A Phase IIR/III Trial of Standard of Care Therapy With or Without Stereotactic Body Radiotherapy (SBRT) and/or Surgical Ablation for Newly Oligometastatic Breast Cancer
Phase: PHASE2
Conditions: Anatomic Stage IV Breast Cancer American Joint Committee on Cancer (AJCC) v8, Metastatic Breast Carcinoma, Metastatic Malignant Neoplasm in the Bone, Metastatic Malignant Neoplasm in the Liver, Metastatic Malignant Neoplasm in the Lung, Metastatic Malignant Neoplasm in the Lymph Nodes, Metastatic Malignant Neoplasm in the Spine, Prognostic Stage IV Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8
Sponsor: NRG Oncology

NRG-BR002 
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NRG ONCOLOGY 
NRG-BR002 
(ClinicalTrials.gov NCT02364557 ) 
 
A Phase IIR/III Trial of  Standard of Care Therapy with or without Stereotactic Body 
Radiotherapy (SBRT) and/or Surgical Ablation for Newly Oligometastatic Breast Cancer 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the 
participation of the network of NCTN organization: the Alliance for Clinical Trials in Oncology, 
ECOG-ACRIN Medical Group, and SWOG 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center 
1600 JFK Blvd, Suite 1020 
 
Study Team (21-SEP-2022) 
Co-Principal Investigator/Radiation Oncology 
Steven Chmura, MD, PhD 
University of Chicago 
5840 S. Maryland Ave, MC9006 
Chicago, Il 60637 
773-702-0817/Fax:773-834-7233 
schmura@radonc.uchicago.edu  
 
 
Radiation Oncology Co-Chair/ALLIANCE 
Joseph K. Salama, MD 
Duke University Medical Center 
Box 3085 
Durham, NC 27710 
919-668-7338/Fax: 919-668-7345 
joseph.salama@duke.edu  
 
Medical Oncology Co-Chair 
Virginia F. Borges, MD, MMSc 
University of Colorado  
Anschutz Medical Center 
19801 E 17th Avenue, RC1S 8112 
Aurora, CO  80045 
303-949-9964/Fax:720-848-1774 
virginia.borges@ucdenver.edu  
 
Co-Principal Investigator/Radiation Oncology 
Julia R. White, MD 
Ohio State University 
Comprehensive Cancer Center 
300 W. 10th Avenue, Suite 094D 
Columbus, OH 43212 
614-688-7373/Fax: 614-688-7356 
julia.white@osumc.edu  
 
Medical Physics Co-Chair 
Hania Al-Hallaq, PhD 
University of Chicago 
5758 S. Maryland Ave., MC9006 
Chicago, IL 60637 
773-702-3309/Fax:773-834-7233 
hal-hallaq@radonc.uchicago.edu  
 
Medical Physics Co-Chair 
Martha Matuszak, PhD 
University of Michigan 
1500 E. Medical Center Dr. 
Ann Arbor, MI 
734-232-6195/Fax:734-936-7859 
marthamm@med.umich.edu  
 
 

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     NRG ONCOLOGY  
 
NRG-BR002 
 
A Phase IIR/III Trial of  Standard of Care Therapy with or without Stereotactic Body 
Radiotherapy (SBRT) and/or Surgical Ablation for Newly Oligometastatic Breast Cancer 
 
Study Team Continued 
Translational Research Co-Chair 
Wendy A. Woodward, MD, PhD 
M.D. Anderson Cancer Center 
1515 Holcombe Blvd, Box 1202 
Houston, TX 77005 
713-563-8481/Fax: 713-563-6940 
wwoodward@mdanderson.org  
 
Surgical Oncology Co-Chair/ALLIANCE 
Nora Jaskowiak, MD 
University of Chicago 
5841 S. Maryland Ave.  MC 4052 
University of Chicago Medical Center 
Chicago, IL 60637 
773-834-7032/Fax: 773-834-4022 
njaskowi@surgery.bsd.uchicago.edu  
 
Lead Statistician 
Kathryn Winter, MS 
NRG Oncology 
50 South 16th  Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3198  
winterk@nrgoncology.org  
 
Translational Research Statistician 
Hanna Bandos, PhD 
Department of Biostatistics, GSPH 
University of Pittsburgh 
NRG Oncology 
201 North Craig St., Suite 350 
Pittsburgh, PA 15213 
412-383-2554/Fax: 412-383-1387 
bandosh@nrgoncology.org 
 
 
 
 
 
 
 
Quality Assurance Co-Chair 
Michael T. Milano, MD, PhD 
University of Rochester 
601 Elmwood Ave. Box 647 
Rochester, NY 14642 
585-273-4096/Fax: 585-275-1531 
michael_milano@urmc.rochester.edu 
 
Protocol Administrator 
Kathryn Okrent 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-0856 
okrentk@nrgoncology.org  
 
 
Data Managers  
Debora Washington, RN, MSN 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3206 
washingtond@nrgoncology.org    
 
Wendy Bergantz, RN 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3230 
bergantzw@nrgoncology.org 
 
RT Technical Details 
Susan McNulty, BS, RT (R) (T),CMD 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-940-8907 
smcnulty@acr.org   
 

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The following NCTN Group Study Champion has been added to this trial: 
SWOG 
Reshma Jagsi, MD 
University of Michigan Health System 
1500 E. Medical Center Drive 
Ann Arbor, MI 48109 
734-936-4300 
rjagsi@med.umich.edu  
 
 
NRG ONCOLOGY  
 
NRG-BR002 
 
A Phase IIR/III Trial of Standard of Care Therapy with or without Stereotactic Body 
Radiotherapy (SBRT) and/or Surgical Ablation for Newly Oligometastatic Breast Cancer 
 
 
 
Participating Sites 
 U.S. 
 Canada 
 Approved International Member Sites 
 
 
Document History 
 
Version Date 
Broadcast Date 
Amendment 7 
September 21, 2022 
N/A 
Amendment 6 
August 12, 2021 
N/A 
Amendment 5 
July 11, 2018 
N/A 
Amendment 4 
June 14, 2018 
N/A 
Amendment 3 
July 12, 2017 
August 28, 2017 
Amendment 2 
9/16/16 
10/10/16 
Amendment 1 
1/12/16 
2/22/16 
Activation 
12/05/2014 
12/24/2014 
 
 
 
 
  
 
 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with institution-specific IRB approval for 
study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of 
this protocol. 

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    NRG ONCOLOGY 
 
NRG-BR002 
 
A Phase IIR/III Trial of Standard of Care Therapy with or without Stereotactic Body 
Radiotherapy (SBRT) and/or Surgical Ablation for Newly Oligometastatic Breast Cancer 
 
CONTACT INFORMATION (21-SEP-2022) 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must be 
submitted to the Cancer Trials Support 
Unit (CTSU) via the Regulatory 
Submission Portal. 
Regulatory Submission Portal: (Sign in at 
http://www.ctsu.org, and select  
Regulatory > Regulatory Submission.)  
 
Institutions with patients waiting that are 
unable to use the Portal should alert the 
CTSU Regulatory Office immediately by 
phone or email: 1-866-651-CTSU (2878), 
or CTSURegHelp@coccg.org to receive 
further instruction and support. 
 
Contact  the CTSU Regulatory Help Desk 
at 1-866-651-CTSU (2878) for regulatory 
assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the Oncology 
Patient Enrollment Network 
(OPEN). OPEN is accessed at 
https://www.ctsu.org/OPEN_SYSTE
M/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with 
any OPEN related questions by 
phone or email: 1-888-823-5923, or  
ctsucontact@westat.com 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave. Refer to 
the data submission 
section of the protocol for 
further instructions. 
   
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific page located on the CTSU member’s website (https://www.ctsu.org).  Access to the CTSU 
members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and Access 
Management (CTEP-IAM) registration system and requires log in with a CTEP-IAM username and password. 
 
Permission to view and download this protocol and its supporting documents is restricted and is based on 
person and site roster assignment housed in the CTSU Regulatory Support System (RSS).    
For patient eligibility or treatment-related questions: Contact the study data manager listed on the NRG 
Oncology contact information table on the protocol cover page 
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 imaging data submission questions: 
IROCimagearchive@acr.org; please include trial number in the email subject line 
 
For TRIAD access and installation support: 
TRIAD-Support@acr.org    

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Triadhelp.acr.org 
 
TRIAD Software Installation: 
https://triadinstall.acr.org/triadclient/ 
 
 
 
 
 
 

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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................8 
1. OBJECTIVES ..............................................................................................................................9 
1.1 
Primary Objectives ...................................................................................................9 
1.2 
Secondary Objectives ...............................................................................................9 
1.3 
Exploratory Objectives ............................................................................................9 
1.4  
Translational Research Objectives ...........................................................................9 
2.BACKGROUND ........................................................................................................................10 
2.1 
NRG-BR002 Rationale and Trial Design ..............................................................13 
2.2 
Translational Research ...........................................................................................15 
3.PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA ..........................17 
3.1 
Patient Selection Guidelines ..................................................................................17 
3.2 
Eligibility Criteria ..................................................................................................17 
3.3 
Ineligibility Criteria ...............................................................................................18 
4.REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ...................20 
4.1   
Response/Failure Definitions .................................................................................22 
4.2  
Disease Progression and Subsequent Treatment ....................................................23 
5. TREATMENT PLAN/REGIMEN DESCRIPTION..................................................................24 
5.1 
Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy ..........................24 
5.2 
Radiation Therapy (This section applies to Arm 2 only) .......................................25 
5.3 
Surgery (Arm 2) .....................................................................................................63 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................64 
5.5 
Duration of Therapy ...............................................................................................65 
6. TREATMENT MODIFICATIONS/MANAGEMENT .............................................................66 
7.ADVERSE EVENTS REPORTING REQUIREMENTS ..........................................................66 
7.1  
Protocol Agents ......................................................................................................66 
7.2  
Adverse Events and Serious Adverse Events ........................................................66 
7.3 
Expedited Reporting of Adverse Events ................................................................66 
7.4 
Routine Reporting Requirements for Adverse Events ...........................................70 
8.REGISTRATION AND STUDY ENTRY PROCEDURES ......................................................70 
8.1 
CTEP Registration Procedures and Access Requirements for OPEN, 
Medidata Rave, and TRIAD .................................. Error! Bookmark not defined. 
8.2 
Site Registration Requirements ..............................................................................71 
8.3   
RT-Specific Pre-Registration Requirements ..........................................................74 
8.4  
Patient Enrollment .................................................................................................77 
9.DRUG INFORMATION ............................................................................................................78 

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10.PATHOLOGY/BIOSPECIMEN ..............................................................................................78 
11.SPECIAL STUDIES .................................................................................................................85 
12.MODALITY REVIEWS ..........................................................................................................85 
12.1 
Radiation Therapy Quality Assurance Reviews ....................................................85 
12.2 
Surgical Quality Assurance Reviews .....................................................................86 
13.DATA AND RECORDS ..........................................................................................................86 
13.1 
Data Management/Collection ................................................................................86 
13.2 
Summary of Data Submission ...............................................................................87 
13.3 
Data Quality Portal ................................................................................................87 
            13.4     Global Reporting Monitoring  
 
 
 
        88 
14.STATISTICAL CONSIDERATIONS .....................................................................................88 
14.1 
Study Design ..........................................................................................................88 
14.2 
Study Endpoints .....................................................................................................88 
14.3 
Primary Objectives Study Design ..........................................................................88 
14.4 
Study Monitoring of Primary Objectives ...............................................................93 
14.5 
Accrual Considerations ..........................................................................................95 
14.6 
Secondary or Exploratory Elements ......................................................................95 
14.7 
Gender/Ethnicity/Race Distribution .......................................................................97 
REFERENCES ..............................................................................................................................98 
 
 
 

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PATIENT POPULATION 
Patients with locally controlled metastatic breast cancer with≤ 4 metastases in permissible metastatic sites seen 
on standard imaging within 60 days prior to registration ( See  eligibility  section 3.2.3 ); and at least 1 
pathologically confirmed visualized on CT or PET/CT.  
   
STRATIFICATION  

Number of metastases  (1 vs. > 1) 

Hormone receptor status  (ER and/or PR positive vs. ER and PR negative) 

HER2 status (Positive vs. Negative) 

First-line standard systemic chemotherapy (Yes vs. No) 
      RANDOMIZATION  
Arm 2 

Standard of care systemic 
therapya  

Ablation of all metastases  
(SBRT or surgery ablation)c 
Arm 1 
Standard of care systemic therapya, b 
 
         NRG ONCOLOGY 
 
NRG-BR002  
 
A Phase IIR/III Trial of Standard of Care Therapy with or without Stereotactic Body 
Radiotherapy (SBRT) and/or Surgical Ablation for Newly Oligometastatic Breast Cancer 
 
 
SCHEMA (14-JUN-2018) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Standard of care systemic therapy for metastatic disease will be given as appropriate for the patient’s 
disease subtype (ER+, HER2 +, TNBC) at the discretion of the treating physician.  
b Metastatic sites present at registration that require palliation in Arm 1 can be addressed by standard 
palliative therapy (i.e., radiotherapy), surgery, or interventions such as vertebroplasty, RFA, etc.) (see 
Section 5.0).  
c The selection of either surgery or radiation for ablation of a given metastasis in Arm 2 is at the 
discretion of the treating physician. See Sections 5.2 and 5.3.  
 
 

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1.  OBJECTIVES 
1.1 
Primary Objectives 
Phase II-R 
To determine whether ablation (through SBRT and/or surgical resection of all known 
metastases) in oligometastatic breast cancer patients provides a sufficient signal for 
improved progression-free survival (PFS) to warrant full accrual to the Phase III portion 
of the trial 
 
Phase III 
To determine whether ablation (through SBRT and/or surgical resection of all known 
metastases) in oligometastatic breast cancer patients significantly improves overall 
survival (OS) 
 
1.2 
Secondary Objectives (14-JUN-2018) 
 To evaluate treated metastasis control according to tumor receptor status (ER, PR, 
HER-2), use of chemotherapy, surgery vs. ablative therapy, and number of 
metastases 
 To evaluate whether the addition of ablative metastasis directed therapy 
significantly reduces the number of distant recurrences (new metastases) in 
patients who progress according to tumor receptor status (ER, PR, HER-2); use of 
chemotherapy, and number of metastases. 
 To evaluate adverse events in patients who receive ablative metastasis-directed 
therapy to all known metastases in addition to standard medical therapy compared 
with those treated with standard medical therapy alone. 
 
1.3 
Exploratory Objectives (14-JUN-2018) 
 To explore the  most appropriate and clinically relevant technological parameters 
to ensure quality and effectiveness throughout the radiation therapy processes, 
including imaging, simulation, target and critical structure definition, treatment 
planning, image guidance, and delivery. 
 
1.4 Translational Research Objectives (14-JUN-2018) 
 
1.4.1 Primary Objective 
To determine whether < 5 CTCs (per 7.5ml of blood) is an independent prognostic 
(outcome) marker for improved PFS and OS in oligometastatic breast cancer 
1.4.2 Secondary Objectives 
 To determine whether < 5 CTCs (per 7.5ml of blood) is an independent predictive 
(response to therapy) marker for improved PFS and OS in oligometastatic breast 
cancer 
 To determine whether eliminating CTCs (0/7.5ml of blood in patients with at least 
2 CTCs at registration) is both a prognostic and predictive marker for improved 
PFS and OS. 
 To evaluate the prognostic and predictive properties of CTC count as a continuous 
measure of PFS and OS 
 To store material for retrospective analysis of ctDNA. 

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 To store material for retrospective analysis of circulating microRNA. 
 
 
2. BACKGROUND 
Several clinically-based hypotheses have attempted to explain the metastatic spread of breast 
cancer. Halsted (1907) argued for an orderly spread from primary tumor to regional lymph 
nodes to metastases. Rubin and Green were the first to suggest, in 1968, (Rubin Solitary 
Metastases 1968) the notion of “solitary metastases” and that such metastatic tumors could 
be treated with curative intent. A systemic hypothesis articulated most clearly by Fisher 
(1980) suggested that widespread dissemination of disease occurred before clinical detection. 
Based on the observation that not all breast cancer may be widely metastatic at initial 
presentation, Hellman advanced our understanding of the natural history of metastasis by 
proposing a spectrum hypothesis of metastasis. Within this model, some breast cancers 
remain locoregionally confined, others metastatic at presentation, and some progress from 
locoregional confinement to metastatic (Hellman, 1994). Soon thereafter, Hellman and 
Weichselbaum described the clinically relevant oligometastatic state in patients with limited 
number of metastases and where long-term disease control may be achievable with 
metastasis-directed therapy (Hellman 1995).   
The current standard of care (SOC) for metastatic breast cancer (MBC) patients is to deliver 
palliative chemotherapy, biologic and/or hormonal therapy when appropriate, with radiation 
and/or surgery reserved for the management of symptomatic or non-responsive metastases. In 
this paradigm, a very small number of MBC patients are alive long-term. A population-based 
analysis by Greenberg et al. (1996) reported the outcomes of over 1,500 women with MBC 
treated at M.D. Anderson Cancer Center with doxorubicin and alkylating agent-based 
chemotherapy; 1.6% remained free of relapse at 15 years. These data, coupled with the 
accepted curative role that adjuvant chemotherapy plays in the non-metastatic setting  
suggests that systemic therapies are helpful in addressing micrometastatic spread of breast 
cancer. However, single or poly-agent chemotherapy is unlikely to be curative in patients 
with gross (image detected) metastases.    
For selected patients with limited metastatic disease, metastasis-directed therapy, either 
surgical resection or ablative radiotherapy (in addition to standard systemic therapies) to lung 
(Simpson 1997, Rusthoven 2009, Fumagalli 2012)  liver (Fong 1997, Rusthoven 2009, 
Dewas 2012, Vlastos 2004, Fumagalli 2012), CNS (Wronski 1995, Kocher 2011, Maclean 
2013), adrenal (Tanvetyanon 2008, Torok 2011), and multiple organs (Salama 2012, Milano 
2012) has been shown to result in long-term disease control numerically superior to that seen 
when systemic therapy is administered alone. Specifically in breast cancer patients, ablative 
metastasis-directed therapies have been shown to result in promising PFS and OS (Abbott 
2012, Fridel 2002, Staren 1992, Pockaj 2010, McDonald 1994, Milano 2009). While these 
reported series have been primarily retrospective, taken together they identify long-term 
survival from metastasis-directed therapy in patients with limited breast cancer metastases. 
The benefits these patients derive may come from delaying progression in known metastases, 
as well as preventing known metastases from seeding new metastases. Furthermore, ablative 
radiation may have an abscopal effect, improving outcomes by inhibiting progression of 
micrometastatic foci (Demaria 2004, Formenti 2008, Stamell 2012).  
We hypothesize that ablative metastasis-directed therapy with either Stereotactic Body 

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Radiotherapy (SBRT) or surgery in combination with standard systemic therapy may 
meaningfully impact the natural history of some oligometastatic breast cancers. Indeed, Tree 
and colleagues observed in a 2013 review that a large number of non-randomized studies 
have found a 2-5 year progression-free survival rate approaching 20%, signaling a 
tremendous improvement with the application of SBRT to oligometastatic disease ( Tree 
2013).  
In order to provide improved prognostic information for patients with oligo MBC and 
potentially to predict those patients likely to respond favorably to aggressive chemotherapy 
or biologic agents, new biomarkers have been developed. One of the most promising 
techniques relies on detecting the presence of circulating tumor cells (CTCs) in patients with 
MBC. Data suggest these circulating tumor cells may be close in origin to the tumor stem 
cells responsible for metastatic disease. Using the FDA-approved and commercially available 
CellSearch™ assay, ≥ 5 CTCs (per 7.5ml of blood) prior to first or second line chemotherapy 
predicts progression-free survival (PFS) and overall survival (OS) (Cristofanilli 2004). The 
prognostic value of CTCs in response to chemotherapy appears superior to other widely used 
prognostic tools such as metastases location or type of chemotherapy employed.  
A recently completed Phase III trial (SWOG S0500) altered treatment selection of 
chemotherapy based on ≥ 5 CTCs (per 7.5ml of blood) detected and levels in the blood.  
These recently reported results showed those with high levels of CTCs that decreased with 
therapy did better than those with high levels of CTCs that persisted after therapy. 
Unfortunately, changing therapy did not improve outcomes for patients with high CTCs, 
potentially because the standard next line therapies available do not often have significant 
clinical benefit for this cohort. It is important to note that the current trial represents a very 
different population than the SWOG 0500 study. Herein the patients have oligometastatic 
disease as opposed to unselected metastatic disease. Further, those who progress on standard 
therapy will not be eligible representing a selection for good prognosis oligometastatic 
disease in this trial.  
The challenge for ablative therapy in MBC is to identify those patients for whom this 
approach might be at least beneficial and possibly curative. Pragmatically, it should be 
curative for patients in whom the visible disease to be treated is truly all of the disease, and 
where the ability of existing circulating disease to seed new sites is minimal, either because 
there are few circulating cells being shed, or because a high volume of cells are circulating 
but they lack the biology to seed. The former is easier to identify using CTCs. One might 
expect that in metastatic patients with few or no CTCs, ablative therapy may provide durable 
NED status, since new metastases are less likely to form because small volume circulating 
disease that is not seeding may be eradicated by systemic agents more readily than gross 
deposits of tumor. For those with high levels of CTCs, we hypothesize that eradication of 
CTCs by ablative therapy will indicate that the primary source of CTCs is the known and 
treatable metastases, and not occult metastases likely to re-seed after ablative therapy and 
prevent durable no evidence of disease (NED) status. Of course, failure to ablate the known 
disease would also fail to eradicate CTCs.  
The proportion of MBC patients who present with 1-2 metastases is high. Prior first-line 
MBC trials were reviewed to determine an estimated frequency of patients who would fit the 
inclusion criteria for this clinical trial. Approximately 50% of the patients from these trials 
representing differing ER and HER2 status enrolled with ≤  2 metastases. A current Phase I 

