Impact of Breast Conservation Surgery on Surgical Outcomes and Cosmesis in Patients With Multiple Ipsilateral Breast Cancers (MIBC)
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Alliance for Clinical Trials in Oncology

 
1 
 
Update #08 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
 
PROTOCOL UPDATE TO ALLIANCE Z11102 
_________________________________________ 
 
Impact of Breast Conservation Surgery on Surgical Outcomes and Cosmesis in Patients with 
Multiple Ipsilateral Breast Cancers (MIBC) 
 
Clinicaltrials.gov identifier: NCT01556243 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
 
Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
X Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
 
Other : 
 
 
 
 
Expedited review is allowed. IRB approval (or disapproval) is required within 90 days. Please follow 
your IRB of record guidelines.  
 
UPDATES TO PROTOCOL: 
 
Cover page (page 1): 
The study document history table has been removed. This table now appears as a separate document on 
the protocol landing page, on the member side of the Alliance website. 
 
CTSU Contact Information (page 3): 
The CTSU Contact Information Table has been updated with the current CTSU boilerplate language. 
 
Protocol Resources (page 4): 
-Laura Hoffman has replaced Heather Becker as Protocol Coordinator. All contact information has been 
updated. 
-Tiffany Winter’s last name has been updated to Bainter in her name and email address. 
- In the table entitled “Protocol-related questions may be directed as follows,” the contact name and email 
address for questions regarding CTEP-AERS reporting has been updated from Regulatory Affairs 
Manager to Alliance Pharmacovigilance Inbox and from 
to 
 respectively. The phone number previously listed for the 
Regulatory Affairs Manager has been removed as all questions should be submitted via email. 

 
2 
 
Section 6.1 CTEP Investigator Registration Procedures (page 23): 
This section has been retitled “CTEP Registration Procedures” and updated with the current CTSU 
boilerplate language. 
 
Section 6.2 CTEP Associate Registration Procedures (page 24): 
This section has been removed as it is now encompassed within Section 6.1. 
 
Section 6.3 CTSU Site Registration Procedures (page 26): 
This section has been renamed “CTSU Registration Procedures” and renumbered as Section 6.2. It has 
been updated with the current CTSU boilerplate language. All subsequent sections have been 
renumbered. 
 
Section 6.3.3 Submitting Regulatory Documents (page 25): 
This section has been renumbered as Section 6.2.3. The suite number in the CTSU mailing address has 
been changed to “3000.” 
 
Section 10.0 Adverse Event (AE) Reporting and Monitoring (page 40): 
All references to “AdEERS” have been replaced with “CTEP-AERS” due to the new CTEP expedited 
reporting requirements. 
 
Section 10.1 Adverse Event Characteristics (page 40): 
-After the first sentence, a second sentence has been added due to the change in CTCAE version for 
reporting serious adverse events. 
-The “4.0” in the third sentence has been changed to “5.0” with regards to the new CTCAE version 
number used for expedited adverse event reporting. 
-The last four sentences have been added to describe the use of CTEP-AERS. 
 
Section 10.11 Adverse Event Monitoring, Data Collection and Reporting (page 40): 
-In the fourth sentence of the second paragraph, AdEERS has been replaced with the CTEP-AERS for 
expedited adverse event reports. 
-In the fifth sentence, the phrase “using CTCAE version 5.0” has been added due to the change in 
CTCAE version requirements for expedited reporting. 
 
Section 10.33 Death (page 42): 
-The first four bullets have been deleted. 
-The now first bullet point has been replaced with updated CTCAE version 5.0 language. 
-Three more bullet points have been added to the end of the section to reflect updated reporting 
requirements for pregnancy loss and neonatal death in CTCAE version 5.0. 
 
Section 10.34 Secondary Malignancy (page 43): 
This section has been replaced in its entirety with the updated CTEP-AERS reporting requirements. 
 
Section 10.4 Expedited Reporting Requirements: Studies Using Commercial Agent(s) ONLY (page 
44): 
-The sentence beginning with “Refer to 10.41…” under the chart has been removed due to the removal of 
the 10.41 contact table. 
-The sentence beginning with “in the rare event…” has been replaced with a new sentence with updated 
CTEP contact information. 
 
Section 10.41 (Contact Information for NCI Safety Reporting): 
This section has been removed as safety reporting is now done through CTEP-AERS (website URL listed 

 
3 
 
previously). 
 
Section 16.64 Adverse Events (page 59): 
A second sentence has been added to reflect the updated requirement to use CTCAE version 5.0 for 
expedited adverse event reporting. 
 
UPDATES TO THE MODEL CONSENT FORM: 
 
No updates have been made to the model consent form. 
 
 
 
A replacement protocol document has been issued. 
 
This study remains closed to new patient accrual. 
____________________________________________________________ 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
____________________________________________________________ 

 
1 
Version Date: 09/11/2018 
 
Update #08 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
Z11102: Impact of Breast Conservation Surgery on Surgical Outcomes and Cosmesis in Patients 
with Multiple Ipsilateral Breast Cancers (MIBC) 
 
 
For any communications regarding this protocol, 
please call the protocol resource person on the following page. 
 
ClinicalTrials.gov Identifier: NCT01556243 
 
Study Chairs: 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
*Investigator having NCI responsibility for this protocol 
 
 
 
Study Participants 
Date Activated 
Alliance/Alliance for Clincal Trials in Oncology (lead)  
July 23, 2012 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
November 12, 2012 
NRG/NRG Oncology 
November 12, 2012 
SWOG/SWOG 
November 12, 2012 
 
 

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Update #08 
Study Staff 
 
Study Statistician 
  
 
 
 
 
 
Study Co-Chairs 
Radiation Oncology 
 
 
 
 
Radiation Oncology 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Radiation Oncology 
 
 
 
 
Radiology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Sciences 
 
 
 
 
 
 
 
 
 
 
 
√Study contributor(s) not responsible for patient care.

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Update #08 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory 
requirements: 
For patient enrollments:  
Submit study data: 
Regulatory 
documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
 
Regulatory Submission 
Portal (Sign in at 
and select the 
Regulatory Submission sub-
tab under the Regulatory 
tab.)  
 
Institutions 
with 
patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 
to 
receive 
further 
instruction and support. 
 
Contact the CTSU 
Regulatory Help Desk at 
for regulatory 
assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
 
 
 
Data collection for this study will be 
done exclusively through Medidata 
Rave.  Please see the data submission 
section of the protocol for further 
instructions. 
 
Do not submit study Data or forms to 
CTSU Data Operation. Do not copy the 
CTSU on data submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member website located at 
 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with CTEP-
IAM username and password. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the CTSU RSS. 
For clinical questions (i.e. patient eligibility or treatment-related) see the Protocol Contacts, Page 
4. 
For non-clinical questions (i.e. unrelated to patient eligibility, clinical treatment, or data 
submission contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 
All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU website is located at 
 
 
 

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Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*; test schedule; 
treatment delays, interruptions or 
adjustments; dose modifications;  
adverse events; forms completion and 
submission 
 
  
Nursing guidelines 
 
 
 
 
 
  
Protocol document; consent form; 
regulatory issues 
  
  
 
Radiation quality control  
 
 
 
 
 
 
 
Adverse events (CTEP-AERS; 
MedWatch; Non-AER and AML/MDS) 
 
 
Tissue Specimens/Central Specimen 
Bank 
 
 
 
 
 
  
 
*No waivers of eligibility per NCI 

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Table of Contents 
Z11102: Impact of Breast Conservation Surgery on Surgical Outcomes and Cosmesis in Patients 
with Multiple Ipsilateral Breast Cancers (MIBC) ............................................................................ 1 
1.0 
Background ...................................................................................................................................... 8 
1.1 
Introduction ......................................................................................................................... 8 
1.2 
Current Study Rationale .................................................................................................... 11 
2.0 
Goals .............................................................................................................................................. 14 
2.1 
Primary Clinical Goal ....................................................................................................... 14 
2.2 
Secondary Clinical Goals .................................................................................................. 14 
2.3 
Correlative Goals .............................................................................................................. 15 
3.0 
Patient Eligibility ........................................................................................................................... 15 
3.1 
Registration Inclusion Criteria .......................................................................................... 15 
3.2 
Registration Exclusion Criteria ......................................................................................... 17 
4.0 
Test Schedule ................................................................................................................................. 20 
4.1 
Test Schedule for Patients Registered Prior to Surgery .............................................. 20 
5.0 
Stratification Factors/Grouping Factor .......................................................................................... 23 
6.0  
Registration Procedures ................................................................................................................. 23 
6.1 
CTEP Investigator Registration Procedures ..................................................................... 23 
6.2 
CTSU Site Registration Procedures .................................................................................. 24 
6.3 
Patient Registration Requirements .................................................................................... 26 
6.4 
Patient Registration Procedures ........................................................................................ 26 
6.5 
Registration to Correlative and Companion Studies ......................................................... 27 
6.6 
Treating Physician and Site .............................................................................................. 27 
6.7 
Start of Study Participation ............................................................................................... 27 
6.7a 
Surgery .............................................................................................................................. 27 
6.7b 
Completion of Tests and Procedures ................................................................................ 27 
6.7c 
Grading of Baseline Symptoms ........................................................................................ 27 
6.7d 
Confirmation of Eligibility ............................................................................................... 27 
6.7e 
Questionnaire Booklets Availability ................................................................................. 28 
7.0 
Protocol Treatment......................................................................................................................... 28 
7.1 
Preoperative Evaluation Imaging ...................................................................................... 28 
7.2 
Surgery .............................................................................................................................. 30 
7.3 
Pathology .......................................................................................................................... 31 
7.4 
Cosmesis ........................................................................................................................... 31 
7.5 
Adjuvant Therapy ............................................................................................................. 32 
7.6 
Adjuvant Whole Breast Irradiation (WBI) ....................................................................... 32 
7.7 
Patient Follow-up After Completion of WBI ................................................................... 39 
8.0 
Dosage Modification Based on Adverse Events ............................................................................ 39 
8.1 
No Expected Adverse Events............................................................................................ 39 
8.2 
Dose Modifications as per Standard Institutional Practice ............................................... 39 
8.3 
Table of Modification of WBI Schedule Based on Adverse Events ................................. 40 
9.0 
Ancillary Treatment/Supportive Care ............................................................................................ 40 
10.0 
Adverse Event (AE) Reporting and Monitoring ............................................................................ 40 
10.1 
Adverse Event Characteristics .......................................................................................... 40 
10.2 
Expected vs. Unexpected .................................................................................................. 41 
10.3 
Assessment of Attribution ................................................................................................ 41 
10.4  
Expedited Reporting Requirements: Studies using Commercial Agent(s) ONLY: .......... 44 
10.5 
Other Required Expedited Reporting ................................................................................ 45 
11.0 
Diagnosis of Breast Cancer Recurrence and Other Cancer Events ................................................ 46 
11.1  
Local Recurrence .............................................................................................................. 47 
11.2  
Regional Recurrence ......................................................................................................... 47 

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11.3  
Distant Recurrence ............................................................................................................ 47 
11.4  
Second Primary Breast Cancer ......................................................................................... 47 
11.5  
Second Primary Cancer (Non-breast) ............................................................................... 47 
11.6  
Death ................................................................................................................................. 47 
12.0 
Descriptive Factors ........................................................................................................................ 47 
12.1 
Menopausal Status ............................................................................................................ 47 
12.2 
Time of Registration: Pre-surgery vs Post-surgery ........................................................... 47 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................... 48 
13.1 
Follow-Up After Completion of WBI ............................................................................... 48 
13.2 
Conditions Requiring Study Termination ......................................................................... 48 
13.3  
Discontinuation After Surgery but Prior to Completion of WBI ...................................... 48 
13.4 
Conditions Requiring Study Discontinuation ................................................................... 48 
13.5 
Definition of Ineligible ..................................................................................................... 48 
13.6 
Definition of Cancel .......................................................................................................... 49 
13.7 
Recommendations for Local Recurrence .......................................................................... 49 
14.0 
Biospecimen Submission ............................................................................................................... 49 
14.1 
Tissue and Blood Collection Requirements for Correlative Studies ................................ 49 
14.2 
Biospecimen Collections .................................................................................................. 50 
14.3 
Biospecimen Processing and Submission ......................................................................... 51 
14.4 
Biospecimen Use .............................................................................................................. 54 
14.5 
Return of Genetic Testing Research Results .................................................................... 55 
15.0 
Whole Breast Irradiation (WBI) Risks........................................................................................... 55 
15.1 
Risks and Side Effects Related to the Whole Breast Irradiation (WBI) ........................... 55 
16.0 
Statistical Considerations and Methodology.................................................................................. 56 
16.1 
Overview ........................................................................................................................... 56 
16.2  
Study Endpoints ................................................................................................................ 56 
16.3 
Sample Size Determination............................................................................................... 57 
16.4 
Accrual Time .................................................................................................................... 57 
16.5 
Study Monitoring .............................................................................................................. 57 
16.6 
Analysis Plan .................................................................................................................... 58 
16.7 
Data and Safety Monitoring .............................................................................................. 60 
16.8 
Inclusion of Women and Minorities ................................................................................. 61 
17.0  
Pathology Considerations/Tissue Biospecimens ........................................................................... 61 
18.0 
 Data Collection Procedures ........................................................................................................... 61 
18.1 
Medidata Rave .................................................................................................................. 61 
18.2 
Submission Timetable ....................................................................................................... 62 
19.0  
Budget ............................................................................................................................................ 67 
19.1 
Costs Charged to Patient ................................................................................................... 67 
19.2 
Tests to be Research Funded............................................................................................. 67 
20.0 
References ...................................................................................................................................... 67 
Appendix I: Breast Lesion Position Diagram ............................................................................................. 72 
Appendix II: Baseline Patient Questionnaire Booklet ................................................................................ 74 
Appendix III: Patient Information Brochure ............................................................................................... 76 
Appendix IV : Active Monitoring Patient Questionnaire Booklet .............................................................. 77 
Appendix V: Surgeon Questionnaire Booklet ............................................................................................ 84 
 
 
 

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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R
E
G
I 
S
T
R
A
T 
I
O
N
* 
 
Breast Conservation Surgery 
Lumpectomy with nodal staging 
Radiation Therapy 
Whole breast irradiation (WBI); Regional nodal irradiation at MD discretion 
Patients receiving chemotherapy will have radiation therapy within 8 weeks 
following the last dose of chemotherapy. 
Patients not receiving chemotherapy will have radiation therapy within 10 
weeks following surgery. 
 
Observation 
Every 6 months until 5 years after the end of WBI 
Pre-op 
Post-op 
* Registration can occur prior to surgery OR after surgery (either before or after adjuvant chemotherapy). 
Registration must occur prior to radiation therapy. 
 
OR
Adjuvant Chemotherapy at the physician’s 
discretion. Patients receiving chemotherapy will 
start treatment within 12 weeks following surgery. 
 
Endocrine Therapy at the physician’s discretion 
 

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1.0 
Background 
 
1.1 
Introduction 
Over 207,090 women are diagnosed with invasive breast cancer in the United States each 
year (Jemal et al., 2010). An additional 52,000 are diagnosed with ductal carcinoma in 
situ (DCIS) (American Cancer Society statistics). Of women newly diagnosed with breast 
cancer, studies have reported that between 14 and 51 percent will undergo preoperative 
MRI (Arrington et al., 2009; Jones et al., 2009; Sorbero et al., 2009; Wood, 2009). In an 
era of increasing breast MRI usage and improved radiographic imaging modalities, the 
incidence of preoperatively identified multiple ipsilateral primary breast cancers (MIBC) 
including multicentric (MC) and/or multifocal (MF) breast cancer is increasing 
(Bendifallah et al., 2010; Berg and Gilbreath, 2000; Berg et al., 2011; Houssami et al., 
2008; Moon et al., 2002; Wilkinson et al., 2005). Data show that MRI is more accurate 
than mammography alone in detection of MIBC. A meta-analysis performed in 2008 
demonstrated that MRI identified additional tumor foci in 16 % of newly diagnosed 
breast cancer patients (Houssami et al., 2008).  Increased utilization of bilateral whole 
breast sonography in women with a new breast cancer diagnosis has also led to increasing 
detection of MIBC (Wilkinson et al., 2005). Other novel imaging modalities, for example 
positive emission mammography (PEM), breast specific gamma imaging (BSGI) and 
Molecular Breast Imaging (MBI), may continue to increase the detection of MIBC. A 
PEM/MRI study reported 14 % of patients enrolled were converted to mastectomy based 
on findings from these novel images (Berg and Gilbreath, 2000).  
 
The prevalence of MIBC ranges across studies from 13 to 75 % but the true incidence is 
difficult to ascertain given the varying definitions of multifocal and multicentric used 
between studies (Bendifallah et al., 2010).  Classically, multifocal disease is defined as 
two or more foci of disease within the same quadrant of the breast and multicentric 
disease as two or more foci of disease in different quadrants of the breast. Differentiating 
between multifocal and multicentric tumors by the use of quadrants of the breast is not 
related to tumor biology and is somewhat arbitrary. A tumor at 11 o’clock can be 2 cm 
away from a tumor at the 1 o’clock position and these would be classified as multicentric, 
whereas 2 tumors both at the 2 o’clock position that are 5 cm apart may be classified as 
multifocal. This issue is more pronounced closer to the nipple, where the distance 
between quadrants is smaller than in the periphery of the breast. The true biologic 
question is whether women with more than one focus of breast cancer can undergo breast 
conservation with minimal morbidity and whether local recurrence is equivalent to 
women with unifocal disease. Therefore, for this study we use the term MIBC defined as 
two or more foci of biopsy proven breast cancer separated by at least 2 cm of normal 
breast tissue. 
 
Studies have confirmed that the rate of mastectomy is increasing in the United States 
(Katipamula et al., 2009; McGuire et al., 2009). This may be linked to several factors 
including use of pre-operative MRI and of the resulting increase in detection of MIBC 
(Bedrosian et al., 2003; Bleicher et al., 2009; Fischer et al., 1999; Lee et al., 2004; 
Morrow and Harris, 209; Touttle et al., 2007). Based on historic, retrospective studies 
from the late 1980s and early 1990s (Kurtz et al., 1990; Leopold et al., 1989; Wilson et 
al., 1993), most surgeons are reluctant to proceed with breast conservation therapy (BCT) 
for women with multicentric or multifocal breast cancer due to a perceived high risk of 
local recurrence (LR). However, no scientific evidence exists to support this increased 
mastectomy rate in MIBC patients (Fisher, 2011). The emotional impact of mastectomy 
on body image and quality of life is well documented (Fung et al., 2001; Kiebert et al., 

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Update #08 
1991); Zhao et al., 2003). The emotional benefit of breast conservation has driven 
surgeons in the United States and Europe to recommend breast conservation to over 50 % 
of women with a single, early stage malignant focus for three decades (Hershman et al., 
2009; Komenaka et al., 2010). BCT is associated with improved patient satisfaction and 
quality of life and has been shown to be cost effective (Al-Ghazal et al., 2000; Barlow et 
al., 2001; Norum et al., 1997)  
 
Retrospective studies from the 1980s and early 1990s demonstrated an increased risk of 
local regional recurrence in women with two or more synchronous lesions in the breast in 
comparison to women with unifocal cancers treated with breast conservation. However, 
imaging was less advanced and the margins in the older trial were assessed grossly rather 
than microscopically (Cho et al., 2002; Kaplan et al., 2003; Kurtz et al., 1990; Leopold et 
al., 1989; Wilson et al., 1993) 
 
In contrast, none of the retrospective studies published since 1993 have reported a 
significant increase in local recurrence rates in women with multicentric/multifocal breast 
cancer who have been treated with BCT (see Table 1.1) (Cho et al., 2002; Gentilini et al., 
Hartsell et al., Kaplan et al., 2003; Lim et al., 2009). Multiple, recent retrospective 
studies support the safety of breast conservation in women with MIBC and confirm a rate 
of recurrence that is comparable to rates observed in women with unifocal disease 
(Bauman et al., 2010; Cho et al., 2002; Gentilini et al., 2009; Hartsell et al., 1994). The 
largest of these contemporary trials, by Gentilini et al., reviewed 476 patients with 
multicentric (12 %) and multifocal (88 %) invasive breast cancer treated between 1997 
and 2002. All patients underwent BCT. Despite significant nodal disease in the study 
population (55 % of all patients), the local recurrence rate in this trial was 5.1 % at 5 
years (Gentilini et al., 2009).  In this study, 98.3 % of the patients received adjuvant 
systemic therapy with 12.6 % receiving adjuvant chemotherapy alone, 40.1 % hormonal 
therapy alone, and 45.6 % both chemotherapy and endocrine therapy. Adjuvant whole 
breast radiation was delivered to 95 %.  Also of interest, a retrospective study of women 
with MIBC treated with neoadjuvant chemotherapy has documented 5 year locoregional 
failure rates of 7 % in patients with MIBC (Oh et al., 2006) .

