A Randomized Phase III Trial of the Value of Early Local Therapy for the Intact Primary Tumor in Patients With Metastatic Breast Cancer
Phase: NA
Conditions: Breast Cancer, Stage IV Breast Cancer
Sponsor: Eastern Cooperative Oncology Group

E2108 
 
1 
A Randomized Phase III Trial of the Value of Early Local 
Therapy for the Intact Primary Tumor in Patients with 
Metastatic Breast Cancer 
STUDY CHAIR: Seema A. Khan, M.D. 
STUDY STATISTICIAN: Fengmin Zhao, Ph.D. 
RADIATION ONCOLOGY CO-CHAIR: Lawrence J. Solin, M.D. 
LABORATORY CO-CHAIR: Brian Leyland-Jones, M.D. 
MEDICAL ONCOLOGY CO-CHAIR: Lori Goldstein, M.D. 
COMMITTEE CHAIR: George W. Sledge, Jr.,  M.D. 
QOL CO-CHAIRS: Lynne Wagner, Ph.D. 
 David Cella, Ph.D. 
NCIC-CTG CO-CHAIR: Mark Basik, M.D. 
CALGB CO-CHAIR: Mehra Golshan, M.D. 
NSABP CO-CHAIR: Thomas Julian, M.D. 
NCCTG CO-CHAIR: Barbara A. Pockaj, M.D. 
SWOG CO-CHAIR: Christine A. Lee, M.D. 
Version Date: March 10, 2015 
 
STUDY PARTICIPANTS 
ACTIVATION DATE 
NCIC-CTG / NCIC Clinical Trials Group 
NRG / NRG Oncology Foundation, Inc. 
ALLIANCE / Alliance for Clinical Trials in Oncology 
SWOG / SWOG 
February 8, 2011 
Addendum #1 – Incorporated Prior to Activation 
Addendum #2 – 7/12 
Addendum #3 – 2/13 
Addendum #4 – 7/13 
Addendum #5 – 4/14 
Addendum #6 -- 4/15 
 
 
 
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Table of Contents 
A Randomized Phase III Trial of the Value of Early Local Therapy for the Intact 
Primary Tumor in Patients with Metastatic Breast Cancer ................................ 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Review of Retrospective Data ................................................................... 8 
1.2 
Observed Selection Biases ........................................................................ 8 
1.3 
Parameters Not Addressed in Most Studies ............................................. 9 
1.4 
Data on Chest Wall Outcomes ................................................................ 10 
1.5 
Health-Related Quality of Life (HRQL) Assessment ................................ 10 
1.6 
Scientific questions regarding the relationship between the primary 
tumor and metastatic sites ..................................................................... 11 
1.7 
Study Design Considerations ................................................................... 12 
2. Objectives ......................................................................................................... 13 
2.1 
Primary Objectives .................................................................................. 13 
2.2 
Secondary Objectives .............................................................................. 13 
3. Selection of Patients ......................................................................................... 14 
3.1 
Registration (STEP 1) ............................................................................... 14 
3.2 
Randomization (STEP 2) .......................................................................... 15 
4. Registration Procedures .................................................................................... 17 
4.1 
Registration (Step 1)................................................................................ 20 
4.2 
Randomization (Step 2) ........................................................................... 21 
4.3 
Instructions for Patients who Do Not Start Assigned Protocol Treatment22 
5. Treatment Plan ................................................................................................. 23 
5.1 
Treatment ............................................................................................... 23 
5.2 
Health-Related Quality of Life Assessment ............................................. 24 
5.3 
Radiation Therapy ................................................................................... 27 
5.4 
Adverse Event Reporting Requirements ................................................. 40 
5.5 
Supportive Care ....................................................................................... 42 
5.6 
Duration of Study Participation .............................................................. 42 
6. Measurement of Effect ..................................................................................... 43 
6.1 
Response to Optimal Systemic Therapy on Step 1 ................................. 43 
6.2 
Changes in Disease Status on Step 2 ....................................................... 43 
6.3 
Endpoints ................................................................................................ 44 
7. Study Parameters .............................................................................................. 45 
7.1 
Therapeutic Parameters .......................................................................... 45 
7.2 
Biological Sample Submissions ............................................................... 47 
8. Statistical Considerations .................................................................................. 49 
8.1 
Primary Endpoint .................................................................................... 49 
8.2 
Secondary Endpoints ............................................................................... 49 
8.3 
Patient Registration ................................................................................ 49 

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8.4 
Sample Size ............................................................................................. 49 
8.5 
Interim Monitoring and Analysis Plan ..................................................... 50 
8.6 
HRQL Power Estimate and Analysis Plan ................................................ 51 
8.7 
Correlative Science (CTC) Power estimate .............................................. 51 
8.8 
Gender and Ethnicity .............................................................................. 52 
8.9 
Compliance Monitoring .......................................................................... 52 
8.10 Study Monitoring .................................................................................... 52 
9. Correlative Studies ............................................................................................ 54 
9.1 
Sample Submission Requirements .......................................................... 54 
9.2 
Shipping Procedures ............................................................................... 57 
9.3 
ECOG-ACRIN Sample Tracking System .................................................... 58 
9.4 
Institutional Reimbursements ................................................................. 58 
9.5 
Banking .................................................................................................... 60 
9.6 
Sample Inventory Submission Guidelines ............................................... 60 
10. Records to Be Kept ............................................................................................ 61 
10.1 ECOG-ACRIN Radiation Oncology Quality Assurance Materials ............. 61 
11. Patient Consent and Peer Judgment ................................................................ 61 
12. References ........................................................................................................ 61 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) - [Deleted in Addendum #3] ............................................................ 67 
Appendix II  Pathology Submission Guidelines ....................................................... 68 
Appendix III  Patient Thank You Letter .................................................................... 73 
Appendix IV  ECOG Performance Status ................................................................. 74 
Appendix V  E2108 Collection and Shipping Kit Order Form ................................... 75 
Appendix VI  E2108 Shipment Notification Form .................................................... 76 
Appendix VII E2108 Biopsy Reimbursement Form .................................................. 77 
 
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STUDY CHAIR 
RADIATION ONCOLOGY CO-CHAIR 
Seema A. Khan, M.D. 
Robert H. Lurie Comprehensive Cancer Center 
Feinberg School of Medicine of Northwestern University 
303 E. Superior, Lurie 4-133 
Chicago, IL 60611 
Phone: 312-503-2880 
Fax: 312-503-2555 
Email: skhan@nmh.org 
 
Lawrence J. Solin, M.D. 
Department of Radiation Oncology  
Albert Einstein Medical Center 
5501 Old York Rd. 
Philadelphia, PA 19141 
Phone: 215-456-6280 
Fax: 215-457-0270 
Email: solin@einstein.edu 
 
MEDICAL ONCOLOGY CO-CHAIR 
NCIC-CTG CO-CHAIR 
Lori Goldstein, M.D. 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia, PA 19111-2497 
Phone: 215-728-0417 
Fax: 212-728-3639 
Email: LJ_Goldstein@fccc.edu 
 
Mark Basik, M.D. 
Department of Surgery and 
Oncology 
Jewish General Hospital 
3755 Côte Ste. Catherine Road 
Montreal, Quebec, Canada H3T 1E2 
Phone: 514-340-8222 
Fax: 514-340-8302 
Email: mark.basik@mcgill.ca 
 
STUDY CHAIR LIAISON (SCL) 
CALGB CO-CHAIR 
Kay Pearson 
Robert H. Lurie Comprehensive Cancer Center 
Feinberg School of Medicine of Northwestern University 
303 E. Superior, Lurie 4-133 
Chicago, IL 60611 
Phone: 312-472-4776 
Email: kpearson@nmh.org 
 
Mehra Golshan, M.D. 
Dana Farber Cancer institute 
75 Francis Street 
Department of Surgery 
Boston, MA 02115 
Phone: 617-632-2174 
Fax: 617-582-7740 
Email: mgolshan@partners.org 
 
NSABP CO-CHAIR 
SWOG CO-CHAIR: 
Thomas Julian, M.D. 
NSABP Foundation, Inc. 
Four Alleghany Center – 5th Floor 
Pittsburgh, PA 15212-5234 
Phone: 412-330-4600 
Fax: 412-330-4661 
Email: tjulian@wpahs.org 
Christine A. Lee, M.D. 
Swedish Medical Center 
First Hill Surgeons 
Health Building 
801 Broadway, Suite 300 
Seattle, WA 98122 
Phone: 206-215-3500 
Fax: 206-215-6499 
Email: christine.lee@swedish.org  
NCCTG CO-CHAIR: 
 
Barbara A. Pockaj, M.D. 
Mayo Clinic 
13400 East Shea Blvd. 
Scottsdale, AZ 85259 
Phone: 480-342-2849 
Fax: 507-284-5280 
Email: pockaj.barbara@mayo.edu 
 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data  directly to 
the Lead Cooperative Group 
unless otherwise specified in 
the protocol:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.coccg.org 
(for submitting regulatory 
documents only) 
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 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
ECOG-ACRIN Operations 
Office - Boston, 
FSTRF, 900 Commonwealth 
Avenue Boston, MA 02215 
(ATTN: DATA). 
Phone # 617-632-3610 
Fax # 617-632-2990 
Data should be sent via postal 
mail. 
Do not submit study data or 
forms to CTSU Data 
Operations. 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 Web site located at https://www.ctsu.org.   
Access to the CTSU members’ websiteis 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. 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission contact the CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU Regulatory 
and Monitoring Policy 
The CTSU Web site is located at   https://www.ctsu.org 
 
 

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Schema 
R
A
N
D
O
M
I
Z
A
T
I
O
N
Optimal 
systemic 
therapy
Follow-up9
PD
Early local 
therapy6
Continued 
systemic therapy7
Arm A
Arm B
Accrual = 368
CR, PR, SD
Stratify:
•
Marker status and treatment plan

ER+ or PR+ and HER2-, plan 
to treat with endocrine therapy 
alone

ER+ or PR+ and HER2-,
       plan to treat with chemo +/- 
endocrine therapy

 ER- and PR- and HER2-

 HER2+
•
# of organs with metastatic 
involvement

 1

 >1
R
E
G
I
S
T
R
A
T
I
O
N2
Diagnosis1
Follow-up8
Follow-up8
Step 1
Step 2
Arm S
3,4,5
1. Women with intact primary tumors AND metastatic disease at any site are eligible. 
2. Patients may register (Step 1) at anytime following the diagnosis of Stage IV breast cancer, either before or after the start of systemic therapy, up to the 30th week of treatment. 
3. Patients must be randomized (Step 2) within 32 weeks after the start of systemic therapy. 
4. Patients may not be randomized (Step 2) less than 16 weeks after the start of systemic therapy. 
5. At the time of randomization, patients must have documentation of CR, PR or SD as response to optimal systemic therapy. 
6. Early local therapy (Arm B) is defined as surgery and radiotherapy for the primary tumor, following induction systemic therapy. Surgery is to occur no later than 10 weeks after 
randomization. 
7. Continued systemic therapy is defined as therapy delivered only as needed for control of distant disease. 
8. All randomized patients will be followed for treatment and disease status for 5 years post randomization. 
9. Patients who are not randomized will be followed for survival for 5 years post registration.
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1. 
Introduction 
The importance of effective local therapy as a means of optimizing survival in women 
with Stages 0-III breast cancer is well established. However, approximately 5% of 
women with primary breast cancer in the United States present with Stage IV disease. 
The traditional approach to this problem has been to treat with systemic therapy, and to 
provide therapy for the primary tumor only when palliation is required. There is presently 
no consensus regarding optimal local therapy for these women, and treatment may vary 
from mastectomy (often justified as “toilette” mastectomy, in order to prevent 
uncontrolled local disease during the remainder of the patient’s life), to obtaining a 
tissue diagnosis with needle biopsy. If the primary tumor is excised for diagnosis, follow-
up radiation is almost never used in the setting of distant metastases. According to the 
present paradigm, once metastases have occurred, local therapy provides no survival 
advantage, and should not be pursued. The alternative paradigm is that the primary 
tumor is a source of re-seeding of distant sites and therefore elimination of this source of 
metastasizing cells may be of benefit. Data from a SWOG trial of renal cell carcinoma 
are pertinent to this argument. The worth of nephrectomy was examined in patients with 
Stage IV disease, who were randomized to interleukin therapy, with or without 
nephrectomy. Results from this trial show an improvement in survival for the 
nephrectomy group, with overall median survival increasing from 8 months without 
nephrectomy, to 11 months for patients in the nephrectomy arm (1). These findings 
raise the possibility that aggressive local therapy may contribute to prolongation of 
survival in other tumors.  
Data from other tumor types may also point to a possible survival advantage for patients 
with distant metastases undergoing resection of the primary tumor. A retrospective 
analysis of patients with asymptomatic primary colon cancer and distant metastases 
experienced longer survival following primary tumor resection (2). Resected patients 
had prolonged median (16 versus 9 months, p < 0.001) and 2-year (25% versus 6%, p < 
0.001) survival compared with patients never resected. Similar results have been 
reported for gastric cancer (58, 59, 60, 61). These findings are undoubtedly influenced 
by a bias favoring patients who were selected for resection, but in the absence of 
randomized trials, the possibility that resection has a salutary effect on survival in 
patients with metastatic carcinomas of the colon or stomach remains open. 
The past seven years have witnessed a re-examination of the use of local therapy in 
women with Stage IV disease, because of an accumulation of retrospective data 
suggesting that local therapy may also be important in this group of women, and may 
improve survival. At least nine retrospective studies (4-12) have examined the impact of 
surgical resection of the primary tumor in the setting of metastatic disease, and eight 
show a reduction in the hazard of death that ranges from 40% to 50%. Despite statistical 
adjustment for biases driving the use of surgery, the improvement in survival seen in the 
surgical group cannot be definitively attributed to the resection of the primary tumor 
since in most studies the women in the surgical groups were younger, had smaller 
tumors, fewer metastatic sites, and were more likely to have bone/soft tissue 
metastases rather than visceral disease. Additionally, it is not possible from these 
retrospective studies to assess the value of local therapy components other than 
resection of the primary tumor (i.e. axillary dissection and local radiotherapy). It is 
therefore necessary to conduct a randomized trial to formally test the hypothesis 
generated by these retrospective reviews. The inclusion of appropriate correlative 
science endpoints will provide unique opportunities to understand the biology of 

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metastatic disease, and will guide further advances in the management of women with 
metastatic breast cancer. The alternative to a randomized trial is a prospective registry 
study, but such a design will serve only to reinforce existing biases (the retrospective 
data discussed below testify to the fact that current clinical decision-making seems to 
reliably identify women who will do better). A prospective registry trial will not allow the 
crucial distinction of whether women chosen for surgery have tumors that are 
biologically indolent, or whether the course of their tumors is being altered by the use of 
local therapy.  
The design of such a randomized trial should incorporate the standard elements of 
current therapy for metastatic breast cancer (i.e. the primacy of systemic therapy), allow 
flexibility in the choice of systemic therapy regimens that accommodate the biologic 
variation of breast cancer, and test the value of early, complete local therapy (resection 
with free surgical margins plus radiotherapy) against the current standard (i.e. local 
therapy at the discretion of the treating physician, only for palliation of progressive and 
symptomatic local disease) 
1.1 
Review of Retrospective Data 
As reported in eight separate retrospective studies in the past four years, 
substantial numbers of women with de novo Stage IV breast cancer undergo 
surgical extirpation of the primary tumor. These studies are based on data from 
the National Cancer Database (NCDB) (4, 13), two European Tumor Registries 
(5, 12), four large comprehensive cancer centers (6, 8, 9, 10) , and the SEER 
database (7) and show that surgical resection of the primary tumor has been 
performed in 30-55% of women with de-novo Stage IV breast cancer. Data on 
the use of follow-up radiation therapy in this setting is very sparse, but a French 
study where primary radiotherapy was used for the in-breast disease shows very 
similar benefit (67). These studies are remarkably consistent in the finding that 
women who undergo surgical therapy for the primary tumor in the setting of 
metastatic disease fare better than those whose primary tumor is left intact. 
However, the entire published literature on this topic consists of retrospective 
reviews, all subject to the same selection bias: i.e., healthier women with lower 
disease burden were offered surgery.  
Evidence supporting the hypothesis that local therapy is useful in women with 
metastatic breast cancer include the time-course of local failure and metastatic 
disease (14), and the survival benefit of locoregional radiotherapy when 
compared to patients treated with adjuvant systemic therapy alone (15-17). 
These data suggest that uncontrolled local disease may act as a source of 
continued seeding of distant metastases. Thus local tumor burden may affect 
outcome for patients with local regional disease and metastases, regardless of 
whether those metastases are covert (Stage II-III) or overt (Stage IV). 
1.2 
Observed Selection Biases 
Across the majority of studies, women treated with surgical resection of the 
primary tumor tend to be younger, with better access to care (in the US, this 
equates with European ancestry and being married), smaller tumors, single 
organ-system metastatic involvement, and bony or soft tissue metastases (rather 
than visceral metastases). In the analyses where margin data were available for 
a majority of patients, the presence of tumor-free margins was significantly 
associated with improved survival and benefit of surgical resection (4, 5). 

