A Phase II Study of Accelerated Hypofractionated Radiotherapy (AHF-RT) After Breast Conserving Surgery (BCS) in Medically Underserved Patients
Phase: NA
Conditions: Breast Cancer
Sponsor: University of Louisville

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A Phase II Study of Accelerated Hypofractionated Radiotherapy (AHF-
RT) after Breast Conserving Surgery (BCS) in Medically Underserved 
Patients. 
 
MULTIDISCIPLINARY BREAST CANCER PROGRAM 
JAMES GRAHAM BROWN CANCER CENTER (JGBCC) 
UNIVERSITY OF LOUISVILLE SCHOOL OF MEDICINE 
Department of Radiation Oncology 
529 South Jackson Street, 4th Floor 
Louisville, KY 40202 
TELEPHONE: 502-561-2700 
FAX: 502-561-2709 
 
CLINICAL TRIALS OFFICE 
UNIVERSITY OF LOUISVILLE SCHOOL OF MEDICINE 
Brown Cancer Center, Room 420 
529 South Jackson Street, 4th Floor 
Louisville, KY 40202 
TELEPHONE: 502- 562-3429 
FAX: 502- 562-3462 
 
KEY STUDY PERSONNEL: 
 
Principal Investigator:  
 
Anthony E. Dragun, M.D. (Radiation Oncology) 
Co-Investigator:   
 
William J. Spanos, M.D. (Radiation Oncology) 
Co-Investigator:  
Michael D. Mills, Ph.D., M.S.P.H. (Radiation Oncology, Medical 
Physics, School of Public Health) 
 
Department Chair:  
 
Shiao Y. Woo, M.D., F.A.C.R. (Radiation Oncology) 
Cancer Center Director:   
Donald M. Miller, M.D., Ph.D. (Medical Oncology)  
Clinical Trials Officer:  
 
Hana Gragg (School of Medicine) 
 
Collaborator:  
 
 
Kelly M. McMasters, M.D., Ph.D. (Breast Surgery) 
Collaborator:  
 
 
Amy R. Quillo, M.D. (Breast Surgery) 
Collaborator:  
 
 
Elizabeth C. Riley, M.D. (Medical Oncology) 
Collaborator:  
 
 
Dharamvir Jain, M.D. (Medical Oncology) 
Protocol Pathologist:  
 
Sunati Sahoo, MD (Pathology) 
Protocol Radiologists:  
 
Lane Roland, M.D. (Radiology),  
Sarah G. Miziguchi, M.D. (Radiology) 
 
Nurse Coordinator:  
 
Barbara Kruse, O.C.N., M.Ed. (Medical Oncology) 
Nursing Support:  
 
Rosemary Wafford, O.C.N. (Radiation Oncology),  
Kathy Hatke, O.C.N. (Radiation Oncology 
Public Health Study Coordinator: Michael D. Mills, Ph.D., M.S.P.H. (Radiation Oncology, Medical 
Physics, School of Public Health) 
Protocol Statisticians:  
 
Shesh N. Rai, Ph.D. (School of Medicine),  
Bin Huang, Ph.D., M.S. (Kentucky Cancer Registry) 
 
 
Version Date: November 2, 2010 (Replaces all other versions) 
 
This protocol was designed and developed by the JGBCC Department of Radiation Oncology. It is  
intended to be used only in conjunction with institution-specific IRB approval for study entry. No other use or 
reproduction is authorized by the JGBCC Department of Radiation Oncology nor does the JGBCC Department of 
Radiation Oncology assume any responsibility for unauthorized use of this protocol. 

2 | P a g e  
 
A Phase II Study of Accelerated Hypofractionated Radiotherapy (AHF-
RT) after Breast Conserving Surgery (BCS) in Medically Underserved 
Patients. 
 
MULTIDISCIPLINARY BREAST CANCER PROGRAM 
JAMES GRAHAM BROWN CANCER CENTER (JGBCC) 
UNIVERSITY OF LOUISVILLE SCHOOL OF MEDICINE 
 
 
 
Trial Activated:  
 
 
 
11/10/11 
 
 
Protocol Revision Record 
 
Original Version:  
 
 
 
11/2/10 
 
 
Amendment #1:  
12/20/12 
 
 
Amendment #2: 
 
Amendment #3: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1.0 STUDY SUMMARY  
 
 
 
 
 
 
 
5 
2.0 BACKGROUND   
 
 
 
 
 
 
 
7 
2.1 Clinical Background 
 
 
 
 
 
 
7 
2.2 Supporting data for AHF-RT 
 
 
 
 
 
9 
2.3 Estimations of eligible patients and enrollment 
 
 
 
10 
3.0 HYPOTHESIS/STUDY AIMS 
 
 
 
 
 
 
13 
3.1 Hypothesis  
 
 
 
 
 
 
 
13 
3.2 Primary aim 
 
 
 
 
 
 
 
13 
3.3 Secondary aims 
 
 
 
 
 
 
 
13 
4.0 ENDPOINTS 
 
 
 
 
 
 
 
 
13 
4.1 Primary endpoint 
 
 
 
 
 
 
 
13 
4.2 Secondary endpoints  
 
 
 
 
 
 
14 
5.0 PATIENT ELIGIBILITY AND INELIGIBILITY  
 
 
 
 
14 
5.1 Conditions for patient eligibility 
 
 
 
 
 
14 
5.2 Conditions for patient ineligibility 
 
 
 
 
 
16 
6.0 REQUIRED ENTRY AND FOLLOW-UP STUDIES 
 
 
 
19 
7.0 QUALITY OF LIFE, COSMESIS AND COST EFFECTIVENESS ANALYSIS 
20 
7.1 Cosmesis   
 
 
 
 
 
 
 
20 
7.2 Quality of Life 
 
 
 
 
 
 
 
21 
7.3 QOL and cosmesis instructions  
 
 
 
 
 
22 
 
7.4 Cost effectiveness analysis  
 
 
 
 
 
22 
8.0 ACCELERATED HYPOFRACTIONATED RADIOTHERAPY (AHF-RT)  
23 
8.1 Treatment overview  
 
 
 
 
 
 
23 
8.2 CT-based treatment planning  
 
 
 
 
 
24 
9.0 SYSTEMIC THERAPY  
 
 
 
 
 
 
 
26 
9.1 Chemotherapy 
 
 
 
 
 
 
 
26 
9.2 Hormonal therapy   
 
 
 
 
 
 
26 
9.3 Trastuzumab 
 
 
 
 
 
 
 
27 
10.0 DIAGNOSIS OF BREAST CANCER EVENTS 
 
 
 
 
27 
10.1 Ipsilateral in-breast recurrence 
 
 
 
 
 
27 
10.2 Local chest wall recurrence  
 
 
 
 
 
27 
10.3 Regional recurrence 
 
 
 
 
 
 
27 
10.4 Distant recurrence  
 
 
 
 
 
 
28 
10.5 Second primary breast cancer 
 
 
 
 
 
28 
10.6 Second primary cancer (non-breast)  
 
 
 
 
28 
10.7 Documentation requested following death  
 
 
 
28 
11.0 ADVERSE EVENT REPORTING REQUIREMENTS 
 
 
 
28 
11.1 Definitions for adverse event reporting  
 
 
 
 
28 
11.2 Adverse event assessment  
 
 
 
 
 
28 
11.3 Routine reporting of adverse events 
 
 
 
 
29 
11.4 Reporting on follow-up Form F 
 
 
 
 
 
29 
12.0 PATIENT ENTRY AND WITHDRAWAL PROCEDURES 
 
 
29 
12.1 Patient entry and consent form  
 
 
 
 
 
29 
12.2 Patient-initiated discontinuation of study therapy  
 
 
 
30 
12.3 Investigator-initiated discontinuation of study therapy  
 
 
30 
13.0 STATISTICAL CONSIDERATIONS 
 
 
 
 
 
30 
13.1 Endpoint Definitions 
 
 
 
 
 
 
30 
13.2 Sample Size 
 
 
 
 
 
 
 
31 
13.3 Accrual 
 
 
 
 
 
 
 
 
31 

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13.4 Statistical Analysis  
 
 
 
 
 
 
31 
13.5 Data Safety Monitoring Board 
 
 
 
 
 
32 
13.6 Monitoring Rule 
 
 
 
 
 
 
 
32 
13.7 Missing Observations 
 
 
 
 
 
 
33 
13.8 Monitoring of adverse events 
 
 
 
 
 
33 
13.9 Analysis schedule  
 
 
 
 
 
 
33 
14.0 REFERENCES 
 
 
 
 
 
 
 
 
34 
 
ATTACHMENTS: 
 
Appendix A - TNM nomenclature and staging for breast cancer 
Appendix B - Determination of menopausal status 
Appendix C - Information basics for adverse event reporting 
Form A1 - Eligibility Checklist 
Form AE - Adverse Event Reporting 
Form BE - BCTOS Patient Breast Evaluation 
Form CE - Physician Assessed Cosmesis Evaluation 
Form F - Follow-up Assessment  
Form QOL - EORTC QLQ-BR23 quality of life questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 STUDY SUMMARY  
 
This Phase II non-randomized trial will evaluate the effectiveness of whole-breast 
accelerated hypofractionated radiotherapy (AHF-RT; 28.5 or 30 Gy in 5 fractions 
delivered once weekly over 5 treatment weeks) following lumpectomy for early stage 
breast cancer. The study will compare the toxicity, local control, overall survival, 
recurrence-free survival, and distant disease-free survival to modern studies of standard 
conventionally fractionated radiotherapy (CF-RT; 50-60 Gy in 25-30 daily fractions 
delivered over 5-6 weeks) and hypofractionated radiotherapy (HF-RT; 42.5 Gy in 16 
daily fractions delivered over 3-4 weeks). It will also look at quality of life (QOL) issues 
related to cosmesis, fatigue, treatment-related symptoms, and perceived convenience of 
care. In addition, a cost-effectiveness analysis will be carried out in conjunction with the 
University of Louisville’s School of Public Health for comparative study with other 
breast radiotherapy regimens. 
  
To qualify for the trial, patients must have stage 0 (DCIS) or stage I or II invasive 
adenocarcinoma of the breast with no evidence of metastatic disease. Eligibility will be 
targeted to patients whose home residence is considered rural or Appalachian by 
Kentucky Cancer Registry criteria, and/or who reside ≥ 10 miles from the nearest 
radiation oncology center, and/or are uninsured, and/or are members of an underserved 
minority group, and/or are judged by their treating physicians to suffer significant 
financial and/or transportation hardship during a typical course of CF-RT or HF-RT.   
Women must have undergone a lumpectomy with the margins of the resected specimen 
histologically free of cancer including DCIS. For patients with positive axillary nodes, 
eligibility is restricted to those with 0 to 3 positive axillary nodes. Patients will be 
analyzed by subgroups according to disease stage, menopausal status, and intention to 
receive chemotherapy. Following stratification, patients will be enrolled to receive AHF-
RT.  Radiotherapy will be given once weekly (ideally on the same day each week) over a 
period of 5 weeks. Patients scheduled to receive cytotoxic chemotherapy will receive 
chemotherapy before their radiation therapy.  
 
This trial is designed to accrue approximately 250 patients over a period of 5 years with 
accrual projected to be approximately 3 patients each month for the first year increasing 
to 5 patients each month in subsequent years (see Section 2.3).  The primary endpoint 
will be to estimate the cumulative incidence of in-breast tumor recurrence (IBTR), which 
is anticipated to be no higher than that seen in similar studies of CF-RT and HF-RT 
(namely, 3-5% at 3-5 years).  In addition, detailed data on radiation quality, dose to 
normal tissues, toxicity and cosmetic outcome (including digital photography) will be 
collected to facilitate meaningful comparison to recently reported and in-progress studies 
of varying breast radiotherapy schedules.  Finally, cost-effectiveness analysis (CEA) and 
quality-of-life (QOL) metrics will be incorporated in order to further characterize factors 
underlying the rural disparity and to track adherence to treatment and follow-up care at 
multiple longitudinal time points.  Please refer to Figure 1 for the study schema and flow 
diagram. 
 