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Table 1.1.  Recurrence Rates in Multicentric/Multifocal Breast Cancer by Study 
 
Primary 
Author of 
Study 
Surgical 
years 
Number of 
Patients 
(n) 
Median 
Follow-up 
(months) 
Number of 
Recurrences 
Outcome 
 
Leopold 
1968–1981 
10 
64 
4 
NA 
 
Kurtz 
1975-1983 
61 
71 
15 
NA 
Wilson 
Prior to 
12/1988 
13 
71 
3 
6 year LRR:  
25 % 
 
Fowble 
1982-1989 
57 
48 
NA 
5 year LRR:  
8 % 
 
Hartsell 
1977-1989 
27 
53 
1 
NA 
 
Cho 
1989-1997 
15 
76 
0 
NA 
 
Kaplan 
1989-2002 
36 
45 
1 
NA 
Gentilini 
1977-2002 
476 
73 
24 
Cumulative 
incidence  
recurrence at  
5 years: 5.1 % 
Lim 
1990-2003 
147 
59 
3 
5 year 
locoregional 
recurrence rate: 
4.7 % 
Table adapted from Bauman et al., 2010. 
 
 
MIBC today includes patients with 2 small foci of disease detected on screening digital 
mammogram and/or MRI compared to decades ago when MIBC often referred to a 
palpable mass. Introduction of routine screening mammography and increased patient 
awareness has led to identification of breast cancer when tumors are smaller in size and 
early stage breast cancer has better survival compared to more advanced disease. 
Therefore, more MIBC patients today are eligible for BCT at time of diagnosis due to the 
smaller tumor size and disease burden, as compared to the 1980s and 1990s when most 
women with MIBC presented with larger, palpable tumors. Moreover, in women with 
newly diagnosed breast cancer who undergo MRI for surgical planning, additional 
malignant lesions which alter the surgical plan (multicentric/multifocal lesions) are 
detected in 8 to 27 % of patients. This makes it important for us to reassess the 
indications for BCT versus mastectomy in women with MIBC in 2012. 
 
The European Breast Cancer Conference (EBCC) has recommended standard 
preoperative breast MRI in all women with newly diagnosed breast cancer given the 
significant number of additional multicentric/multifocal cancers identified using this 
modality (6th European Breast Cancer Conference, Berlin, Germany, 15-19 April 2008). 
In the United States, the role of preoperative breast MRI remains more controversial and 
as such it is difficult, therefore, to determine how many centers are utilizing routine 
preoperative MRI. Using a conservative rough estimate of 30% of breast centers utilizing 

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routine breast MRI (the average of 14 to 51 % documented in the literature (Arrington et 
al., 2009; Sorbero et al., 2009)  we would expect over 55,000 women with breast cancer 
to undergo breast MRI for surgical planning. Currently, meta-analysis suggests a 16 % 
incidence of identification of a second primary in the ipsilateral breast following a cancer 
diagnosis with further work-up after detection of the initial tumor (Houssami et al., 
2008). Given the older retrospective case studies in the literature, the majority of 
surgeons continue to recommend mastectomy for women with multicentric breast cancer 
and many with multifocal breast cancer. Based on estimates above, over 17,000 women 
per year will be triaged to mastectomy based on current algorithms.  
 
1.2 
Current Study Rationale 
 
1.21 
Study Design 
While these retrospective data from the modern era described above are 
encouraging, the safety of BCT in MIBC has not been documented in a 
prospective fashion. A multicenter study with a uniform and consistent follow-up 
schedule, defined criteria for recurrence, and strict statistical analysis is necessary 
to definitively ascertain the safety of breast conservation in the MIBC population. 
Although an ideal trial design would be a randomized study comparing BCT with 
mastectomy for women with MIBC, this is felt not to be feasible due to 
increasing appreciation for shared decision making in the breast cancer 
population. Discussion with American College of Surgeons Oncology Group 
(ACOSOG) breast investigators, patient advocates and the Breast Oncology 
Local Disease (BOLD) taskforce have all indicated that a randomized trial design 
would not be well supported by patients or physicians. Both patient and surgeon 
bias would negatively impact timely patient accrual. Therefore, a prospective 
single arm Phase II trial to address the incidence of local recurrence in women 
undergoing breast conservation surgery and radiation therapy for MIBC is 
proposed. 
 
1.22 
Prognosis 
Controversy exists surrounding the prognosis and treatment of MIBC. No 
prospective trial has addressed this issue. Limited retrospective data debunk the 
notion that MIBC is an independent risk factor for worsened overall survival 
(Bendifallah et al., 2010; Pederson et al., 2004). A study by Nos et al. reviewed 
56 women treated with BCT for MIBC in comparison with 132 women who 
underwent mastectomy for MIBC. In this retrospective study, no differences in 
overall survival or local recurrence were detected. Similarly, a study by Oh et al. 
reviewed this question in a population of women with clinically detected MIBC 
treated with neoadjuvant chemotherapy. This study of 706 women treated with 
mastectomy, mastectomy and adjuvant radiation or breast conservation for MIBC 
concluded that MIBC does not predict for inferior outcome (Oh et al., 2006).  
 
1.23 
Tumor Heterogeneity 
This trial may also have timely and important translational science implications. 
Interest in cancer stem cells and tumor heterogeneity is increasing and a better 
understanding of these concepts may lead to novel diagnostic, therapeutic and 

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Update #08 
preventive strategies. As has been described in hematologic malignancies, human 
breast cancers are heterogeneous, both in their pathology and in their molecular 
profiles (Hwang-Verslues et al., 2009; Shipitsin et al., 2007) This heterogeneity 
may be the result of cancer stem cells/progenitor cells which are capable of 
differentiation along divergent pathways (Nakshatri et al., 2009) Heterogeneity 
exists both within and between breast cancers. The intrinsic heterogeneity in the 
MIBC population provides an in vivo platform to better understand the variation 
within individual tumors in a given patient but more importantly, between 2 or 
more tumors in a given patient. This may expand the growing body of knowledge 
regarding causation of breast cancer, treatments and prognosis. 
 
In an era of individualized medicine, further understanding of the biology of 
MIBC is required. We have increased understanding of cancer tumor cells and 
tumor heterogenicity. For women with more than one tumor, understanding 
whether these tumors are the same or different is important to guide therapy and 
the correlative science section of this study (see Section 14.0) will evaluate the 
similarities and differences of multiple foci of disease within the breast. 
 
1.24 
Cosmesis 
 
1.241 4-point Scoring System of Breast Cosmesis (Winchester and Cox, 1992) 
A single item question will be administered asking both the patient and 
her surgeon to assess the overall cosmetic result (excellent, good, fair, 
and poor) (Olivotto et al., 1989; Winchester and Cox, 1992). This 
questionnaire is also being used in the trial NSABP B-39. Olivotto et al. 
also used this single item questionnaire to assess technical factors 
impacting whether a patient considered the cosmesis a failure following 
BCT. In general, patients with a fair or poor score are considered to be a 
cosmetic “failure”.  Olivotto et al. demonstrated that cosmetic scores for 
patients classified as excellent or good cosmetic score remained 
consistent after 3, 5, and 7 years in 88 %, 90%, and 78 % of the patients, 
respectively. 
 
1.242 BREAST-Q  
The BREAST-Q, a patient-reported outcome (PRO) instrument for 
breast surgery patients, was recently developed to address the lack of 
instruments to measure outcome in the breast surgical population (Pusic 
et al., 2009). The questionnaire was developed with strict adherence to 
guidelines recommended by the Scientific Advisory Committee of the 
Medical Outcomes Trust and the US Food and Drug Administration 
(Lohr, 2002; USDHHS, FDA, CDER, CBER and CDRH (2009). This 
process included development of a conceptual framework, item 
generation, scale formation with item reduction, and psychometric 
evaluation. At present, the BREAST-Q contains three modules (post 
mastectomy reconstruction, breast reduction and breast augmentation), 
each with a preoperative and postoperative version. Each module 
includes six independent scales (satisfaction with breasts, satisfaction 
with overall outcome, psychosocial well-being, sexual well-being, 
physical well-being and satisfaction with care). Psychometric evaluation 

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suggests that it exceeds criteria for rigorous measurement as established 
by quality of life researchers and government regulatory bodies 
internationally. More specifically, each scale fulfilled both Rasch and 
traditional psychometric criteria (including person separation index 0.76 
to 0.95; Cronbach's alpha 0.81 to 0.96; and test-retest reproducibility 
0.73 to 0.96). The Breast Q was developed using patient interviews, 
focus groups, expert panels, and a literature review to develop a 
conceptual framework and a list of questionnaire items. 
 
Current efforts are now underway to develop a fourth module of the 
BREAST-Q (the ‘Breast-conserving therapy (BCT)’ module) to 
specifically evaluate quality of life in breast cancer patients who undergo 
BCT. The addition of this new module will allow meaningful 
comparisons of groups of patients who elect to undergo BCT, 
mastectomy, or mastectomy with reconstruction. Preliminary versions of 
the scale have been developed from three sources: review of the 
literature; qualitative interviews with patients; and expert opinion. Semi-
structured, open-ended interviews (n = 30) were recorded, transcribed 
and analyzed for content. Standard qualitative techniques were then used 
to identify key domains or themes that emerge. Questionnaire items were 
developed to reflect these domains and were phrased to reflect 
terminology and statements typically used by patients. The preliminary 
measure was then pre-tested in a small sample of patients (n = 20) to 
clarify ambiguities in the wording of items, and determine acceptability 
and completion time (personal communication).  
 
Field-testing of this preliminary instrument is now underway (personal 
communication). Using Rasch analysis, seven measurement criteria will 
be examined as follows: clinical meaning, thresholds for item response 
options, item fit statistics, item locations, differential item functioning, 
correlations between standardized residuals, and person separation index. 
The aim will be for each scale to consist of a set of clinically meaningful 
items that satisfy requirements for measurement. This goal will be 
achieved by choosing a set of items hypothesized to constitute a scale for 
each area, analyzing the observed data against measurement criteria and 
making decisions on item selection or deletion. Following item 
reduction, confirmatory tests on the resultant questionnaire will be 
performed using traditional psychometric methods in order to enable 
comparison with existing breast scales and meet regulatory requirements.  
To this end, five measurement properties will be examined: data quality, 
tests of scaling assumptions, acceptability, reliability, and 
responsiveness. 
 
In this study, we will use the independent scales for satisfaction with 
breasts and satisfaction with overall outcome from the Breast Q BCT 
module. Although the final version of the BCT module is still being 
finalized, the individual questions will not change and no questions will 
be added, therefore using these questions will enable calculation of a 
score once the Breast Q BCT scoring is complete.  
 
1.243 Breast Lymphedema (BLE) Symptom Survey (Degnim et al., 2008). 

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Lymphedema in the ipsilateral arm is a well-recognized complication 
following breast/axillary surgery, but can also occur in the breast after 
surgery. We have previously evaluated clinical and surgical factors 
associated with the development of postoperative breast lymphedema 
(BLE); yet, BLE diagnosis is currently non-standardized and is based on 
clinical impression.   
 
Previously, we prospectively evaluated patients undergoing non-
mastectomy procedures for signs and symptoms of lymphedema in the 
operated breast. BLE diagnosis was based on a graded physical exam 
targeting clinical signs of diffuse skin edema, erythema, and their 
location. Diagnosis was independent of patient reported symptoms. 
Additionally, patients also rated symptoms in their operated breast for 
heaviness, discomfort, redness, visible swelling and associated degree of 
distress using a 10-point scale (“not at all” = 0 to “a lot” = 10). In 
subjects with clinical BLE, skin edema and breast erythema were 
observed in 26/26 (100 %) and 13/26 (50 %), respectively, compared to 
5/38 (13 %) and 4/38 (11 %) without clinical BLE, respectively. BLE 
was observed in more than one quadrant for the majority of patients with 
BLE (skin edema 18/26 = 69 %, and erythema 10/13 = 77 %).  
Additionally, BLE patients had significantly higher scores for breast 
heaviness, discomfort, redness, and swelling and distress associated with 
these symptoms was significantly elevated only for symptoms of breast 
heaviness (mean 3.4 vs. 1.0, p = 0.01) and discomfort (mean 2.9 vs. 1.4, 
p = 0.03). 
 
Patients undergoing lumpectomy for MIBC and breast radiation with 
boost to both tumor beds are hypothetically at increased risk of BLE. We 
will evaluate the incidence of BLE and symptoms as diagnosed using 
clinical examination along with the same questionnaire used in the 
previous study to see if BLE is more common in women treated with 
BCT for MIBC than reported in our previous BLE study evaluating 
patients undergoing lumpectomy and radiation for unifocal breast cancer. 
 
1.25 
Linear Analogue Self-Assessment (LASA) 
Both fatigue and overall perception of quality of life will be assessed using 
LASA. Evidence has arisen indicating that baseline single-item assessments of 
fatigue and overall quality of life are strong prognostic indicators for survival in 
cancer patients, independent of performance status (Sloan et al., 2009;  Tan et al., 
2008). 
 
2.0 
Goals 
 
2.1 
Primary Clinical Goal 
To assess the local recurrence (LR) rate with breast conservation in patients with multiple 
ipsilateral primary breast cancer (MIBC). 
 
2.2 
Secondary Clinical Goals 
 

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2.21 
Conversion Rate to Mastectomy 
To examine the conversion rate to mastectomy secondary to persistent positive 
margins; poor cosmesis within the first year of attempting breast conservation 
surgery (BCS) or inability to satisfy the radiation dose constraints on the boost to 
the lumpectomy bed of each site of disease. 
 
2.22 
Analysis of Patients Without Negative Margins 
To assess whether patients who did not undergo re-excision for close margins (< 
2 mm) have a higher local recurrence (LR) rate than patients for whom negative 
margins were achieved. 
 
2.23 
Patient’s Perception of Cosmesis 
To assess patient’s perception of cosmesis and incidence of breast lymphedema. 
 
2.24 
Incidence of Breast Lymphedema 
To assess incidence of breast lymphedema. 
 
2.25 
Adverse Effects of Breast Conserving Surgery 
To examine the type and severity of adverse effects of breast conserving surgery 
and radiation for women with multiple ipsilateral primary breast cancer (MIBC). 
 
2.26 
Adverse Effects of Whole Breast Irradiation  
To examine the radiation-related side effects of whole breast radiation with a 
boost to 1 large or > 1 lumpectomy site. 
 
2.3 
Correlative Goals 
 
2.31 
Comparison of Tissue Protein and Gene Expression Patterns 
To evaluate protein and gene expression patterns in tissue taken from each breast 
lesion and to evaluate the concordance of the findings between these lesions. 
 
2.32 
Comparison of Imaging and Surgical Findings 
To compare the extent of disease described on imaging (mammography, bilateral 
breast MRI and other adjunctive imaging modalities) with surgical findings. 
 
3.0 
Patient Eligibility 
 
3.1 
Registration Inclusion Criteria 
 
3.11 
Age 
Age ≥ 40 years per National Comprehensive Cancer Network (NCCN) 
recommendations for breast conservation. 

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3.12 
Life Expectancy 
Life expectancy of at least 5 years, excluding diagnosis of breast cancer 
(Comorbid conditions should be taken into consideration, but breast cancer 
diagnosis is not a consideration)  
 
3.13 
Female Gender 
Men are excluded from this study. Male breast cancer is a rare event; men are 
rarely candidates for breast conservation surgery due to small breast size. Men 
are less likely to be candidates for breast conservation surgery if found to have 
MIBC. 
 
3.14 
Foci of Breast Cancer 
Upon clinical exam and pre-operative imaging by mammogram +/- MRI, two or 
three foci of biopsy proven breast cancer separated by > 2 cm of normal breast 
tissue.  
Foci must include at least one focus of invasive breast carcinoma with another 
focus of either invasive breast carcinoma or ductal carcinoma in situ (DCIS). 
No more than 2 quadrants with biopsy proven breast cancer. 
Note: The shortest distance between lesions must be reported on mammogram 
+/- MRI and eligibility criteria must be met on both, if both are obtained. 
Note: Patient is eligible for study if lesion is not visualized on all imaging 
modalities (i.e., any of the lesion(s) is/are visualized on MRI but not on 
mammogram OR visualized on mammogram but not on MRI). Ultrasound 
cannot be used to determine patient eligibility; eligibility to be determined by 
bilateral mammogram +/- MRI only. Fine needle aspirate of the second or third 
lesion to document malignancy is allowed if the first focus is shown to be 
invasive by core needle biopsy. Patient may remain on study if, upon 
pathological assessment, two or three lesions identified on pre-operative imaging 
represent one contiguous lesion. 
 
3.15 
Patients may be registered AFTER surgery and PRIOR TO radiation therapy if either of the 
criteria is met: 
1. An area of atypia > 2cm from the index lesion excised at the time of cancer 
operation is upgraded to DCIS or invasive carcinoma thereby identifying 
MIBC. 
OR 
2. Patient underwent resection of two or three foci of malignancy by breast 
conservation surgery with a minimum of one invasive focus of breast cancer 
and a minimum of 2 cm of normal breast tissue between the lesions on final 
pathology.  
 
3.16 
Mammogram Imaging 
Bilateral mammogram ≤ 90 days prior to date of surgery. Note: For patients 
undergoing more than 1 breast operation, this is the date of the first breast 

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surgery for breast cancer treatment. 
 
3.17 
Staging of Cancer 
cN0 or cN1 disease  
 
3.18 
ECOG Performance Status (PS) 
PS of 0, 1, or 2.  
 Note: An ECOG PS scale is available on the CTSU website 
 
 
3.19a Ability to Complete Questionnaires 
Ability to complete questionnaire(s) by themselves or with assistance. 
 
3.19b Ability to Provide Written Informed Consent 
Ability to provide written informed consent. 
 