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1.3 
Parameters Not Addressed in Most Studies 
These include the timing of metastatic diagnosis relative to the surgical 
procedure; the use of axillary dissection; and the use of loco-regional 
radiotherapy. The timing of the surgical procedure is important since women who 
underwent surgery with the diagnosis of Stage I-III breast cancer, were 
radiologically staged in the post-operative period, and found to have metastases 
may have a better prognosis than those who were diagnosed with metastases 
prior to surgery. This issue is not well-addressed in most of the published series, 
raises skepticism about existing retrospective data, and adds justification to the 
need for a randomized trial. In one small study where this distinction was clearly 
made, women who underwent surgery following the diagnosis of metastases 
derived no benefit from surgical resection of the primary (18). In another 
retrospective analysis, three intervals were defined, following diagnosis: less 
than 3 months, 3-9 months, and > 9 months. Women undergoing surgery in the 
first three months following diagnosis had shorter survival than those undergoing 
tumor resection more than three months after diagnosis (19). These authors did 
not specifically examine the timing of systemic therapy, but it is reasonable to 
assume that women undergoing immediate surgery were not known to have 
metastases, and did not receive systemic therapy prior to surgical intervention. 
These results highlight the fact that retrospective analyses will not provide an 
unbiased evaluation of the role of local therapy in the setting of metastatic 
disease, since most of the published studies describe their inclusion criterion as 
“stage IV at diagnosis” with no further discussion of the timing of surgery.  
If surgical resection of the primary tumor is useful for women with metastases, 
this benefit seems to require minimization of the local tumor burden (as 
evidenced by data that suggest greater benefit with resection with tumor-free 
margins); it appears logical therefore that the excision of involved axillary nodes 
would also be beneficial. Such a trend towards a benefit of axillary dissection is 
observed in two studies but most analyses lack the data to examine this effect.   
In the NCDB study (4), although extent of nodal disease was not significantly 
related to survival, women undergoing total mastectomy were much more likely 
to have nodal dissection, and this may have contributed to the survival 
advantage observed in the TM group. In the Geneva study (5), axillary dissection 
was performed in 24% of patients, and there was a trend towards a larger benefit 
for women who had both negative surgical margins and axillary dissection (HR 
0.2, 95% CI 0.02-1.9). 
 Regional radiotherapy data are also lacking in the published studies, although 
local radiation was used in women undergoing breast conserving surgery in 
Geneva, and the lack of radiotherapy increased the hazard of death 
independently. The inability to distinguish local radiation from radiation to 
metastatic sites is a limitation of the data in the NCDB, and in the SEER 
program, where radiotherapy to local or distant sites has not been 
distinguishable.  In general, the use of locoregional radiotherapy is extremely 
variable in the reported literature, although a recent study suggests added 
benefit with the use of surgery plus radiotherapy [79]. Since radiotherapy is 
clearly crucial in the local control of non-metastatic breast cancer, and adds 
survival benefit in most categories of risk [78], radiotherapy constitutes a logical 
component of a test of loco-regional therapy in the metastatic setting. In fact if 
radiotherapy is not included in such a trial, and a benefit of surgical resection is 
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observed, the next logical question will relate to the possible enhancement of 
benefit with the use of radiotherapy. Similarly, if no benefit is observed, the 
obvious question will be whether the omission of radiotherapy was responsible 
for the negative finding. Thus it seems important to test the concept of complete 
local therapy rather than of surgery alone. These factors also argue against the 
option of making radiotherapy discretionary in such a trial; given the survival 
benefit attributable to the use of RT in the non-metastatic setting, and the 
suggestion that local control is associated with improved survival in the 
metastatic setting (20). 
1.4 
Data on Chest Wall Outcomes 
The frequent use of surgical resection in women presenting with Stage IV 
disease is somewhat surprising.  The main justification for surgical extirpation of 
the primary tumor in this setting so far has been the so-called “toilette” resection, 
but many of the patients undergoing partial and total mastectomy had T1 or T2 
tumors. This trend highlights the fact that that uncontrolled local disease, with its 
attendant impact on quality of life, is a feared complication among both 
physicians and patients.  It is reasonable to assume that no (or incomplete) 
resection is a risk factor for the occurrence of uncontrolled chest wall disease, 
but direct data regarding this are limited (68).  A recent retrospective analysis 
included 111 women presenting with Stage IV breast cancer; chest wall 
outcomes were examined relative to the use of early (within 6 months of 
diagnosis) surgical resection of the primary tumor(20). The early use of surgery 
reduced the odds of symptomatic chest wall disease by 86% (adjusted OR 0.14, 
95% CI 0.039,0.491), and a controlled chest wall reduced the hazard of death by 
60% (HR 0.4, 95% CI 0.260, 0.662).  In women with the analogous situation of 
synchronous local and distance recurrence following breast conserving therapy 
for an initial breast carcinoma, women undergoing resection of the in-breast 
recurrence, whether by mastectomy or repeat breast conservation, experienced 
better local control and overall survival (21). 
1.5 
Health-Related Quality of Life (HRQL) Assessment 
Despite the wide recognition of the quality of life impact of uncontrolled chest 
wall disease in women with breast cancer, surprisingly little is known regarding 
the frequency of disease-related symptoms from uncontrolled chest wall disease 
among women with metastatic breast cancer. None of the studies that have 
examined the impact of surgical therapy on survival have looked at HRQL 
outcomes. HRQL is an important question in this population because treatment 
decision-making regarding elective local therapy should be driven by considering 
the side effects of local therapy versus the anticipated symptom burden 
associated with uncontrolled disease. Based on clinical observations, it is 
reasonable to assume that women receiving elective local therapy will  
experience treatment-related symptoms associated with surgery and radiation 
that may adversely impact HRQL. Women in the palliative local therapy may 
experience decrements to their HRQL due to disease-related symptoms, namely 
pain due to tumor replacement of the breast, ulceration, and skin nodules. 
Therefore, both treatment groups may experience decrements to their HRQL but 
from different sources (ie. treatment- vs. disease-related) and at different points 
in time (ie. at the time of elective local treatment vs. later on with disease 
progression). We have designed an HRQL assessment among trial participants 

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to quantify disease- and treatment-related symptoms among trial participants in 
each treatment arm. We anticipate that the overall impact to HRQL will be 
greater for the palliative treatment group. 
We have identified the Functional Assessment of Cancer Therapy - Breast Trial 
Outcome Index as our primary HRQL endpoint. The FACT Trial Outcome Index 
provides a composite score which captures physical well-being, functional well-
being and disease-specific concerns (ie. breast cancer) and is commonly used 
as an HRQL endpoint for cancer clinical trials. The 24-item FACT-Breast Trial 
Outcome Index (FACT-B TOI) consists of the physical and functional well-being 
scales (14 items) from the FACT – General 8 and the Breast Cancer Subscale 
(10 items) of the FACT.  The FACT-General consists of 27 items that assess 
physical, functional, emotional and social well-being 8. The Breast Cancer 
Subscale of the FACT will also be administered to quantify disease- and 
treatment-related symptoms. The FACT Breast cancer subscale includes 10 
items that measure HRQL concerns specific to breast cancer, including 
lymphedema and body image concerns. The FACT-B TOI and the FACT-B total 
score have been used to assess HRQL in numerous ECOG Breast Committee 
protocols (eg. E1193, E2100, E1105). Results from E1193 were used to develop 
minimally important difference scores (MIDs) for the FACT-B TOI (11). 
Secondary HRQL analyses will examine treatment arm differences on the FACT-
Breast subscale score and the FACT-General score. 
Exploratory analyses will examine specific symptoms, namely lymphedema, pain 
and discomfort in the breast and chest wall, and anxiety secondary to tumor 
growth. These target symptoms were selected based on clinical experience of 
the study chair in consultation with expert clinicians. In addition, five items from 
the FACT Breast cancer subscale and four items from the FACT-G have been 
selected a priori for individual item analysis to assess differences in pain, body 
image, and worry between treatment arms. Given the lack of an available scale 
to assess these concerns in a tailored and concise manner, we have written 
additional items for the FACT Breast cancer subscale to capture these concerns. 
We added four items to assess lymphedema. We added one item to assess 
worry about tumor growth. We added two items to assess discomfort in the 
breast and chest wall. We added two items to assess the effects of tumor 
nodules and ulcers on functional well-being. Because these items are 
exploratory, we will examine the psychometric properties of each item as well as 
composite scores (eg. summation of lymphedema items) prior to calculating 
treatment arm comparisons. In addition we will use data collected from this trial 
to validate these items. Since no validated instruments are available for issues 
related to chest wall symptoms, analyses to examine specific symptoms, namely 
lymphedema, pain and discomfort in the breast and chest wall, and anxiety 
secondary to tumor growth will need to be exploratory. 
1.6 
Scientific questions regarding the relationship between the primary tumor and 
metastatic sites 
Data from studies going back several decades raises concerns that resection of 
the primary tumor in the setting of metastatic disease will enhance the growth of 
distant lesions (24, 25), and the pioneering work of Folkman and colleagues has 
identified protein factors synthesized by primary tumors which restrict tumor 
growth at metastatic sites, so that distant lesions grow once the primary is 
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resected (26). However, this phenomenon remains to be demonstrated in 
humans, whereas recent data suggest that the primary tumor may have a unique 
role in the propagation of metastases, by acting as a reservoir for tumor stem 
cells. An increasing body of evidence suggests that there is molecular 
communication between the primary tumor and the pre -metastatic niche (27).  
Secretion of growth factors (such as TGB-β, proliferation factors, and 
stimulatory signals originating from the primary tumor may play a role in priming 
the niche for implantation and growth of the metastatic lesion. Provocative recent 
data suggest a specific role for mesenchymal stem cells which are released from 
the bone marrow and populate primary tumor sites more efficiently than 
metastatic sites (28). These mesenchymal stem cells then endow primary tumor 
cells with enhanced metastatic capacity, providing a possible explanation for a 
beneficial role for resection of the primary tumor even in the setting of 
established distant disease.  
Another potential mechanism for interaction between the primary tumor and 
metastatic lesions is through tumor induced immunosuppression, defects in 
cytokine production, recognition of foreign antigens, and T and B cell function.  In 
a study comparing the peripheral blood samples of breast cancer patients and 
healthy controls.   CD4+ and CD8+ T cell subsets capable of producing type 1 
and 2 cytokines were reduced in breast cancer patients(29).  There was a 
correlation between the number of micrometastases (defined as circulating 
epithelial cells in the bone marrow) and the degree of immunosuppression.  
Using a mouse model, Danna et al were able to demonstrate that removal of an 
intact primary mammary tumor in the setting of metastatic disease could restore 
the immunocompetence of the host (30).  Mice with bulky tumors had T and B 
cell deficiencies compared to healthy mice.  After resection, antigen-specific 
antibody responses and T-cell responses to foreign antigen recovered compared 
to non-surgery mice.   
Thus there are several potential biological explanations for the benefit of primary 
tumor resection which can be formally tested in the setting of a randomized 
clinical trial of local therapy in metastatic disease patients. 
1.7 
Study Design Considerations 
E2108 is designed to examine the value of early local therapy for the primary 
tumor in Arm B versus standard of care in Arm A. Laboratory measurements that 
involve comparison of pre- and post- local therapy values can therefore only be 
performed in Arm B. However, the Circulating Tumor Cell (CTC) burden prior to 
primary site local therapy may be substantially reduced by the preceding 
induction systemic therapy. Statistical testing of CTC values pre and post local 
therapy in Arm B may therefore not be feasible. A more robust comparison 
would be one performed at six months following randomization, where local 
therapy would be completed in Arm B and the CTC burden would represent the 
cumulative effects of local and systemic therapy (Arm B) versus systemic 
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2. 
Objectives 
2.1 
Primary Objectives 
To evaluate whether early local therapy of intact primary disease in patients with 
Stage IV breast cancer whose disease does not progress during initial optimal 
systemic therapy, will result in prolonged survival, compared to patients who 
receive local therapy for palliation only. 
2.2 
Secondary Objectives 
2.2.1 
To compare the time to uncontrolled chest wall disease between 
patients who receive early local therapy versus patients who receive 
palliative local therapy  
2.2.2 
To determine whether there is a difference in HRQL between patients 
who receive early local therapy and those who receive palliative local 
therapy. 
2.2.3 
To determine whether the absolute value of the CTC burden at six 
months following randomization will be lower in Arm B than Arm A and 
whether this value is inversely related to survival. 
2.2.4 
To collect tumor and blood specimens for future exploration of the 
biological interactions between the primary tumor and metastatic 
lesions and the effect of primary tumor resection. 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. 
 
 
Patient’s Initials (L, F, M) 
 
