34   
 
1.3.2 
Dose and Fractionation  
The linear-quadratic formula model has emerged as the preferred method of predicting 
the relationship between fraction size and tissue response of varying radiotherapy 
regimens. Its origins stem from what has been described as a two-component survival 
curve for mammalian cells represented by the curvilinear dose-response curve for the log 
of cell survival.35 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 
 

12 
 
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.36 
 
Several lines of evidence suggest that the α/β ratio of breast cancer may be more in line 
with those of late responding tissues.37,38 Indeed, the most robust data to date suggesting 
this relationship has come from the UK Standardization of Breast Radiotherapy (START) 
trials, two modern 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).39 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. 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.   
 
In START-B, 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.39,40 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 is the case 
with APBI.41,42  
 
The overlying hypothesis of this study is that the low α/β for breast cancer can be further 
exploited by compressing treatment into a 3 fraction daily regimen, provided that care is 
taken not to exceed the tolerance of normal tissues. Previous fractionation schemes for 
APBI have largely been devised empirically. The most common brachytherapy regimen 
in North America has been 3.4Gy delivered in 10 fractions given twice daily, the regimen 
adopted in NSABP B-39/RTOG 0413. This regimen has been reported to result in 
acceptable local control and cosmesis in numerous studies reported to date although 
retrospective population based analyses have suggested brachytherapy may be associated 
with increased frequency of infectious and noninfectious complications, compared with 
whole breast irradiation.18,43-46   Using an α/β ratio of 3.5 for tumor control and late 
effects, this regimen translates into a dose of 43Gy in 2Gy fractions.  
 
For external beam partial breast irradiation, the most common regimen used to date has 
been 38.5Gy delivered in two fractions per day for 10 fractions. This is also the dose 

13 
 
prescribed in NSABP B-39/RTOG 0413 as well as the Canadian Accelerated Partial 
Breast Irradiation Using Three-Dimensional Conformal External Beam Radiation 
Therapy (RAPID) randomized trials. Olivotto et al. recently reported the interim cosmetic 
and toxicity results from the latter study which compared 3D-conformal APBI to whole 
breast irradiation (WBI). 82% of patients in the WBI arm received 42.5Gy in 16 
fractions, and just 21% of patients received a boost. At 3 years, 29% of patients in the 
APBI arm had fair or poor cosmesis compared to 19% at baseline, an absolute difference 
of 10%. In the WBI arm, the rate of fair or poor cosmesis at 3 years was 17%, the same 
rate as at baseline. Telangiectasia and breast induration were also significantly more 
common with external beam APBI (p<0.001), as was fat necrosis (p=0.01).47 Other 
institutions have also noted adverse toxicity with similar regimens.22,48   
 
There are likely several reasons for the higher than expected adverse cosmesis seen in the 
RAPID trial that may be also relevant to the increased complications seen with 
brachytherapy in population based analyses. These considerations have been taken into 
account in the development of the brachytherapy, external beam photon and proton 
fractionation regimens of this study. First, the dose of 38.5Gy in 10 fractions given twice 
daily was too high. The RAPID trial investigators recognized that this prescription had a 
higher biologic equivalence than the whole breast regimens used in the study, but they 
hypothesized that the reduced volume of APBI would make up for this difference. 
Indeed, using an α/β ratio of 3.5 for late effects, the 3.85Gy x 10 fraction regimen 
translates into 51.5Gy in 2 Gy fractions, higher than the 2Gy fraction equivalent dose of 
42.5Gy delivered in16 fractions (47.7Gy2) which was received by the majority of patients 
in the WBI control arm of the study.  
 
Perhaps more importantly, the 6 hour interval between fractions may not have been long 
enough to complete sublethal damage repair of late responding breast tissue following 
3.85Gy fractions, resulting in a much more biologically potent dose to the tissues.49 
Indeed, data from the head and neck cancer CHART study suggested that normal tissue 
recovery halftimes for skin telangiectasia and subcutaneous fibrosis were 3.8h (95% CI 
2.5, 4.6) and 4.9h (95% CI 3.2, 6.4), respectively.50 Therefore, with inter fraction 
intervals of just 6 hours, incomplete repair could have a marked effect on the response of 
normal tissues, particularly in the context of fractions larger than 2Gy. In support of the 
importance of taking into account sublethal damage repair in APBI, cosmesis was rated 
as good/excellent in 89% of patients with at least 36 months follow-up in a prospective 
trial of 3D-CRT APBI of 100 patients treated in the prone position to a total dose of 
30Gy in 6Gy fractions, but delivered over 10 days. This regimen is equal to 51.82Gy2 
with an α/β ratio of 3.5 for tumor control which is comparable, under linear quadratic 
modeling, to the regimen used in the RAPID study but with greater interval between 
fractions for repair of sublethal damage.23  Finally, the volume of breast treated by 
physicians in RAPID, which included a 1.0cm PTV expansion, may have been too high.22  
 
Given this background, this study will explore treating patients with 3 fractions of 7.3Gy 
delivered once daily with 3DCRT and protons and 3 fractions of 7 Gy for brachytherapy. 
Using an α/β ratio of 3.5 for tumor control and late effects, these regimens is 
approximately equivalent to the 3.4Gy x 10 fraction regimen that has been the most 
widely used with promising results to date. We believe late toxicity will be reduced 
because of more complete sublethal damage repair with daily, as opposed to twice daily 
fractionation. Of note, similar 3 fraction regimens have been utilized in other disease sites 
and have been well tolerated with high rates of disease control.51  
 

14 
 
It is understood that the linear quadratic model has been questioned for large doses per 
fraction and alternative models have been proposed.52,53  A simple linear quadratic model 
was implemented here because it has decades of use in the radiotherapy treatment field, it 
is mathematically simple, and biological parameters other than alpha/beta are not well 
established.  It has also been suggested that cell damage from radiotherapy with high 
dose gradients (brachytherapy) may be greater than for a more homogenous dose 
distribution (external beam radiotherapy).54  In the brachytherapy arm, a small volume of 
tissue may receive a higher biologically equivalent dose by linear quadratic modeling due 
to treatment inhomogeneities, compared to 3.4Gy x 10. We expect this to be offset by 
more complete inter-fraction recovery than the commonly used twice daily regimen. The 
dose will also be slightly reduced in this arm (21 Gy in 3 fractions) compared to the 
3DCRT and proton arms (21.9Gy in 3 fractions).49 V400 and V300 for the brachytherapy 
arm will be minimized to the degree possible, and monitored, although a constraint is not 
specified.   Daily image guidance, as described in the radiation therapy section below, is 
used to safely reduce the planning target volume and subsequent normal tissue volume 
treated in photon and proton APBI.    
 
1.4 Rationale for allowing 3 different APBI techniques 
 
Prospectively conducted clinical trials have demonstrated the safety and efficacy of each 
of the APBI techniques that will be allowed on this study. On the recently closed NSABP 
B-39/RTOG 0413 protocol, A Randomized Phase III study of Conventional Whole 
Breast Irradiation Versus Partial Breast Irradiation for Women with Stage 0, I, or II 
Breast Cancer, APBI could be administered with brachytherapy or 3D-CRT at the 
physician’s discretion, highlighting the equipoise that exists between the techniques and 
justifying pooling outcomes of patients treated with either technique on this study to 
assess the primary and secondary endpoints. Given the conformal and homogeneous dose 
distribution of protons as well as the favorable outcomes reported to date, proton APBI 
will also be allowed at centers where this modality is available. At least one of the three 
APBI techniques allowed in this study is available at all participating centers. Similar to 
NSABP-B-39/RTOG 0413, the APBI technique to be 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. In addition, 
after reduction mammoplasty patients will only be allowed if they undergo brachytherapy 
as the extensive manipulation of breast tissue at the time of surgery is felt to preclude 
reliable targeting with external beam photon or proton techniques. 
 
2.0  Goals    
 
 
2.1 
Primary:  
 
2.11 
To evaluate the rate of adverse cosmesis (defined as fair or poor cosmesis) with 
accelerated 3 fraction APBI at 3 years, compared to baseline. 
 
2.2 
Secondary: 
 
2.21 
To evaluate the acute and late toxicities of accelerated 3 fraction APBI 
 
2.22 
To evaluate local disease control of accelerated 3 fraction APBI. 
 
2.23 
To assess the rate of patient reported adverse cosmesis at 2 years, compared to 
baseline 

15 
 
 
2.23 
To assess quality of life and other patient reported outcomes following  
accelerated 3 fraction APBI 
 
2.24 
 To compare the local control, acute and late toxicities, cosmesis, quality of life 
and other patient reported outcomes between the three radiation therapy 
techniques (3D-CRT, proton, brachytherapy). 
 