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trial is assessing the safety of ablating ≤ 4 metastases [NRG-BR001].   If this Phase I trial 
confirms the safety of ≤4 metastases as targetable  for ablative therapy, then an amendment 
to the current protocol would increase the enrolling population to upwards of 75% of first-
line MBC patients as potentially eligible. These studies demonstrate that first-line metastatic 
patients likely to enroll on clinical trials often present with  oligometastatic disease and 
would qualify for enrollment in this clinical trial.  
SBRT is being increasingly used as a technique to treat patients with limited MBC. A recent 
international survey of radiation oncologists (Lewis 2013) found that 61% of respondents were 
using SBRT to treat patients with limited metastatic disease. Furthermore, of those not 
currently offering this treatment, more than half were planning to start offering SBRT for 
limited metastases in the next 3 years. Therefore, at the time of activation of this study, >75% 
of practicing radiation oncologists will be offering this treatment to patients with limited 
metastatic disease. While there is increasing evidence that administration of SBRT for 
oligometastatic disease is measurably beneficial and its use is becoming more common, the 
initiation of randomized trials to ultimately prove clinical benefit will be increasingly difficult 
due to SBRT becoming the de facto standard of care (Tree 2013). Therefore, this proposed 
randomized clinical trial is profoundly important not only due to the anticipated treatment 
outcomes, but also because of the imperative to ensure safety and benefit before an unproven 
consensus of approach becomes more widely accepted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 2-1.  Frequency of patients enrolled on first-line metastatic breast cancer trials with 
limited number of metastatic sites who appear potentially eligible for ablative therapy. 
Author/ 
Study 
Phase 
n 
ER/PR + 
(%) 
HER2+ 
≤ 2 met 
sites 
(%) 
≤ 4 Met 
Sites 
(%) 
Arms 
PFS 
(Mo.) 
Albain 2008 
599 
32 
- 
57 
91 
1. Gem +    
Paclitaxel 
2. Paclitaxel 
9.89 
8.4 
Bergh 2012 
593 
72 
Pos. 
52 
- 
1 Sunitinib+ 
Docetaxel 
2. Docetaxel 
8.6 
8.3 
Tawfik 
2013 
II 
30 
77 
Neg. 
50 
- 
1. Vinorelbine, 
capecitabine 
8.6* 
Hurvitz 
2013 
IIR 
137 
54 
Pos 
49.3 
- 
1. Trastuz + 
Docetaxel 
2. T-DM1 
9.2 
14.2 
Gianni 
2013 
III 
AVEREL 424 
51 
Pos 
50 
- 
1. Docetaxel+ 
Trastuz 
2. Docet + Tras + 
BEV 
13.7 
16.5 
Sledge 
2003 
III 
E1193 
739 
45 
- 
49 
- 
1. Doxorubicin 
2. Paclitaxel 
3. Doxorubicin +     
Paclitaxel 
6* 
6.3* 
8.2* 
     *Time To Failure 
 
2.1 
NRG-BR002 Rationale and Trial Design 
We propose to evaluate an alternative treatment paradigm for this subset of 
oligometastatic MBC patients: elective ablation of all metastases after systemic therapy 
with a Phase II/III trial design.  
The randomized Phase II portion will compare the standard of care, systemic therapy and 
palliative surgery/radiation therapy (non-SBRT) only to areas of pain or potential and 
significant clinical risk (Arm 1), with  ablation of all visible metastases in addition to 
standard systemic therapy (Arm 2). If a PFS signal is observed, a Phase III trial would be 
warranted to determine whether OS at five years is significantly improved. As a 
secondary endpoint, we will evaluate whether 1) the absence or low number of CTCs 
(using the FDA approved Cellsearch™ assay at registration) may be predictive of those 
likely to obtain durable PFS, 2) eradication of CTCs from registration to follow-up 
sufficient to complete SBRT (4 weeks after SBRT) on Arm 2 and initiate SOC therapy on 
Arm 1 (3 months) is predictive of durable PFS, and 3) whether this successful eradication 
can be of prognostic value for PFS and OS. We predict those with few or no CTCs are 
ideal candidates for SBRT and will have longer PFS than those with ≥ 5 CTCs (per 7.5ml 
of blood), and that eradication of CTCs with SBRT will be possible and will identify 

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patients in whom CTCs originated from ablated metastases as opposed to those with 
CTCs from occult disease or CTCs from ablated metastases that seeded prior to ablation 
of metastases. Further, we hypothesize that PFS will be longer in those with zero or low 
levels of CTCs (< 5/7.5ml of blood) treated with ablative therapy than with supportive 
care, and that those with eradication of CTCs in either arm will have longer PFS than 
those with persistent CTCs at the follow-up collection. If the former were true, CTCs 
could be used to identify patients for ablative therapy and if the latter were true, change 
in CTCs could be used to identify those who should receive additional adjuvant therapies 
after ablative therapy. 
This design would directly test the hypothesis that some metastases may be the source of 
new disease spread, as suggested by recent translational studies (Karnoub 2007,Valastyan 
2009). For example, patients for whom there are minimal shed CTCs at the time of 
presentation or in cases where CTCs shed from ablative-treatable lesions lack the biology 
to seed new metastases effectively, ablative therapy may establish durable PFS. If low 
levels of CTCs at registration correlate with PFS after ablative therapy, this would be a 
meaningful adjunct to clinical findings in order to select patients for this approach. Further 
outcome can be compared between those on each arm with low levels of CTCs (< 5/7.5ml 
of blood) for hypothesis generation regarding the optimal therapy in this setting. If ablative 
therapy in the setting of eradication of CTCs correlates with PFS, this could be incorporated 
in future studies to determine the timing and utility of systemic chemotherapy most 
beneficial in these cases. These data would truly help shape practice in the metastatic 
setting, where limited metastatic disease is amenable to ablative therapy. The rate of 
eradication of high levels of CTCs (≥ 5/7.5ml of blood) can be compared in the ablative 
and SOC arms to generate hypotheses regarding the preferred approach in this setting as 
well. 
This would be the first randomized trial to answer whether ablation through surgery or 
SBRT can alter the progression of MBC treated with standard systemic therapy. 
Furthermore, this would be the first  National Clinical Trials Network randomized study 
to evaluate prospectively the multimodal use of ablative metastasis-directed therapy 
(either surgery and/or radiotherapy) integrated into the metastatic treatment. While 
ablative radiotherapy is currently being used either in small, single institution trials or off 
protocol, no data exist in a randomized setting to demonstrate its efficacy or justify the 
adoption. The results of this trial paired with ongoing and recently completed studies 
would significantly enhance our knowledge about the impact of these therapies. A 
seamless randomized Phase II/III design is critical to first observe a signal in PFS 
indicating the need for a Phase III investigation.   
Whether through demonstrating either an improved PFS, OS, or through elucidating a 
better understanding of the biology of metastatic disease, this trial would alter clinical 
practice by determining which, if any, population of patients should be offered elective 
metastasis-directed ablative treatment.  
 
Arm 1 (Standard of Care)  
Patients randomized to standard of care therapy (Arm 1) will continue with their current 
planned systemic therapy as appropriate for their disease subtype (ER+, HER2 +, TNBC) 
at the discretion of the treating physician. National Comprehensive Cancer Center 
(NCCN) guidelines for metastatic breast cancer are recommended. Areas of symptomatic 

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metastatic disease or at risk of injury that require palliation can be addressed by standard 
palliative therapy (i.e., radiotherapy (non-SBRT), surgery, or interventions such as 
vertebroplasty, RFA, etc.) consistent with best medical practice. Radiotherapy in Arm 1 
will be limited to known progressive lesions that are causing symptoms including 
hemorrhage, neurologic deficits, pain, obstruction of a hollow visceral organ, dyspnea, 
etc. Prophylactic treatment of asymptomatic metastasis, unless the risk of an impeding 
clinical event exists, is not allowed in Arm 1 and will represent a treatment violation.  
 
Arm 2 (SBRT +/- Surgery) 
Patients randomized to receive metastasis-directed therapy (Arm 2) will have ablative 
radiotherapy and/or surgical resection to distinct metastases visualized on standard 
imaging studies. Following completion of the radiotherapy and/or surgery, patients will 
then continue with additional systemic therapy as planned, at the discretion of the treating 
physician.   
 
2.2 
Translational Research (14-JUN-2018) 
The translational endpoints of this trial will confirm the prognostic value of CTCs in this 
cohort and investigate the interaction with treatment and effect of change in CTCs in this 
oligometastatic population. Funding for this portion has been obtained through 
philanthropy as outlined in Section 10. We hypothesize baseline zero or low levels of 
CTCs (<5/7.5ml of blood) will be associated with longer PFS (OS) than a baseline of ≥ 5  
CTCs (per 7.5ml of blood). Secondary analysis will examine the interaction of CTC 
number with treatment, and if  eradication of CTCs (among patients starting with any 
number > 2/7.5ml of blood to eliminate false positive findings or sample variability) will 
be associated with longer PFS (OS). For further correlative studies, we will collect and 
store plasma at all CTC timepoints to later isolate the circulating tumor DNA (ctDNA), 
perform the same analyses, and compare directly to CTCs. Standard tumor banking will 
be performed as well. 
 
We propose to collect CTCs for consenting patients at registration, 4 weeks from 
completion of ablative therapy in the ablative therapy study arm and 3 months from 
registration (to be delayed until after first cycle of chemotherapy if none received at 3 
months) in the standard of care arm and at progression in both arms, if applicable, in 
order to address the above hypotheses (see Section 10).  
 
As in Table 2-3, studies of CTC count in metastatic patients reveal CTCs in 40-60% of 
enrolled patients. In the prospective study by Cristofanilli et al. (2004), which enrolled 
patients with measurable disease starting a new therapy, 60% of patients had at least 2 
CTCs per 7.5ml of blood (no healthy control had 2 CTCs), and 49% had 5 or more CTCs 
per 7.5ml of blood. These data are reflected in the recent SWOG 0500 study where 50% 
of patients had ≥ 5 CTCs per 7.5ml of blood. The number of cases with 5 or more CTCs 
per 7.5ml of blood was only influenced by whether they were selected for chemotherapy, 
with 30% of those receiving only hormonal or immunotherapy treatments having 5 or 
greater CTCs per 7.5ml of blood. Therefore, given the fact that some patients will be 
ineligible based on progression on chemotherapy, we conservatively expect 50% of 
patients to have > 2 CTCs per 7.5ml of blood and 25% to have 5 or greater CTCs per 
7.5ml of blood. In addition, we seek to determine whether the conversion of patients with 

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two or more CTCs per 7.5ml of blood to negative following ablative therapy will be 
prognostic for improved PFS and OS. Based on prior published work in both non-
metastatic (Table 2-2) and the first or second line metastatic population (Table 2-3), we 
expect that at least 25% of patients will have CTCs ≥ 5/7.5ml of blood. We estimate, 
based on neoadjuvant CTC conversion rates, that 25% of these patients will be CTC 
positive post-ablative therapy. 
 
Table 2-2 
Prognostic significance of CTCs* in non-metastatic Breast Cancer 
Author 
Year 
# Patients 
CTC+ 
(%) 
Follow-up (months) 
Prognostic 
Rack [19] 
2010 
2026 
22% 
35 
DFS/ OS 
Rack [20] 
2010 
1489 
9% 
32 
DFS/ OS 
Franken [23] 
2012 
404 
19% 
48 
DFS/ OS 
Pierga [28] 
2008 
118 
23% 
18 
DFS c 
Bidard [30] 
2010 
115 
23% 
36 
DFS/ OS 
       * CellSearch™ Assay 
 
Table 2-3 
* CellSearch™ Assay 
 
In addition to CTCs, circulating tumor DNA (ctDNA) has recently been shown in several 
cancer types to also act as a prognostic marker of poor outcomes (Heitzer 2013; Alix-
Panabieres  2012; Bidard 2014). In these small studies, the detection of ctDNA proved to be 
as good as or superior as a prognostic marker to CTCs. By storing plasma from the same time 
points as the CTC collection, we will batch analyze the ctDNA to determine their respective 
clinical significance. Details of this analysis will be determined at the time of batch analysis. 
The Kuhn Laboratory at the University of Southern California (USC) will oversee these 
analyses. This lab is widely recognized as the forefront of the state of the art and USC will 
shortly begin a new institute specifically dedicated to the multi-scale science approach co-
locating Math/Modeling, Rare Cell Analysis, Medical Sciences and Engineering. As such 
from the same ctDNA tube, Dr. Kuhn and his collaborators will use high-content single cell 
Prognostic Significance of CTCs*  Metastatic Breast Cancer 
Author 
Year 
# Patients 
CTC+ (%) 
Prognostic 
Giordano [67] 
2012 
517 
40% a 
PFS/ OS 
Wallwiener [69] 
2013 
486 
42% 
PFS/ OS 
Pierga [68] 
2012 
267 
44% a 
PFS/ OS 
Giuliano [73] 
2011 
235 
40% a 
PFS/ OS 
Cristofanilli [13] 
2004 
177 
60% 
PFS/ OS 
Hayes [65] 
2006 
177 
54% 
PFS/ OS 
Budd [74] 
2006 
138 
43% 
OS 
Nakamura [75] 
2010 
107 
37% 
PFS 
Nole [77] 
2008 
80 
61% 
PFS 

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liquid biopsy (HD-SCA) analyses of all patients before and after treatment, and more 
importantly the mathematical model development to bring together clinical and experimental 
data. This provides the real opportunity to enhance the model with a specific modern data set, 
which in turn has the potential of giving us new insights into the spread of breast cancer to 
guide future treatment concepts. Markovian models have demonstrated the ability to 
recapitulate clinical observations in metastatic progression. The specific setting of 
oligometastatic disease in NRG-BR002 provides an ideal setting for data assimilation into the 
existing mathematical framework. This will involve correlation of the clinical response data 
from the patients on NRG-BR002 to the laboratory based translational science study. 
 
See Section 10 for details. 
 
 
 
3. PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILTY CRITERIA 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.   
For questions concerning eligibility, please contact the Biostatistical/Data Management 
Center (via the contact list on the NRG web site). For radiation therapy-related eligibility 
questions, please contact IROC Philadelphia (via the contact list on the NRG web site).  
 
3.1 
Patient Selection Guidelines 
3.1.1 Patients must have the psychological ability and general health that permits completion of 
the study requirements and required follow up. 
3.1.2 Women of childbearing potential who are sexually active should be willing and able to 
use medically acceptable forms of contraception during protocol treatment.  
 
3.2 
Eligibility Criteria (14-JUN-2018) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
3.2.1 Pathologically confirmed metastatic breast cancer  
3.2.2 Known estrogen, progesterone, and HER2 status of either primary tumor or metastasis; 
Note: estrogen, progesterone and HER2 status of metastasis preferred for 
stratification 
3.2.3 Number of allowable metastases: 
≤ 4 metastases seen on standard imaging within 60 days prior to registration when all 
metastatic disease is located within the following sites: 
 peripheral lung  
 osseous (bone) 
 spine 
 central lung 
 abdominal–pelvic(lymph node/adrenal gland) 
 liver 
 mediastinal/cervical lymph node 
 
3.2.4 All known disease amenable to metastasis-directed therapy with either SBRT or resection; 
 
NOTE: Symptomatic bone metastasis are allowed if ablative therapy can be delivered. 

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NOTE: Sites for possible surgical excision include lung, liver, adrenal gland, bone, small 
intestine, large intestine, ovary, and amenable nodal disease sites. 
 
NOTE: Surgical stabilization is allowed for a metastasis if it is followed by conventionally 
fractionated external beam radiotherapy. 
3.2.5 Maximum diameter of individual metastasis in any dimension ≤ 5 cm; 
3.2.6 There are no restrictions on distance between the metastases. 
3.2.7 
Patients must be registered within 365 days of the initial metastatic breast cancer 
diagnosis. First-line standard systemic therapy (chemotherapy, anti-endocrine therapy, 
anti-HER2 or other standard targeted therapy) for metastatic breast cancer must be given 
or planned to be given.  If given before study entry, it cannot have exceeded a duration 
of  12 months at the time of registration.  (Note: Sequencing of ablative therapy (surgery 
or SBRT) relative to systemic therapy, for patients randomized to Arm 2, is at the 
discretion of the treating physician.) 
 See Section 5.4.1 for washout required for experimental therapeutics; 
3.2.8 
The primary tumor site must be controlled prior to registration 
 For those who present with synchronous primary and oligometastatic disease: 
 Primary must be controlled prior to registration. 
 The definition of control is definitive surgery by excision or mastectomy 
(+/- radiotherapy) per institution preference   
 For those who present with local recurrence and oligometastatic disease, local 
recurrence must be controlled prior to registration 
 The definition of control is definitive surgery by excision or mastectomy 
(+/- radiotherapy) per institution preference  
 
3.2.9 Appropriate stage for study entry based on the following diagnostic workup: 
 History/physical examination within 60 days prior to registration; 
 Clinical grade CT scans of the chest, abdomen, and pelvis with radionuclide bone scan 
OR whole body PET/CT within 60 days prior to study registration; 
3.2.10 Age ≥ 18;  
3.2.11 Zubrod Performance Status ≤ 2 within 60 days prior to registration; 
3.2.12 CBC/differential obtained within 60 days prior to registration on study, with adequate bone 
marrow function defined as follows: 
 Absolute neutrophil count (ANC) ≥ 500 cells/mm3;  
 Platelets ≥ 50,000 cells/mm3;  
 Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb ≥ 8.0 g/dl is acceptable); 
3.2.13  For females of child-bearing potential, negative serum or urine pregnancy test within 14 
days prior to study registration; 
 
3.2.14 The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry. 
3.2.15 Patient must be female 
 
3.3 
Ineligibility Criteria (14-JUN-2018) 
Patients with any of the following conditions are NOT eligible for this study. 
3.3.1 Pathologic evidence of active primary disease or local/regional breast tumor recurrence at 
the time of registration;  

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3.3.2 Co-existing or prior invasive malignancy (except non-melanomatous skin cancer), unless 
disease free for a minimum of 3 years; previous RT dose, date, fraction size, must be 
reported  
3.3.3 Metastases with indistinct borders making targeting not feasible; 
NOTE: A potential issue with bone metastases is that they often are not discrete. Since 
many patients on this protocol will have bone metastases, this will be an important issue. 
Theoretically, Houndsfield units might provide an appropriate measure; however, a 
sclerotic lesion against dense cortical bone will not have a sharp demarcation based on 
HU. Therefore, we acknowledge that such determinations will pose a challenge and thus 
the physician’s judgment will be required; 
3.3.4 Prior palliative radiation treatment for metastatic disease to be treated on the protocol 
(including radiopharmaceuticals); 
3.3.5 Metastases located within 3 cm of the previously irradiated structures: 
• 
Spinal cord previously irradiated to > 40 Gy (delivered in ≤ 3 Gy/fraction) 
• 
Brachial plexus previously irradiated to > 50 Gy (delivered in ≤ 3 Gy/fraction) 
• 
Small intestine, large intestine, or stomach previously irradiated to > 45 Gy (delivered 
in ≤ 3 Gy/fraction) 
• 
Brainstem previously irradiated to > 50 Gy (delivered in ≤ 3 Gy/fraction) 
• 
Whole lung previously irradiated with prior V20Gy > 30% (delivered in ≤ 3 
Gy/fraction) 
 Primary tumor irradiated with SBRT 
 Metastasis irradiated with SBRT 
3.3.6 Brain metastases; 
3.3.7 Exudative, bloody, or cytological proven malignant effusions; 
3.3.8 Severe, active co-morbidity defined as follows: 
 Unstable angina and/or congestive heart failure requiring hospitalization within the last 
6 months; 
 Transmural myocardial infarction within the last 6 months; 
 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration; 
 Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness 
requiring hospitalization or precluding study therapy at the time of registration; 
3.3.9 Pregnancy. Lactating females must cease expression of milk prior to signing consent to 
be eligible.  
3.3.10 HIV positive with CD4 count < 200 cells/microliter. Note that patients who are HIV 
positive are eligible, provided they are under treatment with highly active antiretroviral 
therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to 
registration. Note also that HIV testing is not required for eligibility for this protocol. 
This exclusion criterion is necessary because the treatments involved in this protocol may 
be significantly immunosuppressive. 
 
 
 
 
 

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4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
PRE-TREATMENT ASSESSMENTS (14-JUN-2018) 
Assessments 
Prior to Registration 
 (calendar days) 
Prior to Treatment 
(calendar days) 
Initial diagnosis of metastatic 
breast cancer 
≤ 365 days  
 
 
History/physical examination 
≤ 60 days 
 
CT Scans of the 
chest/abdomen/ pelvis with 
radionuclide bone scan OR 
whole body PET/CT 
 
≤ 60days 
 
Performance Status 
≤ 60 days 
 
CBC w/ diff & ANC, platelets 
≤ 60 days 
 
ALT, AST 
 
If SBRT will be delivered to 
liver  
Serum/urine pregnancy test (if 
applicable) 
≤ 14 days 
 
MRI of the liver 
 
Highly recommended prior to 
initiating SBRT or surgical 
resection to the liver (for 
radiation treatment planning) 
MRI of the vertebral column 
 
Highly recommended for all 
patients with suspected 
epidural tumor extension 
Optional studies:  CTC Blood 
Collection, Whole blood, 
Plasma (for biobanking and 
ctDNA), Serum, and Tissue  
 
<14 days 
 
       ASSESSMENTS DURING SBRT TREATMENT 
Assessment 
Time Points 
 
Week 1 
during 
SBRT 
Week 2 
during 
SBRT 
 (if 
applicable) 
Week 3 during 
SBRT 
(if applicable) 
Last day of SBRT  
Physical examination 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
ALT, AST 
 
 
 
If SBRT delivered 
to liver  

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ASSESSMENTS IN FOLLOW UP: Arm 1 (14-JUN-2018) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Note: CTC and ctDNA collections are only required at month 3 time point; to be delayed until after first 
cycle of chemotherapy if none received at 3 months 
**Note: We strongly encourage the use of PET/CT to follow patients for disease progression in patients 
randomized to Arm 2 and who undergo SBRT. 
 