 
Physician Signature and 
Date 
 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to randomization by the treating 
physician. 
NOTE: 
Patients may register (Step 1) at any time from the time of diagnosis of stage 
IV breast cancer (if eligibility criteria met) to the time when a maximum of 30 
weeks of induction systemic therapy has been completed. (Induction 
systemic therapy includes chemotherapy, endocrine therapy, bone-specific 
agents, and biologic therapy.) 
NOTE: 
Patients must be randomized (Step 2) within 32 weeks after the start of 
systemic therapy.  
NOTE: 
Patients may not be randomized (Step 2) less than 16 weeks after the start 
of systemic therapy. 
3.1 
Registration (STEP 1) 
3.1.1 
Patients (male or female) must be older than 18 years and must have 
an intact primary (not recurrent) invasive carcinoma of the breast. 
Biopsy confirmation of the primary tumor should be by needle biopsy 
(preferred); incisional surgical biopsy is allowed as long as there is 
residual palpable or imageable tumor in the breast. 
3.1.2 
Patients with synchronous contralateral invasive breast cancer are 
excluded. 
3.1.3 
Patients should have at least one organ system involved with distant 
metastatic disease. If only a single metastatic lesion is present, 
biopsy is mandatory. See Section 6 
3.1.4 
Baseline studies must be performed 8 weeks prior to the start of 
systemic therapy, and must document the extent of disease in the 
breast; the specifics of this are at physician discretion, but must 
address clinical signs and symptoms (see Section 7.1). If pre-therapy 
scans were not performed, scans performed within the first 4 weeks 
_____
_____
_____
_____
Rev. 7/12 
Rev. 7/12 
Rev. 7/12 
Rev. 7/12, 2/13,  
7/13 
Rev. 7/12 
Rev. 7/13 
Rev. 4/14 
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of systemic therapy, but prior to registration, will be accepted. 
Radiology reports documenting status of disease must be available. 
3.1.5 
If palliative radiation to non-breast sites is required prior to initiation of 
systemic therapy, scans may be completed within 8 weeks prior to or 
4 weeks following the start of radiation therapy. 
3.1.6 
If patient has only one metastatic lesion/focus, this must be proven by 
biopsy and the pathology report confirming the diagnosis of primary 
breast cancer, as well as the metastatic site, must be available. 
Single metastatic lesion? ______ (Yes/No)  Biopsy? ______ (Yes/No) 
3.1.7 
Patients may have had prior non-invasive (DCIS) cancer if there has 
been no recurrence; prior ipsilateral invasive cancer also allowed if 
more than 5 years previous. 
3.1.8 
Patients with a history of other primary cancers are eligible if the 
pathology report confirming the diagnosis of primary breast cancer is 
available and the other primary cancer was curatively treated with a 
5-year disease-free interval. 
3.1.8.1 
Patients with non-melanoma skin cancer are eligible; 
however, patients with squamos cell carcinoma of other 
sites (except in-situ cervix) are not eligible. 
3.1.9 
Women of childbearing potential and sexually active males must be 
strongly advised to use an accepted and effective method of 
contraception.  
3.1.10 
Patients with CNS metastases are eligible (as long as projected 
survival is > 6 months). 
3.1.11 
Patients who require radiotherapy to distant metastases during 
induction systemic therapy are eligible. 
3.2 
Randomization (STEP 2) 
3.2.1 
Date of randomization must be within 32 weeks of initiation of optimal 
systemic therapy. 
3.2.2 
 Patients must have completed at least 16 weeks of optimal systemic 
therapy (appropriate to the tumor biological profile and the patient’s 
age and menopausal status).  
NOTE: 
The patient will be considered eligible if the last day of the 
treatment cycle meets the 16 weeks criteria. For example, 
the last chemotherapy dose might be administered in 
week 15, while the cycle might end in week 16 or 17. In 
this case, the patient will be considered eligible for the 
study. 
3.2.2.1 
If systemic therapy is discontinued for toxicity, there is no 
distant progression and at least 12 weeks of therapy have 
been delivered, then the patient remains eligible. If 
systemic therapy is changed for reasons other than 
progression of disease (e.g. from chemotherapy to 
endocrine therapy), the patient remains eligible. 
_____
_____
_____
_____
_____
_____
_____
Rev. 7/12 
Rev. 7/12, 7/13 
Rev. 7/12. 4/15 
_____ 
Rev. 7/12 
Rev. 7/12, 7/13 
Rev. 7/12 
_____
Rev. 4/14 
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3.2.3 
Documentation regarding the details of administration of all systemic 
chemotherapy must be available. 
3.2.4 
Patients must not have experienced distant disease progression 
since the start of systemic therapy, as evidenced by clinical and 
radiographic documentation of disease status before treatment and 
within 6 weeks prior to randomization, including: 
a. No new sites of disease 
b. No enlargement of existing sites by 20% or more in longest 
diameter 
c. No symptomatic deterioration 
d. Imaging at step 2 should preferably be the same as at Step 1 
(baseline). It must address all previous sites of disease and all 
clinical signs and symptoms. If all Step 1 imaging tests cannot be 
repeated, the reason should be documented (e.g. declined by 
insurance). Step 2 imaging must evaluate all known sites of 
disease and address all signs/symptoms present at Step 2. 
3.2.5 
Patients must be judged to be candidates for complete resection with 
free margins followed by radiation therapy (if radiation therapy is 
indicated). 
3.2.6 
Local disease at the primary site must be asymptomatic. 
3.2.7 
Patients must have adequate organ function to undergo local therapy 
4 weeks +/ - 2 weeks prior to randomization per investigator 
discretion and institutional guidelines. 
3.2.7.1 
[Removed in Addendum #2] 
3.2.7.2 
[Removed in Addendum #2] 
3.2.7.3 
[Removed in Addendum #2] 
3.2.7.4 
[Removed in Addendum #2] 
3.2.7.5 
[Removed in Addendum #2] 
 
3.2.8 
Women must not be pregnant or breast-feeding due to toxicity of 
systemic therapy and radiotherapy to fetus/infant. 
All females of childbearing potential must have a blood test or urine 
study within 2 weeks prior to randomization to rule out pregnancy. 
Female? ______ (Yes/No) 
Date of blood test or urine study: _______ 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
_____
_____
_____
_____
_____
_____
Rev. 7/12 
Rev. 7/12 
Rev. 7/12 
Rev. 7/12, 2/13 
4/14 
Rev. 7/12 
Rev. 7/12 
Rev. 7/12 
Rev. 7/12 
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4. 
Registration Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
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. Study centers can 
check the status of their registration packets by querying the Regulatory Support 
System (RSS) site registration status page of the CTSU member web site by entering 
credentials at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will 
automatically load to RSS. 

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Downloading Site Registration Documents:   
Site registration forms may be downloaded from the E2108 protocol page located on the 
CTSU members’ website.   
• 
Go to https://www.ctsu.org 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 ECOG-ACRIN link to expand, then select trial protocol E2108 
• 
Click on the Site Registration Documents link 
Requirements for E2108 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) 
Submitting Regulatory Documents 
Submit completed forms along with a copy of your IRB Approval and Model Informed 
Consent to the CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS.  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
FAX: (215) 569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document 
submission only) 
Required Protocol Specific Regulatory Documents 
1. 
CTSU Regulatory Transmittal Form. 
2. 
Copy of IRB Informed Consent Document. 
NOTE: 
Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the 
sample informed consent document must be justified in writing 
by the investigator and approved by the IRB. 
3. 
A.  
CTSU IRB Certification Form. 
Or 
B.  
Signed HHS OMB No. 0990-0263 (replaces Form 310). 
Or 
C.  
IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an 
assurance number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 

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• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
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 https://www.ctsu.org 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 
Patient Enrollment 
Patient registration can occur only after pre-treatment evaluation is complete, 
eligibility criteria have been met, and the study site is listed as ‘approved’ in the 
CTSU RSS.  Patients must have signed and dated all applicable consents and 
authorization forms.   
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 
(check at <https://eapps-ctep.nci.nih.gov/iam/index.jsp>) 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. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following:  
• 
All eligibility criteria has 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. 
Further instructional information is provided on the OPEN tab of the CTSU 
members’ side of the CTSU website at https://www.ctsu.org or at 
https://open.ctsu.org. For any additional questions contact the CTSU Help Desk 
at 1-888-823-5923 or ctsucontact@westat.com. 

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4.1 
Registration (Step 1) 
Patients may register to Step 1 at any time prior to the start of systemic therapy 
or < 30 weeks after the start of systemic therapy, with randomization to step 2 no 
earlier than 16 weeks after start of systemic therapy (once response or stable 
disease is documented).  
[Note deleted in Addendum #2] 
The following information will be requested: 
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
4.1.2.1 
Institution and affiliate name 
4.1.2.2 
Investigator’s name 
4.1.3 
Patient Identification  
4.1.3.1 
Patient’s initials and chart number 
4.1.3.2 
Patient’s Social Security number 
4.1.3.3 
Patient demographics 
4.1.3.3.1 
Sex 
4.1.3.3.2 
Birth date 
4.1.3.3.3 
Race 
4.1.3.3.4 
Ethnicity 
4.1.3.3.5 
Nine-digit ZIP code 
4.1.3.3.6 
Method of payment 
4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3. An eligibility checklist has been appended to the protocol. A 
confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office - Boston. 
4.1.5 
Additional Requirements  
4.1.5.1 
Patients must provide a signed and dated, written 
informed consent form. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office - Boston. 
4.1.5.2 
Pathology materials and blood samples submitted as 
indicated in Section 9 for banking per patient consent. 
NOTE: 
ECOG-ACRIN requires that biological samples 
submitted from patients participating in E2108 
be entered and tracked via the online ECOG-
ACRIN Sample Tracking System (STS). Any 
case reimbursements associated with sample 
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submissions must not be captured if samples 
are not logged into STS.  See Section 9.3 
NOTE: 
Institutions outside of the United States and 
Canada must confer with the receiving 
laboratory and the ECOG-ACRIN Operations 
Office - Boston regarding logistics for 
submission of fresh samples. 
4.2 
Randomization (Step 2) 
Randomization to step 2 is to occur within 16 to 32 weeks after start of systemic 
therapy (once response or stable disease is documented).  
Step 2 treatment must not to start prior to randomization and must start after 
completion of at least 16 weeks of systemic therapy and no more than 32 weeks 
from start of systemic therapy.   
The following information will be requested: 
4.2.1 
Protocol Number  
4.2.2 
Investigator Identification  
4.2.2.1 
Institution and affiliate name. 
4.2.2.2 
Investigator’s name. 
4.2.3 
Patient Identification  
4.2.3.1 
Patient’s initials and chart number. 
4.2.3.2 
Patient’s Social Security number. 
4.2.3.3 
Patient demographics 
4.2.3.3.1 
Sex 
4.2.3.3.2 
Birth date (mm/yyyy) 
4.2.3.3.3 
Race 
4.2.3.3.4 
Ethnicity 
4.2.3.3.5 
Nine-digit ZIP code 
4.2.3.3.6 
Method of payment 
4.2.3.4 
Patient sequence number assigned at pre-registration. 
4.2.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3. An eligibility checklist has been appended to the protocol. A 
confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office - Boston. 
4.2.5 
Stratification Factors 
4.2.5.1 
Marker status and treatment plan 
• 
ER+ or PR+, HER2-, plan to treat with endocrine 
therapy alone 
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• 
ER+ or PR+, HER2-, plan to treat with chemotherapy 
(with or without endocrine therapy) 
• 
ER- or PR-, HER2- 
• 
HER2+ 
4.2.5.2 
Number of involved organ systems (beyond the primary 
tumor, chest wall, and locoregional nodes, i.e., axilla, 
internal mammary, supraclavicular). 
• 
Single organ system with distant disease 
• 
More than one organ system with distant disease 
(regional nodes in the axillary, supraclavicular, and 
internal mammary locations are not considered distant 
sites).  
4.2.6 
Additional Requirements 
4.2.6.1 
Patients must provide a signed and dated, written 
informed consent form. 
4.2.6.2 
Pathological materials and blood samples should be 
submitted as indicated in Section 9 for banking per patient 
consent. 
NOTE: 
The establishment of research rates within the 
institution’s financial office must be in place 
prior to the performance of the additional 
biopsies. See Section 9.4 for guidelines. 
NOTE: 
ECOG-ACRIN requires that biological samples 
submitted from patients participating in E2108 
be entered and tracked via the online ECOG-
ACRIN Sample Tracking System (STS). Any 
case reimbursements associated with sample 
submissions must not be captured if samples 
are not logged into STS.  See Section 9.3. 
NOTE: 
Institutions outside of the United States and 
Canada must confer with the receiving 
laboratory and the ECOG-ACRIN Operations 
Office - Boston regarding logistics for 
submission of fresh samples. 
4.3 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not randomize to Step 2, please document the reason on the 
E2108 Step 1 Vital Status form and submit this form through 5 years per the 
E2108 forms submission schedule. 
After randomization to step 2, if a patient does not receive the assigned protocol 
treatment, follow-up data will still be collected and must be submitted according 
to the instructions in the E2108 Forms Packet. Document the reason for not 
starting protocol treatment on the off-treatment form. 
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5. 
Treatment Plan 
5.1 
Treatment 
 Patients may be registered to Step 1 (Arm S) prior to initiation of systemic 
therapy OR up to 30 weeks after start of systemic therapy. Full local and distant 
disease evaluation (clinical and radiological) must have been performed a 
maximum of 8 weeks prior to start of systemic therapy. Scans performed within 4 
weeks following the start of systemic therapy, but prior to registration, will be 
acceptable as baseline studies, but complete imaging prior to start of therapy is 
preferred. If radiation at a distant site was required prior to start of systemic 
therapy, scans can be 8 weeks prior to or 4 weeks following the start of radiation. 
All baseline studies documenting extent of disease must be repeated prior to 
Step 2 randomization. Patients with progressive disease per the criteria in 
Section 3.2.4 will not randomize to Step 2 but will be followed for survival. Those 
with stable or responsive disease will be randomized to receive elective local 
therapy (Arm B) versus the palliative local therapy (Arm A) when/if needed. 
Systemic therapy will continue on both treatment arms as directed by the treating 
physician. Patients who had advanced local disease at registration can be 
randomized if the local disease is now considered operable by conventional 
criteria. 
5.1.1 
Systemic Therapy (Step 1: Arm S) 
Optimal systemic therapy will be determined by the treating physician 
based on tumor profile, patient age, and menopausal status. The use 
of NCCN or equivalent guidelines are encouraged. First-line systemic 
therapy may also be offered on a Phase II or III trial, and may be 
randomized at Step 2, as long as there is no evidence of progression 
(see Section 6.1). A change in systemic therapy is allowed for toxicity 
or at physician discretion (e.g. switch from chemotherapy to 
endocrine therapy), as long as the change is not for disease 
progression. However, randomization at end of 1st regimen is 
encouraged. 
5.1.2 
Local Therapy Treatments (Step 2: Arms A and B) 
5.1.2.1 
Arm A: Continued Systemic Therapy 
Systemic therapy will continue as directed by the treating 
physician. 
Local therapy should be offered to patients only if needed 
for palliation of symptoms such as tumor ulceration, pain, 
bulky adenopathy causing arm symptoms, and other 
similar situations where therapy is designed specifically to 
address symptoms at the local site. It may consist of 
radiotherapy alone, surgery alone, or the combination. 
5.1.2.2 
Arm B: Early Local Therapy 
Surgery is to occur no later than 10 weeks after 
randomization. 
Surgical treatment will be chosen by patient and physician 
according to the criteria that are generally accepted for 
breast conserving therapy (BCT) or total mastectomy 
Rev. 7/12, 2/13 
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Rev. 2/13 
Rev. 2/13 
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(TM). If BCT is chosen, free surgical margins must be 
achieved with re-excision or mastectomy (no minimum 
margin width is required). Axillary management should 
parallel that used for non-metastatic breast cancer. Axillary 
dissection is required if clinical and radiologic evaluation at 
initial registration was suggestive of axillary disease and 
axillary radiation is not planned. For women not receiving 
axillary dissection, sentinel node biopsy should document 
an axillary nodal burden of 1-2 involved lymph nodes (i.e. 
ACOSOG Z-11 criteria may be applied if axillary radiation 
is not planned). For women undergoing TM, reconstructive 
surgery will be allowed at the discretion of the treating 
physician, recognizing that this may delay the continuation 
of systemic therapy and complicate radiation planning. 
Surgical quality assurance will be coordinated with the 
ECOG-ACRIN Surgery Committee. 
Systemic therapy may resume after recovery from surgery 
as directed by the treating physician. Systemic therapy will 
continue directed by the treating physician. 
Following surgery, radiotherapy is to be given as outlined 
in Section 5.3. 
5.2 
Health-Related Quality of Life Assessment  
Overall health-related quality of life (physical, functional, emotional and social 
well-being) will be assessed by administering the FACT-G. Breast cancer-
specific concerns will be assessed by administering the Breast Cancer subscale 
of the FACT. Participants will complete the 27-item FACT-G, the 10-item FACT-
Breast subscale and 9 additional items that have been written for this trial. We 
will use the FACT-B TOI to assess HRQL. The FACT-B TOI is calculated by 
summing the physical well-being (7 items), functional well-being (7 items) and 
breast cancer-specific (10 items) scales from the FACT. In addition, five items 
from the FACT Breast cancer subscale and four items from the FACT-G have 
been selected a priori for individual item analysis to assess differences in pain, 
body image, and worry between treatment arms. Given the lack of an available 
scale to assess these concerns in a tailored and concise manner, we have 
written additional items for the FACT Breast cancer subscale to capture these 
concerns (four items to assess lymphedema, one item to assess worry about 
tumor growth, two items to assess discomfort in the breast and chest wall, and 
two items to assess the effects of tumor nodules and ulcers on functional well-
being). Because these items are exploratory, we will examine the psychometric 
properties of each item as well as composite scores (eg. summation of 
lymphedema items) prior to calculating treatment arm comparisons. In addition 
we will use data collected from this trial to validate these items. 
 The FACT-Breast and additional items (referred to as the FACT-Breast + Local 
Symptoms-9 or FACT-B + LS-9) to assess HRQL will be administered at five 
time points: step 1: registration (+/- 14 days); step 2: randomization ; six months 
post-randomization (+/- 14 days); 18 months post-randomization (+/- 14 days); 
and 30 months post-randomization (+/- 14 days). It is anticipated that 
participants in the early local therapy arm (Arm B) will have completed surgery 
and radiation therapy at approximately 6 months post-randomization and will 
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likely still experience acute treatment-related symptoms, while most participants 
in the palliative local therapy arm (Arm A) will not have received any treatment 
as of 6 months post-randomization. 
Therefore, a comparison at 18 months post-randomization on the FACT-B TOI 
score will be used as the primary HRQL endpoint analysis. A second HRQL 
analysis will examine FACT-B scores at about 30 months post-randomization. 
We hypothesize that the HRQL for the breast/chest wall items will be better for 
the control arm at the 6 month timepoint, and will be better in the experimental 
arm at the 18 month time point. An additional timepoint for Arm A patients will be 
at the point of decision for local therapy. No formal comparative analysis is 
planned for this data, but it will serve to document the degree of symptoms that 
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Timing of FACT-B + LS-9 Administration 
Rev. 4/14 
Rev. 4/14 
Questionnaires* 
Step 1: 
Registration  
(+/- 14 days) 
Step 2: 
Randomization 
At 6 months post 
randomization  
(+/- 14 days) 
At 18 months 
post 
randomization 
(+/- 14 days) 
At 30 months 
post-
randomization 
(+/- 14 days) 
At decision for early 
local therapy (prior 
to surgery – Arm A 
patients only)  
(+/- 14 days) 
Approximate 
time to 
complete 
 