2.24 
To evaluate clinical features, dose-volume parameters, and genetic variants 
associated with fair and poor cosmetic outcome 
 
3.0 
 Patient Eligibility 
 
3.1  Inclusion Criteria  
 
3.11 
Female 
 
3.12            Age ≥ 50 years at diagnosis 
 
3.13 
Grade 1-3 invasive ductal, mammary, mucinous, tubular, colloidal, or pure ductal 
carcinoma in situ (DCIS) measuring ≤ 2.5 cm on final pathology (the tumor 
should be clinical stage T1N0M0 in patients electing brachytherapy in whom the 
catheter will be placed intraoperatively).  
3.14 
Estrogen Receptor (ER)+ (ER- DCIS meeting other eligibility criteria are 
eligible) 
 
3.15 
Unicentric: Patients with microscopic multifocality are eligible as long as the 
total pathologic tumor size is ≤2.5cm  
3.16 
Surgical treatment of the breast must have been lumpectomy.  
 
3.17 
The final margins of the resected specimen must be histologically free of tumor.  
 
3.18 
Patients with DCIS do not require an axillary staging procedure. For patients 
with invasive breast cancer (except T1mi), an axillary staging procedure should 
be performed (either sentinel lymph node biopsy alone or axillary dissection and 
the axillary node must be pathologically negative) and they should be 
pathologically node negative.  
 
 
Note: Patients with N0 (i+) tumors on sentinel lymph node mapping or dissection 
(i.e., if the tumor deposit is 0.2mm or less as determined by 
immunohistochemistry or hematoxylin and eosin staining) will also be eligible. 
 
3.19            ECOG Performance Status of 0 or 1 
 
3.20 
Negative pregnancy test done ≤7 days prior to registration, for women of 
childbearing potential only. 
 
3.21 
Ability to complete questionnaire(s) by themselves or with assistance. 
 
3.22 
Ability to elect radiotherapy care in conjunction with their physician 
 
3.23           Able and willing to provide written informed consent 
 

16 
 
3.24 
Willingness to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
3.25 
Willing to provide tissue and blood samples for correlative research purposes 
 
3.26 
Rochester and Arizona patients: Willing to sign consent onto the Mayo Clinic 
Radiotherapy Patient Outcomes Registry and Biobanking study and collect 
involved blood specimen prior to the start of radiation therapy, IRB number 15-
000136. 
 
 
 
3.3  Exclusion Criteria  
 
3.31 
Any of the following because this study involves therapy that has known 
genotoxic, mutagenic and teratogenic effects: 
• 
Pregnant women 
• 
Nursing women 
• 
Women of childbearing potential who are unwilling to employ adequate 
contraception 
 
 
 
 
 
3.32 
Neoadjuvant chemotherapy 
 
 
 
 
 
3.33 
Prior history of ipsilateral breast cancer 
 
3.34 
Prior radiation therapy to the ipsilateral breast or thorax 
 
3.35 
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.  
 
3.36 
Active collagen-vascular disease that, in the opinion of the treating physician, 
would make this protocol unreasonably hazardous for the patient. 
 
3.37 
Paget’s disease of the breast 
 
3.38 
Proven multicentric carcinoma (DCIS or invasive) in more than one quadrant or 
separated by 4 or more centimeters or diffuse (>1 quadrant) suspicious 
calcifications 
 
3.39 
Histologic evidence of angiolympatic invasion (ALI).  
Note: Cases termed focally suspicious for ALI but where no definitive ALI is 
found are eligible. 
 
3.40 
Surgical margins that cannot be microscopically assessed or that are positive 
 
3.41 
Pathologic tumor >2.5cm  in size 
 
3.42 
Metastatic disease 
 
 
3.43 
Patients for whom the delivery of APBI is not feasible or any of the dosimetric 
treatment criteria in section 9.7 have not been met.  
 

17 
 
3.44 
BRCA 1/2 mutation 
Note: Patients are not required to undergo BRCA1 and BRCA2 or other genetic 
mutation tests in order to enroll on the study. However, in the event a patient is 
tested and is found to be a mutation carrier, she would be excluded from the 
study. 
 
3.45 
Breast implants (patients who have had implants removed are eligible). 
 
3.46 
Extensive intraductal component 
 
3.47 
Active connective tissue disease 
 
3.48 
Reduction mammoplasty if 3DCRT or proton APBI are planned 
 
3.49 
Last surgery >10 weeks from enrollment 
 
 

18 
 
4.0 
Test Schedule 
 
 
Assessments, tests and 
procedures 
 
Treatment 
 
Observation 
 
Baseline2 
 
Radiation 
Treatment 
Last day of 
radiation 
treatment 
(+/-2 days) 
 
12 weeks (+/- 8 
weeks) post-
radiation 
12 months (+/- 3 months) post 
completion of radiotherapy, annually for 
up to 5 years (+/- 3 months)7 
 
History and Physical exam 
(including breast 
assessment/exam)1 
X 
X 
              X 
X 
 
Mammogram 
 
X11 
 
 
X8 
 
Consent 
 
X 
 
 
Cosmetic and QOL Outcome 
Assessment (see section 11.3 and 
Appendix) 
 
X 
 
 
X 
X 
 
X 
 
 
Digital Photograph 
 
 
X10 
 
 
X 
X 
X 
 
Histologic Assessment  
 
 
X3 
 
 
Radiation toxicity assessment (see 
section 10.4) 
 
X 
 
X 
X 
X 
Serum pregnancy test 
 
X4 
 
 
 
 
 
Blood specimen5,R 
 
X12 
 
X 
 
 
Clinically indicated treatment 
 
 
 
X 
 
 
 
Active Monitoring Phase

19 
 
Surgical tumor    specimen6,R 
 
X9 
 
 
 
 
 
1. A general clinical history & physical must be done ≤ 8 weeks prior to registration. This should include assessment of ECOG 
performance status (see Appendix I). 
2.   Procedures done prior to radiation therapy. 
 
3.     Outside pathology must be reviewed at the treating institution.  
4. For women of childbearing potential only 
5. See section 14 for collection time and preparation of samples 
6. See section 17 for collection time and preparation of samples    
7. Patients that cannot come back to Mayo Rochester within the time constraints of the follow-up schedule; efforts to obtain outside 
records and send QOL’s to be completed will occur however the specifics of the test schedule may not be captured. Observation 
will occur for a total of 5 years unless the patient goes off study.  
8. As clinically indicated 
9. Collect post-surgery 
10. Ideally prior to surgery but can be done prior to radiation 
11. Completed ≤ 6 months prior to study entry 
12.  Radiation Oncology Registry and Biobank (IRB:  15-000136):  Blood specimen is required to be collected prior to the start of 
radiation therapy. 
R.    Research required testing  
 

20 
 
 
5.0           Stratification Factors  
• 
None – Patients, along with their physicians, will determine which treatment arm is 
appropriate for their needs. The APBI technique to be utilized will be based on technical 
considerations, availability at the radiation oncology facility, insurance coverage 
considerations, and patient preference. In addition, after reduction mammoplasty patients will 
only be allowed if they undergo brachytherapy as the extensive manipulation of breast tissue 
at the time of surgery is felt to preclude reliable targeting with external beam photon or 
proton techniques. 
 
6.0 
Randomization/Registration Procedures 
6.1 
Randomization-none 
 
6.2 
Registration Procedures 
 
 
 
Registration will entail confirming patient eligibility and signing the informed consent  
 
 
6.21 
 Pretreatment tests/procedures, (see Section 4.0) will be completed within the 
guidelines specified on the assessment schedule. 
 
 
6.22 
 All required baseline symptoms (see Section 10.0) must be documented and 
graded. 
 
7.0 
Clinical Protocol Treatment 
 
 
7.1 Radiation Therapy  
 
7.11      3D-CRT (photon) APBI 
 
In situations where patients present to a radiation oncologist pre-operatively, if 
they meet study eligibility criteria they may be consented at that time for 3D-
CRT APBI. After lumpectomy and axillary staging, at their postoperative visit in 
the radiation oncology department (generally 1-6 weeks following surgery) final 
pathology and eligibility will be confirmed. Consent may also be obtained for 
photon APBI at that time if it was not provided preoperatively or if the patient is 
consulting with the treating radiation oncologist for the first time. Patient must 
begin treatment  ≤ 10 weeks after their last surgery.  
Radiation Details: 
Localization, Simulation, Immobilization: Prior to the treatment planning CT 
scan patients must be immobilized in the supine position in an arm up or down 
position at the discretion of the treating radiation oncologist.  The CT should start 
at or above the mandible and extend several cm below the inframmamary fold 
(including the entire lung). Slice thickness should be 0.3 cm or less. 
 
Treatment Planning/Delivery: Any combination of photon beams of energy 6MV 
or higher, with or without the addition of electrons of any energy, may be used 
provided that the dosimetric requirements of the planning target volume (PTV) 
and homogeneity are met. 3D-CRT should begin within 10 weeks of lumpectomy 
or re-excision of margins. 
 

21 
 
 
Image Guidance for IGRT: Cone-beam CT (CBCT) matched to soft tissue and or 
fiducial markers/clips placed at the time of lumpectomy or orthogonal 
kilovoltage (KV) images matched to fiducial markers/clips should be performed 
to ensure reproducibility of setup prior to initiation of each treatment. A manual 
registration can also be used to optimize the match prior to treatment.  
 