3.19c Willing to Return to Enrolling Institution 
Willing to return to enrolling institution for follow-up during the Active 
Monitoring Phase (the active treatment and observation portions) of the study. 
Patients are encouraged to return to the enrolling institution; however, patients 
may receive radiation therapy at a different institution other than the enrolling 
institution. Please see Section 7.6 Adjuvant Whole Breast Irradiation (WBI) for 
more information.  
 
3.2 
Registration Exclusion Criteria 
 
3.21 
Pregnancy, Nursing and Requirement for Contraception 
Any of the following because this study involves radiation therapy (WBI) that 
has known genotoxic, mutagenic and teratogenic effects: 
• 
Pregnant women 
• 
Nursing women 
• 
Women of childbearing potential who are unwilling to employ adequate 
contraception (as determined by the treating physician) 
 
3.22 
Size of Single Focus of Disease on Preoperative Imaging 
Largest single focus of disease > 5 centimeters by either mammogram or MRI or 
both. Note: Measurement of the largest single focus should include any satellite 
lesions within 1centimeter of the index lesion. 
 
3.23 
Prior Staging Procedure 
Surgical axillary staging procedure prior to first definitive breast operation.  
Note: FNA or core needle biopsy of axillary node is permitted.  

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3.24 
Evidence of Metastatic Disease 
Clinical or radiographic evidence of metastatic disease 
 
3.25 
Prior History of Breast Cancer 
Prior history of ipsilateral breast cancer [DCIS, LCIS (lobular cancer in situ) or 
invasive] 
 
3.26 
Staging of Cancer 
cNX, cN2, or cN3 disease 
 
3.27 
Breast Implants 
Breast implants at time of diagnosis.   
Note: Patients who have had implants previously removed prior to diagnosis are 
eligible. 
 
3.28 
Systemic Illnesses or Concurrent Disease 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would interfere significantly with whole breast 
irradiation (such as connective tissue disorders, lupus, scleroderma). 
 
3.29a Uncontrolled Intercurrent Illness 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
3.29b Bilateral Breast Cancer 
Prior or current LCIS, DCIS or invasive breast cancer in the opposite breast (i.e., 
bilateral disease is not allowed). 
 
3.29c Disallowed Prior Treatments 
Treatment including radiation therapy, chemotherapy, biotherapy, hormonal 
therapy for this cancer prior to surgery (i.e., any neoadjuvant chemotherapy or 
endocrine therapy is not allowed). Patients who undergo surgical resection with 
breast conservation and then are treated with adjuvant systemic therapy are 
eligible to enroll prior to the start of radiotherapy.  
 
3.29d Partial Breast Radiation 
Planned partial breast radiation. 

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3.29e Known BRCA Mutations 
Patients with known BRCA mutations. Patients who are not tested or whose 
testing result is not returned at the time of registration are not excluded from 
registering to this study. 
 
3.29f Other Active Malignancies 
Other active malignancy ≤ 5 years prior to registration. 
Exceptions: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.  
Note: If there is a history of prior malignancy, they must not be receiving other 
specific treatment for their cancer.

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4.0 
Test Schedule  
4.1 
Test Schedule for Patients Registered Prior to Surgery  
 
Tests and Procedures 
Active-Monitoring Phase 
≤ 60 days 
prior to 
registration 
At time of 
registration, 
prior to 
surgery 
 
 
Surgery6 
 
Adjuvant 
Chemotherapy11 
Radiation 
Therapy 
(WBI 
+/- RNI)13 
Observation16 
History and physical exam, including  
weight, recording of symptoms and 
medications  
X 
 
 
X 
X 
 
ECOG performance status 
X 
 
 
X12 
X14 
 
Height 
X 
 
 
 
 
 
Bilateral mammogram 
≤90 days 
 
 
 
 
X17 
Image submission to IROC Rhode Island 
(QARC) for central review (see Section 7.0) 
 
X2 
 
 
 
 
Biopsy of each suspicious breast lesion 
X 
 
 
 
 
 
Adverse event assessment 
 
 
X7 
 
X 
 
Standard Radiation Treatment Summary 
submission to IROC Rhode Island (QARC)  
(see Section 7.0) 
 
 
 
 
X15 
 
Blood samples 
 
X3 
 
 
 
 
Tissue samples 
 
 
X8 
 
 
 
Patient Information Brochures 
X1 
 
 
 
 
 
Baseline Patient Questionnaire Booklet  
(see Appendix III) 
 
X4,5 
 
 
 
 
Patient Questionnaire Booklet  
(see Appendix IV) 
 
 
X4,9 
 
X4,9 
X5,10 
Surgeon Questionnaire Booklet  
(see Appendix V) 
 
 
X4,10 
 
 
 

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Footnotes for Table 4.1 Test Schedule 
1. Patient information brochures are available to give to potential study patients. Brochures can be ordered from CTSU using the order form posted 
on the CTSU website. Note: CTSU will not send brochures until a site has submitted their IRB approval letter to the CTSU Regulatory Office. 
 
2. The required diagnostic mammograms, along with any optional additional imaging modality (such as MRI, breast ultrasound, BSGI, MBI, PEM, 
breast tomosynthesis) performed will be submitted to IROC Rhode Island (QARC) for central review. Also, send the reports to the study 
QAS/Data Manager listed on the Protocol Resources page using the Report Submission Form in Rave. Sites who are not able to scan and attach 
the reports should contact the QAS/Data Manager for further instructions. 
 
3.  For patients who consent, blood collection may be performed within 4 weeks following registration. See Section 14.0 for details. 
 
4. Questionnaire booklets must be ordered from CTSU using the order form posted on the CTSU website. Note: CTSU will not send booklets until 
a site has submitted their IRB approval excerpt to CTSU Regulatory Office.   
 
5. The baseline patient questionnaire booklet will be administered to patients at the time of registration or at any time up to surgery. 
 
6. The first surgical procedures must be performed ≤ 28 days following registration. 
 
7. Adverse events are to be recorded from the start of the first surgery to 30 days after the last surgery performed. 
 
8. For patients who consent, either paraffin-embedded OR frozen tissue will be submitted within 30 days following surgery (see Section 14.0 for 
details).  
 
9. Active Monitoring patient questionnaire booklets will be administered to patients at the following timepoints: 5 to 30 days following final 
surgery (initial post-operative visit); every six months (± 1 month) for the first 2 years following completion of WBI; then yearly (± 2 months) 
for the next 3 years. 
 
10. Surgeon questionnaire booklets will be completed by the patient’s surgeon 5 to 30 days following final surgery (initial post-operative visit) to 
assess cosmetic outcome. 
 
11. Adjuvant chemotherapy is at the discretion of the study physician and should begin within 12 weeks following surgery. 
 
12. Performance status is completed prior to the start and at the end of adjuvant chemotherapy. 
 
13. WBI is performed daily, one session every day, typically Mondays to Fridays for about 6 weeks. See Section 7.6 for details.  
 

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14. Performance status is completed prior to the start and at the end of WBI. 
 
15. The radiation plan and standard radiation treatment summary must be submitted to IROC Rhode Island (QARC) for central review. Treatment 
plan documents are available on the website at 
 
 
 
16. Observation will be every 6 months (± 1 month) for 5 years beginning at the end of WBI. 
 
17. First observation mammogram should be done at 1 year following completion of WBI, then yearly after that (i.e., at 1, 2, 3, 4 and 5 years, ± 2 
months) for a total of 5 years. 
 
4.2 
Test Schedule For Patients Registered Following Surgery 
 
Tests and Procedures 
Registration 
Adjuvant Chemo 
Radiation 
Observation7 
History and physical exam, including  
weight, recording of symptoms and 
medications  
X 
X 
 
 
ECOG performance status 
X 
X5 
 
 
Height 
X 
 
 
 
Bilateral mammogram 
≤90 days prior 
to surgery 
 
 
X8 
Image submission to IROC Rhode Island 
(QARC) (see Section 7.0) 
X1 
 
 
 
Standard Radiation Treatment Summary 
submission to IROC Rhode Island (QARC)  
(see Section 7.0) 
 
 
 
 
X6 
 
Research tissue samples 
X2 
 
 
 
Research blood samples 
X3 
 
 
 
Patient Questionnaire Booklet  
(see Appendix IV) 
 
X4 
X4 
X4 

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Footnotes for Table 4.2 Test Schedule 
1. The required diagnostic mammograms along with any optional additional imaging modality (such as 
breast ultrasound, MRI, BSGI, MBI, PEM, breast tomosynthesis) performed are required to be 
submitted. Images and reports should be sent to IROC Rhode Island (QARC) for central review. Also 
send the reports to the study QAS/Data Manager listed on the Protocol Resources page using the Report 
Submission Form in Rave. Sites who are not able to scan and attach the reports should contact the 
QAS/Data Manager for further instructions. 
 
2. For patients who consent, either paraffin-embedded OR frozen tissue will be submitted within 30 days 
of registration (see Section 14.0 for details).  
 
3. For patients who consent, a blood sample will be submitted within 30 days of registration (see Section 
14.0 for details).  
 
4. Questionnaire booklets must be ordered from CTSU using the order form posted on the CTSU website. 
Note: CTSU will not send booklets until a site has submitted their IRB approval excerpt to CTSU 
Regulatory Office.  
Patient questionnaire booklets will be administered to patients at the following 
timepoints:  
every six months (± 1 month) for the first 2 years following completion of WBI; then yearly (± 2 
months) for the next 3 years.  
 
5. Performance status is to be assessed prior to the start and at the end of adjuvant chemotherapy, and 
prior to the start and at the end of WBI. 
 
6. The radiation plan and standard radiation treatment summary must be submitted to IROC Rhode Island 
(QARC) for central review. Treatment plan documents are available on website at 
 
 
 
7. Follow-up will be every 6 months (± 1 month) for 5 years beginning at the end of WBI. 
 
8. The first follow-up mammogram should be done at 1 year following the completion of WBI, then 
yearly after that (i.e., at 1, 2, 3, 4 and 5 years, ± 2 months) for a total of 5 years. 
 
5.0 
Stratification Factors/Grouping Factor  
None. 
 
6.0  
Registration Procedures 
 
6.1 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually.  To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based Registration 
and Credential Repository (RCR) 
  Documentation 
requirements per registration type are outlined in the table below. 

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Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list 
all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow 
the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional information can be found on the CTEP website at  
  For questions, please contact the RCR Help 
Desk by email at 
 
 
6.2 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval:   
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory 
Office before they can be approved to enroll patients.  Assignment of site registration status in 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 

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• 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
6.2.1 Downloading Site Registration Documents  
Site registration forms may be downloaded from the Z11102 protocol page 
located on the CTSU members’ website. 
• 
Go to 
and log in to the members’ area using your 
CTEP-IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the Alliance link to expand, then select trial protocol # Z11102 
• 
Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided 
6.2.2 Requirements for Z11102 Site Registration  
• 
CTSU IRB Certification (for sites not participating via the NCI CIRB)  
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating 
via the NCI CIRB)  
• 
CTSU RT Facilities Inventory Form  
NOTE: Per NCI policy all institutions that participate on protocols with a radiation 
therapy component must participate in the Image and Radiation Oncology 
Core(IROC) monitoring program.  If this form has been previously submitted 
to CTSU it does not need to be resubmitted unless updates have occurred at 
the RT facility 
6.2.3 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office, where 
they will be entered and tracked in the CTSU RSS. 
 
 
 
 
 

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(For 
regulatory 
document 
submission only) 
6.2.4 Checking Your Site’s Registration Status  
Check the status of your site’s registration packets by querying the RSS site 
registration status page of the members’ section of the CTSU website.  (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU 
Regulatory Office.) 
Go to 
and log in to the members’ area using your CTEP-
IAM username and password 
Click on the Regulatory tab at the top of your screen 
Click on the Site Registration tab 
Enter your 5-character CTEP Institution Code and click on Go 
6.3 
Patient Registration Requirements 
• 
Informed consent: the patient must be aware of the neoplastic nature of his/her disease 
and willingly consent after being informed of the procedure to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, 
and discomforts. Current human protection committee approval of this protocol and a 
consent form is required prior to patient consent and registration. 
• 
Patient completed booklets: Patient questionnaire booklets are to be ordered prior to 
the registration of any patients. Patient completed booklets can be ordered by 
downloading and completing the CTSU supply request form (located under the site 
registration documents section of the Z11102 website) and faxing the form to the 
CTSU data operations center at 
Samples of the booklets are found in 
the Appendices, which are to be used for reference and IRB submission only. They are 
not to be used for patient completion. 
6.4 
Patient Registration Procedures 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account 
and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database. OPEN can be accessed at 
 or from the 
OPEN tab on the CTSU members’ side of the website at 
  
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records. 
To receive site reimbursement for specific tests and/or bio-specimen submissions, 
completion dates must be entered in the OPEN Funding screen post registration. Please 
refer to the protocol-specific funding page on the Alliance website for additional 

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information. Timely entry of completion dates is recommended as this will trigger site 
reimbursement. 
Further instructional information is provided on the OPEN tab of the CTSU members’ side 
of the CTSU website at 
  For any additional 
questions contact the CTSU Help Desk at 
 
6.5 
Registration to Correlative and Companion Studies 
6.5.1 Registration to Substudies described in Section 14.0  
There are 2 substudies within Alliance Z11102. This correlative science studies 
must be offered to all patients enrolled on Alliance Z11102 (although patients 
may opt to not participate). These substudies do not require separate IRB 
approval. The substudies included within Alliance Z11102 are: 
• 
Blood sample, (Section 14.21) 
• 
Tissue Sample, (Section 14.22) 
If a patient answers “yes” to “My samples and related information may be used 
for the additional studies described above,” Question #1 in the model consent, 
they have consented to participate in the substudy described in Section 14. The 
patient should be registered to the blood sample study at the same time they are 
registered to the treatment trial (Z11102). Blood sample should be submitted 
per Section 14.   
If a patient answers “yes” to “I agree to provide tissue sample(s) to laboratories 
associated with Alliance for research testing including genetic sequencing 
research planned as part of this study,” Question #2 in the model consent, they 
have consented to participate in the substudy described in Section 14. The 
patient should be registered to the substudy at the same time they are registered 
to the treatment trial (Z11102). Samples should be submitted per Section 14.3.   
6.6 
Treating Physician and Site 
Treatment on this protocol must commence at an Alliance or CTSU member institution 
under the supervision of an Alliance or CTSU member physician. 
 
6.7 
Start of Study Participation 
Study participation will begin either before or after surgery. If registration occurs after 
surgery patients must be registered prior to radiation therapy.  
 
6.7a 
Surgery 
Patients registered prior to surgery must have surgery ≤ 28 days after registration (see 
Section 4.0) 
 
6.7b 
Completion of Tests and Procedures 
Tests/procedures (see Section 4.0) must be completed within the guidelines specified on 
the test schedule. 
 
6.7c 
Grading of Baseline Symptoms 
All required baseline symptoms (see Section 10.51) must be documented and graded 
 
 
6.7d 
Confirmation of Eligibility 
Pre-surgery Registration: A surgeon has seen the patient and confirms the patient is a 
suitable candidate for this study. 
Post-surgery registration: A physician has seen the patient and confirms the patient is a 

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suitable candidate for this study. 
 
6.7e 
Questionnaire Booklets Availability 
Patient and surgeon questionnaire booklets are available on site; copies are not acceptable 
for this submission. 
 
 
7.0 
Protocol Treatment 
 
7.1 
Preoperative Evaluation Imaging 
All patients must have a bilateral diagnostic mammogram prior to registration on this trial 
(a bilateral breast MRI is optional). Any additional breast imaging modality (i.e., breast 
sonography, MRI, PEM, BSGI, MBI, breast tomosynthesis or other imaging modality) 
performed should also be documented and reports and images submitted to IROC Rhode 
Island (QARC). These reports should also be submitted to the study QAS/Data Manager 
listed on the Protocol Resources page using the Report Submission Form in Rave. Sites 
who are not able to scan and attach the reports should contact the QAS/Data Manager for 
further instructions. 
 
7.11 
Bilateral Mammography 
The diagnostic mammography should consist of the standard craniocaudal (CC) 
and mediolateral oblique (MLO) views. Additional spot compression views for 
mass lesion and magnification views for micro calcifications should be 
performed, as requested by the interpreting radiologist. The mammographic 
reports should follow the standardized terminology of the American College of 
Radiology Breast Imaging Reporting and Data System (BI-RADS ®), in addition 
to size measurement of the suspicious finding and its distance from the nipple 
(D’Orsi, 2003). This is part of the data collection forms (lesion size, distance 
from the nipple and o’clock position in the breast.) Digital mammography is 
preferred over conventional mammography. All diagnostic mammogram 
images, including images of the computer-aided diagnosis (CAD), and the 
reports must be submitted to IROC Rhode Island (QARC) for central review. 
These reports also should be submitted to the study QAS/Data Manager listed on 
the Protocol Resources Page using the Report Submission Form in Rave. If full 
field breast tomosynthesis is performed, then the images and report are requested 
for submission. Sites who are not able to scan and attach the reports should 
contact the QAS/Data Manager for further instructions. 
  
 
7.12 
Bilateral Breast Magnetic Resonance Imaging (Optional) 
MRI requirements described in the Clinical Imaging Guide from the American 
College of Radiology Accreditation program are highly recommended to ensure 
adequate coverage of the entire breast and axilla.  
[http://www.acr.org/accreditation/Breast-MRI/qc_forms/Clinical-Image-Quality-
Guide.aspx. Accessed November 15, 2010.]   
 
The minimum equipment requirements include: 
• 
Dedicated bilateral breast coil. 
• 
Capability of simultaneous bilateral imaging. 

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• 
Equipment to perform mammographic correlation, directed breast 
ultrasound, and MRI-guided intervention, or create a referral 
arrangement with a cooperative facility for these services.   
• 
Slide thickness of 3 millimeters or less, no gap, in-plane pixel of 1 
millimeter or less, and a dynamic series with pre-contrast T1-weighted 
images followed by at least three post-contrast T1-weight weighted 
images within 8 minutes of completion of IV contrast injection. 
 
All reporting should have final BI-RADS assessment per ACR BI-RADS-
MRI (Ikeda et al., 2003).  
 
The MR imaging protocol should contain the minimum sequences recommended 
by the American College of Radiology listed below: 
• 
T2 images with fat saturation (4-5 millimeter slice thickness), 
• 
Pre-contrast T1 gradient echo images with fat saturation  
(≤ 2 millimeter slice thickness, no gap),  
• 
Post-contrast T1 gradient echo images with fat saturation 
 (≤ 2 millimeter slice thickness, no gap) with at least two sequences with 
images obtained immediately after intravenous injection of gadolinium 
(at T0) and at 3-4 minutes after intravenous injection of gadolinium. 
 
All images including those from the use of computer-aided diagnosis (CAD), 
pharmacokinetic or other parametric mapping along with reports must be submitted 
to IROC Rhode Island (QARC) for central review. MRI reports should also be sent to 
IROC Rhode Island (QARC) and to the study QAS/Data Manager listed on the 
Protocol Resources Page using the Report Submission Form in Rave. Sites who are 
not able to scan and attach the reports should contact the QAS/Data Manager for 
further instructions. 
 
 
7.13 
Additional Imaging 
If any other imaging modality is performed (such as whole breast ultrasound, 
breast specific gamma imaging [BSGI], molecular breast imaging [MBI], 
positron emission mammography [PEM] or breast tomosynthesis), please submit 
these images and reports to IROC Rhode Island (QARC) for central review. 
Reports should also be submitted to the study QAS/Data Manager listed on the 
Protocol Resources Page using the Report Submission Form in Rave. Submit 
these images and reports regardless of whether they detected all sites of MIBC or 
not. Sites who are not able to scan and attach the reports should contact the 
QAS/Data Manager for further instructions. 
 