FACT-B + LS-9 
X 
X 
X 
X 
X 
X 
15 minutes 
* Please note that the QOL questionnaire is only available in English. 
5.2.1 
QOL Instrument Administration Instructions 
5.2.1.1 
The questionnaires must be administered at the timepoints listed above. The patient should be 
instructed to respond to the questionnaires in terms of his/her experience during the time 
frame specified on each questionnaire. 
5.2.1.2 
The CRN/CRA should read the instructions printed on the questionnaire to the patient and 
ensure the patient understands the instructions. It is important to assure the patient that all 
material on the questionnaire is confidential and will not be shared with the health care team 
and that it will not become part of the medical record. It is permissible to assist the patient with 
the completion of the questionnaires as long as the staff person does not influence the 
patient’s responses. 
5.2.1.3 
Whenever possible, the HRQL assessment should be administered at the clinic visit before the 
patient is seen by the physician, before evaluations are performed and before test results are 
shared with the patient. In the event that the questionnaires are not administered at the clinic 
visit, the HRQL data can be collected by telephone or mail as backup methods provided that 
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5.2.1.4 
Assistance in reading the questionnaire is permitted if the 
patient is unable to complete the questionnaire on his/her 
own (e.g. difficulty in reading, elderly). It is important not to 
influence the response of the patient. Note why the patient 
required assistance and the type of assistance given. 
5.2.1.5 
Patients should be instructed to answer all the questions 
regardless of whether the symptoms or conditions asked 
about are related to the cancer or cancer treatment. 
Discourage family members from being present during 
questionnaire completion or from influencing the patient’s 
responses.The questionnaires must be reviewed by the 
protocol nurse or research coordinator as soon as the 
patient completes them to ensure all items were marked 
appropriately. If the patient has marked more than one 
answer per question, ask the patient which answer best 
reflects how they are feeling. If the patient has skipped a 
question or questions, the patient should be asked if 
he/she would like to answer it. If the patient refuses, it 
should be indicated on the questionnaire that he/she 
declined to answer the item.  
5.2.1.6 
If the patient refuses or cannot complete the questionnaire 
at any time point, he or she should be asked to do so at 
the next scheduled HRQL assessment. 
5.2.1.7 
The patient may decline to complete the HRQL 
assessment for any reason. The reason must be 
documented on the Assessment Compliance Form. 
5.2.1.8 
If a patient misses an appointment on the scheduled date, 
the questionnaires may be completed by telephone on the 
appointed date or they may be completed at the time the 
appointment is rescheduled. If the missed scheduled date 
is on a treatment date, the quality of life assessment will be 
done when the patient comes for the rescheduled 
treatment. 
5.2.1.9 
If a patient cannot complete the quality of life 
questionnaires because he/she is too sick, this should be 
documented on the Assessment Compliance Form. 
5.3 
Radiation Therapy 
Radiation therapy (if indicated) must begin within 12 weeks of final therapeutic 
surgical procedure (including re-excision for free margins and completion of 
axillary dissection). After breast conservation surgery, all patients will receive 
definitive breast irradiation. Definitive breast irradiation will include the whole 
breast. A boost to the primary tumor bed is optional, provided that the margins of 
excision are pathologically confirmed as negative. Nodal radiation can be added 
for node positive patients at the discretion of the treating radiation oncologist. 
After mastectomy, post mastectomy radiation treatment (PMRT) will be given at 
the discretion of the treating surgeon and radiation oncologist. All patients with 4 
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or more pathologically positive axillary lymph nodes will be treated with PMRT. 
For patients with 1-3 pathologically positive axillary lymph nodes, consultation 
with a radiation oncologist is recommended to determine whether PMRT is 
indicated. For other borderline indications for PMRT, consultation with a radiation 
oncologist is recommended. Target volumes for PMRT will include at a minimum 
the chest wall plus a supraclavicular field. Other nodal volumes can be included 
within the target volume at the discretion of the treating radiation oncologist. A 
boost within the chest wall field is optional. Bolus for the chest wall field can be 
either 1 cm every other day or ½ cm every day. The chest wall can be irradiated 
using either electrons or tangential photon beams. 
CT based simulation is strongly recommended, but is not required. IMRT is 
allowed provided NCI guidelines are followed and all required Benchmarks have 
been completed (see below).  For left sided radiation treatment, the volume of 
heart included within the radiation fields should be carefully assessed. 
5.3.1 
Required Benchmarks 
Centers participating in this protocol using 3D conformal techniques 
are required to complete the 3D Benchmark; those treating with IMRT 
must complete the IMRT Questionnaire and either the QARC 
Benchmark or irradiate the RPC’s IMRT head and neck phantom. All 
Benchmark material can be obtained from the Quality Assurance 
Review Center (www.QARC.org) and must be submitted before 
patients on this protocol can be evaluated. Contact the RPC 
(http://rpc.mdanderson.org/rpc) for information regarding their IMRT 
phantoms. Patients will be considered unevaluable if approved 
benchmarks are not on file at QARC. 
5.3.2 
Equipment 
Modality:  All patients must be treated with a linear accelerator with 
nominal photon energy between 4 to 18MV (typically 6 MV). Electron 
therapy is permitted for supplemental boost to the intact breast (after 
breast conserving surgery) or to the chest wall. Co-60 may be used 
for post-mastectomy RT. 
Calibration:  The calibration of therapy machines used in this protocol 
shall be verified by the Radiological Physics Center (RPC). 
5.3.3 
Target Dose 
5.3.3.1 
Dose Definition 
The absorbed dose is specified as Gy to muscle. 
5.3.3.2 
Total Dose 
For breast conserving therapy: radiation fractionation 
options for the whole breast treatment are: (a) conventional 
fractionation of 1.8 or 2.0 Gy per day to 45 - 50.4 Gy; or (b) 
accelerated whole breast radiation to a dose of 42.56 Gy in 
16 fractions of 2.66 Gy each (Whelan 2002). If a boost to 
the primary tumor site is given using conventional 
fractionation, then the recommended total dose to the 
primary tumor site is 60-66 Gy. If a boost to the primary 
tumor site is not given, then the whole breast dose is 
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required to be either: (a) 2.0 Gy daily fractions to 50 Gy 
total dose in 25 fractions; or (b) 42.56 Gy in 16 fractions of 
2.66 Gy each.  For accelerated whole breast fractionation, 
a boost to the primary tumor site is optional.  Nodal 
radiation can be added for node positive patients at the 
discretion of the treating radiation oncologist. 
For post mastectomy radiation therapy: Fractionation may 
be either (a) 1.8 Gy per fraction, 50.4 Gy to the chest wall, 
and 45 Gy to the supraclavicular field or (b) 2.0 Gy per 
fraction, 50 Gy to the chest wall, and 46 Gy to the 
supraclavicular field.  IMN's and full axilla may be treated 
at the discretion of the radiation oncologist.  A chest wall 
boost of up to 10 Gy may be given at the discretion of the 
radiation oncologist. 
5.3.4 
Time and Dose Considerations 
5.3.4.1 
Fractionation 
Patients will receive one treatment per day, five days per 
week (Monday through Friday).  All fields will be treated 
each day.  At least two fractions must be given during the 
first week of treatment. 
5.3.4.2 
Interruptions 
No special considerations need to be made for treatment 
delays of 1 week or less.  If treatment is delayed more than 
1 week but less than 2 weeks, notify the study chair.  If 
treatment delays of more than two weeks occur, the patient 
will be considered off-study. The reason(s) for any break 
must be clearly recorded in the treatment record.   
If there are any changes in the patient’s status (i.e., early 
discontinuation of protocol treatment, delay in starting 
radiotherapy, or break in radiotherapy) these should be 
communicated in writing to QARC by fax (401) 753-7601 
or email to ECOG@qarc.org with a copy to the Radiation 
Oncology Co-Chair. 
5.3.5 
Treatment Technique 
Guidelines for breast conservation treatment (i.e., breast conserving 
surgery followed by definitive breast irradiation) have been published 
by a number of expert groups or panels (70,72,76,77).  Similarly, 
guidelines for post mastectomy radiation treatment (PMRT) have 
been published by a number of expert groups or panels 
(70,71,73,74,77). 
It is anticipated that most patients will be planned using CT based 
planning tools. Guidelines are also presented for fluoroscopy based 
planning techniques. 
5.3.5.1 
Fluoroscopy-based WBI Treatment Plan 
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5.3.5.1.1 
Fluoroscopy-based Plan 
Dose distribution is evaluated on an 
external patient contour at central axis after 
tangents are established clinically with 
fluoroscopy. The lumpectomy cavity must 
have been marked with surgical clips. 
Ideally, surgical clips should mark the 
cephalad, caudad, medial, lateral, 
anterior and posterior extent of the 
lumpectomy cavity. 
5.3.5.1.2 
Target breast Volume 
At the time of simulation the clinical breast 
volume to be targeted in the tangent fields 
with appropriate margin is determined by 
the radiation oncologist. 
5.3.5.1.3 
Tangent Fields 
The borders for the tangent fields are set so 
that it includes the targeted clinical breast 
volume determined above plus a 1–2 cm 
margin. It is recommended that techniques 
be applied that assure posterior or deep 
borders are co-planar in order to minimize 
exit into the lungs. 
5.3.5.1.4 
Constraints for Critical Non-Target Organs 
The perpendicular distance from the chest 
wall to the posterior field edge can include 
at maximum 3 cm of lung tissue at any 
point along the length of the tangent on a 
film. For left-sided cancers, field 
arrangements should be used that minimize 
inclusion of the heart-shadow seen on 
fluoro/film within the field, and include no 
more than 1.5 cm of heart within the field. 
5.3.5.1.5 
External Contour Dose Prescription and 
Evaluation of Isodose Distribution 
An external patient contour through the 
central axis is used for dose prescription. 
The whole breast dose will be prescribed to 
two thirds the perpendicular distance from 
the anterior/apical contour surface to the 
posterior border of the tangent field at mid-
separation. Wedges and compensators may 
be used to keep the maximum dose within 
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5.3.5.1.6 
Verification of the Lumpectomy Cavity 
Coverage Within the Prescription Isodose 
for the Whole Breast 
The tangent fields must include the surgical 
clips that demarcate the lumpectomy cavity 
with a 2 cm margin. The radiation oncology 
facility must submit a scanned copy or 
digital picture of one of the tangent films 
demonstrating the coverage of the surgical 
clips around the lumpectomy cavity. 
5.3.5.2 
CT-based WBI Treatment Plan 
5.3.5.2.1 
CT Planning 
This includes dose distribution evaluated on 
a single central axis CT slice or multiple CT 
levels after tangents are established 
clinically (by fluoroscopy or CT) or target 
breast volume defined on CT and tangents 
and dose distribution based on dose-volume 
specification to breast and constraints for 
critical nontarget organs. 
5.3.5.2.2 
Target Breast Volumes 
At the time of the simulation/CT, the clinical 
breast volume to be targeted in the tangent 
fields, with appropriate margin, is 
determined by the radiation oncologist. 
5.3.5.2.3 
Tangential Fields 
The borders for the tangent fields are set so 
that they include the targeted clinical breast 
volume determined above plus a 1–2 cm 
margin. Examples of typical clinical 
boundaries for tangent fields are: 
Medial: usually midsternum 
Lateral: usually midaxillary line 
Caudad: 1-2 cm below the inframammary 
line 
Cephalad: commonly at the base of the 
clavicle heads or the sternal manubrium 
joint. These boundaries may need to be 
modified depending on the location of the 
lumpectomy cavity when it is visualized on 
CT. For CT-based planning, radiopaque 
markers are placed on these borders. It is 
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co-planar in order to minimize exit into the 
lungs. 
5.3.5.2.4 
Nodal Volume Coverage 
If irradiated, the internal mammary lymph 
nodes should be contoured from the inferior 
chest wall field edge and include the medial 
supraclavicular region. These lymph nodes 
follow the contour of the internal mammary 
artery. They do not have to be intentionally 
treated. Axillary and supraclavicular lymph 
nodes at levels 1, 2, and 3 can be 
contoured as a single object, or contoured 
separately. The lower border of the 
supraclavicular field will typically be 
matched to the superior edge of the tangent 
fields, and the upper border will extend on 
or about to the level of C4 to cover the 
supraclavicular lymph nodes. The medial 
field edge will extend to the area of the 
lateral vertebral body and extend laterally 
beyond the humeral head. The humeral 
head and skin folds can be blocked at the 
discretion of the treating radiation 
oncologist. Angled fields are permitted to 
limit swallowing discomfort. It is recognized 
that the most posterior aspect of the axilla at 
the level of the latisimus will not be fully 
covered with an anterior field, and a 
supplemental posterior boost field is 
discretionary. 
5.3.5.2.5 
Constraints for critical non-target organs 
The perpendicular distance from the chest 
wall to the posterior field edge can include 
at maximum 3 cm of lung tissue at any 
point along the length of the tangent on a 
film, or a digitally reconstructed radiograph 
(DRR) of the field. For left-sided cancers, 
field arrangements that minimize inclusion 
of the heart in the field should be used, and 
include no more than 1.5 cm of heart within 
the field. 
5.3.5.2.6 
Dose prescription and evaluation of isodose 
distribution 
The dose will be prescribed at two thirds the 
perpendicular distance from the skin 
overlying the breast to the posterior border 
of the tangent field at mid-separation on the 
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compensators, may be used to keep the 
maximum dose within 15% of the 
prescription. The use of bolus is strongly 
discouraged. 
5.3.5.2.7 
Tissue Heterogeneity 
Calculations shall take into account the 
effect of tissue heterogeneities. 
5.3.5.2.8 
Verification of the lumpectomy cavity 
coverage within the prescription isodose for 
the whole breast 
•  Verification process when the 
lumpectomy cavity can be identified 
on CT: Review of the dose distribution 
on CT slices that include the lumpectomy 
cavity is requested to verify that the 
cavity, as demarcated by surgical clips or 
post operative seroma, is being covered 
by the prescription isodose. Acceptable 
WBI must demonstrate that the cavity is 
included in ≥ 90% isodose line.  If not, 
changes in the field width, gantry, 
collimator, or selection of wedges or 
other adjustment must be done to 
achieve this. The radiation oncology 
facility is to submit one axial CT slice 
demonstrating that the identified 
lumpectomy cavity is covered by > 90% 
isodose line and a DRR of the tangent 
field. 
•  Verification process when the 
lumpectomy cavity cannot be 
identified on CT: For some patients 
receiving WBI after chemotherapy, the 
lumpectomy cavity may have resolved 
and is no longer visible on the CT for 
radiation planning. In these instances, 
the postoperative CT submitted for 
registration to this study can be used. 
The radiation oncologist can identify on 
the postoperative registration CT a 
representative axial slice with the 
lumpectomy cavity present. A 
comparable anatomic axial slice from the 
radiation planning CT with the isodoses 
present should be found and verify that 
the ≥ 90% isodose line is covering the 
region where the lumpectomy cavity was 
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the registration scan demonstrating the 
cavity location and the radiation planning 
scan documenting the isodose coverage 
are to be submitted. A DRR of the WBI 
tangent fields should also be submitted. 
5.3.5.3 
Fluoroscopy-based PMRT treatment plan 
For patients planned using fluoroscopy-based simulation 
techniques, the chest wall will be treated from the inferior 
aspect of the clavicular head to the level of the diaphragm 
or to the level of 2cm below the contralateral inframmary 
fold. A wire will be placed on the chest wall scar to validate 
scar location on simulation images. Medial and lateral field 
edges will extend from the midline to the mid-axillary line. 
Field edges marked on a CT scan will be submitted for 
review. 
For patients treated to the supraclavicular field, the inferior 
border will be matched to the superior border of the chest 
wall field using a non-divergent technique. The medial 
edge will be at the lateral edge of the vertebral body. An 
angled technique is permitted to limit swallowing 
discomfort. The upper border will extend on or about to the 
level of C4 to cover the supraclavicular lymph nodes.. The 
lateral border will be lateral to the humeral head with 
blocking of the humeral head and skin folds based on 
operative findings and judgment of the treating radiation 
oncologist. This field can be treated to a depth of 3-5 cm 
depending on the anatomic location of the nodal 
structures, and a posterior axillary boost is optional. 
5.3.5.4 
CT-based PMRT treatment plan 
The chest wall will be contoured from the level of the 
diaphragm or from the level 2cm below the contralateral 
inframmary fold to the inferior aspect of the clavicular head 
with field edges extending from the midline to the mid-
axillary line. Bolus will be required, either 1cm every other 
day or ½cm daily. 
If irradiated, the internal mammary lymph nodes should be 
contoured from the inferior chest wall field edge and 
include the medial supraclavicular region. These lymph 
nodes follow the contour of the internal mammary artery. 
They do not have to be intentionally treated. Axillary and 
supraclavicular lymph nodes at levels 1,2, and 3 can be 
contoured as a single object, or contoured separately. The 
lower border of the supraclavicular field will typically be 
matched to the superior edge of the tangent fields, and the 
upper border will extend on or about to the level of C4 to 
cover the supraclavicular lymph nodes. The medial field 
edge will extend to the area of the lateral vertebral body 
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humeral head and skin folds can be blocked at the 
discretion of the treating radiation oncologist. Angled fields 
are permitted to limit swallowing discomfort. It is 
recognized that the most posterior aspect of the axilla at 
the level of the latisimus will not be fully covered with an 
anterior field, and a supplemental posterior boost field is 
discretionary. 
5.3.5.5 
IMRT 
5.3.5.5.1 
Treatment Volumes 
The definition of target volumes will be in 
accordance with ICRU Reports #50 and 
#62. 
For patients treated with breast 
conservation, the target volume will include 
the entire breast and surgical cavity. The 
breast will be drawn as a CTV with a 5 mm 
PTV. Modifications of the PTV into 
pulmonary and cardiac tissue are permitted 
based on dose histogram guidelines listed 
below. PTV will be modified to maintain 3-
5mm distance below the skin surface.  The 
surgical cavity will be drawn as a CTV with 
a 5 mm PTV. The breast should be 
contoured from the inframammary fold to 
the inferior clavicular head. The surgical 
cavity should be contoured to include the 
entire excision cavity including a 1-2 cm 
extension beyond the image guided 
abnormality in all planes. 
Extension of radiation therapy into nodal 
regions is permitted on study at the 
discretion of the treating radiation 
oncologist. If the breast is treated with 
IMRT, non-IMRT treatment of nodal regions 
is permitted on study. See Section 5.2.5.2. 
(Nodal Volume Coverage for CT-based WBI 
treatment plan) for guidelines on nodal 
volume coverage. 
Post mastectomy patients can be treated 
with IMRT at the discretion of the treating 
radiation oncologist. The chest wall will be 
contoured from the level of the diaphragm to 
the inferior clavicular head. Bolus will be 
used and incorporated into the treatment 
plan to insure appropriate coverage of skin 
tissue. Nodal volume coverage, as desired, 
will be identical to patients treated for intact 
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wall can be delivered at the discretion of the 
treating radiation oncologist. If IMRT is 
used, this can be done as a continuation of 
the IMRT plan. Alternative plans, including 
electron therapy, are permitted. 
5.3.5.5.2 
Dose Prescription 
Dose shall be prescribed to an isodose 
surface that encompasses the PTV and that 
satisfies the dose uniformity requirements 
below. 
5.3.5.5.3 
Tissue Heterogeneity 
Calculations shall take into account the effect 
of tissue heterogeneities. 
5.3.5.5.4 
Dose Uniformity 
For IMRT the entire PTV shall be 
encompassed within the 95% isodose 
surface and no more than 10% of the PTV 
should receive more than 110% of the 
prescription dose, as evaluated by dose 
volume histogram. 
5.3.5.5.5 
Organs at Risk (OAR) 
Dose constraints and guidelines should be 
as follows: 
No more than 40% of the lung in the 
involved side should receive greater than 
2000 cGy. 
No more than 25% of the total lung volume 
should receive more than 2000 cGy. 
The heart should be contoured as a single 
object from the apex to the aortic root (heart 
base). No more than 30% of the volume 
should receive more than 3000 cGy. 
No more than 10% of the chest wall for both 
intact breast and mastectomy patients 
should receive more than 7000 cGy. 
5.3.6 
Dose Calculation and Reporting 
5.3.6.1 
Isodose Distributions 
Isodose distributions must be submitted for the treatment 
plan. Outlines of the planning target volume and critical 
organs must be shown. Isodose values must be clearly 
labeled.  Isodose distributions shall include axial, sagittal 
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5.3.6.2 
Dose Volume Histograms 
For CT based planning dose volume histograms must 
include the CTV, PTV, and OARs as noted above. If IMRT is 
used, a DVH in absolute dose must also be submitted for 
“unspecified tissue,” i.e., tissue contained within the skin, but 
excluding the CTV, PTV and OARs. 
5.3.6.3 
IMRT Plan Verification 
If IMRT is used, the monitor units generated by the IMRT 
planning system must be independently checked prior to 
the patient’s first treatment.  Measurements in a QA 
phantom can suffice for a check as long as the plan’s 
fluence distributions can be recomputed for a phantom 
geometry. 
5.3.6.4 
Digital Submission 
Submission of treatment plans in digital format (either 
Dicom RT or RTOG format) is encouraged.  Instructions for 
data submission are on the QARC website at 
www.QARC.org. 
Hardcopy isodose distributions for the total dose plan in 
the axial, sagittal and coronal planes, which includes the 
isocenter of the planning target volume, must be submitted 
along with total dose DVHs for digital data validation. 
These may be sent to QARC as screen captures (FTP, 
emailed or mailed on a CD). 
5.3.7 
QA Documentation 
5.3.7.1 
On-Treatment Review 
Submit the following for on-treatment review within the first 
three days of treatment: 
• 
The CT scan used for treatment planning, including 
delineation of the target volumes and critical 
structures. 
• 
Digitally reconstructed radiographs (DRR) for each 
treatment field or simulator films. It is strongly 
encouraged that the CTV and PTV be displayed on 
the DRR’s. 
• 
First day portal films (or hard copy of real time 
portal images) if achievable. 
• 
Pictures of the patient in the treatment position. 
• 
Prescription sheet for the entire treatment course 
(excluding boost treatment). 
• 
RT-1/IMRT Dosimetry Summary Form (located at 
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• 
A room’s eye view (REV), i.e., a composite 
illustration of all the fields and their angles, if 
available from your planning system. 
• 
Treatment planning system summary report that 
includes the monitor unit calculations, beam 
parameters, calculation algorithm, and volume of 
interest dose statistics. 
• 
Color isodose distributions for the total dose plan in 
the axial, sagittal and coronal planes, which 
includes the isocenter of the planning target 
volume. The target volumes and the prescription 
point must be clearly shown. 
• 
Color Dose volume histograms for the entire 
treatment course or total prescribed dose for the 
CTV and PTV and any critical structures (see 
section 5.2.6). If IMRT treatment planning is used, 
a DVH must also be submitted for a category of 
tissue called “unspecified tissue,” which is defined 
as tissue contained within the skin, but which is not 
otherwise identified by containment within any other 
structure. 
• 
Documentation of an independent check of the 
calculated dose if IMRT is used. 
• 
A copy of the ECOG-ACRIN E2108 On Study Form 
• 
Copy of the ECOG-ACRIN E2108 Checklist for 
Submission of Radiation Oncology Quality 
Assurance Materials (located at www.QARC.org). 
5.3.7.2 
Post-Treatment Review 
Within one week of the completion of radiotherapy, the 
following data shall be submitted. 
• 
A copy of the patient’s radiotherapy record 
including prescription, and the daily and cumulative 
doses to all required areas and specified dose 
points. 
• 
Copies of additional simulation and verification 
(portal) films for any field modifications made 
subsequent to the initial reporting of data for on-
treatment review. 
• 
Copies of revised RT-1/IMRT form, when 
modifications have been made subsequent to the 
initial reporting. 
• 
Copies of calculations and isodoses performed 
subsequent to the submission of the on-treatment 
data. 