 
 

6 | P a g e  
 
FIGURE 1: Study Schema/Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SUBJECT IDENTIFICATION 
 
Patients ≥ 21 years of age with AJCC Stage 0, I, or II adenocarcinoma of the breast resected 
by lumpectomy and no more than 3 histologically positive lymph nodes. 
ENROLLMENT/STUDY ENTRY 
 
1. Pathologic criteria and clinical criteria to determine eligibility (Section 5.0) 
2. Metastatic workup (Section 6.0) 
3. Declaration of intention to treat with chemotherapy 
4. Submission of Form A1 (See Section 5.0) and consent form (see Appendix F) 
5. Quality of life and cosmesis study (See Section 7.0) 
TREATMENT DELIVERY
If chemotherapy indicated: 
Chemotherapy followed by 
AHF-RT (see Section 9.0) 
30Gy or 28.5 Gy in 5 fractions 
once weekly over 5 weeks, 
followed by optional boost of 
10-16Gy. (Estimated to be 
~30% of patient population. 
See Table 3) 
If chemotherapy not indicated: 
AHF-RT alone. 
30Gy or 28.5 Gy in 5 fractions 
once weekly over 5 weeks, 
followed by optional boost of 
10-16Gy. (Estimated to be 
~70% of patient population. 
See Table 3)
DURING/IMMEDIATELY POST-THERAPY 
 
1. Data collection (See Sections 6.0 and 10.0) 
2. Pathology and/or radiology studies if breast cancer recurrence (See Section 10.0) 
3. Quality of life and cosmesis study (See Section 7.0) 
FOLLOW-UP 
 
Continued follow-up and monitoring (See Sections 6.0 and 10.0) 

7 | P a g e  
 
2.0 BACKGROUND 
 
2.1 Clinical Background 
 
Appropriate primary local management of pre-invasive and early stage breast cancers 
involves the choice of breast conserving surgery (BCS) followed by radiotherapy (RT) 
verses mastectomy.  Long-term data from multiple randomized studies demonstrates 
equivalence across all major disease-control endpoints for these two approaches, and thus 
BCS with adjuvant RT is preferred by the overwhelming majority of eligible patients1-2.  
As a result, mastectomy rates across the US have steadily declined over the last few 
decades3.  Although recent, less mature studies have suggested that BCS alone may be an 
appropriate choice for well-selected elderly and ductal carcinoma in situ (DCIS) patients, 
the addition of RT is recommended for nearly all patients after BCS for superior local 
control and long-term overall survival4-6. 
 
As mastectomy rates have decreased over time, the challenge has been to ensure adequate 
therapy with consistent delivery of RT after BCS, especially among vulnerable 
populations who may lack access to oncology services7-8. In the United States, reports 
regarding rates of application of RT after BCS contain estimations that vary widely 
(range: 65%-95%) according to study type and makeup of the analyzed cohort7-17.  Larger 
national cross-sectional studies drawn from Surveillance Epidemiology and End Results 
(SEER) and/or Medicare databases tend to show relatively lower rates of RT (range: 
65%-85%)7-12.  On the other hand, comparatively smaller studies that involve data 
extracted from prospective trials17, audits of comprehensive cancer canters16, 18, and 
patient self-reports15 typically show higher RT usage (range: 80-95%).  One consistent 
quality of most of the aforementioned studies is the ability to identify subpopulations of 
patients underserved with regard to RT access and regular application.  These disparities 
are varied and may be dramatic, and are most often associated with age, race, and 
geographic region8-9, 12, 15-20.  In some studies, inadequate treatment has been linked to 
poorer disease-control endpoints and even overall survival in these patients14, 21-25.  
 
During the last decade, major cancer centers in large cities have paved the way for 
significant growth and spread of multidisciplinary breast cancer care with the integration 
of systemic therapies and access to specialized RT procedures. In the US, approximately 
80% of the population lives in or near a major metropolitan center and thus the 
aforementioned studies are heavily influenced by the inclusion of significant number of 
urban patients26. In fact, subset analyses of nearly all national database studies on this 
subject indicate that the lowest relative rates of RT use after BCS exist in more sparsely-
populated regions, especially the South and/or Southeast8-10, 12, 17.  
 
The Commonwealth of Kentucky does not encompass a city listed among the top 25 
incorporated entities (according to the United States Census Bureau) nor a top 40 
metropolitan statistical area (as defined by the United States Office of Management and 
Budget). Additionally, Kentucky does not contain a National Cancer Institute (NCI) 
designated cancer center.  Recently, a collaborative study between investigators at the 
University of Louisville’s James Graham Brown Cancer Center (Louisville, KY) and the 

8 | P a g e  
 
Kentucky Cancer Registry at the University of Kentucky’s Markey Cancer Center 
(Lexington, KY) was completed with the purpose of identifying factors that influence the 
receipt of RT after BCS in Kentucky and the resultant impact on outcome.  The results of 
this study will be presented at the 52nd Annual Meeting of the American Society of 
Radiation Oncology (ASTRO), October 31, 2010. 
 
We analyzed the rate of adjuvant radiotherapy for 11,914 women who underwent BCS as 
primary surgical treatment for stage 0, I or II breast cancer between 1998 and 2007 using 
data from the Kentucky Cancer Registry. We assessed the probability of receiving 
radiotherapy using multi-variable logistic regression, and impact on outcome using Cox 
survival analysis.  In summary, 66.2% of women received adjuvant radiotherapy for BCS 
over a 10-year period (annual rate range: 60.9%-70.1%).  On multi-variable analysis, the 
rate of receiving radiotherapy was drastically lower for women older than 70 years (vs. 
younger, p<0.0001) and rural Appalachia (vs. non-Appalachia, p<0.0001) populations.  
The rate was modestly lower for African American (vs. white, p = 0.0108) women, and 
uninsured/government-insured (vs. privately insured, p = 0.0201) patients.  Lack of 
radiotherapy was associated with an increased hazard ratio for death of 1.67 (95% CI: 
1.508-1.851) on Cox survival analysis factoring age, stage, tumor size, grade, hormone 
receptors, smoking, and insurance. The ten-year overall survival for patients who 
received adjuvant radiotherapy vs. BCS alone was 79.7% vs. 67.6% (p <0.0001). 
 
 
As a result, in Kentucky, adjuvant RT after BCS is disproportionately omitted in elderly, 
rural, racial minority and uninsured populations, and there has been little improvement in 
this measure over the last decade.  This study was the largest of its kind specifically 
focused on an underserved Southern US population and the largest clinically significant 
disparity was found among rural patients.  This report was one of the largest studies to 
date to identify an independent association of lack of RT with an increased hazard ratio 
for death.  Lack of application of RT after BCS is a reliable indicator of inadequate 
access to other adjuvant therapies and poor post-treatment surveillance.  Incentive 
programs focused on multidisciplinary care as a quality endpoint must be targeted to 
these underserved populations.  AHF-RT is a convenient and cost-effective alternative to 
conventionally-fractionated RT and must be investigated to improve treatment access for 
rural and other underserved patients. 
 
The provision of breast cancer therapy is a microcosm of the challenges facing the future 
of healthcare delivery in the United States as a whole.  The widening of the so-called 
“healthcare gap” between the wealthy and poor, urban and rural populations is real, 
insidious and underway, especially with regard radiation therapy services.  The 
explanation for this trend is simple: the current reimbursement model for radiation 
therapy services in the US, whether covered by private or governmental payers, depends 
primarily on the number of treatments delivered over the therapeutic course and/or 
technical complexity.  More pragmatic, cost-effective regimens that are a step toward 
improvement in access, such as three-week HF-RT, are actually discouraged and 
underutilized by physicians, even when highly favored by patients.     
  

9 | P a g e  
 
Public health initiatives, such as AHF-RT, that have the capacity to favorably impact the 
major factors related to cost and access for a disease as prevalent as breast cancer are few 
and far-between.  As the US population ages and screening tests increase in sensitivity, it 
is expected that radiotherapy services in the setting of BCS will continue to be in high 
demand.  Thus, a larger annual population of women entering the age of highest risk for 
breast cancer combined with a projected physician shortage and the questionable long-
term solvency of healthcare entitlement programs requires broad-based novel solutions to 
alter this trend and prevent worsening of current disparities.   Safe and effective 
accelerated radiotherapy regimens that meet the needs of rural populations must be 
inexpensive, easily implemented and widely applicable.  Only then will they result in 
expansion in access not only to radiotherapy, but other “down-stream” adjuvant 
chemo/hormonal therapies and follow-up care.  The opening of the multidisciplinary 
breast cancer system to these underserved patients is thereby likely to significantly 
impact disease-specific endpoints and ultimately mortality. 
 
2.2 Supporting data for AHF-RT 
 
Initial studies of BCS combined with RT as an alternative to mastectomy utilized 
conventionally fractionated radiotherapy (CF-RT), in schedules of daily 1.8-2.0 Gy 
fractions tp a total dose of 45 to 50 Gy with or without an additional radiation boost to the 
tumor bed1-2, 4. Traditionally, this type of RT schedule, CF-RT has been advocated based 
upon the theory that small daily fraction sizes lower the risk of late normal tissue toxicity 
without compromising cancer control27.  As a result, patterns-of-care studies have 
indicated that the vast majority of radiation oncologists in the US primarily employ CF-
RT schedules in the treatment of breast cancer 28-30.  However, CF-RT has significant 
limitations, mainly related to the inconvenience to patients associated with undergoing 
daily treatment for 6 to 7 weeks and the cost of treatment (both direct health care 
expenditures and opportunity costs to the patient and society due to time away from home 
and work)31-32.  In the United Kingdom and Canada, physicians have long used adjuvant 
hypofractionated radiotherapy (HF-RT), which both the total dose and the number of 
fractions are decreased compared to CF-WBI schemes.  Multiple randomized clinical 
trials of HF-RT versus CF-RT show equivalent results, with HF-RT enabling shorter total 
treatment time, enhanced convenience, and lowers cost (Table 1)27, 32-36 37. 
 
Although 3-weeks of daily HF-RT is a significant improvement over the 6-7 week CF-
RT course, the requirement of daily therapy continues to present barriers to underserved 
populations and regions with scarcity of oncology resources.  The favorable results from 
the randomized clinical trials of HF-RT have yielded sufficient data to enable the 
investigation of accelerated hypofractionated radiotherapy (AHF-RT).  AHF-RT, which 
delivers approximately 28.5Gy-33Gy to the entire breast in 5-6 Gy per fraction, once or 
twice weekly, has thus far shown promise in nonrandomized studies throughout France 
and randomized studies in both the United Kingdom and India (Table 2)38-41.  Early Phase 
III data and long-term Phase II results show toxicity, cosmesis, and outcomes that are 
comparable to other traditional whole breast regimens. These favorable results have led 
to the current UK FAST trial (n = 900) testing 50 Gy in 25 fractions of whole breast CF-
RT against two different regimens of AHF-RT delivered in a five-fraction schedule over 

10 | P a g e  
 
5 weeks (5.7 or 6 Gy per fraction, for a total dose of 28.5 Gy or 30 Gy, respectively)42.  
Our proposed study is the first investigation of AHF-RT in the United States as a public 
health intervention to increase the provision of adjuvant radiotherapy services to rural 
women in Kentucky and the wider region.  The ultimate goal is increased utilization of 
RT after BCS among rural and underserved patients. 
 
2.3 Estimations of Eligible Patients and Enrollment.  
 
The James Graham Brown Cancer Center (JGBCC) at the University of Louisville 
School of Medicine (Louisville, KY) houses the only multidisciplinary breast cancer 
program in Kentucky certified by the National Accreditation Program for Breast Centers 
(NAPBC).  The program is comprehensive in its offering of diagnostic, therapeutic, 
complementary and supportive resources to an extensive and diverse geographic region 
in central Kentucky and southern Indiana.  Additionally, the program garners substantial 
clinical trials support, maintains dedicated biostatisticians, and offers a robust nurse 
navigation network.  Table 3 shows the demographics and characteristic of patient seen at 
JGBCC during the period from 2007-2008.  Although eligibility is primarily directed to 
specific patients who have been identified as belonging to an underserved group, overall 
accrual and participation is broad-based with ultimate discretion left to the treating 
physician (see Section 5.1.12). Therefore, a conservative estimate of accrual would be 
approximately 3 patients per month for the first year, increasing to 5 patients per month 
in subsequent years at the primary institution. 
 
The University of Louisville Hospital System and School of Medicine maintain dynamic 
working relationships with the University of Kentucky and University of Indiana as well 
as with multiple regional community cancer centers.  The JGBCC serves as a major entry 
point for newly diagnosed rural breast cancer patients across the region by way of an 
active mobile digital mammography program.  In terms of radiation oncology resources, 
there are currently two (and, in the near future, three) rural satellite cancer centers that are 
staffed with both clinical and physics support from the JGBCC.  After IRB approval at 
the primary site, these affiliated satellite sites and regional partners will be approached 
for participatory interest so that continuing accrual may be maintained and exceeded.  
 

11 | P a g e  
 
TABLE 1: Outcomes for selected randomized clinical trials comparing CF-RT to HF-RT. 
 