Definition of Target Volumes: The radiation oncologist will identify and outline 
the tumor bed by noting contrasting areas of density and architectural distortion 
as well as the presence of clips or fiducials in the breast. Information from the 
surgical report, mammography, MRI and other available imaging should be taken 
into account when available. A margin of 1cm will then be added to the tumor 
bed in order to create the CTV. The CTV will be limited, however, to 5mm from 
the skin surface and by the posterior breast tissue extent (chest wall and 
pectoralis muscles are not to be included). The PTV is defined as a uniform 3mm 
expansion of the CTV to compensate for variability of set-up and any motion of 
the breast during treatment. The PTV is saved and is used to generate the beam 
aperture with an additional margin to take penumbra into account. Since a 
substantial part of the PTV often extends outside other patient (especially for 
superficial cavities), the PTV is then copied to a PTV_EVAL, which is edited. 
The PTV_EVAL is limited to exclude the part outside the ipsilateral breast and 
the first 5mm of tissue under the skin (in order to remove most of the buildup 
region for the DVH analysis). Bolus to improve anterior target coverage should 
not be used. It is preferred that the PTV does not exceed 25% of the breast 
volume. If it does, a delay of 1-3 weeks until the seroma decreases in size and 
another planning session is performed should be considered.  
 
Dose Prescription to PTV: The prescribed radiotherapy dose will be 21.9 Gy in 
7.3 daily fractions (total of 3 fractions). Radiotherapy should aim to be delivered 
on three consecutive work days. Per protocol ≥95% of the target volume PTV 
should be covered by ≥95% of the prescribed dose of 21.9Gy. Variation 
Acceptable ≥90% of the target volume PTV should be covered by ≥90% of the 
prescribed dose of 21.9Gy. The maximum dose should not exceed 115% of the 
prescribed dose. 
 
Definition and Dose Limitations of Normal Tissues/Organs at Risk (OARs): The 
following normal tissue structures should be contoured for all patients by the 
physician: uninvolved normal breast, ipsilateral lung, contralateral lung, and 
heart. 
 
Uninvolved ipsilateral normal breast: Includes the glandular breast tissue 
visualized by CT and the consensus definitions regarding “breast” from the 
RTOG breast atlas.  The structure should be limited to 5mm from the skin 
surface to minimize inaccuracy of dose calculation at the skin surface.  Per 
protocol <35% (variation acceptable <50%) of the whole breast reference volume 
should receive ≥ 50% of the prescribed dose and <20% (variation acceptable 
<30%) of the whole breast reference volume should receive the prescribed dose.  
 
Ipsilateral lung: May be contoured with auto-segmentation with manual 
verification. The volume receiving 20Gy should not exceed 2%. The volume 
receiving 10Gy should not exceed 7%. The volume receiving 5Gy should not 
exceed 15%.  

22 
 
 
 
Contralateral lung: The volume receiving 20Gy should be 0. The volume 
receiving 10Gy should be <1%. The volume receiving 5Gy should be <2%.  
 
Heart: The heart should be contoured beginning just inferior to the level in which 
the pulmonary trunk branches into the left and right pulmonary arteries (PA) and 
extending to its most inferior extent near the diaphragm. Contouring along the 
pericardium itself, when visible, is appropriate.  The esophagus, ascending and 
descending aorta, and inferior vena cava should be excluded. The volume of 
heart receiving 2.5Gy should be less than 40%. 
 
7.12 
Catheter-based Brachytherapy APBI  
 
Patients that elect to undergo brachytherapy APBI will consult with a radiation 
oncologist preoperatively. If they meet study eligibility criteria they may be 
consented at that time for brachytherapy APBI. At surgery (day 1), metal 
vascular or marking clips should not be used during the lumpectomy procedure.  
Immediately following lumpectomy and axillary staging and during the same 
procedure, if the patient still meets eligibility criteria the brachytherapy catheter 
device (SAVI, Mammosite, or Contura) will be placed. Care should be taken to 
direct suture knots and tails away from the cavity and whenever possible position 
tissue between the potential balloon surface and the tails. Prophylactic antibiotics 
should be initiated prior to device placement and continued until the device is 
completely removed from the patient. On day 2-4, the patient will present to the 
radiation oncology department for brachytherapy treatment planning, with the 
first treatment generally administered the following business day but possibly as 
early as day 2. 
 
Radiation Details: 
Localization, Simulation, Immobilization: Prior to the treatment planning CT 
scan patients must be immobilized in the supine position, generally with the arms 
up and resting comfortably in a reproducible position stabilized by an 
immobilization device.  A treatment planning CT scan with the patient in a 
supine position and in a deep inspiratory breath hold will be performed within 4 
days of the lumpectomy and device placement. The CT should start at or above 
the mandible and extend several cm below the inframmamary fold (including the 
entire lung). Slice thickness should be 0.3 cm or less. Skin spacing, symmetry, 
and conformance of the applicator will be assessed at that time. An AP and 
lateral digitally reconstructed radiograph (DRR) should be constructed and the 
skin position of each catheter line should be marked on the skin for pre-treatment 
quality assurance. Finally, a photograph will be taken to document the orientation 
of the patient. 
 
Treatment Planning/Delivery: Standard treatment planning guidelines for APBI 
will be employed and CT imaging is mandatory for treatment planning.  Plans 
will be generated on Varian Eclipse Brachytherapy Treatment Planning software 
to produce the optimal conformal plan in accordance with volume definition and 
dose requirements.  The treatment plan used for each patient will be based on 
analysis of the volumetric dose including dose-volume histogram (DVH) 
analyses of the PTV_EVAL and critical normal tissues. The treatment will be 
performed using the VariSource high dose rate (HDR) brachytherapy afterloader.   

23 
 
 
 
In general, brachytherapy should start between 1-5 days after device placement 
and treatment should be completed within 1 week of device placement. To 
confirm that the patient’s setup is identical to the position of the initial  
planning CT, the applicator’s position and integrity will be verified at the 
discretion of the treating physician with particular attention to applicator rotation 
and changes in soft tissue.  This will be done by repeating the planning CT scan 
in the treatment position, assessing the position of the external catheter marker on 
the skin surface and by obtaining AP and Lateral planar radiographic images, CT 
scouts, or CT AP and Lateral views for verification of the balloon/strut size and 
shape. If a change in geometry is noted, this should be addressed prior to 
additional treatment and repeat planning should be considered at the discretion of 
the treating physician. The device should remain expanded throughout the 
treatment course.  
 
Definition of Target Volumes:  The following structures will be contoured: (a) the 
applicator surface (for example for the SAVI® device, the "device surface" is 
defined as a structure represented by a contour created by smooth contour 
connection of each strut), (b) planning target volume for evaluation 
(PTV_EVAL) – (see below), (c) trapped air and/or fluid, (d) skin (both a 
structure of 5mm of superficial tissue and a structure of the skin surface), (d) 
chest wall (including ribs), and (e) pectoralis major muscle.  The target volumes 
and normal tissue structures should be outlined on all CT slices. 
 
As the implanted device moves with the target, compensation for variability of  
treatment set-up and breathing motion is not needed; therefore planning target 
volume for evaluation (PTV_EVAL) = CTV = PTV.  Therefore, within this 
protocol, only the PTV_EVAL will be referenced.  The PTV_EVAL will be 
delineated as the breast tissue volume bounded by the uniform expansion of the 
applicator surface radius in all dimensions by 10 mm less the applicator volume 
and will be limited to 5 mm from the skin surface and by the posterior breast 
tissue extent (chest wall and pectoralis muscles are not to be included). 
 
The volume of trapped air/fluid that displaces the target beyond 1 cm from the 
balloon/applicator surface should be considered by the physician.  The area of 
trapped air/fluid will be contoured at each level and a total volume obtained. The 
percentage of the PTV_EVAL that the air displaces may be calculated but this 
will not be considered in the PTV prescription constraints outlined below. If 
brachytherapy APBI is attempted but aborted prior to initiation because target 
coverage or normal tissue constraints (see below) cannot be met, then an 
alternative APBI technique (3DCRT photon or proton APBI) may be attempted 
on this protocol.  
 
Dose Prescription to PTV_Eval: The prescribed radiotherapy dose will be 21 Gy 
in 7 Gy daily fractions (total of 3 fractions). Radiotherapy should aim to be 
delivered on three consecutive work days. Per protocol ≥95% of the target 
volume PTV should be covered by ≥95% of the prescribed dose of 21 Gy. High 
dose rate treatment delivery is required. Variation Acceptable ≥90% of the target 
volume PTV should be covered by ≥90% of the prescribed dose of 21 Gy. The 
volume receiving 150% and 200% (V150% and V200%) of the prescribed dose 
or more should be ≤35cc and ≤10cc, respectively. Variation Acceptable V150% 

24 
 
 
<50cc and V200% <15cc. The volume receiving 300% and 400% (V300% and 
V400%) of the prescribed dose should be reported. 
 