 
 
 
 
 
 
Adverse event 
evaluation 
X 
X 
X 
X 
Assessment 
Timepoints 
 
3 mos after 
randomization 
and every 3 
months to 24 
months 
Yearly 
thereafter 
At progression 
Physical 
examination  
X 
X 
 
Assessment by 
treating surgeon 
and/or  Radiation 
Oncologist and/or 
other health care 
provider 
responsible for 
your protocol 
follow-up 
X 
X 
 
Performance status 
X 
X 
 
Adverse event 
evaluation 
X 
X 
 
Optional studies*:  
CTC Collection, 
Plasma (ctDNA)  
X 
 
X 
Tissue (optional) 
 
 
X 
Imaging studies** 
X 
X 
 

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ASSESSMENTS IN FOLLOW UP: Arm 2 (14-JUN-2018) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
**Note: We strongly encourage the use of PET/CT to follow patients for disease progression in patients 
randomized to Arm 2 and who undergo SBRT. 
 
4.1   
Response/Failure definitions  
 
It is strongly preferred that the same imaging method that was used to originally detect the 
metastases be used in follow-up assessments. 
 
 
 
Assessments  
Timepoints 
 
25-35 d 
post 
ablation 
3 mos 
after 
random-
ization 
and every 
3 months 
to 24 
months 
Yearly 
thereafter 
At progression 
Physical examination  
 
X 
X 
 
Assessment by treating 
surgeon and/or  Radiation 
Oncologist and/or other 
health care provider 
responsible for your 
protocol follow-up  
 
X 
X 
 
Performance status 
 
X 
X 
 
ALT, AST 
 
 
 
X 
(If SBRT 
delivered 
to the  
liver) 
 
X 
(If SBRT 
delivered 
to the  
liver) 
 
 
Adverse event evaluation 
 
X 
X 
 
Optional studies:   
CTC Collection,  
Plasma (ctDNA) 
 
X 
 
 
X 
Tissue (Optional) 
 
 
 
X 
Imaging studies** 
 
X 
X 
 

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Arm 1 metastases or Arm 2 metastases treated with SBRT: 
Response and progression for these metastases will be evaluated using the revised 
Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J 
Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used 
in the RECIST criteria. 
 
 Complete Response (CR): Disappearance of the target lesion. 
 
 Partial Response (PR): At least a 30% decrease in the longest dimension (LD) of 
the target lesion, taking as reference the baseline LD. 
 
 Stable Disease (SD): Neither sufficient shrinkage to qualify for CR/PR above nor 
sufficient increase to qualify for progression below, taking as reference the smallest 
LD since the treatment started. 
 
 Progression: At least a 20% increase in the LD of target lesion, taking as reference 
the smallest LD recorded since the treatment started. The measurable tumor with 
criteria meeting progression should be avid on Positron Emission Tomography 
(PET) imaging with uptake of a similar intensity as the pretreatment staging PET 
(if performed), OR the measurable tumor should be biopsied confirming viable 
carcinoma. The EORTC criteria for post-treatment PET evaluation will be used as 
a basis for evaluation in cases more difficult to assign as to whether the uptake is 
pathological for cancer recurrence vs. inflammation vs. treated metastasis 
progression.  
 
 Recurrence: Reappearance of metastases following a CR in the SBRT treated area. 
 
Arm 2 metastases treated with Surgery:  
 
 Complete resection – total resection with negative margins 
 Incomplete resection – gross or microscopic residual disease (i.e. positive margins) 
 Progression: Evidence of tumor/soft tissue mass growth or new metastases in the 
region of prior surgery on imaging (strongly preferred that the same imaging 
method that was used to originally detect the metastases be used in follow-up 
assessments). 
 
4.2  
Disease Progression and Subsequent Treatment: 
Patients who develop progression will be followed on protocol for subsequent disease 
and survival events.  Patients who progress should receive best medical therapy as judged 
per their treating physician.   These may include, but not limited to chemotherapy, 
hormonal therapy, biologic therapy, radiosurgery, cryotherapy, and radio-frequency 
ablation (RFA). 
 
 
 

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5. TREATMENT PLAN/REGIMEN DESCRIPTION (14-JUN-2018) 
Patients randomized to standard of care therapy (Arm 1) will continue with their current 
planned systemic therapy as appropriate for their disease subtype (ER+,HER2 +, TNBC) at 
the discretion of the treating physician. Metastatic disease present at registration that requires 
palliation can be addressed by standard therapy (i.e., radiotherapy, surgery, or other 
interventions such as vertebroplasty, RFA, etc.) consistent with best medical practice. 
Radiotherapy in Arm 1 is permissible with palliative intent to known lesions present at 
registration that are causing symptoms not controlled by medical therapy (e.g. pain 
medications). Typical radiotherapy regimens for symptom control include 30 Gy in 10 
fractions, 24 Gy in 6 fractions , 20 Gy in 5 fractions, 8 Gy in 1 fraction or other similar 
equivalent regimens. As there is not level 1 evidence of improved symptom control with 
SBRT compared to typical palliative radiotherapy regimens its use is strongly discouraged in 
the standard arm.  Prophylactic treatment of metastasis present at registration that are 
asymptomatic, unless at risk for an impeding clinical event such as cord compression or 
pathologic fracture, is not allowed in Arm 1 and will represent a treatment violation.  
 
Patients enrolled onto Arm 2 of this study will be treated with ablative therapy (surgery 
and/or SBRT) to all known metastases. Surgery or SBRT are acceptable treatments for an 
individual metastasis. In a given patient, metastases may be treated with surgery to all, 
radiation to all, or surgery to one and radiation to the other.  
 
NOTE: The combination of surgery and SBRT to the same metastasis is NOT allowed.  The 
selection of surgery or radiation is at the discretion of the treating physicians within the 
following recommendations:  following the completion of ablative therapy (surgery and/or 
SBRT), systemic therapy may be continued at the discretion of the treating oncologist. 
 
NOTE: The clinical scenario where a patient presents with oligometastatic disease with  an 
osseous metastasis requiring surgical stabilization, or decompressive surgery, surgery 
followed by conventionally fractionated RT is allowed at the discretion of the treating 
physician.  SBRT will NOT be delivered post-operatively to the operative bed. There must 
be one metastasis amenable to ablative therapy following surgical stabilization. 
NOTE: For Arm 2 patients, sequencing of ablative therapy (surgery or SBRT) relative to 
systemic therapy is at the discretion of the treating physician. It is anticipated that most 
ablative therapy (surgery or SBRT) will be done after systemic therapy has started. 
 
5.1 
Chemotherapy/Hormonal Therapy/Other Agent-Based Therapy  
Standard of care systemic therapy should be administered at the discretion of the treating 
medical oncologist. It is recommended that the systemic therapy follow standard 
guidelines for use of chemotherapy, hormonal therapy, bone protective therapy, and 
biologic therapy as appropriate for the patient’s metastatic breast cancer. Parameters for 
withholding systemic therapy around the ablative therapy of patient’s randomized to Arm 
2 are outlined in Section 5.4.  
 
 
 

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5.2 
Radiation Therapy (This section applies to Arm 2 only) (14-JUN-2018) 
 
NOTE: PRE-TREATMENT REVIEWS are required for the first patient for each of the 
listed disease site categories (see Section 5.2.1). Three (3) business days are required to 
complete a pretreatment review. See Section 12.1 for more details. 
 
For patients receiving radiation SBRT must begin within 6 weeks of study entry 
 
SBRT for all metastases should be completed within 3 weeks of the first dose of SBRT. It 
is recommended that metastases are treated on an every other day schedule. Not all 
metastases need to receive radiation therapy on the same day.  
 
The goal of SBRT treatment is to deliver appropriate metastasis-directed radiotherapy 
while minimizing exposure of surrounding normal tissues. Many different ways of 
delivering SBRT exist, and all are acceptable as long as the treating institution has 
completed the necessary credentialing. Most commercially available photon-producing 
treatment units are allowed. As such, conventional linear accelerators and specialized 
linear accelerators with image guidance (e.g., Novalis, Trilogy, Synergy, Artiste, 
TrueBeam) are allowed. These units can be used with conformal dose delivery or IMRT. 
Specialized dose painting accelerators (e.g., Cyberknife, or Tomotherapy) are allowed 
provided they meet the technical specifications of the protocol and are used in a fashion 
that passes the credentialing required by the protocol. Conventional linear accelerators 
without add-on IGRT must have some other IGRT capability like CT-on-rails in the 
treatment room. 
 
IGRT is required for this study. Either 3DCRT or IMRT (including VMAT) are 
acceptable planning techniques. IMRT (including VMAT) can result in dosimetric 
inaccuracies in circumstances where tumor motion is not properly considered. Planning 
techniques may differ for each lesion to be treated provided that the tumor motion is 
properly accounted for with each technique when the target or targets are in or near the 
thorax region.  
 
5.2.1 
Dose Fractionation 
Patients will receive 1, 3, or 5 fractions of radiation. SBRT doses to be used are listed 
below in Tables 5-1 and 5-2. Doses were selected based on available evidence. Where 
evidence was minimal, expert consensus was used. Metastases should be assigned to 
one of the following seven metastatic locations to determine preferred dosing 
schedules: 
 
1. Lung Peripheral 
2. Lung Central 
3. Mediastinal/Cervical Lymph Nodes  
4. Liver 
5. Spinal/Paraspinal 
6. Osseous 
7. Abdominal-pelvic (including abdomino-pelvic lymph nodes/adrenal 
glands) 

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Dosing schemes are in general divided between patients with osseous and non-
osseous disease as shown in Tables 5-1 and 5-2.  For each metastatic location, 
preferred dosing schemes are described together with the Variation Acceptable range 
used for plan scoring. Doses falling outside the range of Per Protocol and Variation 
Acceptable will be scored as Deviation Unacceptable. 
 
NOTE: Utilizing the same dosing scheme is strongly suggested when a given OAR 
receives >5Gy (total for the radiation course) contribution from multiple treatment 
sites (see Section 5.2.6).  
 
There should be a minimum of 40 hours between treatments to any single metastasis; 
however, a patient may receive radiation for different metastases on consecutive days  
 
Table 5-1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Doses outside the range of Per Protocol and Variation Acceptable will be 
scored as Deviation Unacceptable. 
 
 
 
 
 
 
 
 
 
 
NON-OSSEOUS SITES 
(Lung Peripheral, Lung Central, Mediastinal/Cervical, Liver, 
Abdominal-pelvic) 
 
Prescription Dose  
Number of Fractions 
Per Protocol  
Variation Acceptable 
1 
(Single fraction regimen will 
be limited to peripheral lung 
and single liver metastases) 
 
 
30 Gy 
 
 
28 - 30.3 Gy 
3 
(Preferred for lung-peripheral, 
liver, and abdominal-pelvic 
metastases) 
 
45 Gy 
 
42.5 – 45.5 Gy 
5 
(Preferred for central lung. 
Mediastinal/ cervical lymph 
nodes) 
 
 
50 Gy 
 
 
48 – 50.5 Gy 

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Table 5-2 
 
OSSEOUS SITES 
(Spinal/Paraspinal, Other Osseous) 
 
Prescription Dose  
Number of Fractions 
Per Protocol  
Variation Acceptable 
1 
(Single fraction regimen will 
be limited to spinal 
metastases) 
 
 
20 Gy 
 
 
14 – 20.2Gy 
3 
(Preferred for non-spinal 
metastases) 
 
30 Gy 
 
27 – 30.3 Gy 
5 
(Preferred for 
thoracic/cervical spine) 
 
35 Gy 
 
30 – 35.4 Gy 
 
Note: Doses outside the range of Per Protocol and Variation Acceptable will be 
scored as Deviation Unacceptable. 
 
The dose per fraction shown in Table 5-1 is to be prescribed to the prescription line 
covering 95% of the PTV (see Section 5.2.5). NOTE: Metastases in different anatomical 
locations may be treated to different doses and with different fractionation schedules in the 
same patient (e.g., spine metastasis treated to 30Gy in 1 fraction while a central lung 
metastasis is treated to 50Gy in 5 fractions). However, it is preferable to use the same dose 
to treat all metastases, when reasonable, to allow for more straightforward dose volume 
analysis of organs at risk (e.g., both spine and central lung metastases treated to 50Gy in 5 
fractions). 
 
5.2.2   Technical Factors 
            Physical Factors 
Only photon (x-ray) beams with photon energies ≥ 6MV will be allowed. For metastases 
located within 3 cm of the lungs, photon energies of 6-10MV are required. Cobalt-60 and 
charged particle beams (including electrons, proton, and heavier ions) are not allowed.   
 
For lung central and lung peripheral metastases, photon beam energies > 10 MV are 
allowed only for a limited number (≤ 50% of all beams or all beam angles) of beams that 
must travel more than a cumulative distance of 10 cm through soft tissue (not lung) to 
reach the isocenter OR a shorter distance if the tumor abuts the chest or abdominal wall 
(i.e., to spare skin dose). 
 
FFF photon beams are allowed if the institution has performed SBRT credentialing with 
FFF beams. 
 
Treatment Technology 
This protocol requires photon treatment. Techniques including 3DCRT, IMRT, VMAT 
are allowed. Delivery on LINACs, Tomotherapy, or CyberKnife are acceptable. 

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Minimum Field Aperture (Field Size) Dimension 
 
Because of uncertainties in beam commissioning resulting from electronic disequilibrium 
within small beam apertures, an equivalent square field dimension of 3 cm is required for 
any field used for treatment delivery for sites using standard 3-D conformal techniques 
where nearly all of the PTV is encompassed for each beam. It is understood that this may 
exceed the technical requirements for small lesions. In such cases, the prescription dose is 
still prescribed to the edge of the defined planning treatment volume (PTV). For sites 
using dose painting including IMRT techniques, where by design the entire PTV is not 
encompassed for each beam, smaller beam apertures are allowed. In addition, if the site 
has specifically commissioned the beams for smaller field sizes, and if these same beams 
have been employed in IROC Houston QA Center credentialing, they may reduce the 
minimum field aperture requirement to the size commissioned after pre-approval by the 
physics co-chairs. 
 
All institutions must use heterogeneity correction dose calculation algorithms approved 
by the IROC Houston QA Center independent of the treatment planning technique. All 
doses should be reported in terms of dose-to-water and not in terms of dose-to-medium.  
 
Stereotactic Targeting 
 
For the purposes of this protocol, the term ‘stereotactic’ implies the targeting, planning, 
and directing of radiation beams along any trajectory in 3-D space toward a target of 
known 3-D coordinates. The coordinate system is defined by reliable ‘fiducials.’ A 
fiducial may be external or internal to the patient’s body. External fiducials may relate to 
a frame or treatment device.  Internal fiducials may be implanted markers OR reliably 
identifiable anatomy that is clearly visible on orthogonal kV imaging, including the 
tumor itself. In all cases, the relationship between the fiducial and the actual tumor 
position in real-time should be reliably understood for both planning and treatment. 
 
 
Isocenter Placement  
When using a gantry mounted linear accelerator for this protocol, the isocenter is defined 
as the common intersection point of gantry, collimator, and couch rotation for the 
treatment unit. For other types of treatment units (e.g., Tomotherapy or CyberKnife), a 
reference point in space that is typically positioned at the center of the target is used 
instead of a mechanical isocenter.  
 
When treating multiple lesions, it is best to use multiple isocenters, each centered on a 
separate lesion, and to treat different targets on different days in order to decrease 
treatment time for a single day. For widely spaced lesions (over 10 cm apart), localization 
is improved when the isocenter is placed in the center of each target and image guidance 
is performed individually for each target. This is due to the limitation of most IGRT 
systems, which ignore necessary rotational corrections when table shift coordinates are 
derived. Some platforms, including Cyberknife and Tomotherapy, are inherently non-
isocentric. These platforms take special account in the setup and treatment process to 
rigorously detect and account for rotations to avoid errors, making them exempt from the 
separate isocenter for each lesion requirement. For other platforms, the use of a single 
isocenter to treat multiple lesions in proximity to each other may be allowed if the 

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institution has successfully been credentialed by IROC Houston QA Center’s phantom 
irradiation for SBRT treatment of 2 lesions with a single isocenter setup. Please contact 
the PIs directly before utilizing a single isocenter to treat multiple metastases.  
 
 
Composite Dose Calculations 
Composite plans must be generated to incorporate the dose to surrounding normal tissues 
from each metastasis treated. The composite doses to critical normal tissues will be used 
to evaluate plan compliance. Composite planning refers to dose summation from multiple 
treatment sites on a single CT scan that encompasses the relevant anatomy. Composite 
treatment planning is best accomplished by obtaining a planning CT dataset that 
incorporates all targets and relevant critical structures in the imaging study. If this is not 
possible due to restrictions on the size of the imaging study that can be managed by the 
treatment planning system, CT datasets should be divided into two parts and treatment 
fields should be adjusted so that dose spillage from the treatment of targets in one dataset 
to the next is minimal such that the dose contributions do not require summation. The two 
datasets should be obtained so that they have some amount of overlap that can be used to 
fuse the information using a rigid registration technique. The use of deformable 
registration to sum dose is not allowed. In general, it is best to perform CT scanning with 
the patient in the same position. This implies that, for example, all lesions planned on a 
gated CT scan must be treated with gating. If technical limitations are encountered in 
summing dose, contact the Study Chairs with questions regarding composite planning. 
 
5.2.3  Localization, Simulation, and Immobilization 
Patient Positioning (Immobilization) 
Patients will be positioned in a stable pose conducive to allowing accurate reproducibility 
of the target position throughout treatment. Positions uncomfortable for the patient should 
be avoided so as to prevent uncontrolled movement during treatments. Patient 
immobilization must be reliable enough to ensure that the gross tumor volume (GTV) 
does not deviate beyond the confines of the planning treatment volume (PTV). 
Positioning patients directly on the couch and relying solely on image-guidance for 
reproducible set-up is strongly discouraged. 
 
 
Simulation 
All patients will undergo CT-based treatment planning in custom made immobilization 
devices. CT scan range must allow simultaneous view of the patient anatomy and fiducial 
system for stereotactic targeting (if used), and be adequate to ensure contouring of all 
targeted metastases,  as well as necessary organs at risk (OAR), defined below. High-
resolution CT scans should be obtained with uniform slice thickness of ≤ 3mm 
throughout. If a single CT scan cannot be obtained due to a large spatial separation 
between metastases (i.e., cervical and femoral metastases), or planning system slice 
number limitation, multiple CT scans are allowed provided that OAR are entirely 
encompassed in a single CT scan. CT imaging should be performed so that a composite 
dose distribution including all treated metastases can be created. Ideally, all metastases 
will be treated in one treatment position. When treating multiple metastases such as a 
lung and extremity, varying the treatment position may be necessary (i.e., simulation with 
arms up and arms to the side). Thus, more treatment positions can be used at the 

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discretion of the treating oncologist, but every effort should be made to obtain a 
composite distribution.  
 
Use of Contrast Agents 
The use of IV contrast will be required for liver metastases. For other metastases (central 
& peripheral lung, cervical/mediastinal, abdominal-pelvic, and spinal/paraspinal), the use 
of IV contrast is encouraged but will be left to the discretion of the treating physician. 
The use of other contrast agents is left to the discretion of the treating oncologist. 
Vascular contrast from the planning dataset is recommended to be converted to water 
equivalent density if used for planning. Duplicate planning datasets obtained prior to 
injection of intravenous contrast may be used for dose calculation. 
 
Respiratory Motion Assessment and Management 
All metastases with potential for respiratory motion should be evaluated by appropriate 
means including 4D CT scan, implanted fiducial marker, or fluoroscopy at the time of 
simulation.  
 
Respiratory motion management (RMM) including abdominal compression, active 
breathing control, breath hold, end expiratory gating, or fiducial marker tracking, is 
recommended for any metastasis to be treated with motion > 5mm. A recommended 
approach would be to use an ITV technique for motion < 1cm, but for motion > 1cm 
(typically too large for a free breathing ITV) motion management including but not 
limited to abdominal compression, active-breathing control (ABC), gating, breath hold, 
etc. should be used.  
 
If a treatment for multiple metastases (i.e., lung and spine) is designed on a CT scan 
employing motion management (i.e., abdominal compression), all metastases should be 
treated with the chosen motion management technique in order to generate an accurate 
composite dose calculation. (see Section 5.2.2) 
 
Localization Using Daily IGRT 
As an SBRT protocol, this study requires the use of IGRT. NRG Oncology defines IGRT 
as a computer assisted process that uses imaging devices that generate a series of 
coordinates for shifting the patient support system in three orthogonal directions 
(sometimes also including rotational changes) to position the treatment beams relative to 
target regions. The allowed technologies are as follows: cone-beam CT (CBCT) using 
either a specially mounted kV imaging head or the MV treatment beam with an opposed 
electronic imaging panel, dual fixed-position in-room kV imaging systems that are 
orthogonal or near orthogonal, an in-room standard diagnostic CT scanner that is 
geometrically linked to the treatment unit, and the Tomotherapy approach.  Although all 
of these units are allowed, some might not be appropriate for some disease sites.  For 
example, orthogonal imaging techniques result in overlapping structures that are not as 
easily visualized compared to 3D cone-beam approaches. Simple portal imaging 
approaches that do not use computer assistance are not considered suitable for this study.  
 
 

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When the treatment equipment does not include any device that allows direct 
visualization of anatomical structures using the treatment beam, the recommendations of 
AAPM Task Group Report 142 for testing the coincidence of the imaging and treatment 
reference points must be implemented. For example, verification of treatment and 
imaging isocenter coincidence  must be performed routinely for the CyberKnife, 
Tomotherapy units as well as any BrainLab equipment that does not include an electronic 
portal imaging device (EPID) that intercepts the treatment beam. 
 