 
TRIAL 
 
MEDIAN 
FOLLOW-UP 
(YEARS) 
 
N 
 
DOSE 
(Gy) 
 
# 
FRAC 
 
IBTR* 
(%) 
 
LRR* 
(%) 
 
DFS* 
(%) 
 
OS* 
(%) 
COSMESIS* 
(% GOOD or 
EXCELLENT) 
ACUTE 
TOXICITY* 
(% ≥ GRADE 3) 
Canada35 
10 
612 
622 
50 
42.5 
25 
16 
6.7 
6.2 
-- 
-- 
-- 
-- 
84 
85 
71.3 
69.8 
3.0 
3.0 
Royal Marsden33 
10 
470 
466 
474 
50 
42.9 
39 
25 
13 
13 
12 
9.6 
15 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
-- 
71 
74 
58† 
-- 
-- 
-- 
START A37 
5 
749 
750 
737 
50 
41.6 
39 
25 
13 
13 
3.2 
3.2 
4.6 
3.6 
3.5 
5.2 
86 
88 
85 
89 
89 
89 
-- 
-- 
-- 
0.3 
0.0 
0.0 
START B27 
6 
1105 
1110 
50 
40 
25 
15 
3.3 
2.0 
3.3 
2.2 
86 
89 
89 
92 
-- 
-- 
1.2 
0.3 
Abbreviations: N = number of patients; FRAC = fractions; IBTR = in-breast tumor recurrence; LRR = locoregional recurrence; DFS = disease free survival; OS 
= overall survival. 
*All statistical p-values are non-significant in the comparison of CF-RT to HF-RT, unless otherwise specified. 
†Measure found to be statistically inferior to CF-RT (p < 0.05). 
 
 
TABLE 2: Outcomes for selected clinical trials of AHF-RT. 
 
 
TRIAL 
 
 
DESIGN 
MEDIAN 
FOLLOW-
UP (YEARS) 
 
N  
 
DOSE 
(Gy) 
 
# 
FRAC 
 
IBTR* 
(%) 
 
LRR*
(%) 
 
DFS* 
(%) 
COSMESIS* 
(% GOOD or 
EXCELLENT) 
ACUTE 
TOXICITY* 
(% ≥ GRADE 3) 
Ortholan et al.40 
Prospective, Single 
Arm 
5 
150 
32.5 
5 
-- 
2.3† 
80 
-- 
-- 
Martin, et al.39 
Prospective, Single 
Arm 
3 
59 
30 
5 
0† 
0† 
-- 
77 
3 
Kirova, et al.38 
Prospective, Non-
Randomized 
5 
317 
50 
50 
32.5 
25 
5 
-- 
-- 
5‡
6‡ 
96 
95 
88 
85 
“NS” 
Saha, et al.41 
Prospective 
Randomized 
4 
62 
69 
50 
30 
25 
5 
-- 
-- 
4.8§ 
5.8§ 
-- 
-- 
87 
80 
1.6 
0 
Abbreviations: N = number of patients; FRAC = fractions; IBTR = in-breast tumor recurrence; LRR = locoregional recurrence; DFS = disease free survival. 
*All statistical p-values are non-significant in the comparison of CF-RT to HF-RT, unless otherwise specified. †At minimum of 2 year followup.  ‡At minimum 
of 5 years followup. §At minimum of 3 years followup.  

12 | P a g e  
 
TABLE 3: Characteristics of patients who underwent breast conserving surgery at the University 
of Louisville School of Medicine in 2007-2008 and who would potentially fit eligibility criteria 
for this protocol (source: JGBCC Tumor Registry). 
   
 
CHARACTERISTIC 
CATEGORY 
# 
% 
Total Number of Patients 
 
273 
100 
 
 
 
 
Stage 
 
 
 
 
0 
57 
20.9 
 
I 
135 
49.4 
 
II 
81 
29.7 
Age 
 
 
 
 
<50 years 
85 
31.1 
 
51-70years 
153 
56.0 
 
>70 years 
35 
12.9 
Geographic Location 
 
 
 
 
Urban 
177 
64.8 
 
Rural 
96 
35.2 
Race 
 
 
 
 
Non-minority 
199 
72.9 
 
Minority 
74 
27.1 
Insurance Status 
 
 
 
 
Private 
132 
48.4 
 
Government/Grant 
124 
45.4 
 
Uninsured 
17 
6.2 
Chemotherapy 
 
 
 
 
No 
186 
68.1 
 
Yes 
87 
31.9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

13 | P a g e  
 
3.0 HYPOTHESIS/STUDY AIMS 
 
3.1 Hypothesis 
 
• 
AHF-RT will be a practical, safe and cost-effective radiotherapy regimen that will 
offer disease-specific outcomes comparable to those achieved with CF-RT and 
HF-RT for selected patients with early stage breast cancer.  AHF-RT will be 
widely-applicable for the purpose of correcting disparities in the receipt of 
radiotherapy observed in medically underserved populations.     
 
3.2 Primary aims 
 
• 
To estimate the in-breast tumor recurrence rate (IBTR) of accelerated 
hypofractionated radiotherapy (AHF-RT) delivered to the whole breast in five 
treatments once weekly following breast conserving surgery (BCS) in the local 
management of early stage breast cancer. 
 
• 
To monitor for adverse events and futility at a planned interim analysis. 
 
3.3 Secondary aims 
 
• 
To estimate overall survival, recurrence-free survival, and distant disease-free 
survival among patients receiving AHF-RT and to compare these endpoints and 
IBTR to historical controls of CF-RT and HF-RT. 
 
• 
To estimate radiation-induced adverse events (such as radiation dermatitis, 
radiation-induced pain, lymphedema, and fibrosis) among patients receiving 
AHF-RT and to compare to historical controls of CF-RT and HF-RT. 
 
• 
To explore quality-of-life endpoints among patients who undergo AHF-RT 
(including cosmetic outcome, convenience of care, and treatment-related fatigue) 
and to compare to historical controls of CF-RT and HF-RT. 
 
• 
To explore cost-effectiveness endpoints among patients who undergo AHF-RT 
and to compare to historical controls of CF-RT, APBI and HF-RT. 
 
 
4.0 ENDPOINTS 
 
4.1 Primary endpoint 
 
The primary endpoint for analysis is the time from enrollment to the diagnosis of 
in-breast tumor recurrence (IBTR) as a first event. Ipsilateral chest wall, regional 
and distant failures, and death prior to IBTR will be treated as competing risks 
when calculating the frequency, crude hazard and cumulative incidence of IBTR. 
Contralateral breast and non-breast second primary cancers will not be considered 

14 | P a g e  
 
to be competing risks (i.e., patients will be followed beyond the diagnosis of 
contralateral breast and non-breast second primary cancers for the subsequent 
occurrence of IBTRs). Both invasive and non-invasive IBTRs are considered in 
calculating the primary endpoint. 
 
4.2 Secondary endpoints 
 
4.2.1 Distant disease-free interval, defined as the time from enrollment to first 
diagnosis of distant disease, regardless of the occurrence of any intervening local 
or regional failure, contralateral breast cancer, or non-breast second primary 
cancer (see Section 10.0). 
 
4.2.2 Recurrence-free survival defined as the time from enrollment to first 
diagnosis of a local, regional, or distant recurrence, regardless of any intervening 
contralateral or other second primary cancer. 
 
4.2.3 Overall survival defined as the time from enrollment to death due to any 
cause. 
 
4.2.4 Treatment toxicities (acute and late) 
 
4.2.5 Quality of life: 
• cosmesis; 
• treatment-related symptoms; 
• fatigue;  
• perceived convenience of care. 
 
 
4.2.6 Cost effectiveness  
 
 
5.0 PATIENT ELIGIBILITY AND INELIGIBILITY 
 
5.1 Conditions for patient eligibility 
 
Women who satisfy all of the following conditions are the only patients who will be 
eligible for this study. 
 
5.1.1 The patient must consent to be in the study and must have signed an 
approved consent form conforming with federal and institutional guidelines. 
 
5.1.2 Patients must be ≥ 21 years old. 
 
5.1.3 The patient must have stage 0, I, or II breast cancer.  
 
5.1.4 On histological examination, the tumor must be DCIS or invasive 
adenocarcinoma of the breast. 

15 | P a g e  
 
 
5.1.5 Surgical treatment of the breast must have been BCS. The margins of the 
resected specimen must be histologically free of tumor (including DCIS 
component). Reexcision of surgical margins is permitted. 
 
5.1.6 Gross disease may be unifocal or multifocal with pathologic (invasive 
and/or DCIS) tumor size excised with negative margins. 
 
5.1.7 Patients with invasive breast cancer are required to have axillary staging 
which can include sentinel node biopsy alone (if sentinel node is negative), 
sentinel node biopsy followed by axillary dissection or sampling with a minimum 
total of 6 axillary nodes (if sentinel node is positive), or axillary dissection alone 
(with a minimum of 6 axillary nodes). (Axillary staging is not required for 
patients with DCIS.) 
 
5.1.8 The patient must begin adjuvant therapy (chemotherapy or radiotherapy) 
within 9 weeks following the last surgery for breast cancer (lumpectomy, re-
excision of margins, or axillary staging procedure). 
 
5.1.9 Patients must have all usual and customary hormone receptor (ER/PR) and 
estrogen receptor (ER) analysis performed on the primary tumor prior to 
enrollment.  Patients with invasive disease must have HER2 receptor status 
determined (positive or negative) with immunohistochemistry (IHC) and/or 
fluorescent in-situ hybridization (FISH).  
 
5.1.10 At the time of enrollment, patients must have had an H&P within 4 months 
and a bilateral mammogram within 6 months. 
 
5.1.11 Patients with a history of non-breast malignancies are eligible if they have 
been disease-free for 5 or more years prior to randomization and are deemed by 
their physician to be at low risk for recurrence. Patients with the following 
cancers are eligible if diagnosed and treated within the past 5 years: carcinoma in 
situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell 
and squamous cell carcinoma of the skin. 
 
5.1.12 Patients must live in a county that is designated as Appalachian and/or 
rural by Kentucky Cancer Registry Criteria (See Figures 2 and 3) and/or must 
hold their primary residence ≥ 10 miles from the nearest radiation facility.  
Patients who do not fit these criteria may still be considered eligible if they are 
determined to suffer significant financial and/or transportation hardship during a 
typical course of CF-RT or HF-RT (in the judgment of any of their treating 
physicians).  Patients who live outside the Commonwealth of Kentucky are 
eligible if they fit any of these aforementioned conditions. Form A1 specifying 
patient’s eligibility must be completed prior to enrollment. 
 
 

16 | P a g e  
 
5.2 Conditions for patient ineligibility 
 
Men are not eligible for this study. Women with one or more of the following conditions 
also are ineligible for this study. 
 
5.2.1 T3, stage III, or stage IV breast cancer (see Appendix A for TNM 
nomenclature and staging). 
 
5.2.2 More than 3 histologically positive axillary nodes. 
 
5.2.3 Axillary nodes with definite evidence of microscopic or macroscopic 
extracapsular extension. 
 
5.2.4 One or more positive non-axillary sentinel node(s). (Note that 
intramammary nodes are staged as axillary nodes.) 
 
5.2.5 Palpable or radiographically suspicious ipsilateral or contralateral axillary, 
supraclavicular, infraclavicular, or internal mammary nodes, unless there is 
histologic confirmation that these nodes are negative for tumor. 
 
5.2.6 Suspicious microcalcifications, densities, or palpable abnormalities (in the 
ipsilateral or contralateral breast) unless biopsied and found to be benign. 
 
5.2.7 Non-epithelial breast malignancies such as sarcoma or lymphoma. 
 
5.2.8 Proven multicentric carcinoma (invasive cancer or DCIS) in more than one 
quadrant or separated by 4 or more centimeters. 
 
5.2.9 Paget's disease of the nipple. 
 
5.2.10 Synchronous bilateral invasive or non-invasive breast cancer. 
 
5.2.11 History of invasive breast cancer or DCIS. (Patients with a history of LCIS 
treated by surgery alone are eligible.) 
 
5.2.12 Surgical margins that cannot be microscopically assessed or are positive at 
pathologic evaluation. (If surgical margins are rendered free of disease by 
reexcision, the patient is eligible.) 
 
5.2.13 Treatment plan that includes regional nodal irradiation. 
 
5.2.14 Current therapy with any hormonal agents such as raloxifene (Evista®), 
tamoxifen, or other selective estrogen receptor modulators (SERMs), either for 
osteoporosis or breast cancer prevention. (Patients are eligible only if these 
medications are discontinued prior to enrollment.) 
 