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• 
Copy of the ECOG-ACRIN E2108 Checklist for 
Submission of Radiation Oncology Quality 
Assurance Materials (located at www.QARC.org). 
NOTE: Black and white copies of color documentation 
are not acceptable. 
5.3.8 
Address 
These data should be forwarded to: 
Quality Assurance Review Center 
640 George Washington Highway Suite 201 
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax:  (401) 753-7601 
Instructions on digital data submission are available on line from 
the QARC website at http://www.qarc.org/ (see Digital Data 
section). 
E-mailed data can be sent to:  ECOG@QARC.org 
5.3.8.1 
Questions 
Questions regarding the dose calculations or 
documentation should be directed to: 
Physics/Dosimetry 
Quality Assurance Review Center 
640 George Washington Highway Suite 201 
Lincoln, RI 02865-4207 
Phone: (401) 753-7600 
Fax:  (401) 753-7601 
Questions regarding the radiotherapy section of this 
protocol should be directed to the Radiation Oncology Co-
Chair. 
5.3.9 
Definitions of Deviations in Protocol Performance 
5.3.9.1 
Prescription Dose 
Minor Deviation: The dose to the prescription isodose 
surface differs from that in the protocol by between 6% and 
10%. 
Major Deviation: The dose to the prescription isodose 
surface differs from that in the protocol by more than 10%. 
5.3.9.2 
Dose Uniformity 
Fluoroscopy based (2D) Treatment Planning: The dose 
variation on an axial contour through the center of the 
target volume is greater than -5% or +15% of the protocol 
dose. 
3D/IMRT Treatment Planning: Any part of the CTV 
receives less than 95% of the protocol dose, or more than 

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10% of the PTV receives more than 110% of the protocol 
dose. 
5.3.9.3 
Volume 
Minor Deviation: Margins less than specified or fields 
excessively large as deemed by the study. 
Major Deviation: Transection of tumor or potentially tumor 
bearing area (CTV). 
5.4 
Adverse Event Reporting Requirements  
Step 1: Identify the type of event: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized. All appropriate treatment areas should have access to 
a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). 
Step 2:  Grade the event using the NCI CTCAE v 4.0. 
5.4.1 
Reporting Methods 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to 
• 
the AE Team at ECOG-ACRIN (617-632-3610)  
• 
the NCI (301-230-0159) 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (617-632-2990), 
Attention: AE within 48-72 hours.  In addition, supporting or follow up 
documentation must be faxed to the NCI (301- 230-0159) in the same 
timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.4.2 
Other Recipients of Adverse Event Reports 
ECOG-ACRIN will forward CTEP-AERS reports to the appropriate 
regulatory agencies and pharmaceutical company, if applicable. 
Adverse events determined to be reportable must also be reported by 
the institution, according to the local policy and procedures, to the 
Institutional Review Board responsible for oversight of the patient.
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5.4.3 
Expedited Reporting for Protocol E2108 – Arms A and B 
Attribution 
 
Grade 5a 
 
 
 
Unexpected 
Expected 
 
Possible,  
Probable,  
Definite 
 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: 
Indicates a full CTEP-AERS report is to be submitted within 7 calendar 
days of learning of the event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution.  
NOTE:  Any death on either arm that occurs > 30 days after the last dose of treatment and 
is attributed possibly, probably, or definitely to the treatment must be reported 
within 7 calendar days of learning of the event.   
5.4.4 
Reporting secondary primary cancers 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN: 
• A second malignancy is a cancer that is UNRELATED to 
any prior anti-cancer treatment (including the treatment on 
this protocol). Second malignancies require ONLY routine 
reporting as follows: 
1. Submit a completed Second Primary Form within 30 days 
to ECOG-ACRIN at 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Submit a copy of the pathology report to ECOG-ACRIN 
confirming the diagnosis 
3. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-
ACRIN 
• A secondary malignancy is a cancer CAUSED BY any prior 
anti-cancer treatment (including the treatment on this 
protocol).  Secondary malignancies require both routine 
and expedited reporting as follows: 
1. Submit a completed Second Primary Form within 30 days 
to ECOG-ACRIN at 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Report the diagnosis via CTEP-AERS at 
http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
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3. Submit a copy of the pathology report to ECOG-ACRIN 
and NCI/CTEP confirming the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-
ACRIN and NCI/CTEP. 
NOTE: The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even if 
ECOG-ACRIN was not the patient's most recent trial. 
NOTE: Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should be 
submitted via CTEP-AERS or by the Second Primary Form. 
5.5 
Supportive Care  
5.5.1 
All supportive measures consistent with optimal patient care will be 
given throughout the study. Growth factor support while on cytotoxic 
chemotherapy is allowed at the discretion of the treating physician. 
5.6 
Duration of Study Participation 
All patients will be followed until progression and for survival. Those randomized 
to Early Local Therapy will receive protocol-specified surgery and radiation 
immediately after randomization. Study participation will continue for 5 years 
unless: 
5.6.1 
Patient withdraws consent. 
5.6.2 
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6. 
Measurement of Effect 
6.1 
Response to Optimal Systemic Therapy on Step 1 
6.1.1 
To be randomized, patients must not have experienced disease 
progression since the start of systemic therapy, as evidenced by 
clinical and radiographic documentation of disease status at baseline 
(see 3.1.4 for definition of baseline evaluation) compared to 
equivalent tests performed within 6 weeks prior to randomization, 
including: 
6.1.1.1 
No new sites of disease 
6.1.1.2 
No enlargement of existing sites by 20% or more (sum of 
the longest diameter of measurable lesions) 
6.1.1.3 
No symptomatic deterioration, defined as a global 
deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease 
progression. Women whose loco-regional disease remains 
symptomatic at the end of induction therapy (i.e. 
ulcerations, skin nodules or pain from replacement of the 
breast with tumor or chest wall invasion) so that they 
require immediate local therapy for palliation are classified 
as having symptomatic deterioration and will not be 
randomized. They will be followed for survival. 
6.2 
Changes in Disease Status on Step 2 
6.2.1 
Local/Regional Assessment 
The breast as well as cervical, supraclavicular, infraclavicular and 
axillary lymph nodes and chest wall disease must be assessed. 
Breast evaluation will consist of: 
a) physical examination with complete documentation of the 
following: tumor in two longest dimensions; skin invasion 
(yes/no) skin ulceration (yes/no); tumor mobility (free/attached to 
fascia/chest wall fixation). 
b) Breast imaging studies with mammogram OR ultrasound OR 
breast MRI measurement are requested at baseline (see 3.1.4 
and 7.1 for definition of baseline evaluation). However, if in the 
judgment of the physician, physical exam provides sufficient 
documentation of tumor size and T stage, and breast imaging 
has not been performed in the baseline period, the patient is still 
eligible. Preferably, the same imaging studies should be 
repeated in the pre-randomization interval (within 6 weeks prior 
to randomization).  If the same study cannot be repeated (e.g. 
insurance denial of MRI), an equivalent study (e.g. mammogram 
or ultrasound) may be performed. 
c) [Deleted in Addendum #2] 
d) nodal evaluation and documentation of nodal involvement by 
physical examination is required 
Rev. 7/12, 2/13 
 
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e) documentation of chest wall disease: if skin nodules are present, 
the sum of the longest diameter of the largest five nodules 
should be recorded. If ulceration is present, this should be 
recorded (yes/no) and the area of ulceration measured in cm. 
6.3 
Endpoints 
6.3.1 
Local Regional Recurrence (among patients randomized to Arm B) 
The new development or clinically significant increase in size of any 
supraclavicular, 
infraclavicular, 
internal 
mammary 
or 
axillary 
adenopathy or chest wall disease or invasive in-breast recurrence  
6.3.2 
Local/Regional Progression (among patients randomized to Arm A) 
The development of symptoms leading to a decision for local therapy. 
6.3.3 
Uncontrolled Chest Wall Disease 
Clinical or radiological evidence of local tumor on the chest wall or the 
presence of skin involvement, ulceration, or symptoms. 
6.3.4 
Distant Progression 
The development of new sites of non-local/regional metastatic 
disease or clinically significant increase in the size of existing lesions. 
6.3.5 
Survival  
Date of randomization to date of death. 
6.3.6 
Quality of Life 
Quality of life endpoints will be measured using patient-reported 
outcomes questionnaires. Domains to be assessed and instruments 
to be administered include FACT-G physical and functional well-being 
(FACT-B TOI), and domains specific to breast cancer (FACT Breast 
cancer subscale).  
 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. Prestudy scans and x-rays used to assess all measurable or non-measurable sites of disease must be done  
≤ 8 weeks prior to the initiation of systemic therapy. If pre-therapy scans were not performed, scans performed 
within the first 4 weeks of systemic therapy will be accepted. The same window applies to history and physical, 
Local/Regional assessment, ECOG PS, weight and height. 
2. Step 2 CBC (with differential and platelet count) must be done during the 6 weeks preceding randomization. 
3. All required Step 2 chemistries must be done 6 weeks preceding randomization. 
4. Step 2 scans and x-rays used to assess all measurable or non-measurable sites of disease must be done within 
the 6 weeks preceding randomization. The same window applies to history and physical, Local/Regional 
assessment, ECOG PS, weight. 
 