IGRT Requirements 
The minimum IGRT requirement for each metastatic location is listed in Table 5-3. 
Volumetric imaging refers to 3D modalities (e.g., kV cone-beam, MV cone-beam, CT on 
rails), while orthogonal imaging refers to 2D modalities (e.g., kV OBI, ExacTrac). For 
volumetric imaging, appropriate CT window/level thresholds must be employed for 
registration at each metastatic location as outlined in Table 5-4. Additional IGRT may be 
employed at the discretion of the treating physician (i.e., orthogonal kV imaging prior to 
required volumetric imaging or volumetric imaging even if only orthogonal kV imaging 
is required). Note that when orthogonal kV imaging is employed for sites where 
respiratory motion is expected and not controlled via motion management techniques, 
care must be taken to ensure accurate targeting of the ITV within the treatment.  For 
example, static kV imaging at an undetermined breath hold position would not be 
adequate IGRT for treating a free-breathing lung tumor. 
 
Table 5-3 
Metastatic Location 
Minimum IGRT Requirement 
 
No Fiducials 
 With Fiducials** 
Lung--Peripheral+    
Volumetric (3D) 
Orthogonal kV (2D) 
Lung—Central+ 
Volumetric (3D) 
Orthogonal kV (2D) 
Mediastinal/Cervical LN 
Volumetric (3D) 
N/A 
Liver+ 
Volumetric (3D) 
Orthogonal kV (2D) 
Spinal 
Orthogonal kV (2D) 
Orthogonal kV (2D) 
Osseous* 
Orthogonal kV (2D) 
N/A 
Abdominal-pelvic+ 
Volumetric (3D) 
Orthogonal kV (2D) 
*NOTE: When osseous/rib metastases are classified into another metastatic location, 
follow the IGRT guidelines for that site.  
 
**NOTE: When a metastasis contains an implanted fiducial that is clearly visible on kV 
orthogonal or volumetric imaging, either method can be used. 
 
+NOTE: Registration to a soft tissue surrogate for the tumor is recommended for lung, 
liver, and abdominal-pelvic metastases for both 3D and 2D IGRT datasets. 
 
Use of a shortened CT planning scan for registration may be important for IGRT systems 
that cannot handle a large number of CT slices. A subset of the planning CT scan can be 

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uploaded to the IGRT system for localization of each metastasis. The CT data should 
include the metastasis of interest plus at least 5cm superiorly and inferiorly. Please note 
that the composite dose must be calculated on a single CT scan encompassing all 
pertinent OAR (see Section 5.2.2) 
 
5.2.4  Target Volumes 
Metastasis Location Definition:   
Each metastasis to be treated will be assigned to one of the seven “Metastasis Locations” 
as described below for determination of preferred radiation schedules as shown in Tables 
5-1 and 5-2. 
 
Metastatic Locations: 
Lung Central: GTV within 2 cm of proximal bronchial tree as described in RTOG 
0813/0915: 
Tumor within or touching the zone of the proximal bronchial tree, defined as a volume 2 
cm in all directions around the proximal bronchial tree (carina, right and left main 
bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe 
bronchus, lingular bronchus right and left lower lobe bronchi) [See Figure 5-1]. Tumors 
that are immediately adjacent to mediastinal or pericardial pleura (PTV touching the 
pleura) also are considered central tumors and are eligible for this protocol. A visual 
representation is shown below in Figure 5-1. 
 
 
 
                 
 
Figure 5-1 
 

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Lung Peripheral:  Metastases within the lung parenchyma with GTV outside of the 
proximal bronchial tree as described above.  
Mediastinal/Cervical LN: Mediastinal: GTV arising within the anatomic space 
between the lungs, above the diaphragm, and below the thoracic inlet at the level of 
the top of the sternal notch.  Cervival Lymph nodes:  GTV occurring within cervical 
lymph node Levels I-VI and/or retropharyngeal spaces 
 
 
Sternal metastases will be assigned to the mediastinal/cervical lymph 
node location based on potential for normal tissue toxicity. 
 
Liver:  GTV arising within the liver. 
 
Rib metastases immediately adjacent to the liver will be assigned to 
the liver metastasis location based on potential for normal tissue 
toxicity. 
 
 
Spinal:  Metastases will be assigned to the spinal/paraspinal site if the GTV arises 
within the vertebral bodies expanded by 1 cm. Spinal metastases, shown in Figure 5-2 
in black, can involve:  
 
(a) The vertebral body only OR 
(b) The vertebral body and pedicle OR 
(c) Posterior elements only 
 
 
 
Figure 5-2 
 
For each of these metastases, the PTV delineation will include: 
(a) the involved vertebral body and both pedicles (solid red line in Figure 5-2a) 
OR 
(b) a more generous delineation of the involved vertebral body and both pedicles 
(dashed red line in Figure 5-2b) OR  

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(c) the involved vertebral body, both pedicles, and the anterior and posterior 
elements of the spine (solid red line in Figure 5-2b) OR 
(d) the spinous process and laminae (solid red line in Figure 5-2c) 
 The target volume may be chosen at the discretion of the treating 
Radiation Oncologist based on the extent of tumor involvement. 
 Spinal metastases with epidural extension will only be included if 
there is > 3 mm gap between the edge of the epidural metastasis and 
edge of the spinal cord. 
 Metastases arising in the ribs within 1 cm of the edge of the vertebral 
body should be included in the spinal metastasis location, but osseous 
metastases planning guidelines are to be used. 
Osseous: GTV arising within an osseous structure, part of the axial skeleton, not 
included in the spinal definition. 
 Rib metastases that are within 1 cm of the vertebral bodies will be classified 
into the spinal metastasis location given the similar normal tissues at risk. 
 Rib/scapular metastases within the thorax adjacent to lung parenchyma will be 
classified into the lung metastasis location given the similar normal tissues at 
risk. 
 Rib/osseous metastases adjacent (< 1cm) to mediastinal or cervical structures 
will be classified into the mediastinal/cervical lymph node location given the 
similar normal tissues at risk. 
 Rib metastases adjacent (< 1cm) to the liver will be classified into the liver 
location given the similar normal tissues at risk 
 Rib metastases adjacent to the stomach/abdominal wall will be classified into 
the intra-abdominal location given the similar normal tissues at risk 
 Sternal metastases will be considered part of the mediastinal/cervical lymph 
nodes location given the similar normal tissues at risk. 
 
Abdominal-pelvic: GTV arising within the anatomic space defined by the diaphragm 
superiorly, the genitourinary diaphragm inferiorly including the peritoneal and 
retroperitoneal spaces, not including liver, osseous, or spinal metastases. 
 
Target Volume Definition Based on Metastatic Location: 
Specific SBRT planning parameters depend on the location of the treated metastasis as 
well as mechanism used for motion management/evaluation. The table below defines 
appropriate planning CT window/leveling, recommended additional modality scans to be 
fused, as well as how to define the GTC, ITV, CTV, and PTV for each metastatic 
location. Only rigid registration will be permitted for multi-modality fusion. In general, 
the GTV is defined as the entirety of the metastasis as seen on planning CT scan aided by 
additional diagnostic imaging studies (i.e., PET/CT or MRI). Use of additional diagnostic 
studies is left to the discretion of the treating physician. The CTV=GTV; there is no 
margin added for microscopic extension. In general, either a helical CT or 4DCT will be 

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used for defining the GTV/ITV depending upon the tumor motion encountered, although 
both scans may be acquired at the time of simulation. Typically, the ITV is generated 
using either expiratory/inspiratory phase scans or from reconstructed maximum intensity 
projection (MIP) scans. Maximum/minimum intensity projections (MIP/MinIP) should 
be used with caution because the MIP reconstruction for lung or MinIP reconstruction for 
liver may erroneously define an ITV in cases of significant irregular breathing or when 
tumors abut soft tissue structures (e.g., the diaphragm for MIP) or fat (for the MinIP). 
 
 
      Table 5-4 
 
                                                Metastatic Location 
Planning 
Parameter
 
 
Lung 
Central  
Lung 
Periphera
l 
Liver 
Abdominal-
pelvic 
Mediastinal/
Cervical 
Lymph 
Nodes 
Osseous 
Spinal 
CT 
window/level 
Pulmonary/ 
Mediastinal 
Pulmonar
y/ 
Mediastin
al 
Hepatic 
Soft tissue 
Pulmonary/ 
Mediastinal 
Bone/soft 
tissue 
Bone/soft 
tissue 
Additional 
Studies 
PET/CT 
PET/CT 
PET/CT 
MRI 
PET/CT 
MRI 
PET/CT 
PET/CT 
MRI 
PET/CT 
MRI 
Multiphase 
CT 
N/A 
N/A 
N/A 
Yes 
N/A 
N/A 
N/A 
 
 
 
 
 
 
 
 
Anatomy of 
focus for 
multi-
modality 
fusion 
Bony 
Anatomy 
Bony 
Anatomy 
Liver 
Bony 
Anatomy 
Bony 
Anatomy 
Bony 
Anatomy 
Bony 
Anatomy 
GTV 
definition 
Metastasis 
Metastasis 
Metastasis 
Metastasis 
Metastasis 
Metastasis 
Metastasis 
CTV 
definition 
= 
GTV/ITV* 
= 
GTV/ITV
* 
= 
GTV/ITV
* 
=GTV/ITV* 
=GTV/ITV
*+ 
= GTV 
= GTV 
PTV axial 
expansion 
= CTV + 
5mm** 
= CTV + 
5mm** 
= CTV + 
5mm** 
= CTV + 
5mm** 
= CTV + 
5mm** 
= CTV + 
5mm** 
= PTV in 
RTOG 
0631** 
(see Figure 
5-2) 
PTV 
craniocaudal 
expansion  
= CTV + 
7mm** 
= CTV + 
7mm** 
= CTV + 
7mm** 
= CTV + 
7mm** 
= CTV + 
7mm** 
= CTV + 
7mm** 
= PTV in 
RTOG 
0631** 
(see Figure 
5-2) 
*NOTE: A GTV to ITV expansion of greater than 1cm in any one direction is strongly 
discouraged and alternative respiratory management technique is suggested. 
 
**NOTE: When osseous/rib metastases are classified into other specific metastatic 
locations, the planning guidelines for that metastatic location should be used. If rib 

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metastases are grouped into the spinal metastasis location, then the metastasis should be 
contoured as defined for osseous metastases, but the prescription doses for the spinal 
region should be used.  
 
+NOTE: Mediastinal lymph nodes should undergo motion assessment and an ITV should 
be generated to account for motion.  
 
5.2.5 Treatment Planning 
Note: also see Composite Dose Calculations in Section 5.2.2  
Planning Techniques 
General Considerations:  A variety of planning techniques can be used to deliver SBRT 
for each metastasis. General guidelines include the following: 
 Multiple coplanar or non-coplanar beam arrangements are acceptable. 
 Typically 7-13 static radiation beams with equal weighting are used. It is 
recommended that at least 10 beams be used when possible.  
 A minimum field dimension of 3 cm should be observed while treating small 
metastases with 3D-CRT. 
 Dynamic conformal arcs are acceptable. It is recommended that arcs span a total 
for all beams of 340 degrees. 
 For non-IMRT or dose painting techniques, the conformal field aperture size and 
shape should correspond nearly identically to the projection of the PTV along a 
beam’s eye view (i.e., no additional “margin” for dose buildup at the edges of the 
blocks or MLC jaws beyond the PTV). The only exception will be when 
observing the minimum field dimension of 3 cm when treating small lesions. 
 The prescription isodose line covering 95% the PTV will generally be 80-90%, 
but may range from 60-90% where the maximum dose is 100%. As a result, a 
“hotspot” will exist within the PTV that is equal to the prescription dose divided 
by the prescription isodose line (i.e., 45 Gy/0.6 = 75 Gy when 45 Gy is prescribed 
to the 60% isodose). 
 Doses higher than the prescription isodose (i.e., hotspots) should be manipulated 
to occur within the target. 
 
Dose calculations: All dose distributions shall include corrections for tissue 
heterogeneities.  The approved algorithms to be used are found on the IROC Houston 
website (http://irochouston.mdanderson.org). All doses should be reported in terms of 
dose-to-water and not in terms of dose-to-medium.  
Successful treatment planning will require accomplishment of all of the following 
criteria; these criteria will be assessed on dose calculated independently for each 
metastasis (i.e., not from composite dose calculations): 
 
1. Normalization: The treatment plan should be initially normalized such that 
100% corresponds to the maximum dose within the PTV (MAXPTV). While 

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this point will typically correspond to the PTV center of mass, it can be 
located elsewhere within the PTV. 
2. Prescription Isodose Surface Coverage: The prescription isodose surface will 
be chosen such that 95% of the target volume (PTV) is conformally covered 
by the prescription isodose surface. Doses less than 95% of the prescription 
dose are restricted to the outside edges of the PTV as shown in Figure 5-3. 
The prescription isodose surface selected MUST be ≥ 60% and ≤ 90% of the 
dose maximum within the PTV (MAXPTV). The MAXPTV corresponds to 
the normalization point (100%) of the plan as noted in number 1 above. 
3. Target Dose Heterogeneity: Rather than prioritizing target dose homogeneity, 
SBRT treatment planning prioritizes adequate minimum target coverage and 
rapid dose fall-off gradients outside of the target. Hot spots within targets are 
generally accepted without consequence since targets are mostly tumor. The 
only exception is when the hotspot within the PTV also intersects an OAR 
(see Figure 5-3). 
4. Critical Organ Doses: Respect all critical organ dose-volume limits listed in 
Section 5.2.6). 
5. High-Dose Spillage: 
a. Location: Any dose > 105% of the prescription dose should occur 
within the PTV and not within the normal tissues outside the PTV. See 
Figure 5-3. 
b. Volume: Acceptable isodose distributions should be as conformal as 
possible. To this end, the ratio of prescription isodose volume to PTV 
should be as small as possible. 
i. The ratio of the prescription isodose volume to the PTV 
volume should be < 1.2. Acceptable variations include a ratio 
of 1.2-1.5. Ratios above 1.5 will be considered unacceptable 
variations. The prescription line for each lesion will be 
contoured for calculation of this ratio. The prescription line 
will be labelled as V_5000 with the 5000 changing to reflect 
the prescription dose in cGy. Contours with identical doses 
should be distinguished according to the convention described 
in section 5.2.6. 
ii. Guidelines for the ratio of the 50% prescription isodose volume 
to the PTV volume (R50%) and for the maximum dose at 2cm 
(D2cm) from the PTV are given in Table 5-5. Because it may 
become more difficult to restrict the 50% isodose volume when 
dose is summed from treatment of multiple metastases, this 
ratio should be evaluated for dose calculated for a single 
metastasis at a time  (i.e., not for composite dose). 
Additionally, the 50% isodose volume may be elongated 
deliberately in order to avoid OAR, thereby making it difficult 
to meet the guidelines in Table 5-5. This is acceptable as long 
as normal tissue constraints are met. 

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iii. Given that conformal tumor coverage is often more difficult to 
achieve in lung than in more homogeneous organs, these ratios 
should serve as a guide for liver, abdominal-pelvic, 
mediastinal/cervical metastases as well. 
iv. Elliptically shaped metastases as well as extremity metastases 
may not meet these guidelines. This is acceptable as long as 
normal tissue constraints are respected. These criteria will not 
be required in treating very small tumors (< 2.5 cm axial GTV 
dimension or < 1.5 cm craniocaudal GTV dimension)  in which 
the required minimum field size of 3 cm (see Section 5.2.2) 
results in the inability to meet a conformity ratio of 1:5 
 
Table 5-5 
PTV Volume (cc) 
Ratio of 50% Prescription 
Isodose Volume to PTV 
Volume, R50% 
Maximum Dose at 2cm 
(D2cm) from PTV in any 
direction as % of 
Prescribed Dose 
1.8 
< 7.5 
<57.0 
3.8 
< 6.5 
<57.0 
7.4 
< 6.0 
<58.0 
13.2 
< 5.8 
<58.0 
22.0 
< 5.5 
<63.0 
34.0 
< 5.3 
<68.0 
50.0 
< 5.0 
<77.0 
70.0 
< 4.8 
<86.0 
95.0 
< 4.4 
<89.0 
126.0 
< 4.0 
<91.0 
163.0 
< 3.7 
<94.0 
 
NOTE: For values of PTV dimension or volume not specified, linear interpolation 
between table entries is required. 
 
NOTE: For tumors within 2 cm of the skin, it may be difficult to meet the values for 
D2cm and R50%. In these cases, these criteria will not be used. 

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Figure 5-3 
 
Planning Priorities 
Every attempt should be made to successfully satisfy all of the planning goals and OAR 
criteria without receiving a plan score of Deviation Unacceptable. In some 
circumstances, it may not be possible to meet all the ideal criteria, leading to plans in 
the Variation Acceptable range. Thus, suggested priority of planning goals in order of 
importance is:  
1.  Respect spinal cord, cauda equina, sacral plexus and brachial plexus dose 
constraints.  
2.  Meet dose “compactness” constraints including the prescription isodose 
surface coverage, high-dose spillage (location and volume), and intermediate 
dose spillage (D2cm, and R50%) as these define the aim in using SBRT. Dose 
compactness should be assessed for plans based on treatment dose for a single 
lesion at a time. OAR dose constraints should be met based on composite dose 
planning as discussed in the last subsection of Section 5.2.2. 
 
3.  Meet critical structure constraints other than those listed in 1. The OAR 
constraints are last in priority (except for nervous system tolerance) because 
they are the least validated. The aim of a stereotactic plan is captured mostly 

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in the dose compactness criteria, thereby justifying their higher priority. As an 
example, in a case where not all goals can be met, it would be suggested to 
meet dose compactness goals without deviation, even at the expense of a non-
spinal cord normal tissue having acceptable deviation. Unacceptable 
deviations should be avoided in all cases.  
4. In cases where PTV coverage cannot be achieved while avoiding unacceptable 
deviations to OAR (see Section 5.2.6), coverage of a section of PTV including 
or immediately adjacent to the OAR may be as low as 70% of the prescription 
dose ONLY in this situation . Please contact Study Team when this is done to 
ensure this is not scored as a Deviation Unacceptable.  
 
5.2.6   Critical Structures 
Note: All required structures must be labeled as listed below in Table 5-6 for digital 
RT data submission. Resubmission of data will be required if labeling of structures 
does not conform to the standard DICOM name listed. 
 
The following table outlines the naming of the various normal and critical structures for 
submission to TRIAD. If multiple lesions named PTV_4500 exist, each should be 
labelled according to numerical order of the anatomical sites listed in 5.2.1 (e.g., 
“PTV_4500_1” is a peripheral lung lesion while “PTV_4500_4” is a liver lesion). If 
multiple lesions exit within a single anatomical site, each lesion can be distinguished by 
adding a letter to the end of the PTV name (“PTV_4500_1a” and “PTV_4500_1b”).      
  