17 | P a g e  
 
5.2.15 Cosmetic breast implants. (Patients who have had implants removed are 
eligible.) 
 
5.2.16 Prior breast or thoracic RT for any condition. 
 
5.2.17 Collagen vascular disease, specifically dermatomyositis with a CPK level 
above normal or with an active skin rash, systemic lupus erythematosis, or 
scleroderma. 
 
5.2.18 Pregnancy or lactation at the time of proposed randomization. Women of 
reproductive potential must agree to use an effective non-hormonal method of 
contraception during therapy. 
 
5.2.19 Psychiatric or addictive disorders or other conditions that, in the opinion of 
the investigator, would preclude the patient from meeting the study requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

18 | P a g e  
 
FIGURE 2: Kentucky Cancer Registry county designation “Appalachia” (yellow) versus “Non-
Appalachia” (red). 
 
 
 
 
 
FIGURE 3a: Kentucky Cancer Registry county designation “rural” (yellow) versus “non-rural” (red). 
 
 
 
 
 
 
 
 
 
 
 

19 | P a g e  
 
6.0 REQUIRED ENTRY AND FOLLOW-UP STUDIES 
 
TABLE 3: All studies required for study entry; studies required during study therapy; studies 
required as part of long-term follow-up. 
 
 
 
Acute Toxicity 
Late Toxicity/Disease 
Outcome 
Required 
studies1 
Prior to 
enrollment 
 
At end of 
RT 
 
At 4 weeks 
following 
therapy2 
 
At 6 months 
and 12 months 
following 
therapy2 
 
Years 2-5 
 
History & 
physical exam, 
including Breast 
exam 
 
X3 
 
X4 
 
X4 
 
X4 
 
X4,5 
Adverse event 
assessment7 
 
 
 
 
X 
 
X 
 
X 
 
X6 
 
Menopausal 
status8 
 
 
X 
 
 
 
 
Routine 
serologic 
studies9 
 
 
X 
 
 
 
 
Pregnancy test 
(serum beta HCG) 
9 
 
 
X 
 
 
 
 
Routine 
radiologic 
imaging 
(perioperative) 9 
 
X 
 
 
 
 
Routine 
radiologic 
imaging 
(staging) 9 
 
 
X 
 
 
 
 
Bilateral 
mammogram 
 
 
X10 
 
 
 
X11 
 
X6 
1H&P, bloodwork, x-rays, scans, and other testing may be performed more frequently according to physician preference and 
when symptoms suggest metastatic disease. 
2From end of RT (if no chemotherapy) or from end of both RT and chemotherapy (if chemotherapy is given). 
3Complete H&P within 4 months prior to enrollment. 
4Updated H&P including disease status. 
5Every 6 months. 
6Every 12 months. 
7RT-related assessment; refer to Section 11.0 for timing of Form AE submissions. 
8See Appendix B. 
9At the discretion of treating physicians (radiology, surgery, medical oncology and/or radiation oncology) 
10Within 6 months prior to enrollment. 
11A mammogram of the ipsilateral breast is required at 6 months following study therapy. The next bilateral mammogram 
should be timed to be no more than 12 months from the most recent 
bilateral mammogram.  
 
 
 
 
 

20 | P a g e  
 
TABLE 4. Required studies for QOL and cosmesis patient population (see Section 7.0) 
 
 
 
Required Studies 
 
 
Prior to 
enrollment 
 
Peri-treatment period 
Follow-up1 
Last 
Day of 
AHF-
RT 
4 weeks 
after 
AHF-
RT 
6 
months 
after 
AHF-
RT 
 
Year 1 
 
Year 2 
 
Year 3 
QOL 
Questionnaire(s) 
X 
X 
X 
X 
X 
X 
X 
BCTOS 
X 
 
 
X 
X 
 
X 
MD-Reported 
Cosmesis 
X2 
 
 
X2 
X2 
 
X 
Digital Images 
(Breast Photos) 
X 
 
 
X 
X 
 
X 
1From end of AHF-RT.  
2A radiation oncologist should complete these reports. If this is not possible, the patient's surgeon may complete the 
reports.  
Every effort should be made to have these assessments performed by the same physician at all 3 time points. 
 
 
7.0 QUALITY OF LIFE, COSMESIS AND COST-EFFECTIVENESS ANALYSIS  
 
Primary hypothesis: 
• Cosmetic results after AHF-RT following lumpectomy will be comparable to that 
historically reported in modern clinical trials of CF-RT vs. HF-RT (Table 1). 
 
Secondary hypotheses: 
• Among patients not receiving chemotherapy, treatment-related symptoms at the 
end of radiotherapy for patients undergoing AHF-RT will be comparable to that 
historically reported in modern clinical trials of CF-RT vs. HF-RT (Table 1). 
• The perceived convenience of care and treatment compliance will be greater for 
patients undergoing AHF-RT than for patients historically reported in modern 
clinical trials of CF-RT vs. HF-RT (Table 1). 
• The cost effectiveness of delivery of adjuvant radiotherapy will be superior for 
AHF-RT than comparable studies of CF-RT, HF-RT and accelerated partial breast 
irradiation. 
 
7.1 Cosmesis 
 
The quality of life component contains provisions to evaluate cosmetic results.  
In terms of cosmesis, we expect that AHF-RT will yield equivalent results to published 
studies of HF-RT. Because cosmetic outcome stabilizes several years post-treatment, the 
primary cosmetic endpointwill be taken 3 years post-treatment, however intervening data 
will be collected for the purpose of early result reporting as well as for tracking how 
cosmetic outcome resolves over time. 
 
Cosmetic results will be evaluated in several ways. First, the Breast Cancer Treatment 

21 | P a g e  
 
Outcome Scale (BCTOS, Form BE)43 will be used to assess cosmetic results using patient 
self reports.  This brief self-report instrument has high reliability and validity, and has 
been used in a variety of previous studies on recovery from breast cancer treatment. The 
first patient-rated cosmetic evaluation will occur after informed consent but prior to 
randomization. The BCTOS will be used to assess cosmesis, pain and functionality at 
baseline, 6 months, 1 year and at the final 3-year endpoint. (see Table 4). Second, after 
consent but prior to randomization, a cosmetic evaluation will be made by the radiation 
oncologist (or surgeon), using the physician-assessed Harvard Scale (Form CE). Ratings 
of cosmetic outcome will then be made by the radiation oncologist (or surgeon) at 
baseline, 6 months, 1 year and at the final 3-year endpoint. (see Table 4).  This will 
facilitate comparison of physician-generated versus patient-generated ratings, and to 
characterize the evolution of cosmetic outcome from multiple perspectives.  
 
Finally, digital images (photographs) will be taken of the treated and untreated breasts at 
baseline, 6 months, 1 year and at the final 3-year endpoint. (see Table 4). Two digital 
images will be taken at each of these assessment points. One will be a close up of the 
treated breast alone, in order to provide detailed information regarding the treatment 
effects. The second digital image will be a straight frontal view of both breasts taken in 
either a standing or seated position with the patient's hands symmetrically placed on her 
hips, taking care to exclude her face and framing or focusing on both the treated and 
untreated breast to allow optimal comparison of the breasts for symmetry. These digital 
images will then be evaluated for cosmetic results by a panel of physicians using 
diagnostic criteria (e.g., degree of scarring, extent of pock marks and/or dimpling, degree 
of symmetry between the breasts, extent of changes to the skin). In total, these multiple 
measures of cosmetic outcome will be used to assess the degree of correspondence 
between physician-generated and patient-generated outcomes.  
 
7.2 Quality of life 
 
Studies of women receiving breast-conserving surgery followed by WBI generally report 
adequate quality of life43-45. The current trial presents an excellent opportunity tostudy the 
treatment-relevant components of quality of life of women undergoing AHF-RT and to 
compare their experiences to historical controls of women undergoing various breast 
radiotherapy regimens. Patients undergoing AHF-RT will receive a higher dose-per-
fraction of radiation than patients who undergo CF-RT or HF-RT. However, due to the 
fewer overall treatments and fewer weekly trips to the radiation facility, we believe the 
ratings of fatigue and treatment-related symptoms at the end of radiotherapy will be 
lower than those historically reported.   We also believe that women undergoing AHF-RT 
will perceive their convenience of care to be greater than that historically reported with 
CF-RT or HF-RT. Although ratings of fatigue, treatment-related symptoms, and 
perceived convenience of care among women receiving AHF-RT will be clearest among 
women who receive radiation therapy alone, not in combination with chemotherapy. To 
examine this possibility, we plan to measure fatigue, treatment-related symptoms, and 
convenience of care among women who receive both treatment modalities at the point at 
which their combined treatment ends.  
 

22 | P a g e  
 
7.2.1 QOL Metrics: The following validated QOL metrics will be employed in-
whole or in-part to assess QOL at baseline and regular intervals during and after 
AHF-RT: 
 
• 
The EORTC QLQ-BR23 (Form QOL02), a validated breast-cancer specific QOL 
instrument. 
 
All appropriate and required permissions for use will be obtained for the aforementioned 
instrument prior to its use in this study. 
 
7.3 QOL and cosmesis instructions 
 
The patient-completed quality of life questionnaire will be administered at baseline, after 
informed consent has been obtained and after enrollment. It will also be completed by 
patients in both arms at the close of adjuvant (non-hormonal) therapy (i.e., at the end of 
radiotherapy for the RT only group and at the end of both chemotherapy and RT for the 
combined therapy group). Other patient-administered follow-ups will occur 
approximately 4 weeks after the completion of adjuvant (non-hormonal) therapy (i.e., at 
the end of radiotherapy for the RT only group and at the end of both chemotherapy and 
RT for the combined therapy group), and at 6 months, 1 year, 2 years, and 3 years 
following completion of adjuvant(non-hormonal) therapy. The timing of assessments will 
coincide with other protocol requirements wherever possible in order to reduce patient 
burden and enhance compliance. The QOL questionnaires should be administered during 
an office visit if at all possible, preferably while the patient is waiting to be seen.  When 
absolutely necessary, it may also be administered by mail or phone. A planned interim 
QOL analysis will be conducted and reported according to section 13.10. 
 
7.4 Cost Effectiveness Analysis 
 
The provision of breast cancer therapy is a microcosm of the challenges facing the future 
of healthcare delivery in the United States as a whole.  The widening of the so-called 
“healthcare gap” between the wealthy and poor, urban and rural populations is real, 
insidious and underway, especially with regard radiation therapy services.  Well-funded, 
highly specialized facilities in large urban centers continue to compete with one another.  
Investments are made in novel, expensive and largely unproven modalities such as 
robotic radiosurgery, intraoperative radiotherapy, and proton/particle therapy.  Often, the 
solvency of these major capital investments depends on the treatment of a high volume of 
privately-insured patients from a large referral base with the financial means to provide 
their own transportation and housing during a course of therapy.    
 
The explanation for this trend is simple: the current reimbursement model for radiation 
therapy services in the US, whether covered by private or governmental payers, depends 
primarily on the number of treatments delivered over the therapeutic course and/or 
technical complexity.  More pragmatic, cost-effective regimens that are a step toward 
improvement in access, such as three-week HF-RT, are actually discouraged and 
underutilized by physicians, even when highly favored by patients.  Most accelerated 
radiotherapy courses currently under investigation in the treatment of breast cancer 

23 | P a g e  
 
involve the more expensive treatment-delivery techniques of accelerated partial breast 
irradiation (APBI).  Given that APBI requires specialized training on the part of 
physicians and significant capital equipment investment by hospitals, they are likely to be 
accessible mainly to urban and suburban populations.  Thus far, the popular accelerated 
regimens of APBI have significantly broadened the menu of choices for women already 
in the system, but have had little impact on healthcare disparity. As a result, they not only 
put undesirable upward pressure on healthcare costs, but also further widen the access 
gap currently experienced by rural breast cancer populations.  
 
In terms of broader public-health impact, AHF-RT has a significant potential for the 
generation of cost-effectiveness data that will be vital to the debate over allocation of 
limited healthcare resources.  Provision of oncology resources is problematic for many 
patients in the more sparsely populated states of the Southeast, Southwest and 
Midwest/Mountain regions of the US.  The availability of multidisciplinary care centers 
is insufficient.  Financial assistance for or coordination of transportation services for 
lower-income rural patients varies widely from community to community.  Even when 
free transportation is provided, rural patients disproportionately shoulder the burden of 
loss of time and productivity due to daily round-trip travel and treatment times, which 
may total several hours per day.   
 