 
7.14 
Image-Guided Biopsy and Specimen Radiographs 
All suspicious imaging abnormalities (BI-RADS® 4 or 5 lesions) amendable to 
biopsy should undergo imaged guided biopsy, preferably with clip marker 
placement at the time of biopsy. Fine needle aspiration or core biopsy is 
permissible, however, a minimum of one lesion must have core biopsy 
documenting invasive disease. Submit images of biopsies of each suspicious 

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lesion. Submit procedure reports and pathology reports from each site biopsy. If 
specimen radiographs are performed at the time of the surgery, please submit 
these images as well. The means of diagnosis (percutaneous core or 
excisional/incisional) will be documented and tracked.  
 
Submit images and the reports from all image-guided biopsies performed 
(mammogram, ultrasound, MRI, breast-specific gamma imaging (BSGI), PEM, 
and/or tomosynthesis guided biopsies) with the procedure report and pathology 
report from the biopsy. 
 
7.15 
Central Radiologic Review    
The mammograms and any other adjuvant imaging performed will be centrally 
reviewed using a process that is blinded to the results of the surgery and 
pathology. If mammograms, breast MRI and other imaging studies were not 
performed or will not be submitted for technical reasons, notify IROC Rhode 
Island (QARC) by email at 
 Digital files must be in 
DICOM format and include all image attributes. These files can be submitted 
electronically via sFTP. Details for obtaining an sFTP account and submission 
instructions can be found at 
 Follow the link labeled digital 
data. Alternatively, if sFTP is not feasible, the imaging may be burned to a CD 
and mailed to IROC RI (QARC) at the address below. Multiple studies for the 
same patient may be submitted on one CD; however, please submit only one 
patient per CD. Contact IROC RI (QARC) with questions or for additional 
information. 
 
7.16 
Image Submission 
Submit required images as follows:  
 
• 
Diagnostic mammogram images and report 
• 
Diagnostic breast MRI images and reports (if MRI performed) 
• 
Images by any additional imaging (by any modality) and reports 
• 
Image guided biopsy images, procedure report and pathology report 
from the biopsy 
 
Complete and include an Image Submission Checklist with submission to IROC 
Rhode Island (QARC); checklists may be downloaded from the IROC Rhode 
Island (QARC) website 
  
 
Send to IROC Rhode Island (QARC) at the address listed on the Protocol 
Resources page of the protocol.  
 
 
7.2 
Surgery 
Patients undergoing breast conserving therapy (BCT) for multiple ipsilateral breast 
cancers should have all lesions resected to negative margins, either using one 
lumpectomy or two/three separate lumpectomy incisions at the discretion of the surgeon. 
Lumpectomy specimens must be oriented and submitted for pathological assessment of 
margins. Intra-operative confirmation of tumor resection is recommended with intra-

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operative specimen radiograph. All sites of biopsy proven malignancy (DCIS or invasive 
breast cancer) and atypia (atypical ductal hyperplasia (ADH), atypical lobular hyperplasia 
(ALH) and flat epithelial atypia (FEA)) should be resected at time of surgery. 
 
Primary tumor bed will be defined as the area of invasive and/or DCIS and include 
nearby small satellite nodules within 1 centimeter of the index lesion. 
 
Each tumor must be resected to negative margins (no tumor at ink).  
 
Re-excision should be done to achieve negative margins as needed. Patients with 
persistent positive margins should be converted to mastectomy or go off study. For 
patients who convert to mastectomy within one year of initial surgery, see Section 13.2.  
 
Where possible, surgical clips must be placed to outline the surgical bed for all patients. 
For patients where an oncoplastic approach to the surgical resection is undertaken, clips 
must be placed to outline the surgical bed. For the oncoplastic patients, the tissue 
rearrangement must be clearly documented in the operative report to facilitate radiation 
planning. Oncoplastic tissue rearrangement by the breast surgeon or plastic surgeon is 
permitted. Planned autologous tissue flaps (such as latissimus flap, etc.) or implants are 
not permitted. 
 
Axillary staging is required for all invasive breast cancers with sentinel lymph node 
(SLN) surgery and/or axillary lymph node dissection (ALND). Completion ALND in the 
setting of one or two positive sentinel lymph nodes is at the discretion of the treating 
surgeon. Surgeons are encouraged to perform ALND for patients with three or more 
positive sentinel nodes or evidence of extra nodal extension in any of the positive sentinel 
nodes. The status of the axilla will be documented in the trial data collection. 
 
7.3 
Pathology 
Margin assessment of each lumpectomy specimen is required. For this study negative 
margin is defined as no tumor at ink. The size of the closest margin should be measured 
and reported for each lesion. The anterior and posterior margins are excluded from this 
restriction if the fascia and/or skin are taken. 
 
When 2 or more lesions are excised en bloc, surgical pathology review is required to 
assess whether the lesions are separate foci of cancer separated by 2 cm or more of 
healthy breast tissue.  
 
In consenting patients, tissue from each site of disease within the breast will be submitted 
for tissue banking and correlative science section. Tissue from axillary lymph nodes 
(sentinel lymph nodes and/or axillary lymph node dissection dependent on case) will also 
be collected for correlative science evaluation. 
 
Patient may remain on study if, upon pathological assessment, two or three lesions 
identified on pre-operative imaging represent one contiguous lesion. 
 
7.4 
Cosmesis 
Following surgery, patients will complete questionnaire booklets at the following time 
points: 5 to 30 days following final surgery (initial post-operative visit); every six months 
(± 1 month) for the first 2 years following completion of WBI; then yearly (± 2 months) 
for the next 3 years following completion of WBI to assess cosmetic outcome. The 

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patient’s surgeon will complete the surgeon questionnaire 5 to 30 days following final 
surgery (initial post-operative visit) to assess cosmetic outcome. Patients registered after 
surgery will still complete the questionnaire at the timepoints feasible, based on the 
timing of their registration. 
 
7.5 
Adjuvant Therapy 
The use of adjuvant chemotherapy or endocrine therapy will be at the discretion of the 
treating medical oncologist at the individual institutions based on tumor characteristics. 
Patients being treated with adjuvant therapy should be treated within 12 weeks following 
surgery. It is recommended that patients with hormone responsive tumors receive 
tamoxifen or an aromatase inhibitor. It is recommended that patients with Her2 positive 
tumors receiving adjuvant chemotherapy receive targeted anti-Her2 therapy. 
 
7.6 
Adjuvant Whole Breast Irradiation (WBI) 
Patients receiving BCT should receive adjuvant whole breast radiation with a boost to the 
lumpectomy bed of each site of disease. The boost will be limited to two quadrants of the 
breast only. Note: Patients who cannot or do not receive boost radiation are ineligible and 
must discontinue the study. The end of study information should be collected and the 
patient referred to clinical care. Addition of nodal radiation fields will be at the discretion 
of the treating radiation oncologist. 
 
Patients may receive WBI at an institution other than the enrolling institution. Note that 
the enrolling institution is responsible for the correct performance of WBI at the other 
institution and the reporting of all study data. The institution performing WBI must 
follow all requirements for WBI listed in the protocol, including regulatory requirements 
such as submission of an RTFI form to CTSU and submission of treatment plans to IROC 
Rhode Island (QARC). 
  
7.61 
Treatment Planning/Delivery 
7.611 Three-dimensional CT-based treatment planning is required. 
7.612 Heterogeneity corrections are required. 
7.613a Intensity modulated radiotherapy (IMRT) with inverse planning is  
allowed. 
7.613b Breath hold technique is allowed 
7.614 Optimization with forward planning is allowed. 
7.615 Linear accelerators with minimal photon energies of 6MV and electron 
energies of 6eMEV-20eMEV are required. 
7.616 Either electrons or photons may be used for boost treatment. 
7.617 Boost treatment to each lumpectomy cavity is required. 
Note: Patients who cannot or do not receive a boost are ineligible and 
must discontinue the study. The end of study information should be 
collected and the patient referred to clinical care. 
7.618 Boost with intraoperative radiotherapy or HDR brachytherapy is not 
allowed. 
7.619 Hypofractionation is not allowed. 
 
 
7.62 
Timing of WBI for Patients Receiving Adjuvant Chemotherapy 

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7.621 For patients receiving adjuvant cytotoxic chemotherapy, radiation 
treatment planning and cavity assessment is performed after completion 
of chemotherapy. WBI should be initiated ≤ 8 weeks after the last dose 
of cytotoxic chemotherapy. For patients receiving trastuzumab as part of 
their therapy the trastuzumab can continue during WBI. 
 
7.622 Patients not meeting the dose constraints by 8 weeks after 
completion of adjuvant cytotoxic chemotherapy should discontinue 
protocol therapy and are recommended to undergo mastectomy (see 
Section 13.2). 
 
 
7.63 
Timing of WBI for Patients Not Receiving Adjuvant Chemotherapy 
7.631 For patients not receiving adjuvant cytotoxic chemotherapy, radiation 
treatment planning is to be performed within 6 weeks of lumpectomy (or 
final operation for re-excision of margins) to determine if the volume of 
breast tissue receiving 60 Gy is less than or equal to 50% of Breast PTV 
Eval (see below). If the dose constraint is met, WBI should be initiated 
by no later than 10 weeks following lumpectomy or re-excision of 
margins, provided surgical incisions have healed adequately.   
 
7.632 WBI can be carried out concurrently with hormonal therapy; hormonal 
therapy can be started at any time at the discretion of the treating 
physician.   
 
7.633 If the dose constraint is not met, patients will be re-scanned no later than 
10 weeks after lumpectomy (or final margin re-excision) to allow for 
cavity shrinkage.   
 
7.634 If the dose constraint is not met within 10 weeks from the last surgery, 
these patients will discontinue protocol therapy and are recommended to 
undergo mastectomy, see Section 13.2.  
 
 
7.365 For patients who are re-scanned at 10 weeks and the dose constraint is 
met at that time, radiation should start no later than 12 weeks post-
surgery. 
 
7.64 
Patient Positioning, Immobilization and Imaging 
7.641 Simulation CT and treatment delivery should be performed according to 
institutional standards. 
 
7.642 Radio-opaque markers placed on the lumpectomy incisions, around the 
palpable breast tissue, and at the borders of the “clinical” tangent fields 
are often helpful. 
 
7.643 Immobilization using alpha cradle, vac-loc, or breast boards is highly 
recommended to ensure reproducibility.  Prone position is permitted. 
 

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7.644 The CT should extend cephalad to start at or above the mandible and 
extend sufficiently caudally (or inferiorly) to the inframammary fold to 
encompass the entire lung volume.  A CT scan image thickness of ≤ 0.5 
cm should be employed. 
 
7.645 External skin localizing marks, which may include permanent tattoos, are 
recommended for radiation daily localization and set-up accuracy. 
 
7.646 The patient may be re-positioned for boost delivery at the discretion of 
the treating physician. 
 
7.65 
Target Volumes 
The definitions for the CTV, PTV and normal structures used in this protocol 
generally conform to the RTOG-endorsed consensus guidelines for delineation of 
target and normal structures for breast cancer 
 
 
7.651 Breast volumes   
7.6511 Breast CTV 
Includes the palpable breast tissue demarcated with radio-opaque 
markers at CT simulation, the apparent CT glandular breast 
tissue visualized by CT, consensus definitions of anatomical 
borders, and the Lumpectomy CTV from the breast cancer atlas. 
The breast CTV is limited anteriorly within 5 mm from the skin 
and posteriorly to the anterior surface of the pectoralis, serratus 
anterior muscle excluding chest wall, boney thorax, and lung. In 
general, the pectoralis and/or serratus anterior muscles are 
excluded from the breast CTV unless clinically warranted by the 
patient’s pathology. The breast CTV should generally follow 
consensus guidelines 
 
7.6512 Breast PTV 
Breast CTV + 7 mm 3D expansion (exclude heart and do not 
cross midline). 
 
7.6513 Breast PTV Eval  
Since a substantial part of the Breast PTV often extends outside 
the patient, the Breast PTV is then copied to a Breast PTV Eval 
which is edited. This breast PTV Eval is limited anteriorly to 
exclude the part outside the patient and the first 5 mm of tissue 
under the skin (in order to remove most of the build-up region 
for the DVH analysis) and posteriorly is limited to no deeper 
than the anterior surface of the ribs (excludes boney thorax and 
lung). This Breast PTV Eval is the structure used for DVH 
constraints and analysis. This Breast PTV Eval cannot be used 
for beam aperture generation. 
 
7.652 Lumpectomy volume 

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7.6521 Lumpectomy GTV 
Contour using all available clinical and radiographic information 
including the excision cavity volume, architectural distortion, 
lumpectomy scar, seroma and/or extent of surgical clips.  
Patients without a clearly identifiable lumpectomy bed are not 
eligible for protocol participation. 
 
7.6522 Lumpectomy CTV 
Lumpectomy GTV + 1 cm 3D expansion. Limit the CTV 
posteriorly at anterior surface of the pectoralis major and 
anterolaterally 5 mm from skin and should not cross midline. In 
general, the pectoralis and/or serratus anterior muscles are 
excluded from the lumpectomy CTV unless clinically warranted 
by the patient’s pathology. 
 
7.6523 Lumpectomy PTV 
Lumpectomy CTV + 3-5 mm 3D expansion (excludes heart). 
 
7.6524 Lumpectomy PTV Eval  
Since a substantial part of the Lumpectomy PTV often extends 
outside the patient (especially for superficial cavities), the 
Lumpectomy PTV is then copied to a Lumpectomy PTV Eval 
which is edited. This Lumpectomy PTV Eval is limited to 
exclude the part outside the ipsilateral breast and the first 5 mm 
of tissue under the skin (in order to remove most of the build-up 
region for the DVH analysis) and excluding the Lumpectomy 
PTV expansion beyond the posterior extent of breast tissue 
(chest wall, pectoralis muscles and lung) when pertinent. The 
lumpectomy PTV should not cross midline. This Lumpectomy 
PTV Eval is the structure used for DVH constraints and analysis.  
This Lumpectomy PTV Eval cannot be used for beam aperture 
generation. 
 
7.653 Normal Tissues 
7.6531 Ipsilateral lung.  
This may be contoured with auto-segmentation with manual 
verification. 
 
7.6532 Contralateral lung.  
This may be contoured with auto-segmentation with manual 
verification. 
 
7.6533 Heart.   
The heart should be contoured beginning just inferior to the level 
in which the pulmonary trunk branches into the left and right 
pulmonary arteries (PA). Above the PA, none of the 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) and defined as “heart”. The heart 
should be contoured on every contiguous slice thereafter to its 
inferior most extent near the diaphragm. If one can identify the 

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esophagus, this structure should be excluded from the heart. One 
need not include pericardial fat, if present. Contouring along the 
pericardium itself, when visible, is appropriate. 
 
 
7.66 
Target Dose Fractionation and Dose Prescription 
 
7.661 Whole breast 
46-50 Gy in 2 Gy daily fractions or 45-50.4 Gy in 1.8 Gy daily fractions, 
5 days a week.  
Per protocol: ≥ 95% of the breast PTV Eval will receive ≥ 95% of the 
prescribed dose. Maximal point dose will be ≤ 115% of the prescribed 
dose, not including the boost dose. 
Acceptable Variation: ≥ 90% of the breast PTV Eval will receive ≥ 90% 
of the prescribed dose. Maximal point dose will be ≤ 120% of the 
prescribed dose, not including the boost dose. 
 
7.662 Boost 
10-16 Gy in 2 Gy daily fractions, 5 days a week (10 Gy for those 
receiving 50-50.4 Gy to the whole breast, 14 Gy for those receiving 46 
Gy to the whole breast, 16 Gy for those receiving 45 Gy to the whole 
breast).  
Per protocol: ≥ 90% of the lumpectomy PTV Eval will receive ≥ 90% of 
the prescribed dose. Maximal point dose will be ≤ 115% of the boost 
prescription dose. 
 
7.663 Accumulative Dose (Whole Breast + Boost) 
Per protocol: No more than 50 % of Breast PTV Eval will receive more 
than 60 Gy. 
Acceptable Variation: No more than 60 % of Breast PTV Eval will 
receive more than 60 Gy. 
Every effort should be made to keep no more than 50% of Breast PTV 
Eval receiving more than 60 Gy, including using 3mm margin for 
expansion from Lumpectomy CTV to Lumpectomy PTV, and allowing 
minimum coverage of 90% of the lumpectomy PTV Eval receiving 90% 
of the prescribed dose. 
 
7.67 
Nodal Irradiation 
The addition of nodal irradiation is at the discretion of the treating radiation 
oncologist. 
 
7.671 For those patients with 1-2 positive sentinel lymph nodes (SLNs) not 
undergoing axillary lymph node dissection, the use of either standard 
tangent fields or “high tangent fields” covering part or all level II axillary 
LNs is permitted and is at the discretion of the treating radiation 
oncologist.  
 
7.672 For those patients with ≥ 3+ SLNs undergoing axillary lymph node 
dissection, regional nodal irradiation is encouraged, especially in those 

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with extra capsular extension, nodal ratio > 20 %, high grade disease, 
and LVSI. Coverage of supraclavicular fossa and high axillary lymph 
node regions are recommended. Coverage of the internal mammary 
nodes is at the discretion of the radiation oncologist.    
 
7.673 For those patients with ≥ 3 positive SLNs not undergoing axillary lymph 
node dissection, regional nodal irradiation is required.   
 
7.674 If regional lymph nodes are treated, contouring of regional lymph nodes 
per the RTOG breast contouring atlas is required.  
 
7.675 Nodal irradiation dose 
Undissected axilla, supraclavicular nodes, internal mammary nodes: 46-
50 Gy in 2 Gy daily fractions or 50.4 Gy in 1.8 Gy daily fractions, 5 days 
a week. 
 
7.68 
Dose Limitation for Normal Tissues 
 
7.681 Ipsilateral Lung 
Per Protocol: ≤ 30% of the ipsilateral lung should receive ≥ 20 Gy 
Variation Acceptable: ≤ 35 % of the ipsilateral lung should receive ≥ 20 
Gy 
 
7.682 Contralateral Lung 
Per Protocol: ≤ 10% of the contralateral lung should receive 5 Gy or more 
Variation Acceptable: ≤ 15% of the contralateral lung should receive 5 
Gy or more 
 
7.683 Heart 
Per Protocol: ≤ 5% of the whole heart should receive ≥ 25 Gy for left-
sided breast cancers, and 0% of the heart should receive ≥ 25 Gy for 
right-sided breast cancers  
Variation Acceptable:  ≤ 5% of the whole heart should receive ≥ 30 Gy 
for left-sided breast cancers, and 0% of the heart should receive ≥ 30 Gy 
for right-sided breast cancers 
 Per Protocol: Mean heart dose should be ≤ 400 cGy 
Variation Acceptable:   ≤ 500 cGy. Every attempt should be made to 
make the cardiac exposure to radiation as low as possible 
7.69a Data Submission 
Submission of treatment plans in digital format (either DICOM RT or RTOG 
format) is required. Digital data must include CT scan structures, dose, and plan 
files. Submission may be either by sFTP or CD. Instructions for data submission 
are available on the IROC Rhode Island (QARC) website at 
Any 
items on the list below that are not part of the digital submission may be 
submitted as screen captures along with the digital data. 
 