 
Step 1: 
Registration 
Step 2: At 
randomization 
6 months post 
randomization  
12 months 
post 
randomization 
18 months 
post 
randomization 
30 months 
post 
randomization 
At decision for 
local therapy  
(Arm A)3 
Long-Term 
followup5 
 
History & Physical 
X1 
X4 
X12 
X12 
X12 
X12 
X4 
Q 3 months 
years 0-2; 
Q 6 months 
years 2-5 
Rev. 4/14 
Local/Regional12 
Assessment 
X1,8 
X4 
X12 
X12 
X12 
X12 
X4 
Rev. 4/14 
ECOG PS12 
X1 
X4 
X12 
 
X 
 
X4 
 
 
Weight 
X1 
X4 
X12 
 
X 
 
X4 
 
Rev. 4/14 
Height12 
X1 
 
 
 
 
 
 
 
Rev. 2/13, 4/14 
CT chest/abdomen1,10 
X 
X 
X 
 
X 
X 
X4 
 
 
Bone scan1,10 
X 
X 
X 
 
X 
 
X4 
 
Rev. 7/12, 4/14 
Mammogram9, 
X 
X 
 
 
X 
 
X4 
 
Rev. 7/12 
Breast Ultrasound9 
X 
X 
 
 
X 
 
X 
 
Rev. 7/12, 4/14 
Pregnancy Test2 
X 
X 
 
 
 
 
 
 
Rev. 4/14 
QOL assessment11 
X4 
X7 
X 
 
X 
X 
X 
 
 
CTC Enumeration6 
 
X7 
X 
 
 
 
 
 
Rev.7/12, 
      2/13 
Biological Sample 
Submissions 
See Section 7.2 
1. CT scans with bone windows or PET CT are allowed instead of CT chest/abdomen and bone scan. If performed at baseline, should 
be repeated within 6 weeks prior to randomization and during follow-up, if possible. If not possible (e.g. denied by insurance), other 
appropriate tests can be substituted that will evaluate all prior sites of disease and will address any new signs/symptoms. 
2. Urine or serum pregnancy test must be done in women of child-bearing potential < 2 weeks prior to randomization. 
Rev. 7/12, 
     2/13 
Rev.7/12, 
     2/13 
Rev. 4/14 
Rev.7/12, 
     2/13 
Rev.7/12, 
2/13, 4/14 
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3. In Arm A patients, if a decision is made to deliver palliative local therapy, a complete local-regional assessment must document 
reason for palliative treatment and must include same imaging tests that were performed at start of systemic therapy, if possible  If not 
possible, (e.g. denied by insurance), other appropriate tests can be substituted that will evaluate all prior sites of disease and will 
address any new signs/symptoms. 
4. [Deleted in Addendum #2] 
5. Patients who are not randomized will be followed for survival for 5 years post registration. 
6. Collect only if performed as part of standard clinical assessments and covered by third party reimbursement. 
7. Collect prior to randomization. 
8. Pathology reports confirming diagnosis of breast cancer and, if only one metastatic lesion is present, the metastatic site must be 
submitted to the ECOG-ACRIN Operations Office - Boston within one month of registration to step 1. 
9.  Breast imaging studies with mammogram OR ultrasound OR breast MRI measurement are requested at baseline (see 3.1.4 and 7.1 
for definition of baseline evaluation). However, if in the judgment of the physician, physical exam provides sufficient documentation of 
tumor size and T stage, and breast imaging has not been performed in the baseline period, the patient is still eligible. If possible, the 
same imaging studies should be repeated in the pre-randomization interval (within 6 weeks prior to randomization). If not possible 
(e.g. denied by insurance), other tests can be substituted that will evaluate the breast and will address any new signs/symptoms. 
Mammogram and ultrasound may be unilateral (affected side) or bilateral, at physician discretion. Breast imaging is not required if the 
breast is replaced by tumor or ulcerated in a way that makes breast imaging not feasible. If so, physical exam documentation must 
reflect this. A physical exam can only be used for pre-randomization evaluation of the breast if imaging is not feasible and tumor is 
palpable: in this case, physical exam findings describing the tumor must be documented. During follow-up breast imaging studies with 
mammogram OR ultrasound OR MRI need to be performed. 
10. If the patient is being registered >4 weeks after initiation of systemic therapy, and the test was not performed within the baseline 
window (8 weeks before to 4 weeks after start of systemic therapy), physician may declare (if appropriate) that test was not indicated, 
and the patient may still be registered. 
11. Window is +/- 14 days for each QOL administration time point (except step 2 randomization). 
12. Window is ± 14 days. 
 
Rev. 7/12 
Rev. 7/12 
Rev. 7/12 
Rev. 7/12, 7/13 
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Rev. 4/14 
Rev. 4/14 
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7.2 
Biological Sample Submissions 
Pathology and blood samples should be submitted to the ECOG-ACRIN Central 
Biorepository and pathology Facility (CBPF) for banking per patient consent as 
outlined in Section 9. 
NOTE: It is required that biological sample submissions be logged into the 
ECOG-ACRIN Sample Tracking System (STS) (see Section 9.3) 
NOTE: [Deleted in Addendum #3] 
NOTE: Institutions outside of the United States and Canada must confer with 
the receiving laboratory and the ECOG-ACRIN Operations Office - 
Boston regarding logistics for submission of fresh samples. 
Rev. 7/12 
Biological Samples 
Step 1: 
Registration 
Step 2: 
Randomization3 
Six (6) Months 
Post 
Randomization 
 
Twelve (12) 
Months Post 
Randomization 
 
Submit from patients who answer “YES” to “I agree my tissue will be submitted for research.” 
 
 
 
Rev. 7/12 
Block from Primary Tumor 
X1 
Arm B 
(Surgical 
Specimen) 
 
Arm A 
(Palliative Care 
Surgical Specimen) 
 
 
 
Block from Metastatic Site 
X2 
 
 
 
 
Submit from patients who answer “YES” to “I agree biopsies may be done to obtain research specimens” at sites 
that have met the guidelines outlined in Section 9.45    
Rev. 7/12 
Block from Primary Tumor 
 
Arm A3 
 
 
Rev. 7/12 
Block from Metastatic Site 
 
X7 
 
 
Rev. 7/12 
Submit from patients who answer “YES” to “I agree to provide additional blood for research.” Collection and 
shipping kits are available4 
 
Peripheral Blood: DNA 
PAXgene  or ACD tube, (1) 
8.5mL 
Sample may be drawn any time while participating in the protocol, 
although baseline (prior to treatment) preferred 
 
Serum: SST Red/Grey 
Marble top tube, (1) 10mL  
 
X 
X 
X 
 
Plasma and residual cells: 
EDTA Purple top tube (1) 
10mL 
 
X 
X 
X 
1. 
Time of diagnosis/staging, prior to beginning induction systemic therapy. 
2. 
If available/feasible from both Arm A and Arm B participants. Submit per patient consent.  If not 
considered clinically necessary will qualify for research biopsy rates as outlined below. 
3. 
Collect at the time of local therapy/at randomization for Arm B patients. For Arm A patients collect 
within three (3) months of randomization. If palliative surgery is performed for Arm A patients, the 
primary tumor block should be submitted. 
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4. 
To order kits, complete the E2108 Collection and Shipping Kit Order Form (Appendix VI) and Fax 
to Zemotak – International at (800) 815-4675. 
5. 
Biopsy research rates and reimbursement guidelines are outlined in Section 9.4. Prior to 
recruiting patients to the additional biopsy portion, the following conditions must be met: 
a. 
The research rates of $950 per breast biopsy and $2,350 for metastatic biopsy are deemed 
acceptable by the IRB or central research office. 
b. 
The research rate is reported to the institution’s financial office and an account established in 
the cooperative group’s principal investigator’s name. 
6. 
[Footnote deleted in Addendum #2] 
7. 
Collect within three (3) months of randomization for Arms A and B, if clinically indicated or if 
patient consents to research biopsy. 
 
 
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8. 
Statistical Considerations 
8.1 
Primary Endpoint 
Overall survival, defined as time from randomization to death from any cause. All 
patients will be followed for survival through 5 years. Cases with incomplete 
follow-up or without record of vital status will be censored at the date of last 
contact. 
8.2 
Secondary Endpoints 
8.2.1 
Uncontrolled Chest Wall Disease 
The chest wall/breast will be called “controlled” if there is no clinical or 
radiological evidence of the local tumor; or if there is evidence of the 
primary tumor but no skin nodules, ulceration, or chest wall fixation. 
Time to uncontrolled chest wall disease is defined as time from 
randomization to the development of uncontrolled chest wall disease. 
Patients with controlled chest wall will be censored at the last date of 
evaluation.  
8.2.2 
Health-related Quality of Life 
The FACT-Breast Trial Outcome Index will be used as the primary 
HRQL endpoint. FACT-B TOI scores at baseline, randomization, 6, 18 
and 30 months after randomization will be calculated and compared 
for participants randomized to early local therapy versus palliative 
local therapy. The change of FACT-B TOI scores over time will be 
compared between treatment arms as well. For the palliative local 
therapy arm, the change of QOL from randomization to the time of 
decision for local therapy will also be measured. 
8.3 
Patient Registration 
Registration must occur prior to or within 30 weeks of initiation of systemic 
therapy and prior to any local therapy. Patients who have not progressed during 
induction systemic therapy will be randomized between the two arms: Arm A 
(control: delayed palliative local therapy for symptomatic local progression) and 
Arm B (experimental: immediate local therapy). Randomization will be conducted 
using permuted blocks within strata with dynamic balancing within main 
institutions and their affiliate networks. Institutions obtain treatment assignments 
through the ECOG-ACRIN web registration program. Patients who progress 
during induction systemic therapy will undergo therapy at their physician’s 
direction and will be monitored for local and distant events.  
8.4 
Sample Size 
The primary comparison will be an intention-to-treat analysis including all 
randomized patients. It is expected that the three-year survival in the control arm 
will be 30%. The primary analysis of survival will be performed using a one-sided 
logrank test stratified on the stratification factors including marker status and 
treatment plan, number of involved organ systems, using an overall type I error of 
5%. Allowing for the interim analysis plan discussed below, a total accrual of 186 
responders and a total information of 110 deaths is planned, to give 85% power 
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to detect a 19.3% difference in the three-year survival rates (i.e., 49.3 % in the 
experimental arm). To allow for 15% probability of crossover between two arms 
(sum of the probabilities of patients on the experimental arm crossing over to the 
control arm and vice versa), both numbers are inflated by a factor of 1.38 (based 
on the Lachin-Foulkes correction)(53) to a total accrual of 258 responders and a 
total information of 152 deaths. Assuming an exponential distribution, this 
difference corresponds to an improvement in median survival from 21.4 to 33.5 
months. Assuming 70% of the recruited patients are eligible and responding, a 
total of 368 patients will be needed to accrue 258 responders. Assuming an 
accrual rate of 6 patients per month, 62 months of accrual will be needed. The 
sample size was computed using seqopr6 (part of the study design library at the 
ECOG-ACRIN Statistical Office). 
8.5 
Interim Monitoring and Analysis Plan 
Interim analyses of survival will be performed for all semi-annual DSMC meetings 
beginning when approximately 23% of the planned full information (36 deaths) 
has been observed; continuing until either the criterion for early stopping is met 
or full information is reached. To preserve the overall type I error rate, critical 
values at the interim analyses will be determined using a truncated version of the 
Lan-DeMets error spending function corresponding to the O’Brien-Fleming 
boundary (54). Boundary values at a minimal significance less than .0005 will be 
truncated at .0005, with the boundary also adjusted to preserve the overall type I 
error rate of 5%. Under the accrual and death rate assumptions above, interim 
analyses would be expected to occur at 28, 34, 40, 46, 52, 58 and 64 months 
after activation, at information times of 23%, 33%, 43%, 54%, 65%, 77%, 89% 
with a final analysis at approximately 70 months after activation at 100% of the 
information time. Due to delays in initiation of accrual and delays in data 
submission and processing, it is likely that the actual analysis times will be 6-12 
months later. 
The study will also be monitored for early stopping in favor of the null hypothesis 
using Jennison-Turnbull repeated confidence interval (RCI) (52) methodology. At 
each interim analysis the RCI on the hazard ratio will be computed using the 
critical values from the error spending function. If this RCI does not include the 
target alternative hazard ratio of 1.57 (control/experimental), then the study 
would be stopped early for lack of benefit. The hazard ratio of 1.57 is attenuated 
for the effect of noncompliance based on Lachin-Foulkes‘ modified hazards (53) 
while the actual hazard ratio will be adjusted at the time of analysis based on 
actual compliance rates. If criteria for early stopping are not met, then the final 
analysis will be performed when approximately 152 deaths have been observed.  
Secondary objectives include comparison of proportions of patients with 
uncontrolled chest wall, time to uncontrolled chest wall disease and 
HRQLbetween arms. The proportion of patients with uncontrolled chest wall at 18 
and 30 months post randomization will also be compared using the two-point 
procedure described in Freidlin, Korn, and et. al. (51). The fraction of 
uncontrolled chestwall at 6 months post randomization will also be compared 
using Fisher’s exact test. HRQL scores will be compared using the methods 
described below. 
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8.6 
HRQL Power Estimate and Analysis Plan 
Health Related Quality of Life (HRQL) will be assessed using the FACT-B TOI, 
FACT-G, FACT Breast cancer subscale score and the additional items added to 
the Breast Cancer Subscale. The average total score for each scale will be 
recorded for both arms at baseline, randomization, six months post-
randomization, 18 months post-randomization, and 30 months post-
randomization and their change over time will be compared using mixed effects 
models. More specifically, we will fit a model with treatment assignment, 
assessment time, treatment assignment by assessment time interaction and 
other possible predictors. If the interaction of treatment assignment and 
assessment time is significant, then the change of HRQL over time would be 
different for the two arms.  This model also accommodates inter-patient variability 
by modeling patient-specific regression lines. If there is high proportion of 
informative missingness in the HRQL data, we will analyze the data using the 
joint modeling of longitudinal data (here, HRQL) and survival time as described in 
Schluchter, 1992 and Schluchter, Greene and Beck, (55, 56). We will also test 
whether the HRQL increase or decrease from randomization to the time of 
decision for local therapy for the palliative local therapy arm, using a paired t test. 
The primary endpoint for HRQL is FACT-B TOI. Looking at FACT-B TOI data, 
using a 2-sided t test at level 0.20, there is 79% power to detect a difference of 
4.5 points between the two arms with SD 14 (from E2100), assuming 69% of 
responders who received assigned treatment (89 per arm) have HRQL data at 18 
months post-randomization. The Wilcoxon Rank Sum test will be used to 
compare the two arms if the scores are not normally distributed. 
8.7 
Correlative Science (CTC) Power estimate  
Two sample t-test/Wilcoxon test will be conducted to test whether the CTC 
burden at 6 months after randomization will be lower in Arm B than in Arm A. Cox 
proportional hazards (PH) model will be used to examine whether patients with 
lower CTC burden at 6 months after randomization have prolonged survival. The 
treatment assignment, CTC burden or possibly their interaction will be included in 
the Cox PH model. 
Assuming 60% of the patients would provide their CTC at 6 months after 
randomization, we would have 155 evaluable patients, with 77 patients per arm. 
Assuming the standardized difference is 0.339 (difference in mean/standard 
deviation; e.g. the difference in CTC at 6 months after randomization for the two 
arms is 1 and the SD is 3), then the given sample size will provide 77% power 
using a two sample t test with two-sided significance level of 0.20.  
A paired t-test/ Wilcoxon test would be used to test whether there is a reduction 
in CTC burden from randomization to 6 month assessmentsin Arm B. A Cox PH 
model will be conducted to evaluate whether a larger reduction in CTC predicts 
longer survival. 
A two sample t-test/Wilcoxon test would be used to test whether the reduction in 
CTC in Arm B is larger than Arm A.  A Cox PH model will be used to evaluate 
whether a larger reduction predicts longer survival. 
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8.8 
Gender and Ethnicity  
Based on previous data from E2100 and E1100, the anticipated accrual in 
subgroups defined by gender and ethnicity/race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
27 
0 
27 
Not Hispanic or Latino 
339 
2 
341 
Ethnic Category: Total of all subjects 
366 
2 
368 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
8 
0 
8 
Black or African American 
34 
0 
34 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
324 
2 
326 
Racial Category: Total of all subjects 
366 
2 
368 
The accrual targets in individual cells are not large enough for definitive 
treatment comparisons to be made within these subgroups. Therefore, overall 
accrual to the study will not be extended to meet individual subgroup targets.  
8.9 
Compliance Monitoring 
The DSMC will monitor the compliance throughout the trial. If there is large 
deviation from the assumed compliance rate, i.e., the sum of the cross-over rates 
in either direction cross 15%, the design modification or early termination of the 
trial will be discussed at the DSMC meeting.  We would also consider a formal 
stopping rule if the cross-over rate is higher than expected after recruiting 200 
patients, by evaluating the impact of the unexpected accumulative cross-over 
rate on the power. If the accumulative cross-over rate is higher than assumed, for 
example, 20%, then the power would be reduced to 82%. A 30% rate yields a 
power as 71%, which might be considered as acceptable.  In a more extreme 
case, if the rate reaches 50%, then the power would be only 46%, which is too 
low to detect any benefit for the elective local therapy. On the other hand, if the 
accumulative cross-over rate is lower than assumed (15%), then we would gain 
more power with the current design. For example, if the rate is 10%, the power 
would increase to 89%. 
8.10 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Safety Monitoring 
Committee (DSMC). The DSMC meets twice each year. For each meeting, all 
monitored studies are reviewed for safety and progress toward completion. When 
appropriate, the DSMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DSMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DSMC may review unblinded toxicity data, while only pooled or 
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blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DSMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DSMC. Any DSMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DSMC Policy can be 
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9. 
Correlative Studies 
Tumor tissue (primary and metastatic) and blood specimens are to be submitted per 
patient consent for future exploration of the biological interactions between the primary 
tumor and metastatic lesions and the effect of primary tumor resection on survival. 
9.1 
Sample Submission Requirements 
ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System (STS).  An STS 
shipping manifest form must be generated and shipped with the sample 
submissions.  See Section 9.3.  
A table summarizing the biological sample submissions is located in Section 7.2 
9.1.1 
Tumor Tissue 
The clinical investigator and the submitting pathologist have the 
responsibility for submitting pathology materials for banking. When a 
patient is registered to receive protocol therapy, the submitting 
pathologist and clinical research associate should refer to Appendix II 
(Pathology Submission Guidelines). 
Pathology samples are submitted per patient consent as indicated 
below. 
Forms to be submitted with each submission 
• 
Pathology Material Submission Form (#638 v04.2), Parts A & B 
completed. Please identify the clinical status of the submitted 
material (i.e., pretreatment as opposed to remission and relapse). 
• 
A copy of the surgical pathology report. 
• 
Immunologic studies, if available. 
• 
Sample Tracking System Shipping Manifest Form. 
Pathology Sample Submissions   
• 
From patients who consent “YES” to “I agree my tissue will be 
submitted for research”. 
o 
Diagnostic primary tumor tissue block collected prior to start 
of systemic therapy. 
o 
Metastatic tumor biopsy tissue block collected prior to start 
of systemic therapy, if available. 
NOTE: 
If unable to submit blocks, submit fifteen (15) 5-micron 
sections on uncharged slides and, if materials are 
available, two (2) 4-mm core punches.  Contact the 
ECOG-ACRIN CBPF for alternatives at 1-844-744-
2420 or eacbpf@mdanderson.org. 
o 
Surgical primary tumor tissue block 
 