Detailed cost-effectiveness analysis (CEA) will be performed during this study in order to 
quantify these factors and make valuable comparisons with other forms of breast 
radiotherapy: CF-RT, HF-RT and APBI. Similar models have been employed to model 
cost-effectiveness and quality-adjusted life years to compare CF-RT to HF-RT and APBI 
(breast brachytherapy and 3-dimensional conformal radiotherapy)31, 46.  Similar standard 
analysis techniques (will be developed to make meaningful comparisons of AHF-RT with 
these previously published studies.  A planned interim CEA will be conducted and 
reported according to section 13.10.  
 
 
8.0 ACCELERATED HYPOFRACTIONATED RADIOTHERAPY (AHF-RT) 
 
The intent of AHF-RT is to treat the entire breast through tangential fields and ensure that the 
lumpectomy cavity is dosimetrically covered within the irradiated volume. 
 
8.1 Treatment overview 
 
8.1.1 Treatment planning 
 
• 
CT-based treatment planning is required. Any CT-based treatment approach can be 
used, including forward-planned, segment-weighted approaches. Acceptable 
coverage of the lumpectomy cavity within the whole breast dose must be 
documented. (See Section 8.2.) 
 
• 
Regional nodal irradiation is NOT allowed. 
 
• 
Fluoroscopic 2-D treatment planning is NOT allowed. 
 
 

24 | P a g e  
 
8.1.2 Timing 
 
• 
If the patient is not receiving chemotherapy, AHF-RT is to be initiated within 9 
weeks following lumpectomy or re-excision of margins and within 3 weeks following 
study entry.  
 
• 
For patients receiving chemotherapy, AHF-RT is to begin no fewer than 2 weeks and 
no more than 8 weeks after the last cycle of chemotherapy. 
 
8.1.3 AHF-RT Whole breast dose 
 
• 
Acceptable dose for the AHF-RT prescription point/volume is 30Gy in 6Gy per 
fraction, or 28.5Gy in 5.7Gy per fraction, delivered once weekly over 5 treatment 
weeks.  Total dose prescribed is left to the discretion of the treating physician. 
   
      8.1.4 Boosts 
 
• 
Boost therapy by either photons or electrons to the lumpectomy cavity plus margin is 
permitted but not required. Brachytherapy or intraoperative boosts are allowed. The 
boost technique and dose is left to the discretion of the treating radiation oncologist, 
but CT-based targeting/planning is encouraged. 
 
• 
Total boost dose to the prescription point/volume is to be between 10-16Gy in a 
fractionation schedule to be determined by the treating radiation oncologist, based on 
the technique used. 
 
8.1.5 Patient positioning/immobilization 
 
• 
Patient positioning and immobilization should be performed according to usual and 
customary facility standards with regard to CT-based planning.  The patient's position 
must be reproducible through the entire course of treatment. Typically, patients are 
treated in the supine position with the arms extended overhead using immobilization 
techniques, such as a tilt board, to ensure reproducibility. Prone positioning is 
permitted. 
 
     8.1.6 Equipment 
 
• 
Linear accelerator (LinAc) with minimal photon energies of 4MV. 
 
8.2 CT-based WBI treatment plan 
 
     8.2.1 CT planning 
 
• 
Must include dose distribution evaluated on multiple CT levels after the target breast 
volume is defined on CT and tangents.  Dose distribution based on dose-volume 
specification to breast tissue and constraints for critical non-target structures must 
also be specified. 
 
 
 

25 | P a g e  
 
     8.2.2 Target breast volumes 
 
• At the time of the simulation/CT, the clinical breast volume to be targeted in 
the tangent fields, with appropriate margin, is determined by the radiation 
oncologist. For the purposes of this protocol, the whole breast volume will be 
referred to as the whole breast reference volume and defined as all tissue 
volume, excluding lung, within the boundaries of standard whole breast 
tangential fields.  The whole breast reference volume should also exclude any 
non-breast structure deep to the lung-rib interface such as heart, pre-cardiac 
fat, and liver.  This is meant to be only an approximation of the actual breast 
tissue volume, and it is recognized that the chest wall and some degree of 
adjacent soft tissue will be included. However, with this definition it is 
anticipated that this volume will be reproducible and consistent from case to 
case and that the process can be automated within the 3D planning system for 
time conservation 
 
      8.2.3 Tangential fields 
 
• 
The borders for the tangent fields are set so that they include the targeted clinical 
breast volume determined above plus a 1–2 cm margin. Examples of typical clinical 
boundaries for tangent fields are: 
 
o Medial: usually midsternum 
o Lateral: usually midaxillary line 
o Caudad: 1-2 cm below the inframammary line 
o Cephalad: commonly at the base of the clavicle heads or the sternal-
manubrial joint 
 
• 
For CT-based planning, radiopaque markers are placed on these borders. These 
boundaries may need to be modified depending on the location of the lumpectomy 
cavity when it is visualized on CT. It is recommended that techniques be applied that 
assure posterior or deep borders are co-planar in order to minimize exit into the 
lungs. 
 
     8.2.4 Constraints for critical non-target organs 
 
• 
Contouring of critical structures: 
o Ipsilateral Lung:  The lung tissue is easily visible on “mediastinal 
window preset” of a non-contrast CT due to the differential 
Houndsfield units from surrounding tissue.  All ipsilateral lung tissue 
should be contoured. The “autocontour” feature available on some 
treatment planning CT scans may be used. 
o Heart: The heart should be contoured beginning just below the level 
in which the pulmonary trunk branches into the left and right 
pulmonary arteries (PA). Above the PA, none of the heart’s 4 
chambers are present. All the mediastinal tissue below this level 
should be contoured, including the great vessels (ascending and 
descending aorta, inferior vena cava). The heart should be contoured 

26 | P a g e  
 
on every contiguous slice thereafter to its inferiormost extent near the 
diaphragm. If one can identify the esophagus, this structure should be 
excluded. One need not include pericardial fat, if present. Contouring 
along the pericardium itself, when visible, is appropriate. 
 
• 
The perpendicular distance from the chest wall to the posterior field edge can include 
at maximum 3 cm of lung tissue at any point along the length of the digitally 
reconstructed radiograph (DRR) of the tangentialfield. For left-sided cancers, field 
arrangements that minimize inclusion of the heart in the field should be used. 
 
     8.2.5 Dose prescription and evaluation of isodose distribution 
 
• 
The dose will be prescribed to the 100% isodose line encompassing at least 90% of 
the breast tissue as specified on the CT contours OR to a point located at two thirds 
the perpendicular distance from the skin overlying the breast to the posterior border 
of the tangent field at mid-separation on the central axis slice (also specified on CT 
plan). Wedges, compensators, etc. are to be used to keep the maximum dose less than 
115% of the prescription, and, ideally less than 110% of the prescription dose. Dose 
calculations are to be done WITH heterogeneity corrections. 
 
     8.2.6 Verification of lumpectomy cavity coverage within the prescription isodose for     
              the whole breast 
 
• 
Verification process for the lumpectomy cavity: Review of the dose distribution on 
CT slices that include the lumpectomy cavity is requested to verify that the cavity 
(identified on CT by either the post-operative seroma, postoperative scar, surgical 
clips or a combination thereof) is covered by the 100% isodose line. Acceptable 
AHF-RT must demonstrate that the entire cavity is included in ≥ 90% isodose line. If 
not, changes in the field width, gantry, collimator, or selection of wedges or other 
adjustment must be done to achieve this.  
 
     8.2.7 Boost 
 
• 
Refer to Section 8.1.4. 
 
 
9.0 SYSTEMIC THERAPY 
 
9.1 Chemotherapy 
Chemotherapy may be given at the discretion of the patient's medical oncologist. The use of 
concurrent chemotherapeutic agents during radiation therapy is not allowed.  For patients 
undergoing chemotherapy, the adjuvant chemotherapy will be given prior to AHF-RT, as 
prescribed by the treating physician. Initiation of AHF-RT should be at least 2 weeks after the last 
cycle of chemotherapy. 
 
9.2 Hormonal therapy 
Patients with ER-positive and/or PR-positive tumors should be treated with hormonal therapy for 
a minimum of 5 years. The dose and schedule of the drug(s) used for hormonal therapy should be 
consistent with the instructions in the drug package insert(s). 
 

27 | P a g e  
 
9.2.1 Patients receiving chemotherapy 
Hormonal therapy should begin no sooner than 3 weeks and no later than 
12 weeks after the last dose of chemotherapy. 
 
9.2.2 Patients not receiving chemotherapy 
Hormonal therapy may be initiated before, during, or after completion of AHF-
RT at the discretion of the investigator. 
 
9.3 Trastuzumab 
Trastuzumab is permitted at the investigator's discretion for patients whose tumors are HER2-
positive. The timing and other treatment logistics are also at the investigator's discretion.  
Concurrent use with AHF-RT is permitted. 
 
 
10.0 DIAGNOSIS OF BREAST CANCER EVENTS 
 
The diagnosis of a first breast cancer recurrence or second primary cancer can be made only when 
both the clinical and laboratory findings meet "acceptable" criteria as defined below. All 
documentation will be performed using Form F.  Suspicious findings do not constitute criteria for 
breast cancer recurrence, nor are they an indication to alter protocol therapy. The listing below is 
offered as a guide. 
 
Treatment of a breast cancer recurrence or second primary cancer will be at the discretion of the 
investigator. 
 
Patients will be followed beyond the diagnosis of contralateral breast and non-breast second 
primary cancers for the subsequent occurrence of IBTRs. 
 
 
10.1 Ipsilateral in-breast recurrence 
 
Defined as evidence of invasive or in situ breast cancer (except LCIS) in the ipsilateral breast. 
Patients who develop clinical evidence of tumor recurrence in the remainder of the ipsilateral 
breast must have a biopsy of the suspicious lesion to confirm the diagnosis with documentation of 
the location. 
 
Acceptable: positive histologic biopsy (positive cytology is not acceptable) 
 
10.2 Local chest wall recurrence 
 
Defined as evidence of invasive or in situ breast cancer (except LCIS) in the ipsilateral chest wall. 
Patients who develop clinical evidence of tumor recurrence in the ipsilateral chest wall must have 
a biopsy of the suspicious lesion to confirm the diagnosis. 
 
Acceptable: positive histologic biopsy (positive cytology is not acceptable) 
 
10.3 Regional recurrence 
 
Defined as the development of tumor in the ipsilateral internal mammary, ipsilateral 
supraclavicular, ipsilateral infraclavicular and/or ipsilateral axillary nodes, as well as the soft 
tissue of the ipsilateral axilla, after operation. 

28 | P a g e  
 
 
Acceptable: positive cytology or histologic biopsy 
 
10.4 Distant recurrence 
 
Defined as evidence of tumor in any area of the body, with the exception of those described in 
Sections 10.1 and 10.2. 
 
Acceptable: positive cytology, histologic biopsy, or clear and convincing radiologic evidence of 
metastatic disease. 
 
10.5 Second primary breast cancer 
Defined as evidence of invasive or in situ breast cancer (except LCIS) in the contralateral breast 
or chest wall. The diagnosis of a second primary cancer must be confirmed histologically. 
Acceptable: positive histologic biopsy 
 
10.6 Second primary cancer (non-breast) 
 
Any non-breast second primary cancer other than squamous or basal cell carcinoma of the skin, 
melanoma in situ, or carcinoma in situ of the cervix will be reported on Form F. The diagnosis of 
a second primary cancer must be confirmed histologically whenever possible. 
 
10.7 Documentation requested following death 
 
Autopsy reports should be secured whenever possible and should be submitted into the medical 
record. A copy of the death certificate should be submitted into the medical record if it is readily 
available or if it contains important cause-of-death information not documented elsewhere. A 
physician's note summarizing the death will suffice if the aforementioned are not obtainable. 
 
 
11.0 ADVERSE EVENT REPORTING REQUIREMENTS 
 
Please refer to Appendix C "Information Basics for Adverse Event Reporting" for general 
information required for adverse event reporting. 
 
11.1 Definitions for adverse event reporting 
 
Study therapy: In this study, therapy is AHF-RT. 
 
11.2 Adverse event assessment 
 
The NCI’s Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 must be 
used to identify the type and to grade the severity of the adverse events in this study. 
 
11.2.1 Pregnancy occurring while patient is on study therapy 
 
If a patient becomes pregnant while receiving study therapy, notify the PI or any 
Co-Investigators immediately. 
 
11.2.2 Other recipients of adverse event reports 
 

29 | P a g e  
 
Adverse events determined to be reportable must also be reported by the 
investigator to the Institutional Review Board responsible for oversight of the 
patient according to the local policy and procedures. 
 