7.69a1 Prior to the Start of Radiotherapy 
The following data should be submitted prior to the start of radiotherapy: 
 

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a. Treatment Planning System Output 
1.  RT treatment plan including CT, structures, dose, and plan 
files. These items are included in the digital plan. 
2. Dose volume histograms (DVH) of target volumes, 
ipsilateral and contralateral lung and heart. DVH’s are 
included in the digital plan. 
3. Digitally reconstructed radiographs (DRR) for each 
treatment field. 
4. Treatment planning system summary report that includes 
the monitor unit calculations, beam parameters, calculation 
algorithm, and volume of interest dose statistics. 
 
b. Supportive Data 
1. Prescription Sheet for Entire Treatment 
 
c. Forms 
1. RT-1 Dosimetry Summary Form 
This form is available on the IROC Rhode Island (QARC) 
website at 
 
 
7.69a2 Within One Week of the Completion of Radiotherapy 
The following data should be submitted within one week of the 
completion of radiotherapy: 
 
a.  The RT-2 Radiotherapy Total Dose Record Form 
This form is available on the IROC Rhode Island (QARC) 
website at 
 
 
b.  A copy of the patient’s radiotherapy record including 
prescription, and the daily and cumulative doses to all required 
areas, critical organ, and reference points 
 
c.  Documentation listed above showing any modifications from 
original submission. 
 
 
7.69a3 Supportive data and forms may be included with the transmission of the 
digital RT data via sFTP or submitted separately via e-mail 
(
) or mailed to IROC Rhode Island (QARC) at the 
address listed on the Protocol Resources page of the protocol. 
 
7.69a4 Questions regarding the dose calculations or documentation should be 
directed to the protocol dosimetrist at IROC Rhode Island (QARC) at the 
address, email and telephone number listed on the Protocol Resources 
page of the protocol. 
 
 
7.69b Quality Assurance 
 
7.69b1 Whole Breast Dose 

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Variation Acceptable: < 95% of the Breast PTV Eval receives < 95% of 
the whole breast prescription dose (not including 
boost dose) 
 
 Deviation Unacceptable: < 90% of the Breast PTV Eval receives < 90% 
of the whole breast prescription dose (not 
including the boost dose) 
 
 Deviation Unacceptable: Maximal point dose is > 120% of the whole 
breast prescribed dose (not including the 
boost dose) 
 
7.69b2 Boost Volume Coverage 
 Deviation Unacceptable: < 90% of the lumpectomy PTV Eval 
receives < 90% of the boost prescription 
dose.  
 
7.69b3 Accumulative Breast Dose  
Variation Acceptable: 
Between 50% and 60% of Breast PTV Eval 
receives more than 60Gy 
Deviation Unacceptable: 
More than 60 % of Breast PTV Eval 
receives more than 60 Gy. 
 
7.69b4 Volume 
Deviation Unacceptable: 
Whole breast or boost volumes incorrectly 
defined as deemed by study co-PI. 
 
7.69b5 Critical Organ 
The dose to lung or heart exceeds the protocol’s limits specified in 
Section 7.68 
 
 
7.7 
Patient Follow-up After Completion of WBI 
All eligible patients will enter the observation phase of this trial after completion of WBI 
(see test schedule, Section 4.0). At the follow-up visits, patients will complete a symptom 
survey and undergo a physical examination. The breast lymphedema symptom survey 
will assess breast heaviness, swelling, redness, and discomfort. The physical examination 
will assess the presence or absence of breast edema, which will combine with the 
symptom score to define cases of breast lymphedema. Lymphedema should be graded 
using CTCAE version 4.0 (see Section 10.51).   
 
8.0 
Dosage Modification Based on Adverse Events 
 
8.1 
No Expected Adverse Events  
There are no expected adverse events from surgery beyond those related to the standard 
breast cancer surgery. 
 
8.2 
Dose Modifications as per Standard Institutional Practice 
Dose modifications for adverse events occurring during physician’s choice of adjuvant 
hormonal or chemotherapy will be managed according to the physician’s standard 
institutional practice. 

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8.3 
Table of Modification of WBI Schedule Based on Adverse Events 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified  
 
System Organ Class (SOC) 
 
ADVERSE EVENT 
 
ACTION 
 
Injury, poisoning and 
procedural complications 
 
Dermatitis radiation, 
grade 3 
 
Hold WBI treatment for one week or 
until skin reaction improves to < grade 3. 
 
Any hematologic or non-
hematologic adverse event 
 
 
≥ grade 4 
 
Report to the principal investigator at the 
time of occurrence. 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 
 
 
9.0 
Ancillary Treatment/Supportive Care 
Patients should receive full supportive care while on this study according to institutional 
standard of care. This includes blood product support, antibiotic treatment, and treatment of 
other newly diagnosed or concurrent medical conditions.   
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. However, CTCAE version 5.0 must be used for 
serious AE reporting through CTEP-AERS as of April 1, 2018. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. The CTCAE is available 
at 
All reactions 
determined to be “reportable” in an expedited manner must be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS), accessed 
via the CTEP website, 
Attribution to protocol 
treatment for each adverse event must be determined by the investigator and reported on 
the required forms. Please refer the NCI Guidelines: Adverse Event Reporting 
Requirements for further details on AE reporting procedures. CTEP-AERS reports 
should be submitted electronically. 
 
10.11 Adverse Event Monitoring, Data Collection and Reporting 
Adverse event monitoring, 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 future studies using similar agents. 
Adverse events are reported in a routine manner at scheduled times during the 
trial using Medidata Rave. Additionally, certain adverse events must be reported 
in an expedited manner for timelier monitoring of patient safety and care. 
Following sections provide information about expedited reporting. 
 

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First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3). With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4). Important: Expedited adverse 
event reporting requires submission of a CTEP Adverse Event Reporting System 
(CTEP-AERS) report(s). Expedited reports are to be completed using CTCAE 
version 5.0, within the timeframes and via the mechanisms specified in Section 
10.4 and 10.5 All AEs reported via expedited mechanisms must also be reported 
via the routine data reporting mechanisms defined by the protocol (see Sections 
10.4 and 18.0). 
 
10.12 CTCAE and Grade 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).  Grade is an essential element of the Guidelines and, in 
general, relates to severity for the purposes of regulatory reporting to NCI. 
  
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same 
as serious AE which is defined in the table in Section 10.4. 
 
 
10.2 
Expected vs. Unexpected 
• 
The determination of whether an AE is expected is based on the treatment-
specific information provided in Section 15.0 of this protocol. 
 
• 
Unexpected AEs are those not listed in the treatment-specific information 
provided in Section 15.0 of this protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is 
neither identified in nature, severity, or frequency of risk in the information 
provided for IRB review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite – The adverse event is clearly related to the agent(s). 
Probable – The adverse event is likely related to the agent(s). 
Possible – The adverse event may be related to the agent(s). 
Unlikely – The adverse event is doubtfully related to the agent(s). 
Unrelated – The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the treatment and the adverse event.  
 
10.31 Special Situations for Expedited Reporting  

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An expedited report is not required for a specific protocol where an AE is listed as 
expected. These events must still be reported via routine reporting as specified in 
Section 10.5.  The protocol-specific guidelines supersede the NCI Adverse Event 
Reporting Guidelines (See Section 10.4) for AE reporting. 
 
10.32 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
anomalies, or birth defects,must be reported via CTEP-AERS if they occur at any time 
following treatment since they are considered to be a serious AE and must be reported 
to the sponsor as specified in 21 CFR 312.64(b). 
 
10.33 Death 
Reportable categories of Death 
 
 
• 
Death due to progressive disease should be reported as grade 5 
“Disease progression” in the system organ class (SOC) 
“General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease 
process) should be submitted.  
 
• 
Any death occurring within 30 days of the last dose, regardless 
of attribution to the investigational agent/intervention requires 
expedited reporting within 24 hours.  
 
• 
Any death occurring greater than 30 days after the last 
intervention requires expedited reporting within 24 hours only 
if it is possibly, probably, or definitely related to the 
intervention. 
 
• 
When submitting CTEP-AERS reports for “Pregnancy”, 
“Pregnancy loss”, or “Neonatal loss”, the Pregnancy Information 
Form should be completed and submitted, along with any 
additional medical information (form is available on the CTEP 
website at http://ctep.cancer.gov/). The potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” 
section of the CTEP-AERS report. 
 
• 
In CTCAE v5.0, pregnancy loss is defined as “Death in utero,” 
and any pregnancy loss should be reported expeditiously as 
Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and 
perinatal conditions SOC. A pregnancy loss should NOT be 
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and perinatal conditions SOC as currently CTEP-AERS 
recognizes this event as a patient death.  
 
• 
A neonatal death should be reported expeditiously as Grade 4, 
“Death neonatal” under the General disorders and 
administration SOC. 
 
 
10.34 Secondary Malignancy 
All new malignancies must be reported via CTEP-AERS whether or not they 
are thought to be related to either previous or current treatment. All new 
malignancies should be reported, i.e. solid tumors (including non-melanoma 
skin 
malignancies), 
hematologic 
malignancies, 
myelodysplastic 
syndrome/acute myelogenous leukemia, and in situ tumors. In CTCAE v5.0, 
secondary malignancies may be reported as one of the following three options: 
1) Leukemia secondary to oncology chemotherapy, 2) Myelodysplastic 
syndrome, or 3) Treatment-related secondary malignancy. Whenever possible, 
the CTEP-AERS reports for new malignancies should include tumor pathology, 
history or prior tumors, prior treatment/current treatment including duration, 
any associated risk factors or evidence regarding how long the new malignancy 
may have been present, when and how the new malignancy was detected, 
molecular characterization or cytogenetics of the original tumor (if available) 
and of any new tumor, and new malignancy treatment and outcome, if available. 
 
10.35 Second Malignancy 
• 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  Second 
malignancies require ONLY routine reporting via CDUS.

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10.4  
Expedited Reporting Requirements: Studies using Commercial Agent(s) ONLY: 
 
Expedited Reporting Requirements for Adverse Events that Occur in a Non-IND/IDE trial 
within 30 Days of the Last Administration of a Commercial Agent 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” – The AE must initially be reported via CTEP-AERS within 
24 hours of learning of the AE, followed by a complete expedited report within 3 calendar 
days of the initial 24-hour report. 
o “7 Calendar Days” – A complete expedited report on the AE must be submitted within 7 
calendar days of learning of the AE
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• 
All Grade 4, and Grade 5 Aes 
Expedited 7 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half- lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
 

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In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to CTEP 
by telephone at 
Once Internet connectivity is restored, the 24-hour notification phoned 
in must be entered electronically by the original submitter at the site. 
 
10.5 
Other Required Expedited Reporting 
 
EVENT TYPE 
 
REPORTING PROCEDURE 
Other Grade 4 or 5 Events 
and/or Any Hospitalizations 
During Treatment Not 
Otherwise Warranting an 
Expedited Report 
 
NCCTG institutions only: Complete a Notification Form: Grade 4 
or 5 Non-AER Reportable Events/Hospitalization Form within 5 
working days of the date the clinical research associate (CRA) is 
aware of the event(s) necessitating the form. 
 
If a CTEP-AERS report has been submitted, this form does not need 
to be submitted. 

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10.51 Adverse Events and Symptoms/Conditions to be Graded at Baseline 
Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per CTCAE v4.0 grading unless 
otherwise stated in the table below: 
 
 
System Organ Class 
(SOC) 
 
Adverse event 
 
Baseline 
Each 
evaluation 
post-surgery 
Each 
evaluation 
post WBI 
Infections and 
infestations 
Wound Infection 
 
X 
X 
Injury, poisoning and 
procedural 
complications 
Dermatitis radiation 
 
 
X 
Postoperative hemorrhage 
 
X 
 
Seroma 
 
X 
X 
Vascular disorders 
Lymphedema 
X 
X 
X 
 
10.52 Adverse Event Submission Using Case Reports Forms (CRFs) 
Submit via appropriate Alliance Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.51: 
 
10.521  
Grade 2 AEs deemed possibly, probably, or definitely related to study 
surgery or radiation. 
 
10.522 
Grade 3 and 4 AEs regardless of attribution to study surgery or 
radiation. 
 
10.523  
Grade 5 AEs (Deaths) 
 
10.5231 Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to study 
surgery or radiation. 
 
10.5232 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
study related must also be submitted as a Grade 5 AE, with a 
CTCAE type and attribution assigned. 
 
10.53 Submission of Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
 
11.0 
Diagnosis of Breast Cancer Recurrence and Other Cancer Events 
 

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11.1  
Local Recurrence 
Local recurrence is defined as histologic evidence of ductal carcinoma in situ or invasive 
breast cancer in the ipsilateral breast or ipsilateral chest wall.  
 
11.2  
Regional Recurrence 
Regional recurrence is defined as the cytologic or histologic evidence of disease in the 
ipsilateral internal mammary, ipsilateral supraclavicular, ipsilateral infraclavicular and/or 
ipsilateral axillary nodes or soft tissue of the ipsilateral axilla. 
 
11.3  
Distant Recurrence 
Distant recurrence is defined as the cytologic, histologic, and/or radiographic evidence of 
disease in the skin, subcutaneous tissue, lymph nodes (other than local or regional 
metastasis), lung, bone marrow, central nervous system or histologic and/or radiographic 
evidence of skeletal or liver metastasis.  
 
11.4  
Second Primary Breast Cancer  
Second primary breast cancer is defined histologic evidence of ductal carcinoma in situ 
or invasive breast cancer in the contralateral breast or contralateral chest wall.  
 
11.5  
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 is to be reported and should 
be confirmed histologically whenever possible. 
 
11.6  
Death 
Underlying cause of death is to be reported. 
 
 
12.0 
Descriptive Factors 
 
12.1 
Menopausal Status  
Pre vs. post vs. above categories not applicable (age < or ≥ 50) 
 
• 
Pre is < 6 months since last menstrual period (LMP) and no prior bilateral 
ovariectomy and not on estrogen replacement; 
 
• 
Post is prior bilateral ovariectomy or >12 months since LMP with no prior 
hysterectomy and not currently receiving therapy with LH-RH analogs (e.g., 
Zoladex))  
 
• 
Above categories not applicable and age < 50  
 
• 
Above categories not applicable and age ≥ 50. 
 
12.2 
Time of Registration: Pre-surgery vs Post-surgery  

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13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
 
13.1 
Follow-Up After Completion of WBI 
Patients will be followed as per the test schedule for 5 years after completion of WBI. 
 
13.2 
Conditions Requiring Study Termination 
Patients who convert to a mastectomy for any reason within a year of initial surgery will 
go to the observation phase of the study. All data and forms prior to and up to 
mastectomy must be submitted. Tissue from the mastectomy should be submitted if 
possible. Patients will be followed for survival yearly for 5 years after treatment 
discontinuation. 
 
Patients found to have any of the following: 
• 
those with persistent positive margins who decline mastectomy; 
• 
the dose constraint is not met (≤ 10 weeks of initial attempt of WBI planning in 
patients not receiving adjuvant chemotherapy, or ≤ 8 weeks after completion of 
chemotherapy for those patients receiving chemotherapy)  
 
will have participation in the study terminated. The on-study material, surgery forms, 
pathology forms and the End of Active Treatment/Cancel Notification Form must be 
submitted. No further data submission is needed. 
 
13.3  
Discontinuation After Surgery but Prior to Completion of WBI 
Patients who discontinue the study after surgery but prior to completion of WBI due to 
any of the following:  
 
• 
patient refusal to undergo or complete WBI; 
• 
physician discretion; 
• 
unacceptable toxicity preventing administration/completion of WBI  
 
will go to the observation phase of this trial; that is, they be followed as per the test 
schedule for 5 years after treatment discontinuation. 
 
Note: Patients who cannot or do not receive boost radiation are ineligible and must 
discontinue the study. The end of study information should be collected and the patient 
referred to clinical care. 
 
13.4 
Conditions Requiring Study Discontinuation 
Patients who discontinue the study at any time due to any of the following:  
 
• 
patient refusal to continue study tests and/or procedures  
• 
develop disease recurrence 
• 
administration of anti-neoplastic (non-protocol) treatment   
 
will enter the event monitoring phase where disease and vital status will be collected 
yearly for 5 years after completion of WBI (or treatment discontinuation). 
 
13.5 
Definition of Ineligible 
A patient is deemed ineligible by the data center if, after registration, it is determined that 
at the time of registration, the patient did not satisfy each and every eligibility criteria for 

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study entry.   
 
• If the patient did undergo surgery with/without radiation, submit all 
treatment/intervention forms and the Off Treatment/Cancel Notification Form.  
 
• If the patient did not undergo surgery, submit on-study material and the Off 
Treatment/Cancel Notification Form. No further data submission is necessary. 
 
Note: If, after a site has registered a patient into the study, the site becomes aware 
of information that questions the patient’s eligibility for the study, the site should 
contact the QAS/Data Manager at the telephone number and/or email address listed 
on the Protocol Resources page of the protocol. 
 
13.6 
Definition of Cancel 
A patient is deemed a cancel if she withdrew consent prior to surgery. On-study material 
and the End of Active Treatment/Cancel Notification Form must be submitted. No further 
data submission is necessary. 
 
13.7 
Recommendations for Local Recurrence 
Patients who develop local recurrence are recommended to be evaluated by having a 
mammogram and MRI and to undergo a mastectomy. 
 
 
14.0 
Biospecimen Submission 
 
14.1 
Tissue and Blood Collection Requirements for Correlative Studies 
Table 14.1 Summary of Z11102 Tissue and Blood Collection Requirements for Correlative Studies 
Biospecimen 
Optional/Mandatory 
Collection 
time point 
 
 
Comment 
EDTA whole blood 
(2 x 10 mL tubes) 
Optional  
 
Within 4 weeks 
after registration 
 
Frozen tissue 
specimens1 
Optional1 
Breast conservation 
surgery 
 
Representative frozen 
tumor tissue from each site 
of disease, including 
positive dissected lymph 
nodes, if applicable from 
the first surgery only 2 

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Biospecimen 
Optional/Mandatory 
Collection 
time point 
 
 
Comment 
Formalin fixed, 
paraffin-embedded 
(FFPE) tissue 
blocks1 
Optional1 
Breast conservation 
surgery or at 
registration if 
registering after 
surgery 
If it is not logistically 
possible to procure, freeze, 
and ship frozen material, 
one formalin-fixed paraffin-
embedded (FFPE) tissue 
block from each site of 
disease, including positive 
dissected lymph nodes, if 
applicable, with a 
corresponding H&E stained 
slide from each block from 
the first surgery only2,3 
1. For patients registered prior to first surgery either FFPE OR frozen tissue specimens will be 
submitted for patients who consent (both FFPE and frozen are not required). For patients registered 
after surgery, FFPE specimens should be submitted where available, in patients who consent to the 
tissue submission. 
2. For the first surgery only in patients consenting to the tissue submission: when selecting a sample 
for submission, please choose a block or frozen tumor specimen from each site of disease with both 
the greatest amount/area of invasive breast carcinoma/associated stoma and the least amount of non-
invasive mammary epithelium (in situ carcinoma, hyperplastic epithelium, normal epithelium). Note: 
Operative and pathology reports from all surgeries must be submitted. Tissue specimens from 
subsequent surgeries are not required for submission. 
3. An alternative submission for FFPE blocks is fifteen 5-micron positive charged slides from each site 
of disease, including dissected, disease-positive lymph nodes, if applicable, with a corresponding 
H&E stained slide from each block. 
 