Definition and Dose Limitations of Normal Tissues/Organs at Risk (OARs): The 
following normal tissue structures should be contoured for all patients: 
uninvolved normal breast, ipsilateral lung, contralateral lung, heart, skin, adjacent 
ribs. 
Skin: The maximum dose at the skin surface should be reduced to as low as 
achievable while satisfying the other dose parameters but should not exceed 
100% of prescription. If this constraint cannot be met than a different APBI 
technique can be considered on study. Ideally, the maximum dose of the first 
5mm of superficial tissue from the body surface will also not exceed 125% of 
prescription and the maximum dose of the first 10mm of superficial tissue will 
not exceed 150% of prescription. 
 
Chest wall (including ribs): Should be outlined on all CT slices when within 
5mm of the PTV. The maximum dose and V0.1cc will be reduced to as low as 
achievable while satisfying all dose parameters but should not exceed 115% of 
the prescribed dose. 
 
Uninvolved ipsilateral normal breast: Includes the glandular breast tissue 
visualized by CT and the consensus definitions regarding “breast” from the 
RTOG breast atlas.  The structure should be limited to 5mm from the skin 
surface to minimize inaccuracy of dose calculation at the skin surface.  Per 
protocol <35% (variation acceptable <50%) of the whole breast reference volume 
should receive ≥ 50% of the prescribed dose and <20% (variation acceptable 
<30%) of the whole breast reference volume should receive the prescribed dose.  
 
Ipsilateral lung: May be contoured with auto-segmentation with manual 
verification. The volume receiving 20Gy should not exceed 2%. The volume 
receiving 10Gy should not exceed 7%. The volume receiving 5Gy should not 
exceed 15%.  
 
Heart: The heart should be contoured beginning just inferior to the level in which 
the pulmonary trunk branches into the left and right pulmonary arteries (PA) and 
extending to its most inferior extent near the diaphragm. Contouring along the 
pericardium itself, when visible, is appropriate.  The esophagus, ascending and 
descending aorta, and inferior vena cava should be excluded. The volume of 
heart receiving 2.5 Gy should be less than 40%.  
 
 
Applicator Removal: The applicator should be removed after completing the last 
fraction of treatment using standard technique. The applicator entrance/exit site 
should be dressed according to standard medical practice. 
 
7.13 
Proton APBI 
 
In situations where patients present to a radiation oncologist pre-operatively, if 
they meet study eligibility criteria they may be consented at that time for proton 
APBI. After lumpectomy and axillary staging, at their postoperative visit in the 
radiation oncology department (generally 1-6 weeks following surgery) final 
pathology and eligibility will be confirmed. Consent may also be obtained for 

25 
 
 
proton APBI at that time if it was not provided preoperatively or if the patient is 
consulting with the treating radiation oncologist for the first time. Patient must 
begin treatment ≤ 10 weeks after their last surgery. 
 
Radiation Details: 
Localization, Simulation, Immobilization: Prior to the treatment planning CT 
scan patients must be immobilized in the supine position in an arm up or down 
position at the discretion of the treating radiation oncologist.   Slice thickness 
should be 0.3 cm or less.  
 
Treatment Planning/Delivery: Any combination of at least 2 proton beams may 
be used provided that the dosimetric requirements of the planning target volume 
(PTV) and homogeneity are met. Proton APBI should begin within 10 weeks of 
lumpectomy or re-excision of margins. 
 
Image Guidance for IGRT: Orthogonal kilovoltage (KV) images matched to 
fiducial markers placed at the time of lumpectomy should be performed to ensure 
reproducibility of setup prior to initiation of each treatment. 
 
Definition of Target Volumes: The radiation oncologist will identify and outline 
the tumor bed by noting contrasting areas of density and architectural distortion 
as well as the presence of clips or fiducials in the breast. Information from the 
surgical report, mammography, MRI and other available imaging should be taken 
into account when available. A margin of 1cm will then be added to the tumor 
bed in order to create the CTV. The CTV will be limited, however, to 5mm from 
the skin surface and by the posterior breast tissue extent (chest wall and 
pectoralis muscles are not to be included). The proton PTV expansion will be 
defined initially as a 5mm expansion of the CTV to compensate for variability of 
set-up and any motion of the breast during treatment but will be expanded or 
contracted as necessary to maintain a 3.0%/3mm robustness such that the CTV 
coverage of 95% of the volume gets at least 95% of the dose. The border of this 
proton PTV will be limited to within 5mm below the skin surface and posteriorly 
to the anterior surface of the ribs. It is preferred that the PTV does not exceed 
30% of the breast volume. If it does, a patient could potentially wait for 1-3 
weeks until the seroma decreases in size and another planning session is 
performed.  
 
Dose Prescription to PTV: The prescribed radiotherapy dose will be 21.9 Gy in 
7.3 daily fractions (total of 3 fractions). Radiotherapy should aim to be delivered 
on three consecutive work days. Per protocol ≥95% of the target volume CTV 
should be covered by ≥95% of the prescribed dose of 21.9Gy.  
 
Definition and Dose Limitations of Normal Tissues/Organs at Risk (OARs): The 
following normal tissue structures should be contoured for all patients by the 
physician: uninvolved normal breast, ipsilateral lung, contralateral lung, heart 
and skin. 
 
Uninvolved ipsilateral normal breast: Includes the glandular breast tissue 
visualized by CT and the consensus definitions regarding “breast” from the 
RTOG breast atlas.  The structure should be limited to 5mm from the skin 
surface to minimize inaccuracy of dose calculation at the skin surface.  Per 

26 
 
 
protocol <35% (variation acceptable <50%) of the whole breast reference volume 
should receive ≥ 50% of the prescribed dose and <20% (variation acceptable 
<30%) of the whole breast reference volume should receive the prescribed dose. 
 
Ipsilateral lung: May be contoured with auto-segmentation with manual 
verification. The volume receiving 20Gy should not exceed 2%. The volume 
receiving 10Gy should not exceed 5%. The volume receiving 5Gy should not 
exceed 10%.  
 
Contralateral lung: The volume receiving 20Gy should be 0. The volume 
receiving 10Gy should be <1%. The volume receiving 5Gy should be <2%.  
 
Heart: The heart should be contoured beginning just inferior to the level in which 
the pulmonary trunk branches into the left and right pulmonary arteries (PA) and 
extending to its most inferior extent near the diaphragm. Contouring along the 
pericardium itself, when visible, is appropriate.  The esophagus, ascending and 
descending aorta, and inferior vena cava should be excluded. The volume of 
heart receiving 1.5Gy should be less than 40%. 
 
Skin: The maximum dose at the skin surface, defined as the most superficial 
3mm of the body surface, should be reduced to as low as achievable while 
satisfying the other dose parameters but should not exceed 100% of prescription. 
If this constraint cannot be met than a different APBI technique can be 
considered on study.  
 
8.0 
Radiotherapy Dose Modifications Based on Adverse Events 
 
 
8.1 
 Compliance Criteria 
 
Treatment breaks must be clearly indicated in the treatment record along with the 
reason(s) for the treatment break(s). Radiation breaks, if necessary, should not exceed 
one treatment day. Radiation breaks should be allowed only for resolution of severe acute 
toxicity and/or for intercurrent illness and not for social or logistical reasons.  
 
8.2 
Radiation Therapy Adverse Events  
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4 will be utilized for grading all adverse 
events. All appropriate treatment areas should have access to a copy of the CTCAE, v. 4. 
A copy of the CTCAE, v. 4 can be downloaded from the CTEP web site 
(
). 
 
EVENTS EXPECTED 
 
Erythema, dry desquamation, hyper or hypopigmentation are anticipated to occur 
commonly. Some patients may develop moist desquamation, which usually heals within 
2-3 weeks. Mild swelling of the breast or mild breast pain are also likely side effects of 
treatment. It is not anticipated that treatment breaks should be needed, as severe acute 
toxicities are extremely rare.  
 

27 
 
 
Transient, persistent, and occasionally symptomatic seroma formation can occur and will 
be monitored for during treatment and at follow-up. Telangiectasia, and chronic changes 
in pigmentation can also commonly be seen, as can soft tissue fibrosis. 
 
Infection is less likely, occurring in less than 10% of patients, generally following 
brachytherapy.   
 
Skin or subcutaneous toxicity requiring surgery, pneumonitis, rib fractures, or any grade 
3 or greater complications including pain are uncommon after ABPI, and are expected to 
occur in <10% of patients 
 
Patients will also undergo venipuncture as part of the study. Risks of that procedure 
include hematoma, swelling, tenderness and inflammation at the site, persistent bleeding, 
vasovagal response, and rarely thrombosis and infection. 
 