11.3 Routine reporting of adverse events 
Routine reporting includes adverse events for which expedited reporting was required, as well as 
those events that do not require expedited reporting. All adverse events must be reported on Form  
 
AE (Adverse Event Form) as described below and according to instructions on the Form AE. 
 
11.3.1 Reporting on Form AE 
 
Report all grade 1, 2, 3, 4, and 5 adverse events resulting from AHF-RT. 
 
The following adverse events do not require routine reporting on Form AE: 
adverse events resulting from chemotherapy, hormonal therapy, or any other 
systemic cancer therapy, adverse events which occur after breast cancer 
recurrence or development of a second primary cancer 
 
11.3.2 Submission of Form AE 
 
For patients who receive radiotherapy (RT) without chemotherapy, submit 
Form AE according to the following schedule or until the time of breast cancer 
recurrence or second primary cancer: 
 
− At the end of RT 
− 4 weeks from end of RT 
− 6 months from end of RT 
− 12 months from end of RT and every 12 months thereafter 
 
For patients who receive radiotherapy and chemotherapy, submit Form AE 
according to the following schedule or until the time of breast cancer recurrence 
or second primary cancer: 
 
− At the end of RT 
− 4 weeks from end of RT and chemotherapy 
− 6 months from end of RT and chemotherapy 
− 12 months from end of RT and chemotherapy and every 12 months thereafter 
 
11.4 Reporting on follow-up Form F 
 
Report breast cancer recurrence and all second primary malignancies on followup form (Form F). 
Submit supporting documentation that confirms the breast cancer recurrence or second primary 
cancer diagnosis. 
 
 
12.0 PATIENT ENTRY AND WITHDRAWAL PROCEDURES 
 
12.1 Patient entry and consent form 
Patents considered for this trial must conform to all eligibility and ineligibility criteria outlined in 
Section 5.0.  Before the patient is entered, the consent form (see Appendix F), including any 

30 | P a g e  
 
addenda, must be signed and dated by the patient and the person who explains the study to that 
patient. 
 
12.1.1 Patient study number 
After all of the faxed eligibility criteria have been completed, the institution will assign 
the patient an individual, coded study number. 
 
 
12.2 Patient-initiated discontinuation of study therapy 
Even after a patient agrees to take part in this study, she may stop study therapy or withdraw from 
the study at any time. If she stops study therapy but still allows the study doctor to follow her 
care, she should continue to be followed according to the study schedule and should be 
encouraged to continue the QOL/cosmesis assessments on schedule. Alternatively, she may 
choose to have no further interaction regarding the study. In this case, the investigator must 
provide the clinical trials office writtendocumentation of the patient’s decision to fully withdraw 
from the study. 
 
12.3 Investigator-initiated discontinuation of study therapy 
In addition to the conditions outlined in the protocol, the investigator may require a patient to 
discontinue study therapy if one of the following occurs: 
 
• 
The patient develops a serious side effect that she cannot tolerate or that cannot be 
controlled with medications, 
• 
The patient’s health gets worse, 
• 
The patient is unable to meet the study requirements, or 
• 
New information about other treatments for breast cancer becomes available. 
 
If study therapy is stopped but she still allows the study doctor to follow her care, she should 
continue to be followed according to the study schedule. Patients should be encouraged to 
complete the QOL/cosmesis assessments on schedule unless they have a second primary cancer 
or a breast cancer recurrence. 
 
 
13.0 STATISTICAL CONSIDERATIONS 
 
13.1 End-Point Definitions 
 
• Primary endpoint: The primary endpoint for analysis is diagnosis of in-breast 
tumor recurrence (IBTR) as a first event. Regional and distant failures and death 
prior to IBTR will be treated as competing risks when calculating the frequency, 
crude hazard and cumulative incidence of IBTR. Contralateral breast and non-
breast second primary cancers will not be considered to be competing risks, i.e. 
patients will be followed beyond the diagnosis of contralateral breast and non-
breast second primary cancers for the subsequent occurrence of IBTRs. Both 
invasive and non-invasive IBTRs are considered in calculating the primary 
endpoint. 
 
• Secondary endpoints: Secondary endpoints include distant disease-free interval, 
recurrence-free survival, and overall survival (S). Distant disease-free interval is 

31 | P a g e  
 
defined to be the time of enrollment to first diagnosis of distant disease, regardless 
of the occurrence of any intervening local or regional failure, contralateral breast 
cancer, or non-breast second primaries. Recurrence-free survival is defined as the 
time from enrollment to first diagnosis of a local, regional, or distant recurrence, 
regardless of any intervening contralateral or other second primary cancer. 
Overall survival is based on deaths due to all causes. Quality of life endpoints 
include cosmesis, breast-related symptoms, fatigue, and perceived convenience of 
care. 
 
13.2 Sample Size 
 
There is no concrete data from this center to support the sample size justification based 
on efficacy of this treatment combination and low dose involved field RT. Table 2, lists 
some similar studies. When combined IBTR and LRR, the recurrence rate is around 6% 
with an approximate 95% confidence interval of (0-0.12), which is very wide due to 
small sample size.  We justify the sample size using the precision analysis approach 
(Chow et al., 2008, chapter 1.3). Due to limited resources we plan to enroll about 250 
subjects, with n=250 and at alpha=5%, we will have a precision of about 12%.  
 
13.3 Accrual 
 
We estimate that accrual rate will be 60 patients annually. Given the current accrual rate, 
the study will need approximately 4-year accrual with 1-year follow-up. All patients will 
be followed after the closure of the study to accrual.   
 
13.4 Statistical Analysis 
 
Descriptive statistics related to patient characteristics, treatment, and prognostic factors 
will be produced. The Kaplan-Meier method will be used to estimate the overall survival 
(OS), disease-free survival (DFS), and cumulative incidence (CI) in the absence of 
competing risk for the entire cohort and for subgroups of patients. Survival differences 
will be compared using the un-weighted log-rank test. The OS time will be determined as 
the time from enrollment on protocol until death or last follow-up evaluation. DFS will 
be defined as the time from enrollment on protocol until the first adverse event (i.e., 
disease progression, relapse, second malignancy, or death due to any cause).  The time to 
local failure will be defined as the time from enrollment on protocol until local 
recurrence, either with or without simultaneous distant recurrence and with other events 
(only distant failure, death, second malignancy), classified as competing risks. To 
investigate the independent prognostic significance of pretreatment factors, we will 
conduct a multivariable analysis using the Cox regression method.   
 
The CI of local failure will be estimated and effects of prognostic factors will be 
estimated. Effect of competing risk (distant failure, second malignancy and death) will be 
taken into account.  
 
Descriptive statistics will be provided regarding incidence rates of toxicity.  Presence of 
grade 3 or 4 toxicity will be modeled using logistic regression to identify key risk factors.  

32 | P a g e  
 
 
We will explore relationship between quality of life measures and demographic and 
treatment related covariates using regression (linear or logistic) models for repeated 
data47. Multiple correlation structures will be explored for modeling the correlation 
among repeated measurements on the same subject. The most common structure is a first-
order autoregressive correlation structure, which specifies decreased correlation for 
observations taken further apart in time, with a random subject effect. Since the QOL 
measures are based on questionnaire data (summing the countable numbers), the 
normality assumptions may not be valid for some measures. In such cases, we will 
perform analyses on the logit transformed data, provided normality assumption is 
accepted48. If normality is rejected after logit transformation as well, we will use non-
parametric regression which is based on ranks.  
 
All calculations will be performed with SAS statistical software (SAS Institute Inc., Cary, 
NC). Analyses for specific aims are outlined below. 
 
13.5 Data Safety Monitoring Board 
 
The protocol progress will be reviewed and monitored by the BCC Data Safety 
Monitoring Board (DSMB). Data summaries will be provided by the Biostatistics Office 
after review by the Principal Investigator (PI). The data will include patient accrual, 
demographic summaries, grade 3/4 toxicities, major adverse events (i.e., deaths, relapses, 
second malignancies), and results of interim and final analyses of various endpoints as 
specified in the protocol. The PI, in conjunction with the CRAs, will inform the 
biostatistician when the appropriate number of patients has been evaluated; this event will 
thereby trigger interim or final analysis. The first report will be provided to the DSMB 
after all the patients enrolled during the first 6 months of the trial have completed 
chemotherapy. At the DSMB meeting to review the protocol data, the PI and appropriate 
co-Investigators will meet with the DSMB to discuss any relevant issues with the DSMB. 
The DSMB’s report summarizing their evaluation of the data will be simultaneously 
forwarded to the PI, the IRB, and the chief medical officer (CMO). If the investigators 
disagree with the evaluation, a rebuttal will be made within 10 days to the DSMB, and a 
copy of the rebuttal will be sent to the IRB and the CMO. The PI will inform the chair of 
the IRB and the CMO if a rebuttal will be made so that the IRB can decide whether to 
postpone review of the protocol until the rebuttal has been received. If no excessive, 
unexpected events are observed during the first 6 months of the trial, subsequent reports 
to the DSMB will be made every 6 months or annually (as deemed appropriate by the 
DSMB) according to the schedule of the DSMB. The reports to the DSMB may not 
necessarily coincide with the continuing review reports submitted to the IRB. 
 
13.6 Monitoring Rule 
 
Safety monitoring of outcome is intended to identify significant deviations from expected 
results sufficiently early in the clinical trial to reduce the number of patients exposed to 
ineffective therapy. If the observed 3-year cumulative IBTR for falls above 12 % margin, 
we will consider early closure of enrollment. This monitoring rule will serve as a 
guideline for decisions regarding early stopping of the protocol. 

33 | P a g e  
 
 
13.7 Missing Observations 
  
Most of the missing data will be related to QOL measures. In the following, we consider some 
special cases of missing observations. There are two primary mechanisms through which missing 
data may arise in the present study: 1) patients and their parents were unavailable due to various 
reasons and therefore did not complete assessments, or 2) patient deaths. In the event that data on 
some subjects are missing at some time points, the entire subject history is not excluded from the 
analysis; the following steps will be taken: 
 
• 
If independent variables are missing, but the corresponding dependent variable is 
present, we will do multiple imputations for the missing values in order to simplify 
the analysis.  
 
• 
If the dependent variable is partially missing (i.e., follow-up data are available at 
some time points) and the missing mechanism is random, the entire subject history is 
not excluded from the analysis (using the Mixed Procedure in SAS), just the missing 
observations.  
 
• 
If the dependent variable is partially missing and the missing mechanism is 
nonrandom (those experienced event with compromised QOL), but depends on a 
covariate, we will include that covariate always in the model. Violations of the 
missing at random assumption may be investigated49.  
 
• 
If the dependent variable is completely missing (i.e., no follow-up data available at 
all the time points), then that subject’s data will be deleted. 
 
       When computing a total score for a scale or subscale, items missing will be handled by 
assigning the average score from that subject’s nonmissing items to the missing item(s) if the 
subject’s item missing rate is no more than 30%. When the missing rate is greater than 30%, 
the scale (or subscale) total will not be computed and will be treated as missing. 
 
 
13.8 Monitoring of adverse events 
The occurrence of adverse events, including toxicities, second primary cancers, and deaths (on 
therapy or prior to evidence of disease progression), will be monitored continuously. 
Requirements for reporting adverse events to all appropriate parties are detailed in Section 11.0. 
In addition, summaries of adverse events and toxicities will be prepared quarterly and reviewed 
by the PI, clinical trials office, and statisticians.  
 
Throughout the accrual and active treatment periods of the trial, progress reports will be prepared 
and presented to the institutional review board (IRB) at 12-month intervals. These reports will 
include an assessment of toxicities, second primary cancers and on-therapy deaths, a comparison 
of actual and projected accrual, and an assessment of data quality, including data delinquency and 
rates of eligibility. After accrual is closed, adverse events and other information will be presented 
to the IRB, together with interim analysis results. 
 
13.9 Analysis schedule 
 
 
13.9.1 Primary endpoint of ipsilateral breast tumor recurrence (IBTR)  

34 | P a g e  
 
The first interim analysis of the primary endpoint will take place after 3 years or 150 
patients have been accrued, whichever timepoint is reached first. Subsequent definitive 
analyses, which include estimates of overall survival, recurrence-free survival, and 
distant disease-free survival, toxicity and cosmesiswill take place approximately 5- and 
10-years following the initiation of the trial.   
 
 
13.9.2 Interim analysis of adverse events 
Interim analysis of adverse events is planned after 1.5 year or accrual of 75 patients, 
whichever timepoint is reached first.  Rates of radiation dermatitis or radiation-induced 
pain ≥ to grade 3 (CTCE v.3.0) occurring in ≥ 5% of the study population will be 
considered grounds for trial suspension and review.   
 