14.2 
Biospecimen Collections 
 
14.21 Optional Blood Biospecimens 
Two 10-mL EDTA tubes of whole blood are requested for correlative studies and 
for potential future research should the patient consent to giving a blood sample 
for research purposes.  
 
14.22 Optional Tissue Biospecimens 
Either frozen (preferred) or FFPE tissue specimens from each surgical site of 
disease and a sample of the intervening non-malignant tissue will be submitted 
for tissue correlative science evaluation and potentially for future research, 
should the patient consent. Tissue from axillary lymph nodes (sentinel lymph 
nodes and/or axillary lymph node dissection dependent on case) will also be 
collected for correlative science evaluation (see Table 14.1.)  A corresponding 
H&E slide for each submitted block must be provided to permit quality 
assessment of each tissue block.  
 
If frozen tissue cannot be provided, the FFPE tissue block is requested.  
However, if an institution is unable to provide a tissue block, cut fifteen         

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5-micron positive charged slides. Label the slides with patient study ID 
number, pathology accession number, and order in which the sections were 
cut from the block. H&E stain the first and last five micron slide that is cut (i.e., 
slides labeled 1 and 15). These H&E slides will be reviewed centrally for 
assessing tissue quality. The remaining unstained slides will be processed as 
described in section 14.4.  For samples containing less than 7 square millimeters 
of tumor tissue, multiple sections should be mounted onto each slide to ensure 
that the appropriate amount of tumor tissue is available. Ideally, each slide must 
have a minimum of 75 % tumor tissue on the slide to be deemed adequate for 
study. Do not bake or place covers slips on the slides. 
 
14.3 
Biospecimen Processing and Submission 
 
14.31 Biospecimen Kits 
Blood: Blood specimen kits are required.  
 
Tissue: If an institution is capable of collecting and shipping frozen tissue 
specimens, kits are strongly recommended and will be provided to each 
institution on request.  
 
Sites may order these kits in advance at no charge from the Alliance-Central 
Specimen Bank by contacting 
 
 or by email to 
Kits will be sent via 
FedEx® Ground at no additional cost to the participating institutions. Allow at 
least two weeks to receive the kits. Kits will arrive inside the shipping boxes. 
Kits will not be sent via rush delivery service unless the requesting site provides 
their own FedEx® account number or alternate billing number for express 
service. Alliance will not cover the cost for rush delivery of kits. 
 
14.32 Blood Processing and Submission 
Ship two 10 mL EDTA tubes with a properly prepared cold pack.  See kit 
instructions for specific details for cold pack preparation (i.e., frozen or 
refrigerated) and proper packing of blood and cold pack to avoid freezing of 
specimen.  
 
14.33 Tissue Processing and Submission 
 
14.331 
Frozen Tissue Processing and Submission 
 After breast conservation surgery, the specimens should be brought to 
the pathology department as soon as possible (generally speaking, this 
means within 15 minutes after the time of tissue resection). If possible, 
in order to accurately record the ex vivo ischemia time, the time at 
which the specimens are excised from the patient should be 
recorded. The specimens should be kept fresh and not put into any 
type of fixative, although it may be transported to pathology in a 
solution of normal saline or any other physiologic buffer. The 
specimens should be reviewed by the attending pathologist or other 

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authorized individual (pathology resident, fellow, or qualified 
pathologist assistant). Material needed for diagnosis should be 
removed and processed according to the institution's standard 
procedures. Any remaining tissue may be sent to the Alliance Central 
Specimen Bank.  
 
 Where possible, representative and grossly apparent tumor tissue from 
each foci of disease and one sample of intervening normal breast tissue 
should be collected. Where two foci of disease are resected in one 
lumpectomy, non-malignant tissue from the area between the two 
tumors should also be submitted. Where two separate foci of disease 
are resected in separate lumpectomies, non-malignant tissue from the 
area between the two tumors is not required to be submitted. Normal 
tissue from the margin of the lumpectomy specimen can be submitted 
as the intervening normal tissue. Tissue that is grossly necrotic, 
hemorrhagic or cauterized should be avoided. Tissue should be rapidly 
divided into segments no larger than 1 cm3 (1 gram). As many as 
possible (but at least one) of these sized segments should be collected 
from each site of disease.  
 
If the foci are removed separately and margins on both are negative, it 
is assumed that the radiographic distance (closest distance by MRI or 
mammogram) would be the appropriate separation. 
 
 Place the tissue segments in the tissue cassettes provided (usually 2-3 
segments of tissue per cassette). Use multiple cassettes if necessary - 
do not “stuff” large amounts of tissue into a single cassette. Label the 
cassette with 'T' for tumor or 'N' for non-malignant tissue using the 
marker provided. Wrap each cassette in a piece of foil (provided in the 
kit). Place the cassette at one end of the foil and roll the foil around the 
cassette. Carefully fold over the ends of the foil and crease them tightly 
to create a sealed, compact packet. Immediately immerse the foil-
wrapped cassette in liquid nitrogen for 5 minutes. If liquid nitrogen is 
not available, the specimen may be immersed in an isopentane 
cryobath available in most surgical pathology frozen section rooms. If 
using a cryobath, be certain that the temperature of the bath is at or 
below − 40° C. As a last option, specimens may be frozen by complete 
immersion in an ethanol / dry-ice bath. Specimens should be left in the 
cryobath or dry ice bath for at least 15 minutes to ensure complete 
freezing. Specimens should not be frozen by placing fresh tissue in an 
− 80° C freezer or inside a cryostat. The time at which the tissue is 
frozen should be recorded so that, together with the recorded time 
of operative resection, the ex vivo warm ischemia time can be 
calculated.  
 
Once frozen, foil-wrapped tissue cassettes should be placed in one or 
more of the zip-lock bags provided. Be certain that the specimen bag is 
accurately and legibly labeled with the patient study ID number. Once 
frozen, take extreme care not to let the tissue specimen thaw.  If an 
ultra-cold freezer (i.e., − 80° C or colder) is not available, the 
specimens must be shipped the same day they are collected and 

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frozen.  If an ultra-cold freezer is available, specimens may be stored 
at − 80°C or colder until frozen specimens can be appropriately 
shipped (≤ 30 days after surgery). The specimens must be shipped with 
sufficient dry ice for up to two days. Specimens must remain frozen 
at all times. 
 
If resources are not available at the site to collect snap frozen 
surgical tissue, FFPE tissues must be submitted (see next section). 
 
 
14.332 
FFPE Tissue Processing and Submission 
FFPE blocks/slides should be submitted from each of the foci of 
malignancy and also where available from the intervening non-
malignant tissue (as described above). The block/slides must be 
appropriately packed to prevent damage (i.e., slides should be placed in 
appropriate slide container) and placed in an individual plastic bag. 
Tissue specimens must be shipped ≤ 30 days after surgery. 
 
14.34 General Biospecimen Shipping Instructions  
Use of the Alliance Biospecimen Management System (BioMS) is mandatory 
and all specimens must be logged and shipped via this system. 
 
BioMS is a web-based system for logging and tracking all biospecimens 
collected on Alliance trials. Authorized individuals may access BioMS at the 
following URL: 
using most standard web browsers 
such as Internet Explorer, Safari and Firefox. For information on using the 
BioMS system, please refer to the ‘Help’ links on the BioMS webpage to access 
the on-line user manual, FAQs and training videos. To report technical problems, 
such as login issues or application errors, please contact 
For 
assistance in using the application or questions or problems related to specific 
specimen logging, please call 
 
 
After logging collected specimens in BioMS, the system will create a shipping 
manifest. This shipping manifest must be printed and placed in the shipment 
container with the specimens. 
 
All tissue and blood specimens collected for correlative studies are shipped to the 
Alliance Central Specimen Bank (CSB) where they will be permanently stored 
unless a specific request is made to return materials for the purpose of individual 
patient care or if the patient requests that her materials be returned. 
 
Specimens may be shipped Priority Overnight to the Alliance CSB on Monday 
through Thursday for next day delivery. The Bank cannot receive specimens on 
Saturdays, Sundays or holidays. Do not send specimens on Friday, Saturday 
or the day before a holiday. 
 
Sites are responsible for the costs of shipments; however, federal funds for the 
submission of whole blood and FFPE/frozen tissue specimens are included in the 
payment schedule and paid upon confirmation of receipt of the specimens. 
 

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14.4 
Biospecimen Use 
 
14.41 Blood Use 
DNA will be extracted from EDTA whole blood and white blood cells will be 
prepared from residual blood.  Similar to the tumor samples being collected in 
this study (see the following section), DNA will be isolated and subjected to 1) 
gene expression profiling; 2) array comparative hybridization; and 3) gene 
sequencing for significantly mutated genes. These studies will be performed in 
conjunction with the tumor studies. 
 
14.42 Tissue Use 
When patients present with multifocal disease, it is unclear whether this 
represents multiple separate primary cancers or the manifestation of one tumor 
that has disseminated through the breast to create separate nodules but with 
similar genomic characteristics. This distinction may have important clinical 
consequences. Two entirely unrelated cancers arising separately in the same 
breast could quite logically be treated as separate tumors from the surgical 
standpoint, but from the medical standpoint may need different systemic 
approaches. In contrast, tumors that appear separate but are in fact genomically 
similar may represent wide dissemination of the same malignant process and may 
not be suitable for conservative breast surgery, but would be treated with the 
same systemic approach. 
 
To begin to explore this question we will apply genomic approaches, including 
gene expression, gene copy and gene sequencing to the multiple tumor sites to try 
to differentiate between these two possibilities. Tumors with similar gene 
expression profiles, copy number aberrations and somatic mutations will be 
called related; tumors where these features are discordant will be called 
unrelated. Clearly one can also envisage the possibility of multi-clonality where 
two separate nodules have a common precursor but have diverged over time. In 
this setting, the digital nature of next generation sequencing is very valuable, as 
not only will we be able to compare a list of mutations, but their frequency, 
allowing us to study clonality in an efficient way. 
 
These experiments will be conducted in two settings. The first setting is in a 
subset of patients with three available data sources: 1) have consented to whole 
genome sequencing; 2) a frozen specimen from each tumor acquired by the 
surgeon or pathologist; and 3) a germ-line specimen (tube of peripheral blood). 
This will allow a very deep unbiased genomic analysis and will provide the most 
definitive data on the relatedness of two separate sites of disease in the 
breast. The second setting is where one of these three data sources is 
missing.  For patients who did not consent for genomic studies or in whom only 
fixed material is available or the germline DNA is not available we will use 
techniques adapted to formalin fixed material to examine selected breast cancer 
genes for mutation or expression to determine relatedness. 
 
Since this type of analysis has not been attempted before, all statistics will be 
exploratory; however our primary hypothesis is that unrelated tumors that are 

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fully excised have a low local recurrence upon breast conservation surgery. In 
contrast, multiple related tumors will have a high rate of local recurrence because 
functionally tumors are widely disseminated throughout the breast even though 
the margins of excision appear negative.  
 
DNA and RNA will be isolated from each separate tumor site and subjected to 1) 
gene expression profiling (addressing the question of whether the tumor foci 
have the same or different intrinsic subtype (basal-like, luminal A, luminal B, 
HER2-enriched, claudin-low); 2) array comparative hybridization (to determine 
whether they have the same or different patterns of gene copy variation, e.g., 
LOH and amplification) and 3) gene sequencing. The sequencing will be full 
genome in a subset of patients where high quality frozen samples were taken and 
are available from each tumor site. Then in all cases, a sequencing assay for 
significantly mutated genes in breast cancer can be performed on routinely 
formalin-fixed tumor material. 
 
Formalin fixed surgical pathology blocks requested to accommodate individual 
patient management will be returned promptly upon request. 
   
 
14.5 
Return of Genetic Testing Research Results 
 
Because the results generated by the genetic testing described above are not currently 
anticipated to have clinical relevance to the patient or their family members and will be 
conducted in a research facility, the genetic results will not be disclosed to the patients or 
their physicians. 
 
 
If at any time, incidental genetic results are obtained that may have clinical relevance, 
IRB review and approval will be sought regarding the most appropriate manner of 
disclosure and whether or not validation in a CLIA-certified setting will be required prior 
to reporting any finding.  Sharing of research data with individual patients should only 
occur when data have been validated by multiple studies and testing has been done in 
CLIA-approved laboratories or in a setting where a clinical trial is available based on a 
CLIA laboratory validated sequencing result and the patient has consented to re-contact 
for additional studies. 
 
 
15.0 
Whole Breast Irradiation (WBI) Risks  
 
15.1 
Risks and Side Effects Related to the Whole Breast Irradiation (WBI) 
Risks and side effects related to the WBI include the following: 
 
Likely (Events that occur more than 10 % of the time) 
• 
Reddening of the skin during treatment and for several weeks following 
treatment 
• 
Tanning of the skin lasting months and may be permanent 
• 
Slightly smaller breast size or change in the way the breast looks 
• 
Tiredness and weakness during treatment and for several weeks following 
treatment 
• 
Muscles in chest wall under treated breast may feel tight or sore 
• 
Swelling of breast  
 

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Less Likely (Events that occur 3 to 9 % of the time) 
• 
Peeling of the skin in the area treated with radiation 
• 
Pain at the site of radiation treatment 
 
Rare but serious (Events that occur < 3 % of the time) 
• 
Cough 
• 
Difficulty breathing 
• 
Irritation of the sac surrounding the heart 
• 
Inflammation of the heart muscle 
• 
Rib fracture 
• 
Another cancer due to radiation therapy 
 
 
16.0 
Statistical Considerations and Methodology 
16.1 
Overview 
A single arm phase II clinical trial design will be used to assess whether the local 
recurrence (LR) rate at 5 years in women with multiple ipsilateral breast cancers who 
undergo breast conserving surgery is greater than 8 %.  
 
 
16.2  
Study Endpoints 
The primary endpoint for this trial is the diagnosis of a local recurrence as a first event 
where a local recurrence is defined as histologic evidence of ductal carcinoma in situ or 
invasive breast cancer in the ipsilateral breast or chest wall.   
 
The cumulative incidence of local recurrences will be estimated in the competing risk 
framework as described by Marubini and Valsecchi where regional recurrences, distant 
recurrences and death without a local recurrence will be considered competing risks and 
contralateral breast and non-breast second primary cancers will not be considered 
competing risk. 
 
All eligible patients who have undergone breast conservation surgery with 2 or 3 sites of 
disease resected to negative margins (i.e., not converted to mastectomy or have not 
refused mastectomy for positive margins) will be included in the analysis of the primary 
endpoint.  
 
Secondary clinical endpoints are: 
 
• 
The conversion rate to mastectomy secondary to persistent positive margins; poor 
cosmesis within the first year of attempting breast conservation surgery (BCS); 
or inability to satisfy radiation dose constraints on the boost to the lumpectomy 
bed of each site of disease 
 
• 
The type and severity of adverse effects of breast conserving surgery and 
radiation for women with multiple ipsilateral primary breast cancer (MIBC)  
 
• 
The radiation-related side effects of whole breast radiation with a boost to 1 large 
or > 1 lumpectomy site 
 
• 
The patient’s perception of cosmesis.  
 

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16.3 
Sample Size Determination 
Assuming a cohort of 200 eligible patients is enrolled over a 2 year period, the follow-up 
period after the close of enrollment is 5 years, and the number of local recurrences 
follows a Poisson distribution, the upper bounds of 95 % confidence interval for the 
cumulative incidence of a local recurrence within 5 years would fall below 8 % if at most 
8 local recurrences occurred as a first event among these 200 patients.   
 
It was originally planned to have an additional 30 patients enrolled to account for patients 
who withdraw consent prior to surgery, are found to be ineligible after signing a consent 
form, convert to mastectomy, or are found to have a single contiguous area of malignancy 
at final pathology. During the course of the study, it was found that many patients were 
being deemed ineligible after enrollment because the distance between lesions was 
outside the allowable range. This caused a high rate of ineligibilities. The protocol was 
amended and the ineligibility rate has subsequently decreased. However, in order to 
obtain the 200 evaluable patients needed for the primary endpoint, the study will need to 
enroll a total of 265 (35 additional) patients. Hence the target accrual for the study is 265 
patients. 
 
16.4 
Accrual Time 
American Joint Committee on Cancer (AJCC) version 7.0 defines two macroscopic 
cancer foci in the same breast as multiple cancers if they are at least 0.5 centimeters apart. 
No distinction is made as to whether these are multifocal breast cancers (foci no more 
than 5 cm apart from each other in the same quadrant) or multicentric breast cancers (foci 
in different quadrants or foci in the same quadrant but more than 5 cm apart from each 
other). Moreover, the AJCC states that pathologic tumor size should be based only on the 
single largest tumor and recommends that pathologic T stage be designated as pTany(m) 
where m indicated the number of multiple lesions. As the presence of multiple ipsilateral 
breast cancers (MIBC) are not routinely collected through AJCC staging or in the setting 
of breast cancer clinical trials, the incidence of this disease in general is not well known. 
Similarly, it is unknown how many women with MIBC have enrolled in clinical trials.  
Retrospective case studies estimate that 15 % of women diagnosed with breast cancer 
have MIBC. The estimated number of new female breast cancer cases in 2010 is 207,090 
(Jemal et al., 2010).  Assuming that 15 % of these cases will have multiple ipsilateral 
breast cancers (31,064 cases) and 3 to 5 % of these multiple ipsilateral breast cancer cases 
will consider participating in a clinical trial, there will be 932 to 1553 potential 
candidates for this trial per year. The Alliance investigators accruing to currently open 
studies are interested and supportive of this trial design. For these reasons, accrual of 8 to 
9 patients per month is anticipated to be feasible, for a total accrual time of about 25 
months. The study requires and additional 5-6 months of accrual to meet the planned 
sample size. 
 
16.5 
Study Monitoring 
 
16.51 Futility stopping rules 
If more than 8 local recurrences are observed as a first event, the trial will stop as 
the 5 year local recurrence rate is unacceptably high. 
 
A conversion to mastectomy rate of 25 % or more is considered to be 
unacceptably high. As such, consideration will be given to discontinuing 

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enrollment if 35 or more women among the first 100 women enrolled convert to 
mastectomy secondary to persistent positive margins or poor cosmesis within 6 
months of BCS. The lower bound for 95 % binomial confidence interval for the 
conversion rate is 25.7 % (if 35 of 100 women convert to a mastectomy). 
 
16.6 
Analysis Plan 
 
16.61 Local Recurrence Rate 
All eligible patients who have undergone surgery that was not converted to a 
mastectomy and who did not have a finding of single contiguous area of 
malignancy on final pathology will be included in the analysis of the primary 
endpoint. 
 
The cumulative incidence of local recurrences will be estimated in the competing 
risk framework as described by Marubini and Valsecchi where regional 
recurrences, distant recurrences and death without a local recurrence will be 
considered competing risks and contralateral breast and non-breast second 
primary cancers will not be considered competing risk. A 95 % Poisson 
confidence interval for the cumulative incidence of a local recurrence within 5 
years will be constructed.  
 
Gentilini et al. reported that cumulative incidence of local recurrence differed in 
terms of estrogen receptor status, HER2/neu expression, Nottingham grade, and 
Ki-67 expression (univariately) (Gentilini et al., 2009). Gray’s test will be used 
to explore whether the cumulative incidence of local recurrence differs with 
respect to these factors as well as progesterone receptor status, number of 
positive lymph nodes, number of foci, t-stage, age, perception of quality of life as 
measured by LASA at registration (poor: 0 to 3; middling: 4 to7; good/excellent: 
8 to 10), and fatigue as measured by LASA at registration (none to little: 0 to3; 
some: 4 to 7; a great deal: 8 to10).    
 