Method of detection, signs and symptoms, and method of treatment will be reported for 
all detected toxicities 
 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Skin creams/ointments for the treatment of dermatitis may be used at the discretion of the 
treating physicians as per standard practice. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1Definitions 
Adverse Event- An untoward or undesirable experience associated with the use of a 
medical product (i.e. drug, device, biologic) in a patient or research subject. 
Serious Adverse Event - Adverse events are classified as serious or non-serious.  Serious 
problems/events can be well defined and include; 
• 
Death 
• 
life threatening adverse experience 
• 
hospitalization 
• 
inpatient, new, or prolonged; disability/incapacity 
• 
persistent or significant birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-
investigator may have adversely affected the rights, safety, or welfare of the subjects or 
others, or substantially compromised the research data. 
All adverse events that do not meet any of the criteria for serious, should be regarded as 
non-serious adverse events.  
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSO)- Any 
unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may 
be physical, psychological, financial, social, economic, or legal) or increased 
risk for the subject or others (including individuals who are not research 
subjects). These include: (1) death; (2) life threatening adverse experience; (3) 
hospitalization - inpatient, new, or prolonged; (4) disability/incapacity - 
persistent or significant; (5) birth defect/anomaly; (6) breach of confidentiality 
and (7) other problems, events, or new information (i.e. publications, DSMB 
reports, interim findings, product labeling change) that in the opinion of the 

28 
 
 
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. All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site: 
 
 
10.21        Adverse event monitoring and reporting is a routine part of every clinical 
trial. First, identify and grade the severity of the event using the CTCAE 
version 4.0. Next, determine whether the event is expected or unexpected 
and if the adverse event is related to the medical treatment or procedure. With 
this information, determine whether the event must be reported as an expedited 
report (see Section 10.3). 
 
 
  10.22      Assessment of Attribution 
 
                        When assessing whether an adverse event is related to a medical treatment or               
                          procedure, the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event. 
 
 
10.3  Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event 
Worksheet and log.  The investigator will evaluate the event and determine the necessary 
follow-up and reporting required. 
 

29 
 
 
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 time of the 
next continuing review. The investigator monitors the severity and 
frequency of subsequent non-UPIRTSOs. 
 
Consider the following information to collect when developing any 
forms for documentation of adverse events. 
 
Example 
Information collected on the adverse event worksheet (and entered in the 
research database):  
• 
Subject’s name:  
• 
Medical record number:  
• 
Disease/histology (if applicable):  
• 
The date the adverse event occurred:  
• 
Description of the adverse event:  
• 
Relationship of the adverse event to the research (drug, procedure, or 
intervention):  
• 
If the adverse event was expected:  
• 
The severity of the adverse event: (use a table to define severity scale 1-
5) 
• 
If any intervention was necessary:  
• 
Resolution: (was the incident resolved spontaneously, or after 
discontinuing treatment) 
• 
Date of Resolution:  
 
The investigator will review all adverse event reports to determine if 
specific reports need to be made to the IRB and FDA.  The investigator 
will sign and date the adverse event report when it is reviewed.  For this 
protocol, only directly related SAEs/UPIRTSOs will be reported to the 
IRB. 
 
 10.4 
Adverse events to be graded at each evaluation and pretreatment 
 
symptoms/conditions to be evaluated at baseline per the CTCAE v4.0 grading  
 
  
unless otherwise stated in the table below: 
 
 
 
 
Each  
Grading scale 

30 
 
 
System Organ Class 
(SOC)  
Adverse 
event/Symptoms 
Baseline 
evaluation 
(if not CTCAE) 
Skin and Subcutaneous 
tissue disorders 
Dermatitis Radiation 
X 
X 
CTCAE 
Telangiectasia 
X 
X 
See 10.1 
Breast Edema = 
CTCAE Vascular 
Lymphedema 
X 
X 
CTCAE, 
BCTOS 
Superficial soft tissue 
Fibrosis 
X 
X 
CTCAE 
Seroma 
X 
X 
CTCAE 
Skin 
hyperpigmentation 
X 
X 
CTCAE 
Skin 
hypopigmentation 
X 
X 
CTCAE 
Infections and infestations Breast infection 
X 
X 
CTCAE 
Respiratory, thoracic and 
mediastinal disorders 
 
Pneumonitis 
X 
X 
CTCAE 
General disorders and 
administration site 
conditions 
Non-cardiac chest 
pain 
X 
X 
CTCAE 
                                    BCTOS = Breast Cancer Treatment Outcomes Scale 
 
                                 10.41 Grading Scale for other toxicities 
 
 
Telangiectasia: Grade 0 – None; Grade 1 – 1cm2; Grade 2 – 2-4cm2; Grade 3 - >4cm2 
 
 
10.5              Monitoring and Auditing  
 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, 
internal regulatory areas, and government regulatory agencies, of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, 
study data etc.).  The investigator will ensure the capability for inspections of applicable 
study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices 
 
10.51           Medical Monitoring  
It is the responsibility of the Principal Investigator to oversee the safety of the 
study at his/her site.  This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above, as well as the 
construction and implementation of a site data and safety-monitoring plan (see 
section 10.5  “Monitoring and Auditing”).  Medical monitoring will include a 
regular assessment of the number and type of serious adverse events.  “Any 
serious adverse events will be followed up by the sentinel event reporting 
procedure” 

31 
 
 
 
 
10.52          Internal Data and Safety Monitoring 
 
The trial will be reviewed by the Cancer Center Auditing area on a bi-
annual or yearly basis dependent on random study selection to assess 
accrual, adverse events, and any endpoint problems. Any safety issues 
requiring protocol changes will be communicated through protocol 
amendments.   
 
11.0 
Treatment Evaluation  
 
11.1 
Patients will be evaluated at baseline, then in follow-up according to the Assessment 
Schedule (Section 4.0)  
 
11.2          At the time of reevaluation, patients will be classified in the following manner: 
 
 
 
 
 
11.21  No evidence of disease (NED). 
 
 
 
11.22  Recurrence of disease (REC). Recurrence must be confirmed by biopsy.  
 
 
 
11.221 The site of recurrence (or failure) will also be collected and classified as 
local vs. regional vs. distant recurrence.  The specific site of failure will also be 
collected as well. Moreover, if there is an IBTR, the location of the IBTR relative 
to the initial cancer will be documented and the IBTR will be classified 
according to Recht et al. as a “true recurrence/marginal miss” failure if the 
recurrence of the treated cancer occurs within or immediately adjacent to the 
primary tumor site. An “Elsewhere Failure” will be defined as an IBTR several 
centimeters from the primary site. 
 
 
 
11.222 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 
 
11.31 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 and 
both lateral views. Recommended framing should go from the sternal notch to 
the umbilicus. If possible, patients should be photographed against a solid 
colored background. 
 
11.32 The Harvard Cosmesis Scale will be used to score cosmesis according to the 
schedule outlined in section 4.0. The patients will be assessed as one of the 
following: 
 
• 
Excellent: treated breast nearly identical to untreated breast 
 
• 
Good: Treated breast slightly different than untreated (minimal but 
identifiable effects of the treated breast) 

32 
 
 
 
• 
Fair: Treated breast clearly different from untreated but not seriously 
distorted (significant radiation effects readily observable) 
 
• 
Poor: Treated breast seriously distorted (severe sequelae of breast tissue 
secondary to radiation effects) 
 
A modified version of the Harvard Cosmesis Scale will also be used for patient 
reported assessment of cosmesis. 
 
11.33 The Breast Cancer Treatment Outcome Scale (BCTOS) is a self-report 
instrument that has high reliability and validity and will be used for evaluating 
patient-rated cosmesis according to the schedule outlined in section 4.0. 
 
11.34 Patient-Reported Outcomes Version of the Common Terminology Criteria for 
Adverse Events (PRO-CTCAE) will be used for patient self-reporting of 
toxicities in the CTCAE. 
 
11.35 Other Patient Reported Outcome questions (fatigue, pain, arm function etc.) 
included in the appendix. 
 
 
12.0 
Descriptive Factors  
 
• 
Breast Quadrant: upper inner, upper outer, lower inner, lower outer 
• 
AJCC Stage 
• 
Tumor Size 
• 
Invasive vs non-invasive 
 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient   
 
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 that complete all adjuvant treatment will then be followed during the observation 
phase as outlined in section 4.0. 
 
14.0 
Body Fluid Biospecimens 
 
14.1  Summary Table of Research Blood and Body Fluid Specimens to be collected for this 
Protocol 
Collection Tube 
Volume to Collect 
per Tube (Number 
of Tubes to Collect) 

33 
 
 
Collection Tube 
Volume to Collect 
per Tube (Number 
of Tubes to Collect) 
EDTA tubes  
10 mL (1) 
No additive tubes 
(for Serum) 
10 mL (1) 
 
All patients will undergo a blood draw at baseline and following the final administered 
fraction of radiotherapy. Label specimen tube(s) with patient ID number, time and date 
blood is drawn. 
 