Arm B: at time of local therapy/at randomization 
 
Arm A: at time of palliative surgery 
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NOTE: 
If unable to submit blocks, submit two (2) 4-mm core 
punches.  Contact the CBPF for alternatives at 1-844-
744-2420 or eacbpf@mdanderson.org. 
• 
From patients who consent “YES” to “I agree biopsies may be 
done to obtain research specimens” at sites that have met the 
guidelines outlined in Section 9.4.  Biopsies which are not 
performed for clinical purposes, but only to collect research 
specimens will be reimbursed as outlined in Section 9.4 AND are 
not to be billed to insurance.  
o 
ARM A: Primary tumor tissue block collected within three 
(3) months of randomization. 
o 
BOTH ARMS: Metastatic tumor biopsy tissue block. Collect 
within three (3) months of randomization. 
NOTE: 
Only blocks will be accepted, though sites are 
allowed to keep an H&E slide. 
9.1.2 
Blood Sample Submissions 
Blood samples are to be submitted from patients who answer “YES” 
to “I agree to provide additional blood for research.” 
Blood tubes are to be drawn in the following order: No anticoagulant 
(SST or red top), ACD (yellow top), EDTA (purple top), PAXgene DNA 
tube.  
Blood tubes should be labeled with the ECOG-ACRIN protocol 
number “E2108", patient initials, ECOG-ACRIN patient sequence 
number, institution name, date and time drawn and time point. 
Frozen samples are to be shipped on dry ice.  If not shipped the day 
of collection, store frozen below –20oC (-70oC preferred) until shipped.  
Specimens stored at temperatures higher than -70oC are to be 
shipped within one (1) week of collection. 
9.1.2.1 
Collection Time Points 
1.  ACD or PAXgene DNA tube: Baseline prior to start of 
treatment preferred, but may be collected any time 
while on study. 
2.  Serum and Plasma + Residual Cells  
− 
Randomization, prior to start of local therapy. 
− 
Six (6) months post randomization. 
− 
Twelve (12) months post randomization. 
9.1.2.2 
Collection and Shipping Kits 
Kits will include vacutainers and cryovials for the aliquots 
of the serum and plasma. 
Baseline kits must be requested within 48 hours (two 
business days) following registration.  All other kits must be 
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requested at least 48 hours prior to scheduled use.  You 
will need to request kits at each time point. 
Complete the E2108 Collection and Shipping Kit Order 
Form, Appendix VI and Fax to Zemotak – International at 
(800) 815-4675. 
Kits will be shipped overnight on the next working day and 
will include collection and shipping materials, and 
instructions for processing.  
Questions regarding kits should be directed to Zemotak - 
International at zemchi@aol.com. 
9.1.2.3 
Preparation Guidelines 
Serum - SST (red/grey marble top tube) 
NOTE: 
Submit only from patients who have consented 
to banking. 
a. 
Draw peripheral blood into vacutainer. 
b. 
Allow blood to coagulate 20 minutes, then centrifuge 
at 25oC, 1500xg (2700-3000 rpm) for 15 minutes.  
c. 
Pipette the serum into four (4) cryotubes provided in 
the kit. 
d. 
Store frozen, below –20oC (-70 oC preferred), until 
shipped. 
(NOTE: Red top, no anti-coagulant tube may substitute.)  
Plasma - EDTA (purple top tube) + Residual Cells 
(WBC&RBC) 
NOTE:  Submit only from patients who have consented to 
banking. 
a. 
Draw peripheral blood (10mL) into vacutainer and 
gently invert 8-10 times. 
b. 
Within 20 minutes of collection, centrifuge at 1500xg 
(2700-3000 rpm) at 4°C for 15 minutes. 
c. 
Pipette the plasma into four (4) cryotubes provided in 
the kit and store frozen, below –20oC (-70oC 
preferred), until shipped. 
d. 
Remaining Cells: Replace the stopper on the EDTA 
tube containing the cells and ship ambient the day of 
collection. 
Peripheral Blood – ACD (yellow top tube) 
a. 
Blood should be collected directly into vacutainer 
tube using the butterfly needle set. 
b. 
After blood collection, gently invert the tube 8 to 10 
times. 
c. 
May be shipped day of collection at Ambient 
Temperature (or with Cool Pack during hot season). 
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OR below -70oC and ship with serum and plasma samples. 
If specimen is collected at same time as the serum and 
plasma, sample may be stored at –20oC until shipped. 
(NOTE: DNA PAXgene or EDTA tube may substitute). 
9.2 
Shipping Procedures  
These guidelines are for the U.S., Hawaii, Puerto Rico and Proximal Canadian 
sites only. International sites must contact the CBPF to set up special 
arrangements. 
Log the samples into the ECOG-ACRIN Sample Tracking System (STS) the day 
of shipment. If the STS is unavailable, an ECOG-ACRIN Generic Specimen 
Submission Form (#2981) must be submitted with the samples. Once STS is 
available, retroactively log the shipment into STS, using the actual collection and 
shipping dates.   
Access to the shipping account for specimen shipments to the ECOG-ACRIN 
CBPF at MD Anderson Cancer Center can only be obtained by logging onto 
fedex.com with an account issued by the ECOG-ACRIN CBPF. For security 
reasons, the account number will no longer be provided in protocols, over the 
phone, or via email. If your site needs to have an account created, please contact 
the ECOG-ACRIN CBPF by email at eacbpf@mdanderson.org.  
9.2.1 
Submission Schedule  
The pathology samples should be submitted within one month of 
collection. 
Blood samples are to be shipped Sunday through Thursday, to arrive 
Monday through Friday. The laboratory is closed weekends and 
holidays. The DNA blood sample may be shipped at ambient (or cool 
pack if warm) on day of collection or shipped with the serum, plasma 
and cells on dry ice via overnight courier. 
Frozen specimens stored at temperatures higher than -70oC are to be 
shipped within one (1) week of collection. 
 