16.62 Conversion to Mastectomy 
The conversion rate to mastectomy secondary to persistent positive margins; poor 
cosmesis within the first year of attempting BCS; or inability to satisfy the 
radiation dose constraints on the boost to the lumpectomy bed of each site of 
disease 
 
All eligible patients who have initiated surgery will be included in the analysis of 
conversion to mastectomy. A 95 % binomial confidence interval will be 
constructed for the percentage of patients who converted to mastectomy. Logistic 
regression analysis will be used to assess whether the likelihood of conversion to 
mastectomy differed with respect to patient and/or disease characteristics.  
 
An interim efficacy analysis will not be performed; final analysis will performed 
at year 7 after patients have at least 5 years of follow-up. 
 
Patients enrolled subsequent to surgery will be excluded from this analysis. 
 

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16.63 Analysis of Patients With Margins <2mm 
A subset analysis will be done of patients with close margins (< 2 mm) who did 
not undergo re-excision.  
The purpose is to see whether the inclusion of these patients inflated the local 
recurrence (LR) rate. In addition, the LR rate of patients with close margins (< 2 
mm) who did not undergo re-excision will be estimated with point estimate and 
95% confidence interval. 
 
16.64 Adverse Events 
The NCI CTCAE version 4.0 will be used to assess the type and severity of 
adverse effects of breast conserving surgery for women multiple ipsilateral 
primary breast cancer as well as the type and severity of radiation-related adverse 
effects of whole breast radiation with a boost to 1 large or > 1 lumpectomy site in 
women multiple ipsilateral primary breast cancer. However, CTCAE version 5.0 
will be used for expedited adverse event reporting. 
 
16.65 Incidence of Breast Lymphedema (BLE) 
For each time point, a 95 % binomial confidence interval for the proportion of 
patients diagnosed with breast lymphedema will be determined. Breast 
lymphedema will be defined as a patient who has a symptom survey score > 0 
and presence of breast edema by physical examination. 
  
16.66 Patient’s Perception of Cosmesis 
All eligible patients who have undergone surgery that was not converted to a 
mastectomy will be included in these analyses.  
 
Patient’s perception of cosmesis will be assessed at their initial post-operative 
visit as well as 1, 6, 12, and 24 months following completion of WBI using the 
BREAST-Q subscales: satisfaction with breasts, satisfaction with overall 
outcome, and physical well-being.  
 
Patients registered after surgery will not partake in the pre-operative assessment 
but will be asked to complete subsequent cosmesis surveys. 
 
The following statistical analyses will be conducted separately for those women 
who undergo an ALND and those who do not undergo an ALND. 
 
16.661  
At Each Time Point 
 The total score for each of these subscales will be determined using the 
BREAST-Q scoring module 
 
 For each of the subscales, a 95 % binomial confidence interval for the 
proportion of patients reporting deficits in that domain will be 
constructed. Also, a 95 % binomial confidence interval for the 
proportion of patients indicating that their cosmesis result on the one 
item questionnaire was poor or fair (scores: 3 or 4) will be constructed. 
For each of the three subscales, a Wilcoxon rank sum test will be used 

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to assess domain score differs between those women reporting a 
poor/fair cosmesis result on the one item questionnaire (scores 1 or 2)  
and those women reporting a good/excellent cosmesis result on the one 
item questionnaire. 
 
16.662  
Across Time 
 At years 1 and 2 post WBI, logistic regression modeling will be used to 
assess which patients, disease, and/or treatment characteristics as well 
as of breast lymphedema are associated with an increased likelihood of 
each of the following endpoint: reporting a poor to fair cosmesis, poor 
satisfaction with breast cosmesis, poor satisfaction with overall 
outcome, and poor physical well-being.  
 
 The agreement between year 1 post WBI cosmesis findings and year 2 
post WBI cosmesis findings in terms of a poor to fair cosmesis, poor 
satisfaction with breast cosmesis, poor satisfaction with overall 
outcome, and poor physical well-being will be assessed using 
McNemar tests. 
 
16.663 
Agreement with Surgeon’s Perception of Cosmetic Results at Initial 
Post-surgical Evaluation 
 
Impression of cosmesis will be dichotomized as poor to fair versus 
good to excellent. A 95 % confidence interval will be constructed for 
the proportion of cases where the patient and his surgeon agree in 
terms of cosmesis results.   
16.664 
Differences of the Extent of Disease Described on Mammography 
Compared with Surgical Findings 
 All eligible patients who have initiated surgery will be included in the 
analysis of this endpoint. The maximum lesion dimension and location 
of each lesion found on mammogram will be determined on central 
review. Agreement between the lesion size on mammogram and the 
lesion size reported on surgical pathology report will be examined 
using the approaches proposed by Bland and Altman. That is, a plot of 
the average of lesion size on mammogram and the lesion size reported 
on surgical pathology report versus the difference in lesion size 
between that found on mammogram and that found on surgery will be 
constructed to examine systematic biases.  A 95 % z-confidence of the 
difference in lesion size between that found on mammogram and that 
found on surgery will be constructed. Percent agreement will be used 
to assess the extent of agreement between location of the lesion seen 
on mammogram and the location of the lesion reported on surgical 
pathology report. 
 
16.7 
Data and Safety Monitoring 
The principal investigator and the study statistician will review the study at least twice a 
year to identify accrual, adverse event and any endpoint problems that might be 
developing. The Alliance Data Safety Monitoring Board is responsible for reviewing 
safety data for this trial at least twice a year, based on reports provided by the Mayo 
Clinic Cancer Center Statistical Office.  
 

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16.8 
Inclusion of Women and Minorities 
Based on the patient cohort enrolled onto ACOSOG Z1071, we anticipate that the ethnic 
and racial composition of our study cohort will be as follows: 
 
 
 
Racial Categories 
Ethnic Categories 
Not Hispanic or Latino 
Hispanic or Latino 
Total 
Female 
Male 
Female 
Male 
 
American Indian/Alaska Native 
1 
0 
0 
0 
1 
Asian 
6 
0 
0 
0 
6 
Native Hawaiian or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African American 
29 
0 
3 
0 
32 
White 
198 
0 
22 
0 
220 
More Than One Race 
5 
0 
1 
0 
6 
Total 
239 
0 
26 
0 
265 
 
 
 
17.0  
Pathology Considerations/Tissue Biospecimens  
 
See Sections 7.0 and 14.0 
 
18.0 
 Data Collection Procedures 
18.1 
Medidata Rave 
Data collection for this study will be done exclusively through the Medidata Rave clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles in the Regulatory Support System 
(RSS). To access Rave via iMedidata,the site user must have an active CTEP IAM 
account 
 and the appropriate 
Rave role (RAVE CRA, Read-Only, Site Investigator) on eith the LPO or participating 
organization roster ate the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles 
assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata. 
To accept the invitation, site users must log into the Select Login 
using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata page. 
Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed. Trainings will be in the form of 
electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMediata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will also receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website, Rave tab under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave 
is available on the CTSU website under the Rave tab at 
or by 
contacting the CTSU Help Desk at 
 
  

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18.2 
Submission Timetable  
Study phases  
 
Surgery  
Day of the registration to 30 days post the final surgery 
Adjuvant chemotherapy  
Day of evaluation prior to the start of hormone medications or adjuvant 
chemotherapy to the day of evaluation following completion of hormone 
medications or adjuvant chemotherapy 
WBI  
Day of evaluation prior to the start of WBI to day of evaluation following 
completion of WBI 
Observation1  
Six months after the completion of WBI to 5 years after the completion of 
WBI 
1. Patients will go to observation for refusal, adverse events or at the discretion of the treating physician. 
Patients who have recurrence during treatment or during the observation phase and patients who 
refuse to comply with the test schedule during the observation phase will enter the event monitoring 
phase (see Section 13.4).  

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Initial Material(s) 
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Institution Contact Information  
 
 
 
 
 
 
≤ 2 weeks after registration 
 
 
 
 
 
 
 
 
 
 
 
On-Study1  
On-Study: Mammography  
On-Study: MRI2 (if performed) 
On-Study: Ultrasound3  
On-Study: Biopsy Information  
Adverse Events: Baseline 
Imaging Submission: Institution 
Report Submission4 
Reports – Biopsy Procedure, Biopsy 
Pathology, Mammography and MRI (if 
performed) 
Ultrasound (if performed)  
Note: The distance between the lesions must 
be documented on mammogram and/or 
MRI. 
Blood Sample Submission: (Institution) 
Patient Status: Baseline 
 
Patient Questionnaire Booklet- Baseline 
≤ 2 weeks after registration – The Patient Questionnaire 
Booklet must be ordered by the site using the CTSU 
request form located on the CTSU website  
Patient Questionnaire Booklet - Compliance 
≤ 2 weeks after registration - This form must be 
completed only if the Patient Questionnaire Booklet 
contains absolutely NO patient provided assessment 
information. 
Off Treatment 
Submit ≤ 2 weeks after registration if withdrawal/refusal 
occurs prior to surgery  
1. The Breast Lesion Position Diagram must be completed for each patient and uploaded into Rave with the 
On-Study form. Note: Lesions should be numbered clockwise per the breast diagram completion 
instructions. 
2. This form will be required if an MRI was performed. 
3. This form will be required if an ultrasound was performed. 
4. This form is used to record the submission of the baseline reports needed for review by the QAS/Data 
Manager. 

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Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Surgery 
Phase 
At completion of 
adjuvant 
chemotherapy 
(if applicable) 
At completion 
of 
WBI 
Observation 
post WBI 
follow-up 
Patient Status: Treatment 
(Intervention) 
X1 
 
 
 
Surgery  
X1 
 
 
 
Contralateral Surgery 
X1, 9 
 
 
 
Pathology Information  
X 
 
 
 
Adverse Event  
X 
 
X1,7 
 
Other Adverse Event  
X 
 
X,7,8 
 
Patient Questionnaire:  
Active Monitoring 
X2,3 
 
 
X2,3 
Surgeon Questionnaire:  
Active Monitoring 
X2,5 
 
 
 
Patient Questionnaire:  
Booklet Compliance 
X1 
 
 
X4 
Blood Sample Submission: 
Institution 
X1 
 
 
 
Tissue Sample Submission: 
Institution 
X1 
 
 
 
Adjuvant Systemic Therapy 
Evaluation Form 
 
X6 
 
 
Radiation Treatment Plan 
Submission  
 
 
X7 
 
Radiation Therapy  
Information Form 
 
 
X7 
 
Start of Adjuvant Endocrine/ 
Biologic Therapy  
 
 
 
X17 
Patient Status:  
Clinical Follow Up/Observation 
 
 
 
X 
Evaluation/Observation 
 
 
 
X10 
Termination of Endocrine Therapy  
 
 
 
X11 
Termination of Biologic Therapy  
 
 
 
X12 
Off Treatment 
(Completion of WBI) 
 
 
X 
 
NCCTG sites only:  
Notification – Grade 4 or 5 Non-
AER Reportable 
Events/Hospitalization  
 
 
At each 
occurrence 
(see Section 
10.0) 
 
Notice of New Primary13 
 
At each 
occurrence 
At each 
occurrence 
At each 
occurrence 
Recurrence Information14 
 
X 
X 
X 
Local-Regional Recurrence  
Documentation Submission15 
 
X 
X 
X 
Distant Recurrence  
Documentation Submission16 
 
X 
X 
X 

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Early Termination of Follow-Up 
Consent Withdrawal 
Lost to Follow-Up 
 
These forms must be completed when the study 
participant is withdrawing consent for QOL 
(questionnaires), specimens, clinical follow-up only, 
or all follow-up or if they have become lost to 
follow-up. These forms are found in the Add Event 
dropdown list in Rave. Once added, they will be 
found in the Early Termination of Follow-Up 
Folder. Please note: If the study participant is 
refusing further study treatment, document the 
refusal by completing an Off Treatment Form,  
not a Consent Withdrawal Form. 
1. Submit ≤ 30 days following surgery.  
2. Patient and surgeon questionnaire booklets must be ordered by the site from the CTSU using the form 
located on the CTSU website; the forms located in the appendices of the protocol can be downloaded 
and printed directly from the CTSU website for IRB submission only. Forms used by patients must be 
ordered from the CTSU. 
3. Patient questionnaire booklets will be administered to patients 5 to 30 days following final surgery 
(initial post-operative visit); every six months (± 1 month) for the first 2 years following completion 
of WBI; then every year (± 2 months) for the next 3 years to assess cosmetic outcome.  
4. This form must be completed only if the Patient Questionnaire Booklet contains absolutely NO 
patient provided assessment information. 
5. Surgeon questionnaire booklets will be completed by the patient’s surgeon 5 to 30 days following 
final surgery (initial post-operative visit) to assess cosmetic outcome. 
6. Submit ≤ 30 days following completion/discontinuation of adjuvant chemotherapy. 
7. Submit ≤ 30 days following completion/discontinuation of radiation therapy. 
8. The Other Adverse Event form is only completed if there are adverse events other than the ‘solicited’ 
adverse events. 
9. This form is required only if the site indicates on the Surgery form that the patient had surgery to the 
opposite breast. 
10. Complete at each evaluation during observation (See Section 4.0) 
11. Complete this form only if patient has ended all adjuvant endocrine therapy. 
12. Complete this form only if patient has ended all biologic therapy. 
13. If, at any time, the patient has a new primary or contralateral breast disease, complete this form 
14. If a recurrence has been reported on the Patient Status form, complete this form 
15. If a local-regional recurrence has been reported on the Recurrence Information form, complete this 
form. 
16. If a distant recurrence has been reported on the Recurrence Information form, complete this form. 
17. Submit ≤ 30 days following start of adjuvant endocrine therapy. 
 
Follow-up Material(s) 

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CRF 
Event Monitoring Phase1 
every 12 
months 
until PD 
At PD 
After PD 
every 12 
months 
Death 
New Primary 
Patient Status: Survival and Disease 
Status Follow Up/Event Monitoring 
X 
X2 
X 
X 
 
 
Recurrence Information3 
 
X 
 
 
 
Local-Regional Recurrence 
Documentation Submission4 
 
X 
 
 
 
Distant Recurrence Documentation 
Submission5 
 
X 
 
 
 
 
Notice of New Primary6 
 
 
 
 
At each occurrence 
Early Termination of Follow-Up 
Consent Withdrawal 
Lost to Follow-Up 
These forms must be completed when the study participant is 
withdrawing consent for QOL (questionnaires), specimens, clinical 
follow-up only, or all follow-up or if they have become lost to 
follow-up. These forms are found in the Add Event dropdown list in 
Rave. Once added, they will be found in the Early Termination of 
Follow-Up Folder. Please note: If the study participant is refusing 
further study treatment, document the refusal by completing an Off 
Treatment Form, not a Consent Withdrawal Form. 
1.  If a patient is still alive 5 years after the last date of radiation therapy, no further follow-up is 
required. 
2.  Submit copy of documentation via the appropriate Recurrence Documentation Submission form in 
Rave 
3.   If a recurrence has been reported on the Patient Status form, complete this form. 
4.  If a local-regional recurrence has been reported on the Recurrence Information form, complete this 
form. 
5.   If a distant recurrence has been reported on the Recurrence Information form, complete this form. 
6.   If, at any time, the patient has a new primary or contralateral breast disease, complete this form.   
 

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19.0  
Budget 
This study is funded by an NIH grant to Alliance. 
 
19.1 
Costs Charged to Patient   
Routine clinical care 
 
19.2 
Tests to be Research Funded 
 Research blood and tissue sample collection, processing and shipping. 
 
 
20.0 
References 
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18474876. 
 
Hwang-Verslues, W. W., W. H. Kuo, P. H. Chang, C. C. Pan, H. H. Wang, S. T. Tsai, Y. M. Jeng, J. Y. 
Shew, J. T. Kung, C. H. Chen, E. Y. Lee, K. J. Chang and W. H. Lee. Multiple lineages of human breast 
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Imaging Reporting and Data System: ACR BI-RADS – Breast Imaging Atlas. C. J. D'Orsi, E. B. 

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Mendelson, D. M. Ikeda and e. al., (Eds.). Reston, VA, American College of Radiology, 2003. 
 
Jemal, A., R. Siegel, J. Xu and E. Ward. Cancer statistics, 2010.  CA Cancer J Clin 60(5): 277-300, 2010. 
PMID: 20610543. 
 
Jones, N. B., J. Wilson, L. Kotur, J. Stephens, W. B. Farrar and D. M. Agnese. Contralateral prophylactic 
mastectomy for unilateral breast cancer: an increasing trend at a single institution. Ann Surg Oncol 
16(10): 2691-96, 2009. PMID: 19506956. 
 
Kaplan, J., G. Giron, P. I. Tartter, I. J. Bleiweiss, A. Estabrook and S. R. Smith. Breast conservation in 
patients with multiple ipsilateral synchronous cancers. J Am Coll Surg 197(5): 726-29, 2003. PMID: 
14585405. 
 
 Katipamula, R., A. C. Degnim, T. Hoskin, J. C. Boughey, C. Loprinzi, C. S. Grant, K. R. Brandt, S. 
Pruthi, C. G. Chute, J. E. Olson, F. J. Couch, J. N. Ingle and M. P. Goetz. Trends in mastectomy rates at 
the Mayo Clinic Rochester: effect of surgical year and preoperative magnetic resonance imaging. J Clin 
Oncol 27(25): 4082-88, 2009. PMID: 19636020. 
 
Kiebert, G. M., J. C. de Haes and C. J. van de Velde. The impact of breast-conserving treatment and 
mastectomy on the quality of life of early-stage breast cancer patients: a review.  J Clin Oncol 9(6): 1059-
70, 1991. PMID: 2033420. 
 
Komenaka, I. K., R. E. Pennington, Jr., B. P. Schneider, C. H. Hsu, L. E. Norton, S. E. Clare, N. M. Zork 
and R. J. Goulet, Jr. Compliance differences between patients with breast cancer in university and county 
hospitals.Clin Breast Cancer 10(5): 385-91, 2010. PMID: 20920983. 
 
Kurtz, J. M., J. Jacquemier, R. Amalric, H. Brandone, Y. Ayme, D. Hans, C. Bressac and J. M. Spitalier. 
Breast-conserving therapy for macroscopically multiple cancers. Ann Surg 212(1): 38-44, 1990. PMID: 
2363602. 
 
Lee, J. M., S. G. Orel, B. J. Czerniecki, L. J. Solin and M. D. Schnall. MRI before reexcision surgery in 
patients with breast cancer." AJR Am J Roentgenol 182(2): 473-80, 2004. PMID: 14736685 
. 
Leopold, K. A., A. Recht, S. J. Schnitt, J. L. Connolly, M. A. Rose, B. Silver and J. R. Harris (1989). 
Results of conservative surgery and radiation therapy for multiple synchronous cancers of one breast. Int 
J Radiat Oncol Biol Phys 16(1): 11-16, 1989. PMID: 2536361. 
 
Lim, W., E. H. Park, S. L. Choi, J. Y. Seo, H. J. Kim, M. A. Chang, B. K. Ku, B. Son and S. H. Ahn. 
Breast conserving surgery for multifocal breast cancer. Ann Surg 249(1): 87-90, 2009. PMID: 19106681. 
 