14.2 
BAP will process and store specimens per standard operating procedures. 
 
14.3 
 Bloods will be collected prospectively and stored until funding sources have been 
secured to investigate exploratory analyses described in section 16.7 
 
15.0 
Drug Information 
 
Not Applicable 
 
16.0  
Statistical Considerations and Methodology  
 
16.1   
Overview:  This is a single arm phase II study evaluating the rate of adverse 
cosmesis (defined as fair or poor cosmesis) at 3 years, compared to baseline, of 3 
fraction accelerated APBI.  For the analysis of the primary endpoint, patients will 
be pooled across the three treatment techniques (photon, proton, and 
brachytherapy) as was done in the the NSABP B-39/RTOG 0413 national multi-
institutional randomized control trial comparing APBI with WBI. The three 
techniques utilized are recognized as standard options for the delivery of APBI, 
and there is no evidence that any technique is superior to any other with 
commonly used dose and fractionation regimens.4 The primary endpoint is the 
difference from baseline in the percentage of patients with adverse cosmesis (fair 
or poor cosmesis) at 3 years. The intent is to determine whether the difference of 
adverse comesis rate is acceptable. Of interest is whether the 3 fraction 
accelerated APBI results in an unacceptable increase in the adverse cosmesis rate 
at the end of 3 years, compared to baseline. If it does not, then the 3 fraction 
accelerated APBI will be recommended for further study. If the change in 
adverse cosmesis rate is found to be unacceptable, then the recommendation 
would be to do no further studies of the 3 fraction accelerated APBI. In addition 
to adverse cosmesis, this study will assess many additional secondary endpoints 
including IBTR (both invasive and non-invasive IBTRs will be considered), 
acute and late toxicity profile, quality of life measures, and translational studies. 
 

34 
 
 
16.2 
Primary Endpoint: The primary endpoint is the percentage difference in patients with 
adverse cosmesis (fair or poor cosmesis) at 3 years compared to baseline. Cosmesis will 
be assessed by a trained nurse provider using the Harvard Cosmesis Scale.   
 
All patients meeting the eligibility criteria who have signed a consent form, and begun 
treatment will be considered evaluable for the primary endpoint. 
 
16.3  
Secondary Endpoints:  The secondary aims of this study are to characterize acute and late 
adverse events, assess patient self-reported and panel-reported cosmesis, IBTR rate, and 
quality of life as well as exploratory comparisons of cosmesis, toxicity, and IBTR rate 
between the 3 techniques. In addition, regional recurrence rates, distant recurrence rates, 
invasive disease-free survival, and overall survival will be estimated for each patient 
group treated with APBI. Blood will be collected for future studies in order to examine 
molecular and genomic predictors of adverse cosmesis and late toxicity. 
 
The following definitions are used for the secondary endpoints of interest: 
 
• 
Acute adverse events (up to 1 month post-RT): any adverse event, 
regardless of attribution, that occurs in the first month post-RT. 
• 
Late adverse events (up to 3 years post XRT): any adverse event that 
occurred after the first month post-RT and up to 3 years post-RT. 
• 
Patient Reported Outcomes/Quality of life: the Patient-Reported 
Outcomes Version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE) will be used for patient self-reporting of toxicities 
in the CTCAE, along with other measures of fatigue, pain, and arm 
function listed in the appendix.  
• 
Patient self-reported cosmetic outcomes: the patient self-reported 
outcome will be assessed using a modified Harvard Cosmesis Scale in 
the Breast Cancer Treatment Outcome Scale (BCTOS).   
• 
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.  The Panel 
will be blinded to treatment allocation. 
• 
IBTR: this is defined as local recurrence at 3 years from trial registration 
as a first event. 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. 
• 
Distant recurrence: metastatic cancer that has either been biopsy 
confirmed or clinically diagnosed as recurrent invasive breast cancer. 
• 
Invasive disease free survival: this is defined as the time from study 
registration until the occurrence of one of the events in a composite 
endpoint. This endpoint includes invasive IBTR, regional invasive breast 
cancer recurrence, distant breast cancer recurrence, death due to any 
cause, contralateral invasive breast cancer, and second primary non-
breast invasive disease. 
• 
Overall survival: is defined as the time from registration to death due to 
any cause. 
 
16.4 
Study Sample Size, Decision Rule, and Study Duration 

35 
 
 
 
 16.41       Sample size: This study requires 153 evaluable women for the primary         
                         endpoint analysis. We anticipate accruing 15 additional patients to                       
                         account for ineligibility, cancellation, major treatment violation, or other   
                         reasons. The maximum projected accrual is therefore 168 women, and          
                         we expect a maximum of 60 and a minimum of 40 women within each   
 cohort (photon, proton,  and brachytherapy).   
 
16.42 Study Decision Rule and Operating Characteristics: Olivotto et al. 
previously reported interim cosmetic and toxicity results from a 
randomized trial comparing APBI using 3D-CRT versus WBI. In this 
study, the same 3DCRT dose and fractionation was used as in the 
previously discussed NSABP B-39/RTOG 0413 randomized controlled 
trial comparing 3DCRT or brachytherapy APBI with WBI. At 3 years, 
the percentage difference in patients with adverse cosmesis in the APBI 
arm compared to baseline by trained nursing assessment was 10.6%.  
The proposed analysis is to compute the percentage difference in patients 
with adverse cosmesis (fair or poor cosmesis ) at 3 years compared to 
baseline. A one-sided 95% confidence interval (with the upper bound of 
the interval) was computed, by assuming the difference in adverse 
cosmesis rate at 3 years compared to baseline is 10%, and the distance 
from 10% to the upper bound of the CI is 4%. The decision rule would 
be of the following:  
• 
 If the upper bound of the one-sided CI for the difference of adverse 
cosmesis rate lies above 14%, then recommend no further investigation 
and conclude that there is no sufficient evidence to accept the adverse 
cosmesis rate of 3 fraction accelerated APBI.  
• 
If the upper bound of the one-sided CI for the difference of adverse 
comesis rate lies below 14%, then recommend further investigation and 
conclude the increase in 3-year adverse cosmesis rate of 3 fraction 
accelerated APBI is potentially acceptable. 
 
The study operating characteristics is determined as the chance of 
declaring that APBI warrants further study, assuming a true value for the 
difference in adverse cosmesis rate at 3 years compared to baseline for 
APBI. The table below shows the operating characteristics of this trial 
with 153 patients and the decision rule given above. 
 
True increase 
in adverse 
cosmesis rate 
at 3 years 
compared to 
baseline 
Probability of 
concluding 
PBI warrants 
further study 
5% 
98.4% 
10% 
72.8% 
15% 
48.6% 
20% 
29.8% 
 

36 
 
 
If the increase in APBI adverse cosmesis rate from baseline is 5.0%, 
there is a 98.4% chance of concluding that the APBI adverse cosmesis 
increase from baseline is acceptable; this drops to 72.8% if the true rate 
is 10%, and further drops to 49.6% if the true rate is 15%. If the increase 
in APBI adverse cosmesis rate from baseline at 3 years is 20% or greater, 
we are most likely to recommend no further investigations, and conclude 
that the increase in APBI adverse cosmesis rate is unacceptably high.  
 
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. 
 
16.43 Preliminary Analysis: The preliminary analysis is to examine 
whether the data from the three methods (photon, proton and 
brachytherapy PBI) can be combined by assessing any difference in the 
safety profile and baseline patient and tumor characteristics. We will 
conclude that the variability in the three samples is acceptable and 
proceed to the primary analysis if all the following conditions are met: 
• 
The difference in rate of grade 3 toxicity between the groups is 
≤10%. 
• 
There is not a significant difference in the rate of IBTR between 
the groups (using pair-wise chi-squared tests with Bonferroni 
correction for multiple comparisons). 
• 
The distribution of African Americans and the percentage of 
cytotoxic chemotherapy use between the groups is not 
significantly different (using pair-wise chi-squared tests with 
Bonferroni correction for multiple comparisons). 
• 
The distribution of age between the groups is not significantly 
different (p-value ≥ 0.05 using a Tukey’s test). The difference in 
age in 10 increments (50-59, 60-69, and ≤ 70) will be reported.  
• 
Tumor size will be dichotomized to two categories (≤ 1cm vs 1-
2cm). The percentage of larger tumor (1-2cm) between the 
groups is not significantly different (using pair-wise chi-squared 
tests with Bonferroni correction). 
If any of the above conditions are failed to be met, we will only report 
the safety and efficacy of each individual arm as secondary and 
exploratory endpoints. 
 
16.44 Accrual time and Study duration: Since 10/1/2012 patients have been 
treated with brachytherapy APBI using an 8 or 10 fraction regimen and 
prospectively followed as part of a clinical registry at the Mayo Clinic in 
Rochester, MN. Patient interest in the procedure has steadily increased, 
and in the last 3 months, 13 patients have been treated (median 4.3 
patients per month), all of whom would be eligible for this study. A 
similar to increased level of accrual ofbrachytherapy patients is 
anticipated during the course of this study as familiarity with this 
procedure amongst surgical and radiation oncology providers rises. With 
the addition of the photon APBI alternative for patients, we anticipate an 
accrual rate of 5 patients per month for the first year until the opening of 

37 
 
 
the Mayo proton facility, after which an accrual of 8 patients per month 
is anticipated. Therefore, the accrual period for this study is expected to 
be approximately 3 years. We plan to open this study at the Mayo Clinic 
in Scottsdale and Jacksonville which will further enhance accrual. Final 
analysis may begin approximately 5 years after the trial begins, i.e. as 
soon as the last patient registered has been observed for at least 24 
months. A maximum of 60 patients and a minimum of 40 patients will be 
enrolled per treatment arm.  
 