13.9.3 Interim analysis of quality of life (QOL)  
Interim analysis of QOL and cosmesis is planned after 2 years or accrual of 100 patients, 
whichever timepoint is reached first.   
 
13.9.4 Interim analysis of cost effectiveness  
Interim analysis of QOL and cosmesis is planned after 1 year or accrual of 35 patients, 
whichever timepoint is reached first.   
 
 
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Fairclough DL, Peterson HF, Chang V. Why are missing quality of life data a 
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Amendment 1: 
 
The first analysis of the UK FAST Trial, referred to in section 2.2, above has been 
published50, and the early results show equivalent disease control among all three arms of 
the study.  The only difference in toxicity was with regard to cosmetic appearance of the 
breast whish was slightly, but statistically improved among patients who received 28.5 
Gy vs. those who received 30 Gy in 5 weekly fractions. These results were updated and 
presented at the 2012 San Antonio Breast Cancer Symposium, December 4-8, 2012. As a 
result, this amendment is being made to allow the PI to use 28.5Gy in 5 fractions as an 
acceptable choice for radiation total dose on this trial. Appropriate changes were made 
where applicable in the body of the protocol.    
 

 
A Phase II Study of Accelerated Hypofractionated Radiotherapy (AHF-
RT) after Breast Conserving Surgery (BCS) in Medically Underserved 
Patients. 
 
 
APPENDIX A 
 
TNM NOMENCLATURE AND STAGING FOR BREAST CANCER 
(Based on AJCC Staging Manual, 7th ed. 2010) 
 
 
Primary Tumor (T) 
• 
TX Primary tumor cannot be assessed 
• 
T0 No evidence of primary tumor 
• 
Tis Carcinoma in situ 
o 
Tis (DCIS) Ductal carcinoma in situ 
o 
Tis (LCIS) Lobular carcinoma in situ 
o 
Tis (Paget’s) Paget’s disease of the nipple NOT associated with invasive carcinoma 
and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma. 
Carcinomas in the breast parenchyma associated with Paget’s disease are categorized 
based on the size and characteristics of the parenchymal disease, although the 
presence of Paget’s disease should still be noted. 
• 
T1 Tumor ≤ 20 mm in greatest dimension 
o 
T1mi Tumor ≤ 1 mm in greatest dimension 
o 
T1a Tumor >1 mm but ≤ 5 mm in greatest dimension 
o 
T1b Tumor >5 mm but ≤ 10 mm in greatest dimension 
o 
T1c Tumor >10 mm but ≤ 20 mm in greatest dimension 
• 
T2 Tumor >20 mm but ≤ 50 mm in greatest dimension 
• 
T3 Tumor >50 mm in greatest dimension 
• 
T4 Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or 
skin nodules). Note: Invasion of the dermis alone does not qualify as T4 
o 
T4a Extension to the chest wall, not including only pectoralis muscle 
adherence/invasion 
o 
T4b Ulceration and/or ipsilateral satellite nodules and/or edema (including peau 
d’orange) of the skin, which do not meet the criteria for inflammatory carcinoma 
o 
T4c Both T4a and T4b 
o T4d Inflammatory carcinoma. Note: Inflammatory carinoma is a clinicopathologic 
entity characterized by diffuse erythema and edema (peau d'orange) of the breast, 
often without an underlying palpable mass. These clinical findings should 
involve the majority of the skin of the breast. It is important to remember that 
inflammatory carcinoma is primarily a clinical diagnosis. Involvement of the 
dermal lymphatics alone does not indicate inflammatory carcinoma in the 
absence of clinicalfindings. In addition to the clinical picture, however, a biopsy 
is still necessary to demonstrate cancer either within the dermal lymphatics or in 
breast parenchyma itself. 
 
Regional Lymph Nodes (N) Clinical 
• 
NX Regional lymph nodes cannot be assessed (e.g., previously removed) 
• 
N0 No regional lymph node metastases 

• 
N1 Metastases to movable ipsilateral level I, II axillary lymph node(s) 
• 
N2 Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; 
or inclinically detected * ipsilateral internal mammary nodes in the absence of clinically 
evident axillary lymph node metastases 
o 
N2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another 
(matted) or to other structures 
o 
N2b Metastases only in clinically detected * ipsilateral internal mammary nodes and 
in the absence of clinically evident level I, II axillary lymph node metastases 
• 
N3 Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without 
level I, II axillary lymph node involvement; or in clinically detected *ipsilateral internal 
mammary lymph node(s) with clinically evident level I, II axillary lymph node metastases; or 
metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal 
mammary lymph node involvement 
o 
N3a Metastases in ipsilateral infraclavicular lymph node(s) 
o 
N3b Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph 
node(s) 
o N3c Metastases in ipsilateral supraclavicular lymph node(s) 
* Note : Clinically detected is defi ned as detected by imaging studies (excluding lymphoscintigraphy) or 
by clinical examination and having characteristics highly suspicious for malignancy or a presumed 
pathologic macrometastasis based on fi ne needle aspiration biopsy with cytologic examination. 
 
Regional Lymph Nodes (N) Pathologic (pN)*
• 
pNX Regional lymph nodes cannot be assessed (e.g., previously removed, or not removed for 
pathologic study) 
• 
pN0 No regional lymph node metastasis identified histologically 
Note : Isolated tumor cell clusters (ITC) are defined as small clusters of cells not greater than 
0.2 mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-
section. ITCs may be detected by routine histology or by immunohistochemical (IHC) 
methods. Nodes containing only ITCs are excluded from the total positive node count for 
purposes of N classification but should be included in the total number of nodes evaluated. 
o 
pN0(i−) No regional lymph node metastases histologically, negative IHC 
o 
pN0(i+) Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected 
by H&E or IHC including ITC) 
o 
pN0 (mol−) No regional lymph node metastases histologically, negative molecular 
findings (RT-PCR) 
o 
pN0 (mol+) Positive molecular fi ndings (RT-PCR), ** but no regional lymph node 
metastases detected by histology or IHC 
• 
pN1 Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or in internal 
mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically 
detected *** 
o 
pN1mi Micrometastases (greater than 0.2 mm and/ or more than 200 cells, but none 
greater than 2.0 mm) 
o 
pN1a Metastases in 1–3 axillary lymph nodes, at least one metastasis greater than 2.0 
mm 
o 
pN1b Metastases in internal mammary nodes with micrometastases or 
macrometastases detected by sentinel lymph node biopsy but not clinically detected 
*** 
o pN1c Metastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes 
with micrometastases or macrometastases detected by sentinel lymph node biopsy 
but not clinically detected 
• 
pN2 Metastases in 4–9 axillary lymph nodes; or in clinically detected **** internal mammary 
lymph nodes in the absence of axillary lymph node metastases 

o 
pN2a Metastases in 4–9 axillary lymph nodes (at least one tumor deposit greater than 
2.0 mm) 
o 
pN2b Metastases in clinically detected **** internal mammary lymph nodes in the 
absence of axillary lymph node metastases 
• 
pN3 Metastases in ten or more axillary lymph nodes; or in infraclavicular (level III axillary) 
lymph nodes; or in clinically detected **** ipsilateral internal mammary lymph nodes in the 
presence of one or more positive level I, II axillary lymph nodes; or in more than three 
axillary lymph nodes and in internal mammary lymph nodes with micrometastases or 
macrometastases detected by sentinel lymph node biopsy but not clinically detected *** ; or 
in ipsilateral supraclavicular lymph nodes 
o 
pN3a Metastases in ten or more axillary lymph nodes (at least one tumor deposit 
greater than 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) 
nodes 
o 
pN3b Metastases in clinically detected **** ipsilateral internal mammary lymph 
nodes in the presence of one or more positive axillary lymph nodes; or in more than 
three axillary lymph nodes and in internal mammary lymph nodes with 
micrometastases or macrometastases detected by sentinel lymph node biopsy but not 
clinically detected *** 
o pN3c Metastases in ipsilateral supraclavicular lymph nodes 
Notes: * Classification is based on axillary lymph node dissection with or without sentinel lymph node 
biopsy. Classification based solely on sentinel lymph node biopsy without subsequent axillary lymph node 
dissection is designated (sn) for“sentinel node,” for example, pN0(sn). ** RT-PCR: reverse 
transcriptase/polymerase chain reaction. *** “Not clinically detected” is defined as not detected by imaging 
studies (excluding lymphoscintigraphy) or not detected by clinical examination. **** “Clinically detected” 
is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and 
having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based 
on fine needle aspiration biopsy with cytologic examination. 
 
ANATOMIC STAGE/PROGNOSTIC GROUPS 
• 
Stage 0   
Tis  
N0  
M0 
• 
Stage IA  
T1*  
N0  
M0 
• 
Stage IB  
T0  
N1mi  M0 
T1*  
N1mi  M0 
• 
Stage IIA  
T0  
N1**  M0 
T1*  
N1**  M0 
T2  
N0  
M0 
• 
Stage IIB  
T2  
N1  
M0 
T3  
N0  
M0 
• 
Stage IIIA  
T0  
N2  
M0 
T1*  
N2  
M0 
T2  
N2  
M0 
T3  
N1  
M0 
T3  
N2  
M0 
• 
Stage IIIB  
T4  
N0  
M0 
T4  
N1  
M0 
T4  
N2  
M0 
• 
Stage IIIC  
Any T  N3  
M0 
• 
Stage IV  
Any T  Any N  M1 
Notes: * T1 includes T1mi. ** T0 and T1 tumors with nodal micrometastases only are excluded from Stage 
IIA and are classified Stage IB. 
 
 

 
A Phase II Study of Accelerated Hypofractionated Radiotherapy (AHF-
RT) after Breast Conserving Surgery (BCS) in Medically Underserved 
Patients. 
 
 
APPENDIX B 
 
DETERMINATION OF MENOPAUSAL STATUS 
 
Menopausal Status Determination 
 
The following criteria will be used to define postmenopausal: 
• 
A prior documented bilateral oophorectomy, or 
• 
A history of at least 12 months without spontaneous menstrual bleeding, or 
• 
Age 55 or older with a prior hysterectomy, or 
• 
Age 54 or younger with a prior hysterectomy without oophorectomy (or in whom the 
status of the ovaries is unknown), with a documented FSH level demonstrating 
confirmatory elevation in the lab’s postmenopausal range. 
 
Women failing to meet one of these criteria will be classified as pre-menopausal. 

 
A Phase II Study of Accelerated Hypofractionated Radiotherapy (AHF-RT) 
after Breast Conserving Surgery (BCS) in Medically Underserved Patients. 
 
 
APPENDIX C 
 
INFORMATION BASICS FOR ADVERSE EVENT REPORTING 
 
1.0 PURPOSE 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in the future studies 
using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial.  
 
2.0 DEFINITIONS FOR ADVERSE EVENT REPORTING 
 
2.1 Study therapy 
Study therapy is the required treatment or procedure(s) as defined by the protocol. 
 
2.2 Non-protocol therapy 
For the purpose of adverse event reporting, non-protocol therapy is defined as any treatment or procedure 
which is described in the protocol as either optional or prohibited. 
 
2.3 Adverse event assessment 
Reporting requirements are determined by the assessment of the following adverse event characteristics: 
the type or nature of the event; the grade (severity); the relationship to the study therapy (attribution); 
prior experience (expectedness) of the adverse event; and whether the patient has received an 
investigational or commercial agent or both. The recommended assessment steps include: 
• 
Identify the type of event using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0. The CTCAE provides descriptive terminology and a grading scale for each 
adverse event listed. A copy of the CTCAE can be downloaded from the CTEP home page 
(http://ctep.cancer.gov).  
• 
Grade the severity of the adverse event using the NCI CTCAE Version 3.0. 
• 
Determine whether the adverse event is related to the study therapy. Attribution categories are as 
follows: Unrelated, Unlikely, Possible, Probable, and Definite. 
• 
Determine the prior experience of the adverse event. Expected events are those that have been 
previously identified as resulting from either whole breast radiation therapy or partial breast 
irradiation. For expedited reporting purposes, an adverse event is considered unexpected when 
either the type of event or the severity of the event is not listed in the protocol consent. 
 
3.0 PROTECTING PATIENT CONFIDENTIALITY 
Remove patient names and identifiers such as social security number, address, telephone number, etc. 
from reports and supporting documentation. All telephone calls and written reports must reference the 
protocol number, and the patient's study number. 
 

 
A Phase II Study of Accelerated Hypofractionated Radiotherapy (AHF-
RT) after Breast Conserving Surgery (BCS) in Medically Underserved 
Patients. 
 