9.2.2 
Shipping Address 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or 
International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
An STS shipping manifest form must be generated and shipped with 
all sample submissions.   
NOTE: 
A copy of the completed submission form will be sent to 
the Coordinating Center by the Pathology Coordinating 
Office. 
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NOTE: 
If STS is unavailable, please notify the ECOG-ACRIN 
CBPF of the shipment by faxing the Notice of Shipment 
Form (Appendix VII) to 713-563-6506 on the day of 
shipment. 
9.3 
ECOG-ACRIN Sample Tracking System 
It is required (barring special circumstances) that all samples submitted on this 
trial be entered and tracked using the ECOG-ACRIN Sample Tracking System 
(STS).  The software will allow the use of either 1) an ECOG-ACRIN user-name 
and password previously assigned (for those already using STS), or 2) a CTSU 
username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Important:  Additionally, please note that the STS software creates pop-up 
windows, so you will need to enable pop-ups within your web browser while 
using the software.  A user manual and interactive demo are available by clicking 
this link: http://www.ecog.org/general/stsinfo.html Please take a moment to 
familiarize yourself with the software prior to using the system. 
A shipping manifest form must be generated and shipped with all sample 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu. 
Study Specific Notes 
An Generic Specimen Submission Form (#2981) will be required only if STS is 
unavailable at time of sample submission. Indicate the appropriate Lab on the 
submission form: 
• ECOG-ACRIN Central Biorepository and Pathology Facility 
Notify the ECOG-ACRIN CBPF of the shipment by faxing a copy of the Generic 
Specimen Submission Form to 713-563-6506 on the day of shipment. 
Retroactively enter all collection and shipping information when STS is available. 
9.4 
Institutional Reimbursements 
9.4.1 
Accrual to Laboratory Studies 
To receive site reimbursement for biospecimen submissions, 
completion dates must be entered in the OPEN Funding screen post 
registration. Please refer to the protocol specific funding page on the 
CTSU members’ website for additional information. Timely entry of 
completion dates is recommended as this will trigger site 
reimbursement. 
9.4.2 
Biopsy Reimbursements  
Additional research biopsies will be obtained from the primary tumor 
(Arm A only) and metastatic site (both Arms) at randomization, as well 
as in cases where the metastatic biopsy at study entry is not 
considered clinically necessary.  The biopsies are reimbursable up to 
a maximum of $950 per breast biopsy and $2,350 per metastatic 
biopsy.  
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All sites are eligible for the reimbursement for the research biopsies 
regardless of cooperative group.  However, it is up to the site to set up 
the mechanism for the ‘billing’ of these biopsies.  ECOG-ACRIN 
recommends billing the cooperative group Principal Investigator (PI) 
of the site.  Contact your coordinating group’s operations office and 
ask to whom this account should be named 
Please note that blocks MUST be submitted in order to receive the 
reimbursement. Since these biopsies are being performed strictly for 
the research for this trial, blocks are required to be submitted in order 
to receive the reimbursement. 
Prior to recruiting patients to the biopsy portion, the following 
conditions must be met: 
a.  The research rates of $950 per breast biopsy and $2,350 per 
metastatic biopsy are deemed acceptable by the IRB or central 
research office. 
b 
The research rate is reported to the institution’s financial office 
and an account established in the institution’s cooperative group 
principal investigator’s name. 
c.  The patient provides written consent to undergo the additional 
biopsies. 
NOTE: 
If the above rates are not accepted by your central 
research office do not present this additional research 
biopsy option to your patients 
Receipt of the biopsies will be verified prior to the release of any 
funds.  Expenses for biopsies will be paid only to participating 
institutions, not to any other persons or entities, at the stated research 
rate of $950 per breast biopsy and $2,350 per metastatic biopsy. 
NOTE: 
Neither patients nor their insurance companies are to be 
billed for the collection or submission of these research 
biopsy samples. 
Distribution of the reimbursements requires: 
• Submission of the requested biopsy samples using the ECOG-
ACRIN Sample Tracking System (STS) 
• Receipt and verification of the requested biopsy samples by the 
ECOG-ACRIN Central Biorepository and Pathology Facility via the 
ECOG-ACRIN STS.  (Refer to Section 9.3 for STS requirements) 
• Receipt of E2108 Biopsy Reimbursement Form (Appendix VII) to 
the ECOG-ACRIN Operations Office - Boston. 
Reimbursements will be paid from the ECOG-ACRIN Operations 
Office - Boston to the ECOG-ACRIN Principal Investigator (PI) of the 
submitting ECOG-ACRIN institution.   
For sites whose accruals are credited to any other cooperative group 
(including the CTSU), the reimbursements will be routed through the 
respective group’s operations office.  ECOG-ACRIN does not dictate 
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how these funds flow from another cooperative group’s operations 
office to the site.  Please verify this internal billing mechanism with the 
appropriate operations office to determine the routing procedure. 
If your site is associated with more than one cooperative group, you 
will need to determine how your accruals to this trial are credited (e.g., 
if your site belongs to SWOG and CTSU and your accruals are 
credited as CTSU, then the CTSU PI is the individual for whom the 
account and funds are managed) 
Payments are made annually. 
9.5 
Banking  
Specimens will be retained at the ECOG-ACRIN Central Repository for use in 
future ECOG-ACRIN approved studies.  Blocks will be available for purposes of 
individual patient management on specific written request.  If future use is denied 
or withdrawn by the patient, the samples will be removed from consideration for 
use in any future study. 
9.6 
Sample Inventory Submission Guidelines  
Inventories of all samples collected, aliquoted, and used will be submitted 
electronically via secure web application to the ECOG-ACRIN Operations Office - 
Boston on a monthly basis or upon request by any laboratory holding and/or 
using specimens associated with this study. 
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10. 
Records to Be Kept 
Please refer to the E2108 Forms Packet for the forms submission schedule and copies 
of all forms. The E2108 Forms Packet may be downloaded by accessing the ECOG-
ACRIN World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to 
the ECOG-ACRIN Operations Office - Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office - Boston to CTEP by electronic means. 
10.1 
ECOG-ACRIN Radiation Oncology Quality Assurance Materials  
Please see Section 5.3.7 for a list of radiotherapy quality assurance materials 
that should be submitted to QARC. All materials should be sent directly to the 
QARC offices as indicated in Section 5.3.8.  
A checklist detailing the complete list of required data is available on the QARC 
website at www.QARC.org. Click on the ECOG-ACRIN link to access the 
checklist. 
11. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
12. 
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Beerepoot LV, Mehra N, Vermaat JS, et al.: Increased levels of viable circulating 
endothelial cells are an indicator of progressive disease in cancer patients. Ann 
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Cristofanilli M, Budd GT, Ellis MJ, et al.: Circulating tumor cells, disease 
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Racila E, Euhus D, Weiss AJ, et al.: Detection and characterization of carcinoma 
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Budd GT, Cristofanilli M, Ellis MJ, et al.: Circulating tumor cells versus imaging--
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Jiang WG, Martin TA, Mansel RE: Molecular detection of micro-metastasis in 
breast cancer. Crit Rev Oncol Hematol 43:13-31, 2002 
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Xenidis N, Vlachonikolis I, Mavroudis D, et al.: Peripheral blood circulating 
cytokeratin-19 
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completion 
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2003 
43. 
Wulfing P, Borchard J, Buerger H, et al.: HER2-positive circulating tumor cells 
indicate poor clinical outcome in stage I to III breast cancer patients. Clin Cancer 
Res 12:1715-1720, 2006 
44. 
Reinholz MM, Nibbe A, Jonart LM, et al.: Evaluation of a panel of tumor markers 
for molecular detection of circulating cancer cells in women with suspected 
breast cancer. Clin Cancer Res 11:3722-3732, 2005 
45. 
Ignatiadis M, Kallergi G, Ntoulia M, et al.: Prognostic value of the molecular 
detection of circulating tumor cells using a multimarker reverse transcription-PCR 
assay for cytokeratin 19, mammaglobin A, and HER2 in early breast cancer. Clin 
Cancer Res 14:2593-2600, 2008 
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Ignatiadis M, Xenidis N, Perraki M, et al.: Different prognostic value of 
cytokeratin-19 mRNA positive circulating tumor cells according to estrogen 
receptor and HER2 status in early-stage breast cancer. J Clin Oncol 25:5194-
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Carlson RW, Brown E, Burstein HJ, et al.: NCCN Task Force Report: Adjuvant 
Therapy for Breast Cancer. J Natl Compr Canc Netw 4 Suppl 1:S1-26, 2006 
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Whelan T, Olivotto I, Levine M: Clinical practice guidelines for the care and 
treatment of breast cancer: breast radiotherapy after breast-conserving surgery 
(summary of the 2003 update). CMAJ 168:437-439, 2003 
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Whelan T, MacKenzie R, Julian J, et al.: Randomized trial of breast irradiation 
schedules after lumpectomy for women with lymph node-negative breast cancer. 
J Natl Cancer Inst 94:1143-1150, 2002 
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practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 
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51. 
Freidlin B, Korn EL, Hunsberger S, Gray R, Saxman S, and Zujewski JA. 
Proposal for the use  of progression-free survival in unblinded randomized trial. 
JCO. 25(15):2122-2126, 2007.  
52. 
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Lachin, J. M., and M. A. Foulkes. Evaluation of sample size and power for analysis 
of survival with allowance for nonuniform patient entry, losses to follow-up, 
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O’Brien PC and Fleming TR. A multiple testing procedure for clinical trials. 
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Schluchter, M.D. Methods for the analysis of informatively censored longitudinal 
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Schluchter, M.D., Greene, T. and Beck, G.J. Analysis of change in the presence of 
informative censoring application to a longitudinal clinical trial of progressive 
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Hartgrink HH, Putter H, Klein KE, et al.: Value of palliative resection in gastric 
cancer. Br J Surg 89:1438-1443, 2002 
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Wang CS, Chao TC, Jan YY, et al.: Benefits of palliative surgery for far-advanced 
gastric cancer. Chang Gung Med J 25:792-802, 2002 
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cancer. A worthwhile palliative procedure. Cancer 68:1863-1868, 1991 
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Bozzetti F, Bonfanti G, Audisio RA, et al.: Prognosis of patients after palliative 
surgical procedures for carcinoma of the stomach. Surg Gynecol Obstet 164:151-
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Ruiterkamp J, Ernst MF, van de Poll-Franse LV, et al.: Surgical resection of the 
primary tumour is associated with improved survival in patients with distant 
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cancer patients who present with stage IV disease and an intact primary tumor. 
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Associated with Increased Long-Term Survival in Patients with Stage IV Breast 
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Bartelink H, Horiot JC, Poortmans PM, et al.  Impact of a higher radiation dose 
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Carlson RW, Anderson BO, Burstein HJ, et al. Invasive breast cancer.  J Natl 
Compr Canc Netw 5:246-312, 2007. 
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Harris JR, Halpin-Murphy P, McNeese M, et al.  Consensus Statement on 
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Morrow M, Strom EA, Bassett LW, et al.  Standard for breast conservation 
therapy in the management of invasive breast carcinoma.  CA Cancer J Clin 
52:277-300, 2002. 
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Questions for the twenty-first century.  Journal of Clinical Oncology 16:2886-
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Recht A, Edge SB, Solin LJ, et al.  Postmastectomy Radiotherapy:  Clinical 
practice guidelines of the American Society of Clinical Oncology.  Journal of 
Clinical Oncology 19:1539-1569, 2001. 
75. 
Whelan T, MacKenzie R, Julian J, et al.  Randomized trial of breast irradiation 
schedules after lumpectomy for women with lymph node-negative breast cancer. 
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76. 
Whelan T, Olivotto I, Levine M, et al.  Clinical practice guidelines for the care and 
treatment of breast cancer: breast radiotherapy after breast-conserving surgery 
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Rev. 4/14 

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Tumor in Patients with Metastatic Breast Cancer 
 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) - [Deleted in 
Addendum #3] 
 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
 
 
 

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Appendix II 
 
Pathology Submission Guidelines 
The following items are included in Appendix II: 
1. 
Guidelines for Submission of Pathology Materials (instructional sheet for Clinical 
Research Associates [CRAs]) 
2. 
Instructional memo to submitting pathologists 
3. 
List of Required Materials for E2108 
4. 
ECOG-ACRIN Generic Specimen Submission Forms (#2981) 

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Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials to the ECOG-
ACRIN Central Biorepository and Pathology Facility: 
• 
Institutional Surgical Pathology Report 
• 
Pathology materials (see attached List of Required Material) 
Instructions: 
1. Place the Patient ID label provided by the ECOG-ACRIN Operations Office - Boston in Part 
A of the Pathology Material Submission Form. 
If a label is not available, TYPE or PRINT the following information in Part A of the form: 
Patient's name (last, first) 
Protocol number 
Protocol case number (the patient's ECOG-ACRIN sequence number; for 
intergroup studies, include both the ECOG-ACRIN and other group's sequence 
numbers) 
Patient's hospital number 
Institution 
Affiliate (if appropriate) 
2. Complete blank areas of the pathologist's instructional memo and forward it, along with the 
List of Required Material and the Pathology Material Submission Form, to the appropriate 
pathologist.  
3. The pathologist should return the required pathology samples and surgical pathology 
reports, along with the completed Pathology Material Submission Form (#638 v04.2) (Part B 
completed). If any other reports are required, they should be obtained from the appropriate 
department at this time. 
4. Keep a copy of the Pathology Material Submission Form (#638 v04.2) for your records. 
(The original should be sent to the CBPF.) 
5. Double-check that ALL required forms, reports and pathology samples are included in the 
package to the Central Biorepository and Pathology Facility. (See appropriate List of 
Required Material.) 
Pathology specimens submitted WILL NOT be processed by the Pathology Coordinating 
Office until all necessary items are received. 
Mail pathology materials to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd  
Houston, TX 77030 
If you have any questions concerning the above instructions or if you anticipate any problems in 
meeting the pathology material submission deadline of one month, contact the Pathology 
Coordinator at the ECOG-ACRIN Central Biorepository and Pathology Facility by telephone 1-
844-744-2420 or by fax 713-563-6506. 

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LIST OF REQUIRED MATERIAL 
E2108: A Randomized Phase III Trial of the Value of Early Local Therapy for the Intact 
Primary Tumor in Patients with Metastatic Breast Cancer 
Pre-study (collected prior to the start of systemic therapy) 
1. Institutional pathology report (must be included with EVERY pathology submission). 
2. Pathology materials: 
− 
Original diagnostic paraffin embedded primary tumor block  
− 
block from metastatic site (when available)  
NOTE: 
If unable to submit blocks, submit fifteen (15) 5-micron sections on uncharged 
slides and, if materials are available, two (2) 4-mm core punches. 
Randomization or at time of local treatment 
1. Institutional pathology report (must be included with EVERY pathology submission). 
2. Pathology materials: 
− 
ARM B: Surgical primary tumor tissue block  
− 
ARM A: Surgical primary tumor block from palliative care surgery 
NOTE: 
If unable to submit blocks, submit two (2) 4-mm core punches.  Contact the ECOG-
ACRIN PCO CBPF for alternatives at 1-844-744-2420 (312) 503-3384 or 
eacbpf@mdanderson.org 
− 
ARM A: Primary tumor tissue block collected by biopsy (within three (3) months 
of randomization) 
− 
BOTH ARMS: Metastatic tumor biopsy tissue block (collect within three (3) 
months of randomization) 
NOTE: 
Only blocks will be accepted, though sites are allowed to keep an H&E slide. 
 
Rev. 7/12 
Rev. 7/12 

 
Group Chair: Robert L. Comis, M.D. 
Jean MacDonald, Director of Research Operations 
Group Statistician: Robert Gray, Ph.D. 
Mary Steele, Director of Group Administration 
 
71 
Coordinating Center 
Frontier Science 
900 Commonwealth Avenue • Boston, MA 02215 
(617) 632-3610 • Fax: (617) 632-2990 
Randomization: (617) 632-2022 
TO:  
_____________________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., 
Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
___________________ 
SUBJECT: 
Submission of Pathology Materials for E2108:  A Randomized Phase III Trial of 
the Value of Early Local Therapy for the Intact Primary Tumor in Patients with 
Metastatic Breast Cancer 
 
The patient named on the attachedrequest has been entered onto an ECOG-ACRIN protocol by 
______________________________ (ECOG-ACRIN Investigator).  This protocol requests the 
submission of pathology materials for banking. 
Please complete PART B of the Submission Form. Keep a copy for your records and return the 
completed Submission Form, the surgical pathology report(s), the slides and/or blocks and any 
other required material (see List of Required Material) to the Clinical Research Associate (CRA).  
The CRA will forward all required pathology material to the ECOG-ACRIN Central Biorepository 
and Pathology Facility. 
Blocks and/or slides submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies.   
If you have any questions regarding this request, please contact the Central Biorepository and 
Pathology Facility at 1-844-744-2420 or FAX 713-563-6506. 
The ECOG-ACRIN CRA at your institution is: 
Name: ____________________________________________________ 
Address: ___________________________________________________ 
Phone:  ____________________________________________________ 
 
 
Thank you. 
 
 

ECOG-ACRIN Generic Specimen Submission Form     Form No. 2981v3 
Page 1 of 1 
72 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per patient, per time- 
point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all specimens into STS once the system 
is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 
Courier 
Tracking Number    
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
 
Sample Type  
(fluid or fresh tissue, 
 include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or 
Sample ID 
Anatomic 
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
 
 
 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % Lymphocytes % 
 
 
 
 
Study Drug Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
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Appendix III 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can be 
downloaded from the ECOG-ACRIN web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN and the 
NCI to increase awareness of the importance of clinical trials and improve accrual and follow-
through. We appreciate your help in this effort. 
____________________________________________________________________________ 
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions remain 
unanswered in cancer. With the participation of people like you in clinical trials, we will improve 
treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care.  I and my research staff will maintain 
very close contact with you.  This will allow me to provide you with the best care while learning 
as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank you 
again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
[PHYSICIAN NAME] 
 

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Tumor in Patients with Metastatic Breast Cancer 
 
Appendix IV 
 
ECOG Performance Status 
 
 
PS 0 
Fully active, able to carry on all pre-disease performance 
without restriction 
 
PS 1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature e.g. light 
house work, office work. 
 
PS 2 
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours. 
 
PS 3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
 
PS 4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
 
 

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Appendix V 
 
E2108 Collection and Shipping Kit Order Form 
NOTE:  
Starter kits are not available.  It is preferred that kit requests be made AFTER patient 
registration. 
NOTE: 
Please complete this form correctly, including the valid ECOG-ACRIN case number 
and complete shipping address.  If information is missing the kit processing will be 
delayed. 
Date:  
 
ECOG-ACRIN Patient Case Number:  ____________________ 
NOTE: 
 Please note in the comments section if the kit had to be ordered prior to patient 
registration and the justification for this. 
Ship Kit to: 
Institution Contact:   
_________________________________ 
Phone Number for Contact:  _________________________________ 
Fax Number for Contact: 
_________________________________ 
E-mail for Contact: 
_________________________________ 
Institution Address: 
_________________________________ 
 
_________________________________ 
 
_________________________________ 
Fax completed form to Zemotak - International at (800) 815-4675. 
 
NOTE: 
Questions regarding kits should be directed to Zemotak - International at 
zemchi@aol.com and ecog-acrin.tst@jimmy.harvard.edu. 
 
Comments: 
 
 
 
 

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Tumor in Patients with Metastatic Breast Cancer 
 
Appendix VI 
 
E2108 Shipment Notification Form 
Date:   
It is required that samples submitted from patients participating in E2108 be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System (see Section 9.3).   
 

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Breast Cancer 
Appendix VII 
E2108 Biopsy Reimbursement Form 
This form is to be used to request reimbursement for the performance and submission of the additional biopsies as outlined in E2108 
Section 9. 
NOTE: 
Patients (nor their insurance) companies are not to be billed for the collection and submission of the research biopsies. 
 
Today’s Date: ______________________________ 
 
ECOG-ACRIN 
Patient 
Sequence 
Number 
Date Biopsy 
Performed 
Time Point 
 
Tissue Type 
(Primary Site or 
Metastatic Site) 
Type of Biopsy 
(Image-Guided [Deep Seated] 
or Superficial) 
Date Sample 
Shipped 
____________ 
___________ 
_________________ 
___________ 
___________ 
___________ 
____________ 
___________ 
_________________ 
___________ 
___________ 
___________ 
 
 
 
 
 
Institution Contact Name:  __________________________Contact Phone Number:  __________________________  
 
 
Tax ID#: ________________________________________________ 
 
(My signature below confirms that these patients are registered to the protocol referenced above and that the patient numbers and 
dates above are true representations of the costs for which reimbursements are being requested.)  
 
Signature: ________________________________________________ 
 
Name (printed): ____________________________________________ 
 
Please Mail or Fax to: 
ECOG-ACRIN Operations Office - Boston 
Attn: ECOG Translational Science Team (TST) 
900 Commonwealth Avenue 
Boston, MA 02215 
FAX: (617) 582-8578 
Rev. 7/13