     Table 5-6 
Standard Name 
Description 
Group 1: Lung - Peripheral 
 
PTV_4500_1  or PTV_3000_1 
For peripheral lung tumors. 
GTV_4500_1  or GTV_3000_1 
For peripheral lung tumors 
PTV_20_1 
PTV with 2cm expansion 
NonPTV_1 
External minus PTV 
NonPTV_20_1 
External minus PTV_20 (PTV with 
a 2 cm expansion) 
SpinalCord 
Spinal cord 
BrachialPlexus 
Brachial plexus 
BrachialPlex_L 
Left Brachial Plexus 
BrachialPlex_R 
Right Brachial Plexus 
BronchialTree 
carina, right and left main bronchi, 
right and left upper lobe bronchi, 
intermedius bronchus, right middle 
lobe bronchus, lingular bronchus 
right and left lower lobe bronchi 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchTree_20 
proximal bronchial tree expanded by 
2cm 
Larynx 
Larynx 
ChestWall 
Chest wall 
Rib 
Ribs within 5 cm of the PTV should 

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be contoured  
Heart 
Heart 
External 
Body surface 
SkinOAR 
skin will be defined as the outer 0.5 
cm of the body surface 
Lungs 
Combined Left and Right Lungs 
Lung_R 
Right Lung 
Lung_L 
Left Lung 
Trachea 
Trachea 
Stomach 
Stomach 
Liver 
Liver 
BileDuct 
Bile duct 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Group 2: Lung - Central 
Description 
PTV_5000_2 
For central lung tumors 
GTV_5000_2 
For central lung tumors 
PTV_20_2 
PTV with 2cm expansion 
NonPTV_2 
External minus PTV 
NonPTV_20_2 
External minus PTV_20 (PTV with 
a 2 cm expansion) 
SpinalCord 
Spinal cord 
BrachialPlexus 
Brachial plexus 
BrachialPlex_L 
Left Brachial Plexus 
BrachialPlex_R 
Right Brachial Plexus 
BronchialTree 
carina, right and left main bronchi, 
right and left upper lobe bronchi, 
intermedius bronchus, right middle 
lobe bronchus, lingular bronchus 
right and left lower lobe bronchi 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchTree_20 
proximal bronchial tree expanded by 
2cm 
Larynx 
Larynx 
ChestWall 
Chest wall 
Rib 
Ribs within 5 cm of the PTV should 
be contoured 
Heart 
Heart 
External 
Body surface 
SkinOAR 
skin will be defined as the outer 0.5 
cm of the body surface 
Lungs 
Combined Left and Right Lungs 
Lung_R 
Right Lung 
Lung_L 
Left Lung 
Trachea 
Trachea 
Stomach 
Stomach 
Kidney_R 
Right Kidney 

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Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Esoph_NonAdj 
Esophagus (Non-adjacent wall) 
Trachea_NonAdj 
Trachea (Non-adjacent wall) 
GrVess_NonAdj 
Great vessels (Non-adjacent wall) 
Group 3: Mediastinal/Cervical Lymph 
Node 
Description 
PTV_5000_3 
For mediastinal and cervical lymph 
node tumors. 
GTV_5000_3 
For mediastinal and cervical lymph 
node tumors. 
PTV_20_3 
PTV with 2cm expansion 
NonPTV_3 
External minus PTV 
NonPTV_20_3 
External minus PTV_20 (PTV with 
a 2 cm expansion) 
SpinalCord 
Spinal cord 
BrachialPlexus 
Brachial plexus 
BrachialPlex_L 
Left Brachial Plexus 
BrachialPlex_R 
Right Brachial Plexus 
BronchialTree 
carina, right and left main bronchi, 
right and left upper lobe bronchi, 
intermedius bronchus, right middle 
lobe bronchus, lingular bronchus 
right and left lower lobe bronchi 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchTree_20 
proximal bronchial tree expanded by 
2cm 
Larynx 
Larynx 
ChestWall 
Chest wall 
Rib 
Ribs within 5 cm of the PTV should 
be contoured by outlining the bone 
and marrow 
Heart 
Heart 
External 
Skin 
SkinOAR 
skin will be defined as the outer 0.5 
cm of the body surface 
Lungs 
Combined Left and Right Lungs 
Lung_R 
Right Lung 
Lung_L 
Left Lung 
Trachea 
Trachea 
Stomach 
Stomach 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Esoph_NonAdj 
Esophagus (Non-adjacent wall) 
Trachea_NonAdj 
Trachea (Non-adjacent wall) 
GrVess_NonAdj 
Great vessels (Non-adjacent wall) 
Group 4: Liver 
Description 

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PTV_4500_4  or PTV_3000_4 
For liver tumors. 
GTV_4500_4  or GTV_3000_4 
For liver tumors. 
PTV_20_4 
PTV with 2cm expansion 
NonPTV_4 
External minus PTV 
NonPTV_20_4 
External minus PTV_20 (PTV with 
a 2 cm expansion) 
SpinalCord 
Spinal cord 
ChestWall 
Chest wall 
Heart 
Heart 
External 
Skin 
SkinOAR 
skin will be defined as the outer 0.5 
cm of the body surface 
Stomach 
Stomach 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Femurs 
Both Femurs 
Duodenum 
Duodenum 
Bladder 
Bladder 
Liver 
Liver 
BileDuct 
Bile duct 
Ureter 
Ureter 
Bowel 
Large and Small Bowel 
Group 5: Spinal/Paraspinal 
Description 
PTV_2000_5 or PTV_3000_5 or PTV_3500_5 For spinal/paraspinal tumors. 
GTV_2000_5 
or 
GTV_3000_5 
or 
GTV_3500_5 
For spinal/paraspinal  tumors. 
NonPTV_5 
External minus PTV 
NonPTV_10_5 
External minus PTV_10 (PTV with 
a 1 cm expansion) 
NonPTV_20_5 
External minus PTV_20 (PTV with 
a 2.0 cm expansion) 
SpinalCord 
Spinal cord 
SpinalCord_Prt 
A portion of the spinal cord 
contoured near a target 
BrachialPlexus 
Brachial plexus 
BrachialPlex_L 
Left Brachial Plexus 
BrachialPlex_R 
Right Brachial Plexus 
CaudaEquina 
Cauda equine 
SacralPlexus 
Sacral plexus 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchialTree 
Carina, right and left main bronchi, 
right and left upper lobe bronchi, 
intermedius bronchus, right middle 
lobe bronchus, lingular bronchus 
right and left lower lobe bronchi 
BronchTree_20 
Proximal bronchial tree expanded by 
2cm 

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ChestWall 
Chest wall 
Rib 
Ribs within 5 cm of the PTV should 
be contoured by outlining the bone 
and marrow 
Heart 
Heart 
External 
Skin 
SkinOAR 
skin will be defined as the outer 0.5 
cm of the body surface 
Lungs 
Combined Left and Right Lungs 
Lung_R 
Right Lung 
Lung_L 
Left Lung 
Trachea 
Trachea 
Stomach 
Stomach 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Liver 
Liver 
BileDuct 
Bile duct 
Duodenum 
Duodenum 
Bowel 
Large and Small Bowel 
Rectum 
Rectum 
Bladder 
Bladder 
Femurs 
 
Esoph_NonAdj 
Esophagus (Non-adjacent wall) 
Trachea_NonAdj 
Trachea (Non-adjacent wall) 
GrVess_NonAdj 
Great vessels (Non-adjacent wall) 
Group 6: Osseous 
Description 
PTV_2000 _6 or PTV_3000 _6 or PTV_3500 
_6 
For non-spinal osseous tumors. 
GTV_2000_6 or GTV_3000 _6 or GTV_3500 
_6 
For non-spinal osseous tumors. 
NonPTV _6 
External minus PTV 
NonPTV_10 _6 
External minus PTV_10 (PTV with 
a 1 cm expansion) 
NonPTV_20 _6 
External minus PTV_20 (PTV with 
a 2.0 cm expansion) 
SpinalCord 
Spinal cord 
SpinalCord_Prt 
A portion of the spinal cord 
contoured near a target 
BrachialPlexus 
Brachial plexus 
CaudaEquina 
Cauda equine 
BrachialPlex_L 
Left Brachial Plexus 
BrachialPlex_R 
Right Brachial Plexus 
SacralPlexus 
Sacral plexus 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchialTree 
Carina, right and left main bronchi, 
right and left upper lobe bronchi, 

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intermedius bronchus, right middle 
lobe bronchus, lingular bronchus 
right and left lower lobe bronchi 
BronchTree_20 
Proximal bronchial tree expanded by 
2cm 
ChestWall 
Chest wall 
Rib 
Ribs within 5 cm of the PTV should 
be contoured by outlining the bone 
and marrow 
Heart 
Heart 
External 
Skin 
SkinOAR 
skin will be defined as the outer 0.5 
cm of the body surface 
Lungs 
Combined Left and Right Lungs 
Lung_R 
Right Lung 
Lung_L 
Left Lung 
Trachea 
Trachea 
Stomach 
Stomach 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Liver 
Liver 
BileDuct 
Bile duct 
Duodenum 
Duodenum 
Bowel 
Large and Small Bowel 
Rectum 
Rectum 
Bladder 
Bladder 
Femurs 
 
Esoph_NonAdj 
Esophagus (Non-adjacent wall) 
Trachea_NonAdj 
Trachea (Non-adjacent wall) 
GrVess_NonAdj 
Great vessels (Non-adjacent wall) 
Group 7: Abdominal-pelvic metastases 
(lymph node/adrenal gland) 
Description 
PTV_4500 _7 
For abdominal-pelvic tumors. 
GTV_4500 _7 
For abdominal-pelvic tumors. 
PTV_20 _7 
PTV with 2cm expansion 
NonPTV _7 
External minus PTV 
NonPTV_20 _7 
External minus PTV_20 (PTV with 
a 2 cm expansion) 
SpinalCord 
Spinal cord 
CaudaEquina 
Cauda equina 
SacralPlexus 
Sacral plexus 
ChestWall 
Chest wall 
Heart 
Heart 
External 
Skin 
SkinOAR 
skin will be defined as the outer 0.5 
cm of the body surface 
Stomach 
Stomach 
Kidney_R 
Right Kidney 

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Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Femurs 
Both Femurs 
Duodenum 
Duodenum 
Bladder 
Bladder 
Liver 
Liver 
BileDuct 
Bile duct 
Bowel 
Large and Small Bowel 
 
Planning SBRT Near Prior Radiotherapy Volumes 
The toxicity of delivering SBRT to multiple metastases in close proximity to prior 
conventionally fractionated external beam radiotherapy (EBRT) volumes is not known. 
Therefore, overlap of protocol treatment SBRT isodoses with prior fractionated external 
beam volumes must be minimized (see Section 3.3.5).     
 
Organs at Risk 
For all metastases-specific organs at risk (OAR) must be contoured. The specific OAR to 
be contoured will depend on the location of metastases to be treated. The contour of 
structures that have a lumen (bronchus, trachea, esophagus, etc.) will include both the 
“wall” and the “lumen” to result in a cylindrical structure.  In general, OAR within 3 cm 
of any single metastasis should be contoured. To identify these OARs, all PTVs will be 
expanded by 3cm and any OAR that overlaps with PTV + 3cm must be contoured. 
 
Lung Central/Lung Peripheral/Mediastinal/Cervical Lymph Node metastases: 
 Proximal tracheobronchial tree (as defined by Timmerman et al. 2006) 
 Lungs, left/right/combined 
 Heart 
 Great vessels 
 Trachea 
 Esophagus  
 Spinal cord  
 Chest wall 
 Brachial plexus 
 Skin 
 Liver 
 Bile duct 
 Kidney, left/right 
 Larynx 
 Stomach 
 Rib 
 
Liver/Abdominal-pelvic metastases: 
 Heart 
 Stomach 
 Duodenum 
 Spinal cord 

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 Kidney, left/right 
 Bowel 
 Rectum 
 Bladder 
 Skin 
 Lungs, left/right/combined 
 Liver 
 Bile duct 
 Chestwall 
 Sacral plexus 
 Cauda equine 
 Femurs 
 
Spinal Metastases: 
 For all spinal metastases, the partial spinal cord volume as per RTOG 0631 
should be defined as follows: the partial spinal cord should be contoured starting 
from 5-6 mm above the superior extent of the target volume to 5-6 mm below the 
inferior extent of the target volume. 
 For thoracic and cervical spinal metastases, follow guidelines for pulmonary/ 
mediastinal/cervical metastases depending upon nearby organs at risk. 
 For lumbar metastases, follow guidelines for abdominal-pelvic metastases. 
 
Osseous Metastases: 
 OAR for osseous metastases will depend on the location of the osseous 
metastasis. 
 
NOTE: OAR listed above should be contoured in their entirety if a portion of that organ 
is located within 3 cm of the osseous metastases. 
 
 
Contouring of Normal Tissue Structures 
In order to verify each of these limits, the organs must be contoured such that appropriate 
volume histograms can be generated. Instructions for the contouring of these organs are 
as follows: 
 
 
Spinal Cord 
The spinal cord will be contoured based on the bony limits of the spinal canal ending at 
L2. The spinal cord should be contoured starting at least 10 cm above the superior extent 
of the PTV and continuing on every CT slice to at least 10 cm below the inferior extent of 
the PTV. 
 
 
Cauda Equina 
Starting at the conus (end of spinal cord, typically around L1 or L2), include the entire 
spinal canal into the sacrum to the filum. 
 
Sacral Plexus 
Include the nerve roots from L5 to S3 on each side from the neuroforamina to the 

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coalescing of the nerves at the obturator internus muscle. 
 
Esophagus 
The esophagus will be contoured using mediastinal windowing on CT to correspond to 
the mucosal, submucosa, lumen, and all muscular layers out to the fatty adventitia. The 
esophagus should be contoured starting at least 10 cm above the superior extent of the 
PTV and continuing on every CT slice to at least 10 cm below the inferior extent of the 
PTV. 
 
Brachial Plexus 
The defined ipsilateral brachial plexus originates from the spinal nerves exiting the 
neuroforamine on the involved side from around C5 to T2. However, for the purposes of 
this protocol, only the major trunks of the brachial plexus will be contoured using the 
subclavian and axillary vessels as a surrogate for identifying the location of the brachial 
plexus. This neurovascular complex will be contoured starting proximally at the 
bifurcation of the brachiocephalic trunk into the jugular/subclavian veins (or 
carotid/subclavian arteries) and following along the route of the subclavian vein to the 
axillary vein ending after the neurovascular structures cross the second rib. If PTV of all 
metastases are more than 10 cm away from the brachial plexus, this structure need not be 
contoured. 
 
Heart 
The heart will be contoured along with the pericardial sac. The superior aspect (or base), 
for purposes of contouring, will begin at the level of the inferior aspect of the aortic arch 
(aortopulmonary window) and extend inferiorly to the apex of the heart. 
 
Trachea and Proximal Bronchial Tree 
The trachea and proximal bronchial tree will be contoured as two separate structures 
using mediastinal windows on CT to correspond to the mucosal, submucosa, and 
cartilage rings and airway channels associated with these structures. For this purpose, the 
trachea will be divided into two sections: the proximal trachea and the distal 2 cm of 
trachea. The proximal trachea will be contoured as one structure, and the distal 2 cm of 
trachea will be included in the structure identified as the proximal bronchial tree. 
 
 Proximal Trachea 
Contouring of the proximal trachea should begin at least 10 cm superior to the 
extent of the PTV for lung metastases or 5 cm superior to the carina 
(whichever is more superior) and continue inferiorly to the superior aspect of 
the proximal bronchial tree. 
 Proximal Bronchial Tree 
The proximal bronchial tree will include the most inferior 2 cm of distal 
trachea and the proximal airways on both sides, as indicated in Figure 5-1. 
The following airways will be included according to standard anatomic 
relationships: the distal 2 cm of trachea, the carina, the right and left mainstem 
bronchi, the right and left upper lobe bronchi, the intermedius bronchus, the 
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lobe bronchi. Contouring of the lobar bronchi will end immediately at the site 
of a segmental bifurcation. If there are parts of the proximal bronchial tree that 
are within GTV, they should be contoured separately, as “proximal bronchial 
tree GTV,” not as part of the “proximal bronchial tree.” 
 
Whole Lung 
Both the right and left lungs should be contoured as one structure. Contouring should be 
carried out using pulmonary windows. All inflated and collapsed lung should be 
contoured; however, gross tumor (GTV) and trachea/ipsilateral bronchus as defined 
above should not be included in this structure. 
 
Proximal Bronchial Tree Plus 2 cm 
As part of determining if lung metastases are central or peripheral, adhering to the 
eligibility of the zone of the proximal bronchial tree, the RTOG SBRT protocols defined 
an artificial structure 2 cm larger in all directions from the proximal bronchial tree. If the 
GTV falls within this structure, the patient is eligible for this protocol. Most treatment 
planning systems have automatic contouring features that will generate this structure 
without prohibitive effort at the time of treatment planning. This structure is not required 
by the protocol, but its construction is suggested to facilitate appropriateness of patient 
selection. Alternately, participating sites may use ruler tools in the treatment planning 
software to ensure protocol compliance. 
 
Skin 
The external contour of the patient will be contoured. The skin OAR will be defined as 
the outer 0.5 cm of the body surface. As such it is a rind of 
uniform thickness (0.5 cm) which envelopes the entire body in the axial planes. The 
cranial and caudal surface of the superior and inferior limits of the planning CT should 
not be contoured as skin unless skin is actually present in these locations (e.g., the scalp 
on the top of the head). 
 
Great Vessels 
The great vessels (aorta and vena cava, not the pulmonary artery or vein) will be 
contoured using mediastinal windowing on CT to correspond to the vascular wall and all 
muscular layers out to the fatty adventitia. The great vessel should be contoured starting 
at least 10 cm above the superior extent of the PTV and continuing on every CT slice to 
at least 10 cm below the inferior extent of the PTV. For right-sided tumors, the vena cava 
will be contoured, and for left-sided tumors, the aorta will be contoured. 
 
Non-adjacent Wall of a Structure 
For the esophagus, trachea and proximal bronchial tree, and great vessels, the 
nonadjacent wall corresponds to the half circumference of the tubular structure not 
immediately touching the GTV or PTV. These contours would start and stop superiorly 
and inferiorly just as with the named structure. The half lumen of the structure should be 
included in this contour. 
 
 

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Stomach 
The entire stomach and its contents should be contoured as a single structure as a 
continuation of the esophagus and ending at the first part of the duodenum. 
 
Duodenum 
The wall and contents of the 1st, 2nd, and 3rd parts of the duodenum will be contoured as 
one structure beginning where the stomach ends and finishing as the superior mesenteric 
artery crosses over the third part of the duodenum. 
 
Bowel (Large/Small) 
The bowel should be contoured from the ileocecal area to include the ascending, 
transverse, descending, and sigmoid colon as one structure. 
 
Rectum 
The entire rectum with contents from the peritoneal reflection of the sigmoid to the anus 
should be contoured.  
 
Bladder 
This organ will be contoured as bladder wall exclusive of urinary contents. 
 
Kidney (renal cortex) 
Both the right and left kidney, excluding renal pelvis/collecting system, should be 
contoured in their entirety (the renal cortex). 
 
Liver 
The entire liver minus the GTV targets should be contoured. 
 
Bile ducts 
To contour the bile ducts, use the portal vein from its juncture with the splenic vein to its 
right and left bifurcation in the liver (as a surrogate to identify the bile ducts). 
 
Femoral Heads 
The ball of the head and socket joint should be contoured. 
 
Rib  
Ribs within 5 cm of the PTV should be contoured by outlining the cortical bone including 
the intramedullary space. Typically, several portions of adjacent ribs will be contoured as 
one structure. Adjacent ribs, however, should not be contoured in a contiguous fashion 
(i.e., do not include the inter-costal space as part of the ribs). 
 
PTV + 2 cm  
As part of the QA requirements for “low-dose spillage” listed above, a maximum dose to 
any point 2 cm away in any direction is to be determined (D2cm). To facilitate this QA 
requirement, an artificial structure 2 cm larger in all directions from the PTV is required. 
Most treatment planning systems have automatic contouring features that will generate 
this structure without prohibitive effort at the time of treatment planning. If possible, this 

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structure should be constructed as a single contour that is 2 cm larger than the PTV. 
 
Other Structures  
The constraints tables above contain other structures. These are required if the structure is 
within 3 cm of the PTV. 
 
Critical Organ Dose-Volume Limits 
Composite dose distributions of organs at risk are critical to understand toxicity following 
SBRT. Composite dose plans including all treated metastases and organs at risk must be 
submitted, as well as individual SBRT plans, to evaluate protocol compliance. To 
facilitate composite planning, dose to all metastases should be calculated on a single CT 
scan simultaneously with in-plane resolution of at least 2 x 2 x 3mm. If this is not 
possible, composite plans should be generated incorporating the dose from each 
metastasis treated. The composite doses to critical normal tissues will be used to evaluate 
plan compliance. 
 
Tables 5-7, 5-8 and 5-9 list maximum dose limits to a point or volume within several 
critical organs based on the dose fractionation schema (one, three or five fractions) 
assigned based on metastatic tumor location.   
 
NOTE: If a point (0.03 cc) inside an OAR has > 5 Gy total dose contribution on the 
composite plan from multiple treatment sites, it is strongly suggested that the same dose 
scheme be used to treat all sites.  
 
NOTE: If different dose schemes are used in a given patient, dose limits to OAR 
receiving > 1 Gy contribution from treatment of individual metastases will be evaluated 
according to the table with the lowest number of treatment fractions (e.g., Table 5-7 for a 
single fraction will be used to assess OAR limits when a patient is treated with 1 and 5 
fraction dose schemes).  
 
Planning priorities for Organs at Risk: 
The spinal cord doses are absolute limits, and treatment delivery that exceeds these limits 
will constitute an unacceptable deviation. However, some OAR (i.e., the esophagus, 
trachea, bronchi and heart within the lung) may be situated adjacent to the treated 
GTV/PTV. As such, there is no specified limit as tumors that are immediately adjacent to 
that organ will not be able to be treated to the prescription doses without irradiating a 
small volume of that organ to the prescribed dose. In such a case, the planning must be 
accomplished so that there is no hot spot within that organ, even if that organ is part of 
the GTV/PTV, i.e., that no part of any serial OAR receives more than 105% of the 
prescribed dose (deviation unacceptable). In addition, the volume of the OAR in question 
needs to be minimized, both in length and in the width (i.e., circumference), with efforts 
made to reduce the dose to the contralateral wall of the organ. For parallel OAR, 
exceeding the doses in the tables (5-7, 5-8, 5-9) by more than 110% of the prescribed 
dose will be considered an unacceptable deviation.   
 

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For non-spinal cord OAR with known sensitivity to high doses of radiation (including the 
bowel, esophagus, and stomach) included within a PTV or immediately adjacent to 
PTVs, a prescription dose at the lower end of acceptable variation should be used. 
Additionally, every effort should be made to cover the GTV with the prescription dose 
while ensuring rapid falloff to the organ at risk. Coverage of a section of PTV including 
or immediately adjacent to the OAR may be as low as 70% of the prescription dose 
ONLY in this situation. Every effort should be made to cover 100% of the GTV by the 
prescription dose at the lower end of acceptable variation. Since the tumor and normal 
tissue may not allow strict avoidance, the larger volume limits will not be scored as 
unacceptable deviations if exceeded.  
 
The total allowable doses over either a 1, 3, or 5 fraction treatment regimen are based on 
the schema assigned and are listed in Tables 5-7, 5-8 and 5-9. 
 
For tumors that are not immediately adjacent to any OAR, centers are encouraged to 
observe prudent treatment planning principles in avoiding unnecessary radiation exposure 
to critical normal structures; we expect that the OAR doses will be as low as achievable 
(ideally, < 6 Gy/fraction). 
 
NOTE: No studies of OAR limits for multiple metastases have been reported in the 
literature. Thus, organ limits from previously developed protocols, as shown in Tables  
5-7, 5-8 and 5-9 below, will be utilized. 
 