16.5 
Primary Analysis: The primary analysis will be to estimate the percentage 
difference in patients with adverse cosmesis (fair or poor cosmesis ) at 3 years 
compared to baseline. All patients meeting the eligibility criteria who have 
signed a consent form and started treatment will be in the primary analysis. The 
percentage difference in patients with adverse cosmesis will be estimated using a 
binomial estimator (number of women who had an adverse cosmesis event at 3 
years minus number of women who had an adverse cosmesis event at baseline, 
and then divided by total number of women in the primary analysis) and a 95% 
exact binomial confidence interval. As mentioned above, the following decisions 
will be made based on the 95% CI: 
• 
The upper bound of the 95% CI lies below 14%: APBI adverse cosmesis 
is acceptable. 
• 
The upper bound of the 95% CI lies above 14%: No evidence to show 
that APBI adverse cosmesis is acceptable. 
 
16.6    Secondary Analyses 
 
16.61 Acute adverse events (up to 90 days post-RT): All patients who were 
registered to the study and started treatment will be included in the acute 
adverse event analysis. An acute adverse event is an AE, regardless of 
attribution, that occurs up to 90 days post-RT. The maximum grade for 
each type of acute AE will be recorded for each patient. Data will be 
summarized as frequencies and relative frequencies. Additionally, the 
relationship of the adverse event(s) to the study treatment will be taken 
into consideration.   
 
16.62 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 occurs at least 
90 days post-RT and up to 3 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. Additionally, the 
relationship of the adverse event(s) to the study treatment will be taken 
into consideration.  Prior APBI reports have suggested rates of grade 3 or 
4 toxicity to be ≤10%.18,47,55,56  
 
16.63 Quality of life: The QOL measurements will be summarized at each time 
point as mean ± SD and median (minimum value, maximum value). 
Changes in the QOL measurements from baseline will be determined at 
each follow-up measurement. These will be displayed as spaghetti plots. 
The assessment of the changes at each time point will be done with a 
paired t-test or Wilcoxon signed rank test, whichever is appropriate. 

38 
 
 
 
16.64 Cosmesis: The values of the cosmesis instruments (patient self-reported 
and panel-assessed) will be summarized with the frequencies of fair or 
poor cosmesis events at baseline and 3 years, and the difference at 3 
years, as well as their relative exact binomial confidence intervals.  
 
16.65 IBTR incidence: The IBTR cumulative incidence will be estimated using 
a competing risks method (Gooley et al.). The competing risks will be 
regional/distant breast cancer recurrence and death. 
 
16.66 Regional recurrence incidence: The regional breast cancer recurrence 
cumulative incidence will be estimated using a competing risks method 
(Gooley et al.). The competing risks will be local/distant breast cancer 
recurrence and death. 
 
16.67 Distant recurrence incidence: The distant breast cancer recurrence 
cumulative incidence will be estimated using a competing risks method 
(Gooley et al.). The competing risks will be local/regional breast cancer 
recurrence and death. 
 
16.68 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. Estimates will be 
given for specific time points along with 95% CIs. 
 
16.69 Overall survival: The OS will be estimated with a Kaplan-Meier 
estimator and curve. Estimates will be given for specific time points 
along with 95% CIs. 
 
16.7 
Exploratory Analyses: Exploratory comparisons of the local control, acute and late 
adverse events, quality of life, and cosmesis among the three radiation regimens will be 
made.  Comparisons of categorical variables will be done with a chi-square test or 
Fisher’s exact test, whichever is appropriate. Comparisons of continuous variables will be 
done with an ANOVA or Kruskal-Wallis test, whichever is appropriate. Meaurements 
over time (i.e. QOL) will be summarized as area under the curve (AUC) and these values 
will be analyzed as continuous outcomes. All tests will be two-sided and a p-value less 
than 0.05 will be considered significant. No adjustments will be made for multiple 
comparisons.  
 
Correlative Science: Adverse cosmesis has been reported to be significantly increased in 
prior studies of APBI, yet predictors of adverse cosmesis are poorly understood.47,48 If a 
subset of patients at high risk of complications could be identified, their treatment could 
be personalized or they could be counseled to pursue other therapeutic options altogether. 
In the setting of WBI, factors previously reported to be associated with worsened 
cosmesis include inferior tumor location, large excision volume, the presence of 
postoperative breast complications, higher dose (including radiotherapy boost), 
inhomogeneity, and use of concurrent chemotherapy.57-59 In order to begin identifying 
predictive factors for fair and poor cosmesis following 3 fraction APBI we will analyze 
clinical and dose volume parameters correlated with increased risk.  
 

39 
 
 
It is generally believed that clinical and dose-volume factors alone are not sufficient to 
explain the patient to patient variation in late toxicity following a course of radiation 
therapy.60,61  Indeed, patient specific histologic and genomic features may also be of 
significant importance in determing variation in normal tissue radiation response and risk 
of adverse cosmesis. There is considerable variation in sensitivity to radiation across 
tissue type.62 Therefore, as a preliminary step in considering biomarkers of risk of 
adverse cosmesis, we will analyze non-cancerous breast tissue from the lumpectomy 
specimen.  In particular, we will determine whether the ratio of fat, connective tissue, and 
epithelium of the normal breast tissue away from the tumor is predictive of adverse 
cosmesis following APBI. A number of studies have correlated breast histopathological 
findings with mammography.63-65 Mammographic density is largely determined by the 
relative amount of fat, connective tissue, and epithelium. If a correlation is made between 
histologic make-up of the normal breast parenchyma and adverse cosmesis, we will 
explore whether patients can also be stratificatied based on preoperative mammographic 
density, as determined by the qualitative Breast Imaging Reporting and Data System (BI-
RADS) method for density assessment developed by the American College of Radiology. 
 
Cytokines and growth factors are involved in the radiation response and tissue 
remodelling and may serve as predictive factors for normal tissue damage. For example, 
levels of transforming growth factor β1 (TGF- β1) vary substantially between individuals 
and has previously been associated with radiation fibrosis in early-stage breast cancer 
patients.66 TGF- β1 is a multi-functional cytokine that attracts fibroblasts and stimulates 
collagen production.67 Although basal levels may be important, expression levels of this 
protein are induced within an hour or less after exposure to ionizing radiation and 
therefore TGF- β1 induction following radiation may be a better functional marker of an 
elevated fibrotic response.68,69  Therefore, blood will be drawn pre-treatment and on the 
last day of radiotherapy 1 hour following the final fraction. The pre and post radiotherapy 
levels of TGF- β1 and other proteins in the fibrotic response will be compared and 
association with adverse cosmesis following APBI will be determined.   
 
Mounting evidence also suggests that genetic variation may play an important role in 
determining susceptibility to radiation toxicity.70 Radiogenomics is an emerging field 
aimed at studying genetic differences associated with variability in the effectiveness and 
toxicity of radiation.61 We plan to use a candidate gene approach61 to investigate the 
association of single nucleotide polymorphisms (SNPs), previously correlated with 
radiation normal tissue toxicity, with adverse cosmesis following 3 fraction APBI. For 
example, in addition to TGF- β1, SNPs in the XRCC1 (codon 241) and XRCC1 (codon 
399) genes, the protein products of which function in the DNA repair pathways of based 
excision repair and homologous recombination, respectively,  have been correlated with 
increased risk of subcutaneous fibrosis following breast cancer radiotherapy. 
 
laboratory at the Mayo Clinic has used a genome-wide association approach in 
human lymphoblastoid cell lines to identify radiation response biomarkers. C13orf34, 
MAD2L1, PLK4, TPD52, and DEPDC1B were identified and functionally validated as 
modifiers of radiation response. These promising findings, however, require further 
clinical validation.61,71  
 
The final design of these future genomic and proteomic studies will depend on the event 
rate observed in the trial, cost and state of technology at the time of per protocol cosmetic 
evaluation of all patients enrolled. They may occur as part of a meta-analyses of patients 
treated with hypofractionated breast cancer radiotherapy from other institutions. 
 

40 
 
 
Over Accrual: If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any decision making 
processes; however, they will be included in final endpoint estimates and confidence 
intervals. 
 
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 
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 5 years 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 followed for at least 3 years. 
 
16.9            Data & Safety Monitoring 
 
16.91   The principal investigator(s) and the study statistician will review the study at 
least every quarter to identify accrual, adverse events, 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.  
 
 
16.92 Adverse Event Stopping Rules: The stopping rules specified below are based on  
knowledge available at study development.  We note that the Adverse Event 
Stopping Rule may be adjusted in the event of either (1) the study re-opening to 
accrual or (2) at any time during the conduct of the trial and in consideration of 
newly acquired information regarding the adverse event profile of the 
treatment(s) under investigation.  The study team may choose to suspend accrual 
because of unexpected adverse event profiles that have not crossed the specified 
rule below.  The following rule will be evaluated for each arm separately. 
 