Lohr, K. N. Assessing health status and quality-of-life instruments: Attributes and review criteria. Qual 
Life Res 11(3): 193-205, 2002. PMID: 12074258. 
 
Marubini, E. and M. G. Valsecchi (1995). Analysing Survival Data from Clinical Trials and 
Observational Studies. V. Barnett, (Ed.) Chichester, England, John Wiley & Sons Ltd. 
 
McGuire, K. P., A. A. Santillan, P. Kaur, T. Meade, J. Parbhoo, M. Mathias, C. Shamehdi, M. Davis, D. 
Ramos and C. E. Cox. Are mastectomies on the rise? A 13-year trend analysis of the selection of 
mastectomy versus breast conservation therapy in 5865 patients. Ann Surg Oncol 16(10): 2682-90, 2009. 
PMID: 19653046. 
 

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Moon, W. K., D. Y. Noh and J. G. Im. Multifocal, multicentric, and contralateral breast cancers: bilateral 
whole-breast US in the preoperative evaluation of patients. Radiology 224(2): 569-76, 2002. PMID: 
12147858. 
 
Morrow, M. and J. R. Harris. More mastectomies: is this what patients really want? J Clin Oncol 27(25): 
4038-40, 2002. PMID: 19635996. 
 
Nakshatri, H., E. F. Srour and S. Badve . Breast cancer stem cells and intrinsic subtypes: controversies 
rage on. Curr Stem Cell Res Ther 4(1): 50-60, 2009. PMID: 19149630. 
 
Norum, J., J. A. Olsen and E. A. Wist. Lumpectomy or mastectomy? Is breast conserving 
surgery too expensive? Breast Cancer Res Treat 45(1): 7-14, 1997. PMID: 9285112. 
 
Nos, C., D. Bourgeois, C. Darles, B. Asselain, F. Campana, B. Zafrani, J. C. Durand and K. Clough. 
Conservative treatment of multifocal breast cancer: a comparative study. Bull Cancer 86(2): 184-88, 
1999. PMID: 10066949. 
 
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control of clinically diagnosed multifocal or multicentric breast cancer after neoadjuvant chemotherapy 
and locoregional therapy. J Clin Oncol 24(31): 4971-75, 2006. PMID: 17075114 
. 
 Olivotto, I. A., M. A. Rose, R. T. Osteen, S. Love, B. Cady, B. Silver, A. Recht and J. R. Harris 
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Pusic, A. L., A. F. Klassen, A. M. Scott, J. A. Klok, P. G. Cordeiro and S. J. Cano. Development of a new 
patient-reported outcome measure for breast surgery: the BREAST-Q. Plast Reconstr Surg 124(2): 345-
53, 2009. PMID: 19644246. 
 
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D. Brown, C. L. Loprinzi and J. C. Buckner. A patient-level pooled analysis of the prognostic 
significance of baseline fatigue for overall survival (OS) among 3,915 patients participating in 43 North 
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trials.  J Clin Oncol (Meeting Abstracts) 27(15S): 9599, 2009. URL: 
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Sorbero, M. E., A. W. Dick, E. B. Beckjord and G. Ahrendt . Diagnostic breast magnetic resonance 
imaging and contralateral prophylactic mastectomy. Ann Surg Oncol 16(6): 1597-1605, 2009. PMID: 
19330381. 
 
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Sloan. A patient-level meta-analytic investigation of the prognostic significance of baseline quality of life 

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(QOL) for overall survival (OS) among 3,704 patients participating in 24 North Central Cancer Treatment 
Group (NCCTG) and Mayo Clinic Cancer Center (MC) oncology clinical trials. J Clin Oncol (Meeting 
Abstracts) 26(15_suppl): 9515, 2008. 
URL:http://meeting.ascopubs.org/cgi/content/abstract/26/15_suppl/9515. 
 
Tuttle, T. M., E. B. Habermann, E. H. Grund, T. J. Morris and B. A. Virnig. Increasing use of 
contralateral prophylactic mastectomy for breast cancer patients: a trend toward more aggressive surgical 
treatment. J Clin Oncol 25(33): 5203-09, 2007. PMID: 17954711. 
 
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Winchester, D. P. and J. D. Cox. Standards for breast-conservation treatment. CA Cancer J Clin 42(3): 
134-62, 1992. PMID: 1568135. 
 
Wood, W. C. Should the use of contralateral prophylactic mastectomy be increasing as it is Breast 18 
Suppl 3: S93-95, 2003. PMID: 19914552. 
 
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PMID: 14628423. 
 

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Appendix I: Breast Lesion Position Diagram 
 
Page 1 of 2 
 
The Breast Lesion Position Diagram is required to document the location of the breast lesions for all patients. 
The diagram on the following page will be completed by the site investigator and then scanned into Rave by 
site personnel with data entry capabilities in Rave. Save the Breast Lesion Position Diagram to your 
computer. Open Rave and look for the field in the Baseline folder, on the On-Study form, named ‘Attach 
Breast Position Diagram Here’. Then select the ‘Browse’ button to attach the diagram in Rave.    
 
Instructions to site investigator:  
On the appropriate side, label all biopsied lesions found to have breast cancer (either DCIS or invasive 
disease) starting at the 12:01 position and travelling clockwise using the labels lesion 1 and lesion 2 (see 
Example A). If two lesions are at the same o’clock position, the lesion closest to the nipple should be labeled 
first then the lesion more distant from the nipple (see Example B). 
 
Example A 
 
 
Example B 
 
lesion 1 
lesion 2 
lesion 1 
lesion 2 

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Page 2 of 2 
 
Instructions to site investigator:  
On the appropriate side, label all biopsied lesions found to have breast cancer (either DCIS or invasive 
disease) starting at the 12:01 position and travelling clockwise using the labels lesion 1 and  lesion 2 (see 
Example A on previous page). If two lesions are at the same o’clock position, the lesion closest to the 
nipple should be labeled first then the lesion more distant from the nipple (see Example B on previous 
page). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix II: Baseline Patient Questionnaire Booklet 
 
Page 1 of 2 
 
 
PATIENT QUESTIONNAIRE BOOKLET – BASELINE 
_______________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your quality of life and health status as a patient receiving treatment for cancer.  Your 
answers will help us to better understand how the treatment you are receiving is affecting the way 
you feel and tolerate treatment. 
 
1. The booklet contains one set of questions: 
 
a. Linear Analogue Self-Assessment (LASA) (2 questions) 
 
2. Directions on how to complete the set of questions are written on the top of the set. 
 
3. Please complete the booklet during your scheduled clinic visit and return it to your nurse or 
your physician. 
 
 
Thank you for taking the time to help us. 
 
 
 
 
 
 
 

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Page 2 of 2 
 
 
Linear Analogue Self-Assessment (LASA) 
 
Alliance Number: ___________ 
Patient Initials (last, first) 
________ Date: ___________ 
 
 
Directions:  Please circle the one number (0-10) for each item below that best describes you. 
 
How would you describe: 
 
1.  your level of fatigue, on the average in the past week including today? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No   
 
 
 
 
 
 
 
 
Fatigue as  
 
Fatigue 
 
 
 
 
 
 
 
 
bad as it can be 
 
2.  your overall quality of life in the past week including today? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as  
 
 
 
 
 
 
 
As good as 
it can be 
 
 
 
 
 
 
 
 
it can be 
 
 
 

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Appendix III: Patient Information Brochure 
 
Page 1 of 3 
 
Note: The following two pages contain the pink colored patient information brochure available for sites to 
give to patients should they choose to do so. This brochure is ordered from CTSU. This blank lead page 
was necessary to ensure that the Table of Contents is correct. Thank you for your patience. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix IV : Active Monitoring Patient Questionnaire Booklet 
 
Page 1 of 7 
 
 
 
PATIENT QUESTIONNAIRE BOOKLET – ACTIVE MONITORING 
_______________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your cosmetic result, quality of life and health status as a patient receiving treatment for 
cancer.  Your answers will help us to better understand how the treatment you are receiving is 
affecting the way you feel and tolerate treatment. 
 
1. The booklet contains three sets of questions: 
a.   4-Point Scoring System of Breast Cosmesis (1 question) 
b. BREAST-Q Breast-conserving therapy (lumpectomy) Postoperative model (54 
questions) 
c. Breast Lymphedema (BLE) Symptom Survey (5 questions) 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. Please complete the booklet during your scheduled clinic visit and return it to your nurse or 
your physician. 
 
 
Thank you for taking the time to help us. 
 

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Page 2 of 7 
 
4-point Scoring System of Breast Cosmesis 
(Winchester and Cox 1992) 
Patient Questionnaire 
 
Alliance Number: ___________ 
Patient Initials (last, first) 
________ Date: ___________ 
  
 
You have been treated with breast conserving therapy for breast cancer.  As you know, a reason for 
choosing this treatment is to keep a breast that looks and feels as close to normal as possible.  Your 
opinion concerning the appearance of your breast is valuable to us.  Circle the number next to the word 
that best describes how your breast looks now. 
 
1 
When compared to the untreated breast or the original appearance of the breast, there is 
minimal or no difference in the size or shape of the treated breast.  The way the breast 
feels (its texture) is the same or slightly different.  There may be thickening, scar tissue 
or fluid accumulation within the breast, but not enough to change the appearance. 
2 
There is a slight difference in the size or shape of the treated breast as compared to the 
opposite breast or the original appearance of the treated breast.  There may be some mild 
reddening or darkening of the breast.  The thickening or scar tissue within the breast 
causes only a mild change in the shape or size. 
3 
Obvious differences in the size and shape of the treated breast.  This change involves a 
quarter or less of the breast.  There can be moderate thickening or scar tissue of the skin 
and the breast, and there may be obvious color changes. 
4 
Marked change in the appearance of the treated breast involving more than a quarter of 
the breast tissue.  The skin changes may be obvious and detract from the appearance of 
the breast.  Severe scarring and thickening of the breast, which clearly alters the 
appearance of the breast, may be found. 
 
 
 

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Page 3 of 7 
BREAST-Q 
Breast Conservation Therapy (Lumpectomy) 
Postoperative Module 
 
Alliance Number: ___________ 
Patient Initials (last, first) 
________ Date: ___________ 
 
 
The following questions are about your breasts and your breast cancer treatment (by treatment, we mean 
lumpectomy with or without radiation). After reading each question, please choose the response that best 
describes your situation. If you are unsure how to answer a question, choose the answer that comes 
closest to how you feel. Enter only one choice per answer. Please answer every question. Do not leave 
any blank. 
 
1.  With your breast in mind, in the past 2 weeks, how satisfied or dissatisfied have you been with: 
 
 
Very 
Dissatisfied 
Somewhat 
Dissatisfied 
Somewhat 
Satisfied 
Very 
Satisfied 
a.  How you look in the mirror clothed? 
1 
2 
3 
4 
b.  The shape of your lumpectomy breast 
when you are wearing a bra? 
1 
2 
3 
4 
c.  How normal you feel in your clothes? 
1 
2 
3 
4 
d.  Being able to wear clothes that are more 
fitted? 
1 
2 
3 
4 
e.  How comfortably your bras fit? 
1 
2 
3 
4 
f.  How equal in size your breasts are to each 
other? 
1 
2 
3 
4 
g.  How normal your lumpectomy breast 
looks? 
1 
2 
3 
4 
h.  How your lumpectomy breast sits/hangs? 
1 
2 
3 
4 
i.  How soft your lumpectomy breast feels to 
the touch? 
1 
2 
3 
4 
j.  How much your breasts look the same? 
1 
2 
3 
4 
k.  How smoothly shaped your lumpectomy 
breast looks? 
1 
2 
3 
4 
l.  The contour (outline) of your lumpectomy 
breast? 
1 
2 
3 
4 
m. How your lumpectomy breast looks now 
compared to before you had any breast 
surgery? 
1 
2 
3 
4 
n.  How your breasts look in the mirror 
unclothed? 
1 
2 
3 
4 
o.  How your lumpectomy breast looks 
overall? 
1 
2 
3 
4 
 

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Page 4 of 7 
 
2.   With your lumpectomy breast in mind, in the past 2 weeks, how much have you been bothered by: 
 
 
I don’t 
have this 
problem 
I have this problem and it bothers 
me… 
Not at all 
A little 
A lot 
a.  Your lumpectomy breast being too small 
compared to your other breast? 
 
1 
2 
3 
b.  Your lumpectomy breast being an 
irregular shape? 
 
1 
2 
3 
c.  Your lumpectomy breast having dimpled 
(indented) areas? 
 
1 
2 
3 
d.  Areas of your lumpectomy breast that 
look sunken in (hollow)? 
 
1 
2 
3 
e.  How obvious your lumpectomy breast 
scars look? 
 
1 
2 
3 
f.  Lack of sensation (feeling) in your 
lumpectomy breast? 
 
1 
2 
3 
g.  Feeling lopsided in your clothing? 
 
1 
2 
3 
h.  The nipple and areola on your 
lumpectomy breast looking caved in? 
 
1 
2 
3 
i.  The nipple and areola on your lumpectomy 
breast moved from its natural position? 
 
1 
2 
3 
j.  The nipple on your lumpectomy breast 
pointing in an unnatural direction? 
 
1 
2 
3 
k.  The shape of your areola looking 
distorted? 
 
1 
2 
3 

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Update #08 
 
 
Page 5 of 7 
 
3.   With your radiated breast in mind, in the past 2 weeks, how much have you been bothered by: 
 
 
I don’t 
have this 
problem 
I have this problem and it bothers 
me… 
Not at all 
A little 
A lot 
a.  Your radiated breast skin looking different 
(e.g., too dark or too light)? 
 
1 
2 
3 
b.  Your radiated areola looking different 
(e.g., too dark or too light)? 
 
1 
2 
3 
c.  Marks on your breast caused by radiation 
(e.g., small visible blood vessels)? 
 
1 
2 
3 
d.  Tattoo marks placed to guide the radiation 
treatment? 
 
1 
2 
3 
e.  Your radiated breast skin feeling dry? 
 
1 
2 
3 
f.  Your radiated breast skin feeling sore 
(sensitive) when touched (e.g., changes in 
water temperature when you 
bathe/shower)? 
 
1 
2 
3 
g.  Your radiated breast feeling irritated by 
clothing that you wear? 
 
1 
2 
3 
h.  Your radiated breast feeling 
uncomfortable? 
 
1 
2 
3 
i.  Your radiated breast feeling tight? 
 
1 
2 
3 
j.  Your radiated breast feeling heavy? 
 
1 
2 
3 
k.  Your radiated breast feeling swollen? 
 
1 
2 
3 
l.  Your radiated breast feeling unnaturally 
firm? 
 
1 
2 
3 
m. Hard scar tissue in your radiated breast 
that you can feel? 
 
1 
2 
3 
n.  Your radiated breast skin feeling 
unnaturally thick (rough, tough) when you 
touch it? 
 
1 
2 
3 
 

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Update #08 
 
 
Page 6 of 7 
 
4.   In the past 2 weeks, how often have you experienced? 
 
 
None of 
the time 
A little of 
the time 
Some of 
the time 
Most of 
the time 
All of 
the time 
a.  Tightness in your lumpectomy breast? 
1 
2 
3 
4 
5 
b.  Pulling in your lumpectomy breast? 
1 
2 
3 
4 
5 
c.  Tenderness in your lumpectomy breast? 
1 
2 
3 
4 
5 
d.  An aching feeling in your lumpectomy 
breast? 
1 
2 
3 
4 
5 
e.  Sharp pains in your lumpectomy breast? 
1 
2 
3 
4 
5 
f.  Shooting pains in your lumpectomy 
breast? 
1 
2 
3 
4 
5 
g.  Neck pain? 
1 
2 
3 
4 
5 
h.  Upper back pain? 
1 
2 
3 
4 
5 
i.  Shoulder pain? 
1 
2 
3 
4 
5 
j.  Arm pain? 
1 
2 
3 
4 
5 
k.  Difficulty lifting or moving your arms? 
1 
2 
3 
4 
5 
l.  Swelling (lymphedema) of the arm on the 
side that you had your lumpectomy 
surgery? 
1 
2 
3 
4 
5 
m. Difficulty sleeping because of discomfort 
in your lumpectomy breast? 
1 
2 
3 
4 
5 
n.  Difficulty laying on the side of your 
lumpectomy breast? 
1 
2 
3 
4 
5 
 

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Update #08 
 
Page 7 of 7 
 
Breast Lymphedema (BLE) Symptom Survey  
(Degnim et al. 2008) 
 
Alliance Number: ___________ 
Patient Initials (last, first) 
________ Date: ___________ 
 
 
Please answer the following questions regarding current (within the last week) symptoms in the operated 
breast. 
 
1.  Does your breast appear or feel swollen? 
Not at all    0         1        2         3         4         5          6         7          8           9        10 A lot 
           
 
                               
 
 
 
 
 
2.  Does your breast feel heavy? 
 
 
Not at all    0         1        2         3         4         5          6         7          8           9        10 A lot 
 
 
3.  Is your breast redder in color? 
 
Not at all    0         1        2         3         4         5          6         7          8           9        10 A lot 
 
4.  Do you have pain, tenderness, or discomfort in your breast?  
 
Not at all    0         1        2         3         4         5          6         7          8           9        10 A lot 
 
5.  Do you have armpit fullness or numbness? 
 
Not at all    0         1        2         3         4         5          6         7          8           9        10 A lot 
 

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Update #08 
Appendix V: Surgeon Questionnaire Booklet 
 
Page 1 of 2 
 
SURGEON QUESTIONNAIRE BOOKLET 
________________________________________________________________________ 
 
This booklet is to be completed by the surgeon on behalf of the patient prior to completion of the 
Patient Questionnaire Booklet.  
 
1.  The booklet contains the following item: 
 
• 
4-Point Scoring System of Breast Cosmesis (1 question) 
 
2.  Directions on how to complete the questionnaire is written on the top of the page. 
 
3.  Please complete this booklet prior to the patient’s completion of the Patient Questionnaire 
Booklet corresponding to this visit. 
 
 
Thank you for taking the time to help us. 
 
 

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Page 2 of 2 
 
4-point Scoring System of Breast Cosmesis 
(Winchester and Cox 1992) 
Surgeon Questionnaire 
 
Alliance Number: ___________ 
Patient Initials (last, first) 
________ Date: ___________ 
 
 
 
Directions:  Please circle the score best corresponding to your assessment of your patient’s cosmesis. 
 
 
 
 
 
 
1 
When compared to the untreated breast or the original appearance of the breast, there is 
minimal or no difference in the size or shape of the treated breast.  The way the breast 
feels (its texture) is the same or slightly different.  There may be thickening, scar tissue 
or fluid accumulation within the breast, but not enough to change the appearance. 
2 
There is a slight difference in the size or shape of the treated breast as compared to the 
opposite breast or the original appearance of the treated breast.  There may be some mild 
reddening or darkening of the breast.  The thickening or scar tissue within the breast 
causes only a mild change in the shape or size. 
3 
Obvious differences in the size and shape of the treated breast.  This change involves a 
quarter or less of the breast.  There can be moderate thickening or scar tissue of the skin 
and the breast, and there may be obvious color changes. 
4 
Marked change in the appearance of the treated breast involving more than a quarter of 
the breast tissue.  The skin changes may be obvious and detract from the appearance of 
the breast.  Severe scarring and thickening of the breast, which clearly alters the 
appearance of the breast, may be found.