Table 5-7 OAR Per Protocol Dose Limits for Single Fraction SBRT 
 
 
 
Serial Organ 
Volume 
Volume 
Dose 
(Gy) 
Avoidance Endpoint  
(Reference) 
Spinal Cord 
<0.35 cc 
10 
Myelitis  
(RTOG 0915/Timmerman) 
 
<10% 
partial 
spinal cord 
10 
Myelitis (RTOG 0631) 
 
<1.2 cc 
8 
Myelitis  
(Timmerman) 
 
<0.03 cc 
14 
Myelitis 
(0915/Timmerman) 
Ipsilateral Brachial 
Plexus 
<0.03 cc 
17.5 
Neuropathy 
(0915/Timmerman) 
 
<3 cc 
14 
Neuropathy  
(0915/Timmerman) 
Cauda Equina 
<0.03 cc 
16 
Neuritis  
(RTOG 0631/Timmerman) 
 
<5 cc 
14 
Neuritis  
(RTOG 0631/Timmerman) 
Sacral Plexus 
<0.03 cc 
18 
Neuropathy   

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(RTOG 0631) 
 
<5 cc 
14.4 
Neuropathy  
(RTOG 0631/Timmerman) 
Trachea and Ipsilateral 
Bronchus*  
 
<0.03 cc 
20.2 
Stenosis/Fistula  
(0915/Timmerman) 
 
<4cc 
17.4 
Stenosis/Fistula  
(Timmerman) 
Esophagus*  
 
<0.03 cc 
15.4 
Stenosis/Fistula  
(RTOG 0631) 
 
< 5 cc 
11.9 
Stenosis/Fistula 
(RTOG 0915/ RTOG 0631/ Timmerman) 
Heart/Pericardium 
<0.03 cc 
22 
Pericarditis  
(RTOG 0631/Timmerman) 
 
<15 cc 
16 
Pericarditis  
(RTOG 0631/Timmerman) 
Great vessels  
 
<0.03 cc 
37 
Aneurysm   
(RTOG 0915/RTOG 0631/ Timmerman) 
 
<10 cc 
31 
Aneurysm   
(RTOG 0915/RTOG 0631/ Timmerman) 
Skin 
<0.03 cc 
27.5 
Ulceration   
(Timmerman) 
 
< 10 cc 
25.5 
Ulceration   
(Timmerman) 
Stomach 
<0.03 cc 
22 
Ulceration/fistula   
(Timmerman) 
 
< 5cc 
17.4 
Ulceration/fistula   
(Timmerman) 
Duodenum* 
<0.03 cc 
17 
Ulceration   
(Timmerman) 
 
<5 cc 
11.2 
Ulceration  
(RTOG 0631/Timmerman) 
 
<10 cc 
9 
Ulceration   
(Timmerman) 
Bowel* 
<0.03 cc 
29.2 
Colitis/Fistula   
(Timmerman) 
 
<20 cc 
18 
Colitis/Fistula   
(Timmerman) 
Rectum* 
<0.03 cc 
44.2 
Proctitis/Fistula   
(Timmerman) 
 
<3.5 cc  
39 
Proctitis/Fistula   
(Timmerman) 

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<20 cc 
22 
Proctitis/Fistula   
(Timmerman) 
Bladder 
<0.03 cc 
25 
Cystitis/Fistula   
(Timmerman) 
 
<15 cc 
12 
Cystitis/Fistula   
(Timmerman) 
Ureter 
<0.03 cc 
35 
Stenosis   
(Timmerman) 
Penile bulb 
<3 cc 
16 
Impotence  
(Timmerman) 
Femoral heads 
<10 cc 
15 
Necrosis   
(Timmerman) 
Bile duct 
<0.03 cc 
30 
Stenosis  
(Timmerman) 
Renal Hilum/vascular 
trunk 
<15 cc 
14 
Malignant Hypertension  (Timmerman) 
Rib 
<0.03 cc 
33 
Pain or Fracture  
(Timmerman) 
 
<5 cc 
28 
Pain or Fracture  
(Timmerman) 
Parallel Organ 
Volume 
Volume 
Dose 
(Gy) 
Avoidance Endpoint  
(Reference) 
Lung (total) 
<37% lung 
volume 
8 
Pneumonitis   
(Timmerman) 
 
<1500 cc 
7 
Basic lung function   
(Timmerman) 
 
<1000 cc 
7.6 
Basic lung function   
(Timmerman) 
Total kidney 
<200 cc 
9.5 
Basic Renal Function   
(Timmerman) 
Liver 
<700 cc 
11 
Liver function  
(Timmerman) 
 
NOTE: Doses to serial OAR up to and including105% of the dose prescribed to the 
PTV will be scored as Variation Acceptable. Doses to parallel OAR  up to 110% of the values 
listed in the table will be score as Variation Acceptable. Doses above these values will be scored 
as Deviation Unacceptable.  
            
Table 5-8 OAR Dose Limits for 3 fraction SBRT 
Serial Organ 
Volume 
Volume Dose 
(Gy) 
Avoidance Endpoint 
(Reference) 
Spinal Cord 
<0.03 cc 
22.5 
Myelitis 
(Timmerman) 

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<1.2 cc 
13 
Myelitis 
(Timmerman) 
Ipsilateral Brachial Plexus 
< 0.03 cc 
26 
Brachial Plexopathy 
(Timmerman) 
 
<3 cc 
22 
Brachial Plexopathy 
(Timmerman) 
Cauda Equina 
<0.03 cc 
25.5 
Neuritis 
(Timmerman) 
 
<5 cc 
21.9 
Neuritis 
(AAPM TG-101) 
Sacral Plexus 
<0.03 cc 
24 
Neuropathy 
(AAPM TG-101) 
 
<5 cc 
22.5 
Neuropathy 
(AAPM TG-101) 
Trachea and Ipsilateral 
Bronchus*  
<0.03 cc 
30 
Stenosis/Fistula 
(Z4099) 
 
<5cc 
25.8 
Stenosis/Fistula 
(Timmerman) 
Esophagus*              
 
<0.03 cc 
27 
Stenosis/Fistula 
(Timmerman 2006 
/RTOG 0618) 
 
<5cc 
17.7 
Stenosis/Fistula 
(Z4099) 
Heart/Pericardium 
<0.03cc 
30 
Pericarditis 
(Z4099) 
 
<15 cc 
24 
Pericarditis 
(Z4099) 
Great vessels             
 
<0.03cc 
45 
Aneurysm 
(Z4099) 
 
<10 cc 
39 
Aneurysm 
(Z4099) 
Skin 
<0.03cc 
33 
Ulceration 
(Z4099) 
 
<10cc 
31 
Ulceration 
(Timmerman) 
Stomach 
<0.03cc 
30 
Ulceration/Fistula 
(Timmerman) 
 
<10cc 
22.5 
Ulceration/Fistula 
(Timmerman) 
Duodenum* 
<0.03cc 
24 
Ulceration 
(Timmerman 2006) 
 
<10cc 
15 
Ulceration 
(Timmerman 2006) 

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Bowel* 
<0.03 cc 
34.5 
Ulceration 
(Timmerman) 
 
<20cc 
24 
Colitis/Fistula (Z4099) 
Rectum* 
<0.03 cc 
49.5 
Ulceration 
(Timmerman) 
 
<3.5 cc 
45 
Proctitis/Fistula 
(Timmerman) 
 
< 20 cc 
27.5 
Proctitis/Fistula 
(Timmerman) 
Bladder 
0.03cc 
33 
Cystitis/Fistula 
(Timmerman) 
 
<15 cc 
16.8 
Cystitis/Fistula 
(AAPM TG-101) 
Ureter 
<0.03 cc 
40 
Stenosis 
(Timmerman) 
Penile bulb 
< 3cc 
25 
Impotence 
(Timmerman) 
Femoral heads 
<10 cc 
24 
Necrosis 
(Timmerman) 
Bile duct 
< 0.03 cc 
36 
Stenosis 
(Timmerman) 
Renal hilum/vascular trunk 
<15 cc 
19.5 
Malignant Hypertension 
(Timmerman) 
Rib 
< 0.03 cc 
50 
Pain or Fracture 
(Timmerman 
 
<5 cc 
40 
Pain or Fracture 
(Timmerman 
Parallel Organ 
Volume 
Volume Dose 
(Gy) 
Avoidance Endpoint  
(Reference) 
Lung (total) 
<15% lung 
volume 
20 
Pneumonitis/Lung 
Function 
(RTOG 0618) 
 
< 37% lung 
volume 
11 
Pneumonitis 
(Timmerman) 
 
<1500 cc 
10.5 
Basic Lung Function 
(Z4099) 
 
<1000 cc 
11.4 
Pneumonitis 
(Z4099) 
 
 
 
 
Total Kidney 
<200cc 
15 
Basic Renal Function 
(Timmerman) 
Liver 
<700 cc 
17.1 
Basic Liver function 
(Timmerman 

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2006/Z4099) 
*NOTE: Every effort should be made to avoid circumferential irradiation. 
NOTE: Doses to serial OAR up to and including 105% of the dose prescribed to the     
PTV will be scored as Variation Acceptable.  Doses to parallel OAR  up to 110% of the 
values listed in the table will be score as Variation Acceptable. Doses above these values 
will be scored as Deviation Unacceptable 
 
              Table 5-9 OAR Dose Limits for 5 fraction SBRT 
Serial Organ 
Volume 
Volume Dose 
(Gy) 
Avoidance Endpoint 
(Reference) 
Spinal Cord 
<0.03 cc 
28 
Myelitis 
(Timmerman) 
 
<0.35 cc 
22 
Myelitis 
(Timmerman) 
 
<1.2 cc 
15.6 
Myelitis 
(Timmerman) 
Ipsilateral Brachial Plexus 
< 0.03 cc 
32 
Brachial Plexopathy 
(RTOG 0813) 
 
<3 cc 
30 
Brachial Plexopathy 
(RTOG 0813) 
Cauda Equina 
<0.03 cc 
32 
Neuritis 
(AAPM TG-101) 
 
<5 cc 
30 
Neuritis 
(AAPM TG-101) 
Sacral Plexus 
<0.03 cc 
32 
Neuropathy 
(AAPM TG-101) 
 
<5 cc 
30 
Neuropathy 
(AAPM TG-101) 
Trachea and Ipsilateral 
Bronchus*  
 
<0.03cc 
40 
Stenosis/Fistula 
(Timmerman) 
 
<5cc 
32 
Stenosis/Fistula 
(RTOG 0813) 
Esophagus*               
 
<0.03cc 
35 
Stenosis/Fistula 
(Timmerman) 
 
<5 cc 
27.5 
Stenosis/Fistula 
(RTOG 0813) 
Heart/Pericardium 
<0.03 cc 
38 
Pericarditis 
(Timmerman) 
 
<15 cc 
32 
Pericarditis 
(RTOG 0813) 
Great vessels  
 
<0.03 cc 
53 
Aneurysm 
(Timmerman) 
 
<10 cc 
47 
Aneurysm 
(RTOG 0813) 

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Skin 
< 0.03cc 
38.5 
Ulceration 
(Timmerman) 
 
< 10cc 
36.5 
Ulceration 
(Timmerman) 
Stomach 
< 0.5cc 
35 
Ulceration/Fistula 
(Timmerman) 
 
< 5cc 
26.5 
Ulceration/Fistula 
(Timmerman) 
Duodenum* 
< 0.5 cc 
30 
Ulceration 
(RTOG 1112) 
 
< 5 cc 
18.3 
Ulceration 
(Timmerman 2006) 
Bowel* 
< 0.03 cc 
40 
Ulceration 
(Timmerman) 
 
<20 cc 
28.5 
Colitis/Fistula 
(Timmerman) 
Rectum* 
<0.03 cc 
55 
Ulceration 
(Timmerman) 
 
<3.5 cc 
50 
Proctitis/Fistula 
(Timmerman) 
 
<20 cc 
32.5 
Proctitis/Fistula 
(Timmerman 
Bladder 
< 0.03 
38 
Cystitis/Fistula 
(Timmerman) 
 
<15 cc 
20 
Cystitis/Fistula 
(Timmerman) 
Ureter 
< 0.03 cc 
45 
Stenosis  
(Timmerman) 
Penile Bulb 
<3 cc 
30 
Impotence  
(Timmerman) 
Femoral head 
<10 cc 
30 
Necrosis  
(Timmerman) 
Bile Duct 
<0.03 cc 
41 
Stenosis  
(Timmerman) 
Renal hilum/Vascular Trunk 
<15 cc 
23 
Malignant Hypertension 
(Timmerman) 
Rib 
<0.03 cc 
57 
Pain or Fracture 
(Timmerman) 
 
<5 cc 
45 
Pain or Fracture 
(Timmerman) 
Parallel Organ 
Volume 
Volume Dose 
(Gy) 
Avoidance Endpoint 
(Reference) 
Lung (total) 
< 37% lung 
volume 
13.5 
Pneumonitis 
(Timmerman) 
 
< 1500 cc 
12.5 
Basic Lung Function 
(RTOG 0813) 

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< 1000 cc 
13.5 
Pneumonitis 
(RTOG 0813) 
 
 
 
 
Total Kidney 
< 200cc 
18 
Basic Renal Function 
(Timmerman) 
Liver 
<700 cc 
21 
Basic Liver Function 
(Timmerman) 
*NOTE: Every effort should be made to avoid circumferential irradiation. 
NOTE: Doses to serial OAR up to and including 105% of the dose prescribed to the     
PTV will be scored as Variation Acceptable.  Doses to parallel OAR  up to 110% of the 
values listed in the table will be score as Variation Acceptable. Doses above these values 
will be scored as Deviation Unacceptable. 
 
Rib/Chest Wall Dose Constraints 
Recent reports have highlighted that the rib and chest wall in proximity to the treated 
lesion may represent an organ at risk for complication. Tumor location, particularly when 
located peripherally, will enhance the potential risk for chest wall toxicity. While target 
coverage should not be compromised to limit dose to the rib/chest wall, every effort 
should be made to minimize dose to this OAR. 
 
5.2.7 Documentation Requirements 
Treatment Interruptions 
In general, treatment interruptions should be avoided by preventative medical measures 
and supportive therapies. Treatment breaks, including indications, must be clearly 
documented on the treatment record. 
 
Sites will record dose-volume values for all required structures on this datasheet. The 
datasheet must be completed and submitted with the digital RT data via TRIAD for 
review.  
 
5.2.8 Compliance Criteria 
Treatment Duration 
Treatment Duration will be defined per metastasis 
 
Per Protocol:  
 Single Fraction Treatment: SBRT should be completed within 6 weeks of 
randomization/registration 
 3 fraction treatment:  All 3 fractions of SBRT should be completed within 3 
weeks of first SBRT dose and within 6 weeks of randomization/registration 
 5 fraction treatment:  All five fractions of SBRT should be completed within 3 
weeks of first SBRT dose and within 6 weeks of randomization/registration 
  
 
Acceptable Variation: Treatment completing > 3 but < 4 weeks 
 
Unacceptable Deviation: Treatment completed > 4 weeks 
 
 
 
 

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PTV Dosimetry Compliance 
Tables 5-1 and 5-2 describe acceptable variations in the protocol prescription dose (dose 
covering 95% of the PTV). These criteria should be evaluated for each metastasis 
independently (i.e., while suppressing dose from all other metastases), particularly for 
metastases treated on separate days. This may not be possible for metastases treated on 
the same day using a single plan (e.g., VMAT). Prescription doses outside of the 
variation acceptable range will be scored as Deviation Unacceptable. Scoring of PTV 
coverage will be: acceptable if ≥ 95%, variation acceptable if 70-95%, deviation 
unacceptable if < 70%.  
 
Organ at Risk Dosimetry Compliance  
Critical structure doses should be based on composite dose distribution when more than 
one met is treated (as stated in Section 5.2.6). Respect spinal cord, cauda equina, sacral 
plexus and brachial plexus dose constraints. Any dose to spinal cord, cauda equina, sacral 
plexus above that listed in Tables 5-7, 5-8, and 5-9 will be considered an unacceptable 
deviation. For all other OAR, when OAR dose criteria provided in Section 5.2.6 cannot 
be accomplished by following planning priorities outlined in Section 5.2.5, doses to serial 
OAR of more than 105% of the dose prescribed to the PTV will be scored as Deviations 
Unacceptable. Doses to parallel OAR exceeding 110% of the dose prescribed to the PTV 
will be scored as unacceptable deviations. Doses in the range between the numbers in the 
tables and unacceptable deviation will be considered acceptable variations. 
 
5.2.9 Radiation Therapy Adverse Events 
All Radiation Therapy AEs will be scored according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4. 
 
Adverse events related to SBRT for the treatment of metastases are dependent on the 
location of the metastases treated, as well as from exposure of surrounding normal 
tissues.   
 
For all treated metastases, fatigue is likely to occur and should be transient, lasting < 8 
weeks.  Other adverse events are likely to be related to the specific metastatic location 
receiving SBRT. 
 
Lung (Central and Peripheral), Mediastinal/Cervical Lymph Node Metastases:   
Cardiac and Pericardial Injury 
Although cardiac and pericardial injury is uncommon in the conventionally fractionated 
course of RT, with large doses per fraction of SBRT a number of possible side-effects 
can be seen. 
 
Gastrointestinal/Esophageal Injury 
The radiation effects on the esophagus can be acute: esophagitis (i.e., dysphagia, causing 
pain on swallowing, typically relatively soon after RT course is completed, and typically 
resolves on its own within days to a week or longer), or chronic, typically manifesting 
with dysphagia due to stenosis, or esophageal ulceration, with perforation in the extreme 
cases. 

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Central Airway/Bronchial Injury 
This bronchial injury with subsequent focal collapse of lung may impair overall 
pulmonary status. It also makes further assessment of tumor response more difficult as 
the collapsed lung approximates the treated tumor. Because atelectatic lung and tumor 
have similar imaging characteristics, radiology reports will often describe the overall 
process as progressive disease, while the actual tumor may be stable or shrinking. 
 
The consequences of bronchial toxicity, e.g., cough, dyspnea, hypoxia, impairment of 
pulmonary function test parameters, pleural effusion or pleuritic pain (associated with 
collapse), should all be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE), v. 4; MedDRA, v. 12.0. 
 
Lung Injury 
Radiation pneumonitis is a subacute (weeks to months from treatment) inflammation of 
the end bronchioles and alveoli. Radiation fibrosis is a late manifestation of radiation 
injury to the irradiated lung. Given the small amount of lung that is typically included in 
the SBRT portals, lung toxicity has not been as dose-limiting as in conventionally 
fractionated, large-field RT, but it is nevertheless seen, can be symptomatic, and may be 
confused with other causes of respiratory deterioration, including infections, and tumor 
recurrence.  
 
Given that larger volumes of lung may be irradiated in this protocol compared to SBRT 
for primary tumors, it is very important that a Radiation Oncologist participate in the care 
of the patient, as the clinical picture may be very similar to acute bacterial pneumonia, 
with fatigue, fever, shortness of breath, nonproductive cough, and a pulmonary infiltrate 
on chest x-ray. The infiltrate on chest x-ray should include the area treated to high dose, 
but may extend outside of these regions. The infiltrates may be characteristically 
“geometric” corresponding to the radiation portal, but may also be ill defined.  
 
Patients reporting symptoms as above will be promptly evaluated and treated. Mild 
radiation pneumonitis may be treated with nonsteroidal anti-inflammatory agents or 
steroid inhalers. More significant pneumonitis will be treated with systemic steroids, 
bronchodilators, and pulmonary hygiene. Supra- and concurrent infections should be 
treated with antibiotics. Consideration of prophylaxis of opportunistic infections should 
be considered in immunocompromised patients. 
 
Liver/abdominal-pelvic metastases 
Very likely (80-90%): Patients may experience fatigue (which generally goes away after 
the radiation therapy is completed), skin irritation, redness, itchiness, discomfort, 
temporary changes in blood work (decrease in blood counts, increase in liver enzymes), 
without symptoms. 
 
Less likely (30%): Patients may experience nausea, vomiting (during therapy) – more 
common if stomach or gastrointestinal tract irradiated, gastric, esophagus, small bowel or 
large bowel irritation/ulceration, bleeding, fistula, obstruction or changes in motility 

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following therapy (may require medications or surgery) (<10% permanent changes), 
chest wall pain, and rib fracture (< 10%). 
 
Less likely, but serious (<20%): Patients may experience radiation-induced liver disease 
(RILD) (<5%). Classic RILD is a clinical diagnosis of anicteric ascites, hepatomegaly 
and elevation of alkaline phosphatase relative to other transaminases that may occur 2 
weeks to 3 months following radiation to the Liver; non-classic RILD includes elevation 
of liver enzymes and/or any decline in liver function within 12 weeks from start of 
therapy (~20%). RILD can lead to liver failure that could lead to death. There is an 
increased risk of liver toxicity in patients with large tumors and in patients with pre-
existing liver disease. In addition, permanent thrombocytopenia (<1%) may lead to 
bleeding,  and kidney injury (<1%) may lead to changes on imaging and more rarely the 
need for medication. 
 
 
Spinal metastases  
Radiation Myelitis 
Given the proximity and position of the spinal cord in relation to the radiosurgery target, 
every effort should be made to minimize the radiation dose to the spinal cord. Radiation 
myelitis is a subacute or chronic clinical syndrome after radiation. The symptoms may 
include paresthesia, sensory changes, and motor weakness including paralysis. There is 
no active treatment for radiation myelitis; therefore, it is important to prevent any injury 
to the spinal cord. Corticosteroids are used when clinical symptoms develop. 
 
Radiation Esophagitis 
Patients with thoracic spine treatment will likely develop esophageal mucositis within the 
first 2 weeks. These symptoms subside with time; however, adequate symptomatic 
treatment including hydration is advised. There are no long-term adverse events reported 
with spine radiosurgery. However, it is prudent to minimize the radiation spillage in the 
normal esophagus. The consequences of esophageal toxicity, e.g., swallowing difficulty, 
dysphagia, cough, dehydration, and fistula, should be documented. 
 
Radiation Laryngitis or Pharyngitis 
Patients with cervical spine treatment will likely develop laryngopharyngeal mucositis 
within the first 2 weeks. These symptoms subside with time; however, adequate 
symptomatic treatment including hydration is advised. No long-term laryngopharyngeal 
toxicity has been reported with spine radiosurgery. However, it is prudent to minimize 
the radiation spillage in the normal larynx and pharynx. The consequences of toxicity, 
e.g., swallowing difficulty, dysphagia, cough, dysphonia dehydration, and fistula, should 
be documented. 
 