Accrual will be temporarily suspended if at any time we observe events 
considered at least possibly related to study treatment (i.e. an adverse event with 
attribute specified as  “possible,” “probable,” or “definite”) that satisfy one of the 
following:  
• 
If 3 or more patients in the first 15 treated patients experience a grade 3 
or higher adverse event, besides acute dermatitis, that is at least possibly 
related to treatment within 90 days post treatment.. 
• 
After the first 15 patients have been treated: if ≥ 20% of all patients 
experience a grade 3 or higher adverse event, besides acute dermatitis, 
that is at least possibly related to treatment within 90 days post treatment. 
 
Similarly, within each of the modalities (photon, proton, or brachytherapy APBI), 
accrual will be suspended for that modality: 
• 
If 6 or more patients in the first 30 treated patients experience a grade 3 
or higher adverse event at least possibly related to treatment at any time 
after 6 months following completion of the protocol treatment. 
• 
After the first 30 patients have been treated: if ≥ 20% of all patients 
experience a grade 3 or higher adverse event at least possibly related to 

41 
 
 
treatment at any time after 6 months following the completion of 
protocol 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. 
 
16.10 
Inclusion of Women and Minorities 
 
16.11  This study will be available to all eligible patients, regardless of race,  or ethnic 
origin. 
 
16.12  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. Male breast cancer is a relatively rare entity in whom 
APBI would not be appropriate therapy and male gender is an exclusion 
criteria.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. 
 
16.13   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 100% of patients will be women. 
 
17.0  Pathology Considerations/Tissue Biospecimens:  
 
         17.1 Summary Table of Research Tissue Specimens to be collected for this Protocol 
 
 
Mandatory or 
Optional 
Type of 
Tissue to 
Collect 
Block, Slides, 
Core, etc. (# 
of each to 
submit) 
Process at 
Site? (Yes or 
No) 
Temperature 
Conditions for 
Storage/Shipping 
 
Diagnostic 
 
Optional* 
 
Formalin 
Fixed 
2 H&E slides 
 
Yes 
 
Ambient 
 
Lumpectomy 
 
Mandatory 
Formalin 
Fixed  
2 H&E slides  
 
Yes 
Ambient  
*If no tissue available from lumpectomy surgery, obtain diagnostic slides 
 
17.2 
 Blocks from the diagnostic surgery (when applicable) and the clinical lumpectomy surgery, 
that have been identified by 
lab, will be requested from Tissue Registry and 
slides cut (1 slide from the tumor/tumor vicinity and 1 slide distant from the tumor). Slides 
will be clearly labeled (see below for slide label) and forwarded to 
office for 
quantification of the ratio of fat, connective tissue, and epithelium of the normal breast tissue 
away from the tumor. If the patient underwent surgical resection at an outside institution, 
slides and blocks will be viewed and cut the same manner as above and sent to 
 

42 
 
 
Aperio imaging will be done on the H&E slide that is distant from the tumor and archived 
electronically. 
 
 
                                                    
                                                           Slide Label: Protocol Number 
                                                                                                    
 
                                                                                                     
 
 
                                                                                                    
 
 
Send slides with study identifier to: 
 
 
 
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 from accrual 
Patient Eligibility 
Demographics 
On-Study 
Adverse Events- Baseline 
Specimen Submission: Blood (Baseline) 
Specimen Submission: Tissue (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 
Post Radiation (cycle 
2) 
Observation3 
(subsequent cycles) 
Radiation Treatment Form 
X 
 
Patient Assessment 
X 
X 
Specimen Submission: Blood (post rad tx) 
X 
 

43 
 
 
CRF 
Post Radiation (cycle 
2) 
Observation3 
(subsequent cycles) 
Adverse Events Solicited 
X 
X 
Adverse Events Other 
X1 
X1 
Off Treatment: Submit once per patient 
X1 
 
Patient Status form 
X 
X 
Adverse Events: Late 
 
X1 
Specimen Submission: Tissue (Recurrence) 
 
X1 
Consent Withdrawal form  
X1 
X1 
Lost to Follow-up 
X1 
X1 
Breast/Chest Wall Radiotherapy 
Questionnaire 
X 
X 
1. When applicable 
2. Survey will need to be entered manually if has not alternately been  scanned or entered electronically 
3. Observation (Active monitoring phase): 12 weeks (+/- 4 weeks), 12 months (+/- 30 days), annually 
for 5 years (+/-3 months). If a patient is still alive 5 years after registration, no further follow-up is 
required. 
 
 
Follow-up Material(s) 
CRF 
Event Monitoring Phase1 
 
 
12 months  
 
Annually for 5 years2 
Patient Status: 
Survival and 
Disease Status 
Follow-Up/Event 
Monitoring 
 
 
X 
 
 
X 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
2.    If patient has a recurrence prior to being off radiation therapy for 5 years, continue to follow yearly. 
 
18.2 
Data Handling and Record Keeping 
 
18.21 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.  

44 
 
 
(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. 
 
The Medidata Rave database access model is role based and fully auditable at the study, 
form, and field levels.  Data will be de-identified whenever possible and the ability to 
update will be limited to necessary staff.  Access will be managed by the Mayo CTMS 
Service and Solution Center, under a controlled and monitored access request 
system.  Medidata’s platform specifically supports Electronic Record and Electronic 
Signature (ER/ES) requirements, including US 21 CFR part 11.  
 
18.22 Source Documents 
 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents, 
and data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories, and at medico-technical departments involved in the clinical trial. Source 
documents are kept in a secure location that is locked and requires approved access.  
 
18.23  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. 
CRF’s will be built and managed in Rave data capture system. 
 
 
18.24 Data Management  
 
 All data will be entered into electronic case report forms (eCRF’s) through the Medidata 
Rave system. Case report forms will be automatically rolled out based on a 
predetermined, and visit based schedule to improve study staff workflow and data 
quality. Data will be exported nightly to a secure FTP for analysis and reporting.   
  
 
18.26 Data Quality Assurance and Clarification Process 
 
Each eCRF will contain edit checks and custom functions to ensure the highest possible  
 data quality. Only necessary eCRF’s will be available for data entry to reduce the 

45 
 
 
possibility of erroneous entry.   
 
The edit checks and custom functions on the eCRF’s will trigger queries requesting the 
attention     of appropriate study staff. The fields will be marked in pink to allow study 
staff to quickly identify the data fields that require attention or actions. Additionally, 
secure email notifications will be sent for adverse event tracking and monitoring.  
 
19.0 Study Finances 
 
 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.   
 
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50 
 
 
 Appendices 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

51 
 
 
Appendix II 
 
Radiation Therapy Quality Control Guidelines 
 
 
1. 
Tumor Volume Coverage 
a. 
No deviation -- coverage + < 1 cm of specified. 
b. 
Minor deviation -- coverage + > 1 to 2 cm of specified or failure to cover tumor volume + 
> 1/2 specified margin. 
c. 
Major deviation -- > 2 cm of specified or no CT and/or MRI scans available to assess 
treatment volume appropriateness (if not initially available should be requested) or failure 
to cover the target (tumor or tumor + edema) as defined in the protocol. 
 
2. 
Isodoses - initial volume isodose plots are required on a minimum of three contours; one at 
central axis (CA), one superior to CA (2 cm below the superior field edge) and one inferior to CA 
(2 cm above the inferior field edge).  Boost volume isodose plot required at CA. 
  a. 
No deviation -- isodoses submitted as required, and inhomogeneity across the target 
volume shall be no greater than + 5%. 
*b. 
Minor deviation -- isodose information incomplete or inhomogeneity across the target 
volume > 5 but < 10%. 
*c. 
Major deviation -- no isodoses submitted or inhomogeneity across the target volume > 
10%. 
 
* Deviations would occur only if isodose information is incomplete or not submitted after there 
has been a request to submit complete isodose information. 
 
3. 
Normal Tissues 
 
Normal structures are only to be included within the radiation field in as much as this is necessary 
to treat the primary tumor volume.  A minor deviation will result when normal structures are 
unnecessarily included, but this is not felt to result in unacceptable toxicity that would interfere 
with the scientific aims of the protocol.  A major deviation will result when normal structures are 
unnecessarily included in the radiation therapy field and such inclusion is felt likely to result in a 
major increase in toxicity which would potentially compromise the scientific goals of the study. 
 
4. 
Other parameters: (dose per fraction, total dose, overall treatment time and portal films). 
a. No deviation -- +/- < 5% of protocol specification. 
b. Minor deviation -- +/- > 5% to 10% of protocol specification. 
c. 
Major deviation -- +/- > 10% of protocol specification or incomplete data (i.e. no portal 
or sim films, etc.) available for review (after additional request has been made). 
 
5. 
Any individual minor deviation will result in an overall score of minor deviation; any major 
deviation will result in an overall score of a major deviation.  Multiple minor deviations will not 
add up to a major deviation.