Form A1  
 
CHECKLIST FOR PATIENT ELIGIBILITY AND INELIGIBILITY  
 
 
Conditions for patient eligibility (must satisfy all of the following conditions):  
 
________(Y) The patient must consent to be in the study and must have signed an 
approved consent form conforming with federal and institutional guidelines. 
 
________(Y) Patients must be > 18 years old. 
 
________(Y) The patient must have stage 0, I, or II breast cancer.  
 
________(Y) On histological examination, the tumor must be DCIS or invasive 
adenocarcinoma of the breast. 
 
________(Y) Surgical treatment of the breast must have been lumpectomy. The margins 
of the resected specimen must be histologically free of tumor.  
 
________(Y) Gross disease may be unifocal or multifocal with pathologic (invasive 
and/or DCIS) tumor size excised with negative margins. 
 
________(Y/N) Patients with invasive breast cancer are required to have axillary staging 
Axillary staging is not required for patients with DCIS. 
 
________(Y) The patient must begin adjuvant therapy (chemotherapy or radiotherapy) 
within 42 days following the last surgery for breast cancer (lumpectomy, re-excision of 
margins, or axillary staging procedure). 
 
________(Y) Patients must have all usual and customary hormone receptor (ER/PR) an 
estrogen receptor (ER) analysis performed on the primary tumor prior to enrollment  
 
________(Y) At the time of enrollment, patients must have had an H&P within 4 months 
and a bilateral mammogram within 6 months. 
 
________(Y/N) Patients must live in a county that is designated as Appalachian and/or 
rural by Kentucky Cancer Registry Criteria and/or ________(Y/N) must hold their 
primary residence ≥ 10 miles from the nearest radiation facility (distance:_________).   
 
________(Y/N) Patients who do not fit these criteria may still be considered eligible if 
they are determined to suffer significant financial and/or transportation hardship during a 
typical course of CF-RT or HF-RT, in the judgment of any of their treating physicians 
(Reason Specification Required: ______________________________ _______).  

 
CHECKLIST FOR PATIENT ELIGIBILITY AND INELIGIBILITY (FORM A1) 
(CONTINUED) 
 
Conditions for patient ineligibility (men are not eligible/ women with one or more of the 
following conditions also are ineligible). 
 
________(N) T3, stage III, or stage IV breast cancer.  
 
________(N) More than 3 histologically positive axillary nodes. 
 
________(N) Axillary nodes with definite evidence of microscopic or macroscopic 
extracapsular extension. 
 
________(N) One or more positive non-axillary sentinel node(s). (Note that 
intramammary nodes are staged as axillary nodes.) 
 
________(N) Palpable or radiographically suspicious ipsilateral or contralateral axillary, 
supraclavicular, infraclavicular, or internal mammary nodes, unless there is 
histologic confirmation that these nodes are negative for tumor. 
 
________(N) Suspicious microcalcifications, densities, or palpable abnormalities (in the 
ipsilateral or contralateral breast) unless biopsied and found to be benign. 
 
________(N) Non-epithelial breast malignancies such as sarcoma or lymphoma. 
 
________(N) Proven multicentric carcinoma (invasive cancer or DCIS) in more than one 
quadrant or separated by 4 or more centimeters. 
 
________(N) Paget's disease of the nipple. 
 
________(N) Synchronous bilateral invasive or non-invasive breast cancer. 
 
________(N) History of invasive breast cancer or DCIS. (Patients with a history of LCIS 
treated by surgery alone are eligible.) 
 
________(N) Surgical margins that cannot be microscopically assessed or are positive at 
pathologic evaluation. (If surgical margins are rendered free of disease by reexcision, 
the patient is eligible.) 
 
________(N) Treatment plan that includes regional nodal irradiation. 
 
________(N) Current therapy with any hormonal agents such as raloxifene (Evista®), 
tamoxifen, or other selective estrogen receptor modulators (SERMs), either for 
osteoporosis or breast cancer prevention. (Patients are eligible only if these 
medications are discontinued prior to enrollment.) 
 
 
 
 

CHECKLIST FOR PATIENT ELIGIBILITY AND INELIGIBILITY (FORM A1) 
(CONTINUED) 
 
 
________(N) Cosmetic breast implants. (Patients who have had implants removed are 
eligible.) 
 
________(N) Prior breast or thoracic RT for any condition. 
 
________(N) Collagen vascular disease, specifically dermatomyositis with a CPK level 
above normal or with an active skin rash, systemic lupus erythematosis, or scleroderma. 
 
________(N) Pregnancy or lactation at the time of proposed randomization. Women of 
reproductive potential must agree to use an effective non-hormonal method of 
contraception during therapy. 
 
________(N) Psychiatric or addictive disorders or other conditions that, in the opinion of 
the investigator, would preclude the patient from meeting the study requirements. 
 
 
 
 
 
 
__________________________________________ 
Signature of Individual Completing this Form 
 
 
 
 
__________________________________________ 
Signature of PI 
 
 
 
__________________________________________ 
Date 
 
 
 

 
A Phase II Study of Accelerated Hypofractionated Radiotherapy (AHF-
RT) after Breast Conserving Surgery (BCS) in Medically Underserved 
Patients. 
FORM AE 
 
ADVERSE EVENT FORM FOR RADIATION THERAPY  
If patient started radiation therapy (RT), use Form AE to report adverse events that are possibly, 
probably, or definitely related to RT. If patient did not start RT, do not submit Form AE. 
 
Instructions for completing this form: 
• Form AE collects only adverse events that are possibly, probably, or definitely 
related to Accelerated Hypofractionated Radiation Therapy (AHF-RT)), 
regardless of whether these adverse events are expected or unexpected. Do not 
report adverse events resulting from chemotherapy, hormonal therapy or any 
other systemic cancer therapy. 
• Complete Form AE at the end of each Reporting Period, as defined on page 1 of 
form. The Reporting Period Start Date should not lapse or overlap with the 
Reporting Period End Date of the prior Form AE. If the patient has a breast 
cancer recurrence or second primary cancer, please use the date of the cancer 
event as the reporting period end date and submit the form. No additional AE 
forms will be required for this patient. 
• Use NCI Common Terminology Criteria for Adverse Events (CTCAE) 
Version 3.0 to report all grade 1,2, 3, 4 and 5 adverse events.  Access the 
CTCAE v3.0 by going to the NCI/CTEP web site at http://ctep.cancer.gov. 
• When the adverse event is listed on page 2 of the form, circle the highest grade 
that occurred during this reporting period. 
• When the adverse event is not listed on page 2, write the specified information in 
the table provided at the bottom of page 2. It is very important that the exact 
wording of each CTCAE v3.0 Short Name and each CTACE v3.0 “Select 
Term” (when applicable) be used when reporting adverse events. Please do not 
omit words or abbreviate terms that are spelled out in the CTCAE, Version 3.0. 
• Submit pages 1 and 2 of Form AE at the end of each reporting period, as defined 
on page 1 of form. Please do not submit this instruction page. 
 
Supporting Documentation for Form AE 
• Include supporting documentation for all grade 3, 4 and 5 adverse events (AEs)  
If the patient was hospitalized for 24 hours or more, include supporting 
documentation (e.g., H&P, hospital discharge summary, pertinent laboratory and 
radiology reports, consults, physician progress notes). 
• 
Remove patient names and identifiers such as social security number, address, 
telephone number, etc. from supporting documentation. Each page of supporting 
documentation and all written reports must reference the patient’s protocol study 
number. 
 
 

 
 
 
A Phase II Study of Accelerated Hypofractionated Radiotherapy (AHF-
RT) after Breast Conserving Surgery (BCS) in Medically Underserved 
Patients. 
 
ADVERSE EVENT FORM FOR RADIATION THERAPY (FORM AE) 
If patient started radiation therapy (RT), use Form AE to report adverse events that are possibly, 
probably, or definitely related to RT. If patient did not start RT, do not submit Form AE. 
 
Patient Initials:___________  
 
 
Protocol ID #:__________________ 
 
 
 
 
 
 
 
 
 
 

A Phase II Study of Accelerated Hypofractionated Radiotherapy (AHF-
RT) after Breast Conserving Surgery (BCS) in Medically Underserved 
Patients. 
 
ADVERSE EVENT FORM FOR RADIATION THERAPY (FORM AE) 
(CONTINUED) 
 
Patient Initials:___________  
 
 
Protocol ID #:__________________ 
 
 
 
 
 
 

 
A P h ase II St u d y of Acceler ate d H y p ofr acti o n ate d R a di ot her a p y ( A H F-
R T) after Bre ast C o nser vi n g S ur ger y  ( B C S) i n Me dic all y U n derser ve d 
P atie nts. 
F O R M B E  
 
B C T O S P A TI E N T B R E A S T  E V A L U A TI O N F O R M 
 
Patie nt I nitials: _ _ _ _ _ _ _  
Pr ot oc ol I D #: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _       Date: _ _ _ _ _ _ _ _ _ _ 
 
Assess me nt P oi nt:      
 Baseli ne       6 M o nt hs       1 year       
 3 years 
 
 
 
 

A P h ase II St u d y of Acceler ate d H y p ofr acti o n ate d R a di ot her a p y ( A H F-
R T) after Bre ast C o nser vi n g S ur ger y  ( B C S) i n Me dic all y U n derser ve d 
P atie nts. 
F O R M C E  
 
C O S M E SI S P H Y SI CI A N E V A L U A TI O N F O R M  
 
Patie nt I nitials: _ _ _ _ _ _ _ _ _ _ _    
  
  
Pr ot oc ol I D #: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Pers o n C o m pleti n g F or m: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Assess me nt P oi nt:      
 Baseli ne       6 M o nt hs       1 year       
 3 years  
 
 
 
 

 
A Phase II Study of Accelerated Hypofractionated Radiotherapy (AHF-
RT) after Breast Conserving Surgery (BCS) in Medically Underserved 
Patients. 
FORM F 
 
FOLLOW UP EVALUATION FORM  
 
Patient Initials:_______ 
Protocol ID #:________________       Date:__________ 
 
Interval since completion of XRT: ______________________  
 
 
 

A Phase II Study of Accelerated Hypofractionated Radiotherapy (AHF-
RT) after Breast Conserving Surgery (BCS) in Medically Underserved 
Patients. 
 
FOLLOW UP EVALUATION FORM (FORM F) 
(CONTINUED) 
 
 
 
 


EORTC QLQ - BR23


Patients sometimes report that they have the following symptoms or problems. Please indicate the extent
to which you have experienced these symptoms or problems during the past week.
During the past week:
Not at
A
Quite
Very
All
Little
a Bit
Much
31.
Did you have a dry mouth?
1
2
3
4
32.
Did food and drink taste different than usual?
1
2
3
4
33.
Were your eyes painful, irritated or watery?
1
2
3
4
34.
Have you lost any hair?
1
2
3
4
35.
Answer this question only if you had any hair loss:
Were you upset by the loss of your hair?
1
2
3
4
36.
Did you feel ill or unwell?
1
2
3
4
37.
Did you have hot flushes?
1
2
3
4
38.
Did you have headaches?
1
2
3
4
39.
Have you felt physically less attractive
as a result of your disease or treatment?
1
2
3
4
40.
Have you been feeling less feminine as a
result of your disease or treatment?
1
2
3
4
41.
Did you find it difficult to look at yourself naked?
1
2
3
4
42.
Have you been dissatisfied with your body?
1
2
3
4
43.
Were you worried about your health in the future?
1
2
3
4
During the past four weeks:
Not at
A
Quite
Very
All
Little
a Bit
Much
44.
To what extent were you interested in sex?
1
2
3
4
45.
To what extent were you sexually active?
(with or without intercourse)
1
2
3
4
46.
Answer this question only if you have been sexually
active: To what extent was sex enjoyable for you?
1
2
3
4
Please go on to the next page


During the past week:
Not at
A
Quite
Very
All
Little
a Bit
Much
47.
Did you have any pain in your arm or shoulder?
1
2
3
4
48.
Did you have a swollen arm or hand?
1
2
3
4
49.
Was it difficult to raise your arm or to move
it sideways?
1
2
3
4
50.
Have you had any pain in the area of your
affected breast?
1
2
3
4
51.
Was the area of your affected breast swollen?
1
2
3
4
52.
Was the area of your affected breast oversensitive?
1
2
3
4
53.
Have you had skin problems on or in the area of
your affected breast (e.g., itchy, dry, flaky)?
1
2
3
4
©Copyright 1994 EORTC Study Group on Quality of Life. All rights reserved. Version 1.0