Tracheal Injury 
Although no cases of tracheal injury have been reported with spine radiosurgery, it is 
prudent to minimize the radiation spillage in the normal trachea. The consequences of 
tracheobronchial toxicity, e.g., cough, dyspnea, hypoxia, impairment of pulmonary 
function test parameters, pleural effusion or pleuritic pain (associated with collapse), 
should be documented. 

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Radiation Pneumonitis 
There have been no reported cases of symptomatic radiation pneumonitis with spine 
radiosurgery. However, it is prudent to minimize the radiation spillage in the lung tissue. 
It is strongly recommended to use radiation beams directed from the posterior to avoid 
passage of radiation through the lungs.  Patients with symptoms of pneumonitis will be 
promptly evaluated and treated. Mild radiation pneumonitis may be treated with non-
steroidal anti-inflammatory agents or steroid inhalers. More significant pneumonitis will 
be treated with systemic steroids, bronchodilators, and pulmonary hygiene. Supra- and 
concurrent infections should be treated with antibiotics. Consideration of prophylaxis of 
opportunistic infections should be considered in immunocompromised patients. 
 
Compression Fracture of Treated Vertebra 
Radiation doses in excess of 19 Gy for a single fraction are associated with higher rates 
of vertebral body compression (Saghal 2013). In this protocol, doses per fraction this 
high are not used, so that the estimated rate of vertebral body compression fracture 
following spinal metastases treatment should be approximately 10%.   
 
Other Adverse Events 
Short-term or long-term injury to the kidney or upper airway has not been reported. If 
other severe adverse events occur, details should be documented. 
 
Osseous:  
Erythema, desquamation and alopecia are common side effects from radiation therapy for 
osseous metastases; other effects are determinate on location of metastasis, and may 
include pain, edema and neuralgia. 
 
5.3 
Surgery (Arm 2) 
For patients receiving surgery, surgery must occur within 6 weeks of study entry. 
 
5.3.1 Technique, timing, other  
Breast cancer metastases must be proven pathologically prior to surgical resection. All 
surgical resections will be approached with intent of an R0 resection (rendering the 
patient with no evidence of measureable disease and pathologic negative margin). If 
surgical resection of a given metastasis is incomplete with gross or microscopic residual 
(i.e. positive margins) the treating team is encouraged to deliver additional 
therapy  including completion resection, conventionally fractionated radiation therapy, or 
systemic therapy as appropriate.  Given the lack of data in the post-operative setting 
SBRT should NOT be delivered to the incomplete resection site. If a metastases 
undergoes a biopsy only at the time of surgery, SBRT would be allowed per protocol.  
 
Approach to surgery will be based upon the treating surgeon. An open, laparoscopic, or 
thorascopic approach is acceptable.  Surgery that may result in major morbidity and/or 
mortality is discouraged, i.e. major pancreatic resection or pneumonectomy. If at time of 
surgery, an R1 resection is the best outcome, then if possible the surgery should be 
aborted. Standard pre-operative and post-operative evaluation is required.  
 

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5.3.2 Surgery Adverse Events 
Surgical morbidity and mortality must be recorded and reported.  Any adverse event from 
surgery within 30-days must be reported.  Morbidities include, but are not limited to 
hemorrhage, re-operation, infection, bile leak, persistent air leak, anastomotic 
leak/dehiscence, and poor wound healing. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines (1/12/16) 
 
5.4.1 Permitted Systemic Therapy 
Experimental therapeutics need to have a wash out period and must be discontinued 30 
days prior to SBRT therapy being administered or surgery performed.  
 
Participants may receive continuing standard of care systemic therapy management for 
their disease as follows: All hormonal therapy and bone supportive therapy may be 
continued during SBRT and around surgical procedures with interruption only as needed 
for routine surgical care [ie: NPO]. Tamoxifen is recommended to be held for 1 week 
before and after any major surgical procedure due to the increased thrombosis risk. The 
ongoing use of biologic therapy with trastuzumab, pertuzumab, and lapatinib is permitted 
concurrent with SBRT and around surgical procedures with interruptions only as needed 
for routine surgical care. Administration of ado-trastuzumab emantasine, palbociclib and 
everolimus should follow the chemotherapy guideline listed in Section 5.4.3. 
 
5.4.2 Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication. 
 
Anticonvulsants if indicated for reasons other than brain metastasis.  
 
For patients with liver and/or abdominal-pelvic metastases (as well as any other 
patient at the discretion of the treating oncologist) anti-emetics may be given prior 
to each fraction of SBRT to prevent nausea. 
 
For patients with lung (central or peripheral) and/or mediastinal/cervical lymph 
node metastases to be treated with radiation, corticosteroid premedication can be 
used at the discretion of the treating oncologist (in which case, its use needs to be 
reported. 
 
Anticoagulants as indicated for thrombotic disease. These must be held or bridged 
for patients undergoing surgical ablation according to routine surgical practice. 
 
Antidiarrheal as indicated by symptomatic diarrhea. 
 
Routine post-operative bowel regimens. 
 
Analgesic premedication to avoid general discomfort during simulation and 
treatment is recommended when appropriate. 
 
Routine anesthetics and post-surgical pain management. 
 
Hematopoietic growth factors should not be used during SBRT protocol therapy. 
G-CSF or pegylated G-CSF may have been given as part of prior chemotherapy 
as indicated by standard parameters, but ANC must be recovered to entrance 
values for the protocol without ongoing support.   
 
Herbal products are at the treating physicians’ discretion and should be captured 
on the concomitant medication forms. 

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 
Nutritional supplementation may be administered per standard indications and 
should be captured on the concomitant medication forms. 
 
Highly active antiretroviral therapy (HAART) is permitted for HIV affected 
individuals. 
 
Aspirin, non-steroidal anti-inflammatory, or other medications known to affect 
bleeding risks should be held for one week prior to any surgical study procedures, 
according to routine surgical guidelines.  
 
Routine use of blood products in the peri-operative time frame is permitted 
according to standard procedures.  
 
5.4.3 Prohibited Systemic Therapy 
Cytotoxic chemotherapy and select biologics, including palbociblib, everolimus and ado-
trastuzumab-emantasine, are not permitted during the administration of protocol specific 
ablative SBRT or surgery (Arm 2). Cytotoxic chemotherapy/select biologics  should be 
held prior to the initiation of protocol specified SBRT or surgical procedure following 
standard surgical pre-operative guidelines [long enough for bone marrow function to be 
recovered from any anticipated nadir (i.e. 14-21 days for 14-28 day cycles of  scheduled 
chemo, 7 days for weekly regimens)]. Patients on palbociclib must have drug held long 
enough to permit neutrophil count to be greater than 1000, platelets greater than 100  and 
no requirement for ongoing blood transfusions.  Patients on ado-trastuzumab emantasine 
should be held until platelets are 75 or greater. Cytotoxic chemotherapy may not overlap 
the SBRT and can be resumed 28 days after completion of protocol-specified SBRT and 
after the collection of blood for CTC has been completed, provided standard of care 
guidelines for bone marrow and/or liver function are met. Resumption of chemotherapy 
should not occur earlier than 28 days after completion of surgery and CTC collection or 
the recovery of any post-operative complications that would be worsened by re-initiation 
of chemotherapy (ie: infection, non-healing wound, bleeding). It is recommended that the 
decision to re-initiate chemotherapy be made jointly between the treating Radiation 
Oncologist and/or Surgeon and Medical Oncologist according to standard practices. The 
use of bevacizumab for patients on this study is prohibited. Patients may have received 
bevacizumab in the adjuvant setting or prior to study enrollment, as long as the last dose 
was 30 days or more prior to study enrollment. Patients should not resume bevacizumab 
as part of systemic breast cancer treatment as part of their post-ablative or ongoing SOC 
protocol therapy.  Use of bevacizumab for subsequent treatment regimens after disease 
progression is at the discretion of the patients treating physicians.   
  
5.5 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), as described in Section 6, 
 
Patient decides to withdraw consent for participation in the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 

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6. TREATMENT MODIFICATIONS/MANAGEMENT 
Not applicable to this study 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1 Protocol Agents 
 
Not applicable. Standard of care therapy will be given as appropriate for the patient’s 
disease subtype at the discretion of the treating physician. 
 
7.2 Adverse Events and Serious Adverse Events (14-JUN-2018) 
7.2.1 The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, 
for all AE reporting, CTEP-AERS, and case report forms. CTCAE version 5.0 will be 
utilized for CTEP-AERS reporting beginning April 1, 2018; all study case report forms 
will continue to use CTCAE version 4.0. All appropriate treatment areas should have 
access to a copy of CTCAE versions 4.0 and 5.0, which can be downloaded from the 
CTEP web site (https://ctep.cancer.gov/ 
protocolDevelopment/electronic_applications/ctc.htm). 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 
 
7.3 
Expedited Reporting of Adverse Events (9/16/16) 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to the NRG 
Biostatistical/Data Management Center and satisfies NRG requirements for expedited 
adverse event reporting. 
 
 

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CTEP-AERS provides a radiation therapy-only pathway for events experienced that 
involve radiation therapy only. These events must be reported via the CTEP-AERS 
radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to NRG Oncology by phone, 1-215-574-3191. An electronic report must be 
submitted immediately upon re-establishment of the Internet connection. 
 
7.3.1 Expedited Reporting Methods 
 CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification 
is electronically submitted within 24 hours of learning of the adverse event. Each 
CTEP-AERS 24-hour notification must be followed by a complete report within 5 
days.  
 Supporting source documentation is requested by NRG as needed to complete 
adverse event review. Supporting source documentation should include the protocol 
number, patient ID number, and CTEP-AERS ticket number on each page. For 
instructions to submit supporting documentation, contact NRG Oncology at 1-215-
574-3191. 
 A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.3.2 Expedited Reporting Requirements for Adverse Events  
For Arm 2:  Any Phase Study Utilizing Radiation Therapy (including chemoRT 
studies)1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they are considered 
related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered 
serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and 
have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 3 adverse events 
 
 
 
 
 
 

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For Arm 1:  Any Phase Study Utilizing a Commercial Agent1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they are considered 
related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH 
E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
Attribution 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Unlikely 
 
10 day 
10 day 
Possible 
Probable 
Definite 
24-h/5 day 
 
24-h/5 day 
24-h/5 day 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
Unexpected Grade 4 and all Grade 5 AEs 
 
Additional Protocol-Specific Instructions or Exceptions to Expedited Reporting 
Requirements 
Not applicable  
 
7.3.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
7.3.4 Secondary Malignancy  
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treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS . In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS. 
Three options are available to describe the event: 
 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
 
Myelodysplastic syndrome (MDS) 
 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
7.4 
Routine Reporting Requirements for Adverse Events (14-JUN-2018) 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
8. REGISTRATION AND STUDY ENTRY PROCEDURES (21-SEP-2022) 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and renew 
their registration annually.  To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.   
 
RCR utilizes five person registration types: 
 
 IVR — MD, DO, or international equivalent; 
 NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
 AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System [RUMS], OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 
 Associate (A) — other clinical site staff involved in the conduct of NCI-
sponsored trials; and 
 Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) 
with limited access to NCI-supported systems. 

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RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, employment, license, 
and certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards 
(IRBs) covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
 Added to a site roster; 
 Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in 
OPEN; 
 Act as the site-protocol Principal Investigator (PI) on the IRB approval. 
 
In addition, all investigators acting as the site-protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN must be rostered at 
the enrolling site with a participating organization.  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact 
the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
8.1 
Cancer Trials Support Unit Registration Procedures (21-SEP-2022) 
            This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval  
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must 
accept the NCI CIRB review to activate new studies at the site after March 1, 2019. Local 
IRB review will continue to be accepted for studies that are not reviewed by the CIRB, or 
if the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) 

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for Local Context  to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to 
the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at the 
network or protocol level. Questions about establishing site preferences can be addressed 
to the CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
In addition, the site-protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
 Holds an active CTEP status; 
 Active status at the site(s) on the IRB/REB approval on at least one participating 
organization’s roster; 
 If using NCI CIRB, active  on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
 Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile;  
 Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in 
the RCR profile; and 
 Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements  
Additional site requirements to obtain an approved site registration status include: 
 An active Federal Wide Assurance (FWA) number; 
 An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
 An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
 Compliance with all protocol-specific requirements (PSRs). 
 IRB/REB Approved Informed Consent (International sites only: English and native 
language versions*) 
*Note: International and Canadian Institutions must provide certification/verification of 
IRB/REB IEC consent translation to NRG Oncology (described below). 
 
        
Downloading Site Registration Documents:   
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and its associated investigators and staff 
on a participating roster.  Log in to the CTSU members’ website (https://www.ctsu.org) 
using your CTEP-IAM username and password; 
 Click on Protocols in the upper left of the screen 

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o Enter the protocol number in the search field at the top of the protocol tree; 
or 
o Click on the By Lead Organization folder to expand, then select NRG, and 
protocol number NRG-BR002. 
 
Protocol-Specific Requirements for Protocol NRG-BR002 Site Registration: 
 IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC 
Houston to verify credentialing status or to begin a new modality credentialing 
process.  
 For detailed information on the specific technology requirement required for this 
study, please refer to the table below and utilize the web link provided for detailed 
instructions. The check marks under the treatment modality columns indicate 
whether that specific credentialing requirement is required for this study. Specific 
credentialing components may require you to work with various QA centers; 
however, IROC Houston will notify your institution when all credentialing 
requirements have been met and the institution is RT credentialed to enter patients 
onto this study.  The credentialing notification document (email) must be uploaded 
by the site to the CTSU Regulatory Submission Portal for RSS to be updated. 
 Upon site registration approval in RSS, the enrolling site may access OPEN to 
complete enrollments. The enrolling site will select their credentialed provider 
treating the subject in the OPEN credentialing screen and may need to answer 
additional questions related to treatment in the eligibility checklist.   
 IRB/REB approved consent (International and Canadian sites only: English and 
native language versions*)  
 Note: International and Canadian sites must submit an English version of the 
consent form to NRG Regulatory (Regulatory-PHL@nrgoncology.org) for review 
prior to submission to local IRB/REB/IEC. Certification/verification of 
IRB/REB/IECconsent translation must be provided with submission to CTSU 
(described below). 
 
Non-English Speaking Canadian and International Institutions: 
*Translation of documents is critical. The institution is responsible for all translation 
costs. All regulatory documents, including the IRB/REB/IEC approved consent, must 
be provided in English and in the native language. Certification of the translation is 
optimal but due to the prohibitive costs involved NRG will accept, at a minimum, a 
verified translation. A verified translation consists of the actual REB approved consent 
document in English and in the native language, along with a cover letter on 
organizational/letterhead stationery that includes the professional title, credentials, and 
signature of the translator as well as signed documentation of the review and 
verification of the translation by a neutral third party. The professional title and 
credentials of the neutral third party translator must be specified as well. 
 
 
Submitting Regulatory Documents 

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Submit required forms and documents to the CTSU Regulatory Officeusing the 
Regulatory Submission Portal on the CTSU website.  
To access the Regulatory Submission Porta,l log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org in order to receive further instruction and 
support. 
 
 
Checking Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.   
 Click on Regulatory at the top of the screen; 
 Click on Site Registration; and 
 Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
 
8.2   
RT-Specific Pre-Registration Requirements  (21-SEP-2022) 
For detailed information on the specific technology requirement required for this study, 
please refer to the table below and utilize the web link provided for detailed instructions. 
The check marks under the treatment modality columns indicate whether that specific 
credentialing requirement is required for this study. Specific credentialing components 
may require you to work with various QA centers; however, the IROC Houston QA Center 
will notify your institution and NRG Oncology when all credentialing requirements have 
been met and the institution is RT credentialed to enter patients onto this study. This 
document must be uploaded by the site to the CTSU Regulatory Submission Portal for RSS 
to be updated. IROC will automatically send the approval to the Regulatory Support 
System (RSS) to comply with the protocol-specific requirement, unless otherwise noted at 
the bottom of the IROC Credentialing Approval notification. 
RT 
Credentialing 
Requirements 
 
Web Link for Procedures and Instructions:   http//irochouston.mdanderson.org  
Treatment 
Modality 
Key Information 

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NRG does not have a single, specific credentialing method for stereotactic body 
radiotherapy (SBRT). SBRT credentialing consists of a combination of other existing 
credentialing steps.  SBRT requires the use of image-guided radiotherapy (IGRT) with its 
associated credentialing requirement. Therefore, IGRT credentialing is also required 
for this protocol . 
 
Since SBRT can be used for various sites in the body, treatment technique credentialing 
must include some method of addressing motion when lesions in or near the thorax are 
treated.  Credentialing of individual treatment modalities is required for this 
 
SBRT 
IMRT 
 
Facility 
Questionnaire 

  
The IROC Houston electronic facility questionnaire (FQ) should be 
completed or updated with the most recent information about your 
institution. To access this FQ go to 
http://irochouston.mdanderson.org/questionnaires/ 
Credentialing 
Status 
Inquiry Form 

  
To determine whether your institution needs to complete any further 
credentialing requirements, please complete the “Credentialing 
Status Inquiry Form” found under credentialing on the IROC 
Houston QA Center website (http://irochouston.mdanderson.org) 
Phantom 
Irradiation 

  
An  IROC Houston anthropomorphic phantom must be successfully 
completed (if the institution has not previously met this 
credentialing requirement)if the institution plans to deliver SBRT 
with IMRT. Credentialing for IMRT allows the institution to also 
use 3D-CRT SBRT, but credentialing for 3D-CRT SBRT does not 
allow the institution to use IMRT.  Flattening-filter-free (FFF) 
photon beam delivery, Tomotherapy and Cyberknife treatment 
delivery modalities must be credentialed individually. Instructions 
for requesting and irradiating the phantom are available on the 
IROC Houston website under credentialing 
(http//irochouston.mdanderson.org), 
IGRT 
Verification 
Study  

  
Submit a series of daily treatment images along with a spreadsheet 
of IGRT data from 2 anonymized cancer patients treated with SBRT 
to the appropriate site (1. lung/liver and 2. spine). The anonymized 
data must come from a patient treated with an identical motion 
management strategy (i.e., gating, breath-hold, abdominal 
compression, motion tracking), as used with the phantom 
irradiation. 
 

  
 
 
Credentialing Issued to: 
Institution 
  
  
IROC Houston QA Center will notify the institution and NRG 
Headquarters that all desired credentialing requirements have been 
met. 

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protocol.   
 
However, institutions need to credential for only the most complex modality they 
intend to use. The increasing complexity level for treatment modalities is three-
dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy 
(IMRT), and volumetric arc therapy (VMAT). Treating with flattening-filter-free (FFF) 
photon beam, Tomotherapy or the CyberKnife requires separate credentialing.  The 
selected treatment technique(s) have to be coupled with the motion management 
technique that will be used by the institution. Taken together, the various required 
credentialing steps can be considerable. However, the number of steps can be reduced 
through a process of “grandfathering” institutions with appropriate previous 
credentialing. Please contact the Imaging and Radiation Oncology Core (IROC) Houston 
for more information. 
 
NOTE: If the institution wishes to utilize a single isocenter setup to treat multiple lesions, 
which is discouraged (see Section 5.2.2) for lesions more than 10cm away, the SBRT 
credentialing must be performed with two lesions (lung and spine) in the lung SBRT 
phantom provided by IROC Houston. Furthermore the phantom must be irradiated in the 
same manner (i.e., utilizing a single isocenter to treat both the lung and spine metastases 
concurrently) and with appropriate motion management. 
 
8.2.1 Digital Radiation Therapy Data Submission Using Transfer of Images, and Data  
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application. TRIAD provides sites participating in clinical 
trials a secure method to transmit images. TRIAD anonymizes and validates the 
images as they are transferred. 
 
TRIAD Access Requirements: 
 A valid CTEP-IAM account.  
 Registration type of: Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR) registration type. Refer to the 
CTEP Registration Procedures section for instructions on how to request a 
CTEP-IAM account and complete registration in RCR. 
 TRIAD Site User role on an NCTN or ETCTN roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster 
have access to TRIAD and may submit images for credentialing purposes, or 
for enrollments to which the provider is linked in OPEN. 
 
TRIAD Installations: 
To submit images, the individual holding the TRIAD Site User role will need to 
install the TRIAD application on their workstation. TRIAD installation 
documentation is available at https://triadinstall.acr.org/triadclient/. 
 
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RCR registration. 
 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
 
8.3  
Patient Enrollment (12-AUG-2021) 
Patient registration can occur only after evaluation for eligibility 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.   
 
8.3.1 Oncology Patient Enrollment Network (OPEN) 
  
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management system, 
Medidata Rave. 
Requirements for OPEN access:   
 A valid CTEP-IAM account; 
 To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
 If a Delegation of Tasks Log (DTL) is required for the study, the registrars must 
hold the OPEN Registrar task on the DTL for the site; and 
 Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
 
 
 
 
 
 
Prior to accessing OPEN, site staff should verify the following: 
 Patient has met all eligibility criteria within the protocol stated timeframes; and  
 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 

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registration and treatment information. You may print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
9.  DRUG INFORMATION  
 Not applicable to this study  
 
 
10.    PATHOLOGY/BIOSPECIMEN (11-JUL-2018)  
See detailed specimen collection/processing/shipping instructions on the NRG-BR002 
protocol page of the CTSU website. Instructions are also provided with all kits. 
 
Patients must be offered the opportunity to consent to optional specimen collections. If the 
patient consents to participate, the site is required to submit the patient’s specimens as 
specified in the protocol. Sites are not permitted to delete the specimen component from the 
protocol or from the sample consent. 
 
 
 
 
Funding for the following studies has been generously provided from two sources: 
 
Ralph R. Weichselbaum, MD 
Daniel K. Ludwig Distinguished Service Professor & Chair  
Director, Ludwig Center for Metastasis Research 
Ludwig Center for Metastasis Research 
924 E. 57th Street 
Chicago IL 60637-5419 
 
And 
 
Peter Kuhn 
3430 S. Vermont 
Suite #106 
Los Angeles, CA 90089 
 
Optional Study #1: Whole Blood Collection for Translational Research: 
Circulating Tumor Cells (CTCs)  
 
See the NRG-BR002 protocol page of the CTSU website for further details on 
collection logistics.  
Consenting patients will have 7.5 ml of whole blood drawn by phlebotomy or through 
a central venous access device into a “CellSave” tube (included with NRG-BR002 kits) 
to collect and quantify CTCs (see below for collection timepoints). Because the 

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analytes for this study degrade rapidly, only specimens drawn Mon-Wed, and shipped 
overnight no later than Thursday to MD Anderson Cancer Center will be accepted (see 
address below). 
 
NOTE: Samples for CTC analysis must be drawn on a Monday, Tuesday or a 
Wednesday in “CellSave” blood collection tubes containing EDTA and a stabilizer 
(Immunicon Corporation), must be clearly labeled with patient study number, type of 
sample, and date collected, and it must be shipped to UT MD Anderson Cancer Center 
overnight no later than Thursday so samples can be received and processed by Friday 
of the same week. 
 
Specimens are being collected to determine whether a blood test could predict who will 
benefit from ablation of metastatic disease, and to better understand the biology that 
drives metastases. 
 
(see Section 2.2 for further details). 
 Required Forms: ST form. 
 CTC tubes, kits and special CTC shipping supplies will be supplied with the 
Banking Kits (optional Study#3)  from the NRG Oncology Biospecimen Bank- 
San Francisco (NRGBB-SF). Please allow 5-10 days for delivery as kits are 
shipped to sites by Fed Ex ground 
 Shipping days: Monday-Wednesday (U.S. sites); Monday-Tuesday (Canada 
and Non-North American). 
 Shipping costs: Sites will receive BR002 specific Fed Ex account and reference 
number in the kits provided with instructions from the NRBB-SF. Please 
contact wwoodward@mdanderson.org; 713-563-2363 with any questions 
regarding this process 
 
Submit Cell Save tube materials by FedEx priority overnight for CTC analysis (labeled 
NRG-BR002) directly to: 
 
Dr. Carol Hall 
UT MD Anderson Cancer Center 
Dept of Surgical Oncology 
1515 Holcombe Blvd 
CRB T4.3932 
Houston , TX 77030 
713-563-8898/FAX 713-794-4830 
 
Notify both Dr. Carol Hall (cshall@mdanderson.org) and Dr. Wendy Woodward 
(wwoodward@mdanderson.org) by e-mail on the day of submission with the following 
information: (1) that a sample is being submitted with the NRG case number; (2) the 
overnight shipping carrier and tracking number, and (3) e-mail and phone number of 
contact person. 
For questions regarding Kits, contact:  
NRG Oncology Biospecimen Bank- San Francisco 

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415-476-7864/FAX 415-476-5271 
NRGBB@ucsf.edu 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
Whole Blood for 
CTCs: 7.5ml whole 
blood in a 
“CellSave” 
 tube 
(Drawn Mon-Wed 
only) 
(1)Pre-treatment 
 
(2) Post treatment: 
Arm 2:4 wks. post 
SBRT  OR Arm 
1:3 months post 
registration  
 
(3) At disease 
progression (if 
applicable) 
Single tube at room 
temperature 
Ambient 
temperature via 
overnight carrier no 
later than Thursday  
Ship to UT MD 
Anderson; contact 
the lab before 
shipping 
 
 
 
 
 
 
Optional Study #2: Plasma Collection for Translational Research: ctDNA analysis 
See the NRG-BR002 protocol page of the CTSU website for further details on 
collection logistics. 
A special plasma tube manufactured by Streck (tiger lid, 7-10 mL) will be drawn at the 
same time points as the CTC collection into a “Streck” tube (provided by NRG 
Oncology Biospecimen Bank-SF with special NRG-BR002 kits) for eventual ctDNA 
cell-free analysis, high-content single cell liquid biopsy (HD-SCA), and mathematical 
correlation to clinical data.  
This tube must be filled in after the “CellSave” tube in Optional Study #1. If no other 
tube is collected at the time points of CTC collection, then the first 2 mL of blood must 
be drawn into another tube (not “Streck”) and discarded. Then, proceed to draw blood 
into the “Streck” tube. 
The “Streck” tube should be shipped to The Kuhn-Hicks Laboratory at USC (see 
address below). 
 Required Forms: ST form. 
 Streck tubes will be supplied with the special Streck shipping kit  from the 
NRG Oncology Biospecimen Bank-SF. Each kit is for one timepoint. Please 
allow 5-10 days for delivery as kits are shipped to sites by Fed Ex ground 
 Shipping days: Monday-Wednesday (U.S. sites); Monday-Tuesday (Canada 
and Non-North American).  
Shipping costs: Fed ex account information will be provided with each special 
Streck kit instruction packet from the NRGBB-SF. Contact the Kuhn lab at 
(kuhnlab@usc.edu)  for Streck kit collection or shipping information. 
 

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Submit  “Streck” tube ctDNA materials (labeled NRG-BR002) directly to: 
 
Peter Kuhn 
c/o USC Michelson Hall 
Kuhn-Hicks Laboratory 
 
1002 Childs Way, MCB 310 
Los Angeles, CA 90089-3502 
 
Notify Dr. Wendy Woodward (wwoodward@mdanderson.org) and Dr. Peter Kuhn’s 
lab (kuhnlab@usc.edu) by e-mail on the day of submission with the following 
information: (1) that a sample is being submitted with the NRG case number; (2) 
date/time of draw; (3) the shipping carrier and tracking number, and (4) e-mail and 
phone number of contact person.  
 
For questions call Xiomara Villasenor at 213-740-9614 (xvillase@usc.edu) or the 
Kuhn Lab (213-740-9945, kuhnlab@usc.edu); Or Dr. Woodward (713-563-2363) to 
coordinate labels addressed to USC.  
 
NOTE: Guidelines for the shipment of ctDNA/“Streck” tube: 
The Biospecimen bank kit will include instructions with Fed Ex account information 
and a special shipping container for shipping the Streck tube. This includes a white, 
two part “cassette” to hold the blood tube, an air pillow bag, a Paksense probe for 
temperature monitoring, and a blue shipping cardboard box.  
 Open the blue shipping box to extract a silver air pillow bag that contains the 
white cassette. Open the white cassette and extract a 2-layer plastic tube holder.  
 Place the filled ambient Streck tube inside the smaller plastic holder, place the 
lid. Insert smaller plastic holder into the larger plastic holder, place the lid. 
 Prepare the Paksense temperature monitoring probe: Peel off the plastic cover 
over the back of the glue dot that is found in the back of the Paksense probe. 
Place the Paksense, glue dot down in the insert inside one side of the white 
cassette. Activate the Paksense probe by pressing the Start button for 2 seconds, 
then release. A green light should now be blinking. 
 Place the 2-layer plastic tube holder containing the specimen inside the white 
cassette and snap the two halves together. 
 Place the white cassette inside the air pillow bag. It will be a tight fit. 
 Place the air pillow bag into the blue cardboard shipping box with the ST Form. 
No need to use the sticky seal; just fold it over.  
 Verify the FedEx label is addressed to the Kuhn lab at USC and Biohazard 
label is visible. Contact your local Fed-Ex representative for pick-up. 
 Send shipment notification email to kuhnlab@usc.edu. 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
PLASMA 
(ctDNA): 7-10 mL 
(1)Pre-treatment 
 
Collect blood in 
special Streck tube. 
Blood in special 
Streck tube sent in 

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of anticoagulated 
whole blood in tiger 
lid  “Streck” tube  
 
(2) Post treatment:  
Arm 2:4 wks. post 
SBRT  OR Arm 
1:3 months post 
registration  
 
(3) At disease 
progression (if 
applicable) 
Do not process. 
ambient 
temperature 
controlled special 
shipper via 
overnight carrier 
for 10:30am 
delivery 
(Ship to Kuhn Lab 
at USC by 
overnight courier- 
contact Kuhn lab 
before shipping) 
 
 

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Optional Study #3: Specimen Collection for Tissue Banking 
See the NRG-BR002 protocol page of the CTSU website for further details on 
collection logistics. 
Patients must be offered the opportunity to consent to optional specimen collection. If 
the patient consents to participate, the site is required to submit the patient’s previously 
collected diagnostic specimens as specified in the protocol. Sites are not permitted to 
delete the specimen component from the protocol or from the sample consent. 
 
Specimens are being collected for future translational research projects and being 
submitted to the NRG Oncology Biospecimen Bank- San Francisco for banking 
 
 Required Forms: ST form, pathology reports.  All forms must be completely 
filled out with an NRG Label including the Study #, Case #, NRG Institution 
number or Institution NCI ID, and patient initials. The pathology accession 
number must remain visible on the pathology report but all other PHI 
information must be redacted/removed. 
 Kits are available for Frozen biospecimens from the NRG Oncology 
Biospecimen Bank-San Francisco 
 Detailed Processing and shipping instructions are provided on the protocol 
webpage 
 Shipping days for Frozen Specimens: Monday-Wednesday (U.S. sites); 
Monday-Tuesday (Canada and Non-North American). We are unable to accept 
shipments on Saturdays or holidays. 
 Shipping costs: One Prepaid Fed Ex label is provided for batch shipping the 
Frozen biospecimens for banking specimens for each case in the kits. 
 Ship all Biospecimens for Optional Study #3 for banking to: 
NRG Oncology Biospecimen Bank- San Francisco 
UCSF Dept of Radiation Oncology 
2340 Sutter Street- Room S341 
San Francisco, CA 94115 
415-476-7864 
 
For questions about banking biospecimens contact:  
NRG Oncology Biospecimen Bank- San Francisco 
NRGBB@ucsf.edu   
415-476-7864/FAX 415-476-5271 
Specimen Type 
Collection Time 
Points 
Collection 
Information and 
Requirements 
Shipping 
Representative 
H&E stained slides 
of the primary 
tumor 
Pre-treatment:  
obtained as part of 
routine diagnostic 
procedures. 
H&E stained slide. 
Can be a duplicate 
cut slide, does not 
have to be the 
diagnostic slide. 
 
Slide shipped 
ambient to the 
NRGBB-SF  
A paraffin-
Pre-treatment:  
Paraffin-embedded 
Block or punch 

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embedded tissue 
block or one 3mm 
punch from the 
block  of the 
primary tumor 
taken before 
initiation of 
treatment 
 
obtained as part of 
routine diagnostic 
procedures. 
tissue block or 
punch. Must match 
the H&E being 
submitted. 
 
block shipped 
ambient to the 
NRGBB-SF. Ship 
with a cold pack 
during warmer 
weather to avoid 
wax from melting 
 
 
Representative 
H&E stained slides 
of the metastatic 
tumor 
Pre-treatment:  
obtained as part of 
routine diagnostic 
procedures. 
H&E stained slide. 
Can be a duplicate 
cut slide, does not 
have to be the 
diagnostic slide 
 
Slide shipped 
ambient to the 
NRGBB-SF 
A paraffin-
embedded tissue 
block or one 3mm 
punch from the 
block of the 
metastatic tumor 
taken before 
initiation of 
treatment when 
available 
Pre-treatment:  
obtained as part of 
routine diagnostic 
procedures. 
Paraffin-embedded 
tissue block or 
punch from block 
must match the 
same tissue block as 
the H&E being 
submitted 
 
Block or punch 
block shipped 
ambient to the 
NRGBB-SF. Ship 
with a cold pack 
during warmer 
weather to avoid 
wax from melting 
 
 
Representative 
H&E stained slides 
of the metastatic 
tumor 
At Progression:  
obtained as part of 
routine diagnostic 
procedures. 
H&E stained slide. 
Can be a duplicate 
cut slide, does not 
have to be the 
diagnostic slide 
 
Slide shipped 
ambient to the 
NRGBB-SF 
A paraffin-
embedded tissue 
block or one 3mm 
punch of the 
metastatic tumor 
taken at the time of 
progression if 
available 
At progression:  if 
obtained as part of 
routine diagnostic 
procedures. 
Paraffin-embedded 
tissue block or 
punch from block 
 
 
Block or punch 
block shipped 
ambient to the 
NRGBB-SF. Ship 
with a cold pack 
during warmer 
weather to avoid 
wax from melting 
 
 
SERUM: 5-10 mL 
of whole blood in 1 
red-top tube and 
centrifuge 
Pre-treatment 
Frozen serum 
samples containing 
a minimum of 0.5 
mL per aliquot in 1 
mL cryovials (five) 
Serum sent frozen 
on dry ice via 
overnight carrier 
to the NRGBB-SF 

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PLASMA (for 
banking): 5-10 mL 
of anticoagulated 
whole blood in 
EDTA tube #1 
(purple/ lavender 
top) and centrifuge 
Pre-treatment 
Frozen plasma 
samples containing 
a minimum of 0.5 
mL per aliquot in 1 
mL cryovials (five) 
Plasma sent frozen 
on dry ice via 
overnight carrier 
to the NRGBB-SF 
Whole blood for 
DNA: 5-10 mL of 
anticoagulated 
whole blood in 
EDTA tube #3 
(purple/lavender 
top) and mix 
Pre-treatment; 
note: If site missed 
this collection time 
point they may 
collect whole blood 
for DNA at a later 
time point but must 
note this on the ST 
Form. 
Frozen whole blood 
samples containing  
1.5-2 ml per aliquot 
in 2ml cryovials (3) 
Whole blood sent 
frozen on dry ice 
via overnight 
carrier to the 
NRGBB-SF 
 
 
11. 
SPECIAL STUDIES (NON-TISSUE) 
 
 
None 
 
12. 
MODALITY REVIEWS 
12.1 
Radiation Therapy Quality Assurance Reviews 
Arm 2 Pre Treatment Review 
A full 3D dosimetry plan PRE-TREATMENT REVIEW for the first patient registered for 
each disease site category treated at the institution on this protocol must be submitted to 
TRIAD for review PRIOR TO DELIVERY of radiation treatment. If the institution has 
previously treated patients with the same disease site on NRG-BR001  then a  pre-
treatment review is not necessary. If the initial case at the institution treats a single 
metastasis with SBRT, the institution will also be required to submit their first multiple 
metastases case to be treated with SBRT for pre-treatment review PRIOR TO 
DELIVERING ANY PROTOCOL TREATMENT. The plan(s) will be reviewed 
centrally by the PIs, and feedback regarding protocol compliance will be forwarded to the 
participating institution. Based on the results of any of the reviews described above, a 
request for additional pre-treatment reviews might be necessary. In general, the treatment 
plan for subsequent patients enrolled at a site will not be required to be centrally 
reviewed prior to treatment, but will be reviewed for protocol compliance at a later date. 
Allow 3 business days for the results of the pre-treatment review process. The pre-
treatment review process will not start until all required data is submitted to TRIAD.  
 
RT Quality Assurance Review 
The Radiation Oncology Co-Chairs will perform an RT Quality Assurance Review after 
complete data for the first 20 cases enrolled has been received at NRG Oncology. The 
Radiation Oncology Co-Chairs will perform ongoing reviews after complete data for 
each cohort of 20 enrolled cases has been received at NRG Oncology. These reviews will 
be on going.  

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12.2 
Surgical Quality Assurance Reviews 
The Surgical Oncology Co-Chair, Nora Jaskowiak, M.D., will perform a Quality 
Assurance Review on a continuous basis for patients randomized to Arm 2 that receive 
surgery as part of their ablative treatment. After NRG Oncology Statistics and Data 
Management Center (SDMC) has received complete data for each Arm 2 case enrolled that 
receives surgery, Dr. Jaskowiak will perform a review. Documents reviewed will be the 
Pre-operative H&P, the Operative Report, the Pathology Report from the surgical 
procedure, and the Discharge Summary from the surgical admission. In addition, all 
surgical SAEs will be reported in an expedited manner and reviewed regularly by the 
Surgical PI.  Dr. Jaskowiak will utilize the expertise of other surgical oncologists, thoracic 
surgeons, and Orthopedic oncologic surgeons  (at the University of Chicago and Duke 
Medical Center) if sub-specialty quality issues arise.  If concern arises about surgical 
quality upon review, Dr. Jaskowiak will directly communicate with both the PI and surgeon 
at the institution, with possible intervention, if deemed appropriate. 
 
 
13. 
DATA AND RECORDS 
13.1 
Data Management/Collection (12-AUG-2021) 
Medidata Rave is a clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments.  
 
Requirements to access Rave via iMedidata: 
 
A valid CTEP-IAM account; and  
 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
 
Rave role requirements: 
 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
 
Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site staff must log in to the 
Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user name 
and password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Site staff will not be able to access the study in Rave until all required Medidata 
and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings) and can be accessed by clicking on the link in the upper right pane 
of the iMedidata screen. If an eLearning is required and has not yet been taken, the link to 

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the eLearning will appear under the study name in iMedidata instead of the Rave EDC 
link; once the successful completion of the eLearning has been recorded, access to the 
study in Rave will be granted, and a Rave EDC link will display under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com.   
  
 
13.2 
Summary of Data Submission (9/16/16) 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Sections 7.2 and 7.3. for information about expedited and 
routine reporting.   
 
For reporting of second primary cancers or other report forms available in Rave:  
Indicate form for reporting in Rave, timeframes, add if loading of the pathology report is 
required. 
 
Summary of Data Submission: Refer to the protocol-specific website.  
 
See Section 8.4.2 for TRIAD account access and installation instructions. 
 
13.3     Data Quality Portal (21-SEP-2022) 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP 
Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status and 
timeliness reports. Review the DQP modules on a regular basis to manage 
specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
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To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, DQP Delinquent Forms. DQP Form Status, and DQP 
Reports modules 
 
13. 4    Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. 
Reports are due January 31, April 30, July 31, and October 31. 
 
14. 
STATISTICAL CONSIDERATIONS 
14.1 
Study Design (12Jul2017) 
14.1.1 Stratification 
Patients will be stratified before randomization with respect to the following: number of 
metastases (1 vs. > 1), hormone receptor status (ER and/or PR positive vs. ER and PR 
negative), Primary Breast HER2 Status (positive vs. negative), and First-line standard 
systemic therapy (Yes vs. No).  
 
 
 
14.1.2 Randomization 
This study will use a permuted-block randomization with a 1:1 allocation. The treatment 
allocation scheme described by Zelen (1974) will be used because it balances patient 
factors other than institution.   
14.1.3 Total Accrual 
 
Ph II-R: 128 
 
Ph III:    360 patients (including the 128 already accrued in the Ph II-R portion). 
14.1.4  Justification of Design:  
 
This study will be an integrated phase II/III interim analysis trial, proposed by 
Hunsberger et al (2009).  This efficient design allows the patients from the Ph II-R 
portion of the trial to be included in the Ph III portion of the trial, given the Ph II-R 
results provide a go signal for continuation to the Ph III.   
 
14.2 
Study Endpoints 
14.2.1 Primary Endpoints 
Ph II-R: Progression-free survival (failure: progression or death due to any cause) 
Ph III: Overall survival (failure: death due to any cause) 
14.2.2  Secondary Endpoints 
 Existing metastasis control  
 Appearance of new metastases 
 Adverse Events 
 Evaluating impact of ablative therapy on circulating tumor cells (CTCs) in 
oligometastatic breast cancer patients 
 Exploring clinically relevant technological parameters per Section 1.2 
 
14.3 
Primary Objectives Study Design (12-AUG-2021) 
14.3.1 Primary Hypothesis and Endpoints 

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The primary objectives for the study are to evaluate if ablation (through Stereotactic 
Body Radiotherapy (SBRT) or surgical resection of all known metastases) in 
oligometastatic breast cancer patients will (i) show a sufficient signal for improvement in 
progression-free survival (PFS) to warrant (ii) full accrual to a Phase III superiority trial 
with OS as the primary endpoint. 
 
Phase II-R Portion 
The primary endpoint hypothesis is that ablative therapy will provide a signal for 
improved PFS from 10.5 months to 19 months, corresponding to a hazard ratio (HR) of 
0.55 (experimental/control). 
 
Phase III Portion 
The primary endpoint hypothesis is that ablative therapy will improve overall survival 
from 28% to 42.5% at 5-years, corresponding to a HR of 0.67 (experimental/control).  
 
14.3.2 Definitions of Primary Endpoints and How These Will Be Analyzed 
Progression-free survival (PFS) will be estimated by the Kaplan-Meier method (1958), 
with PFS failure defined as: progression of initial/treated metastases (see Section 4), 
appearance of new metastases, or death due to any cause. The distribution of PFS estimates 
between the two arms will be compared using the log rank test (Mantel 1966). PFS time 
will be measured from the date of randomization to the date of first PFS failure or last 
follow-up. Imaging will be every 3 months for 2 years or until progression. After 2 years, 
imaging will be lengthened to every 6 months or until progression. After 5 years without 
progression, imaging per best clinical practice is recommended. 
 
Overall survival (OS) will be estimated by the Kaplan-Meier method (1958). The 
distribution of OS estimates between the two arms will be compared using the log rank test 
(Mantel 1966). OS time will be measured from the date of randomization to the date of 
death or last follow-up.  The Cox proportional hazard regression model will be used to 
analyze the effects of factors, in addition to treatment, that may be associated with OS. 
 
Analysis for Reporting the Initial Treatment Results 
 
Ph II-R Portion   
This major analysis will occur after at least 69 PFS failure events have been observed. It 
will include: 
 tabulation of all cases entered and those excluded from the analyses with the reasons 
for exclusion given 
 distributions of important prognostic baseline variables  
 the frequencies and severity of adverse events by treatment arm 
 compliance rate of treatment delivery 
 observed results with respect to the primary endpoint of PFS 
 
All eligible patients randomized will be included in the comparison and will be grouped by 
assigned treatment in the analysis. The primary hypothesis of treatment benefit will be 
tested using the log-rank statistic with a  1-sided significance level of 0.15. If there is a 

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signal of an improvement in PFS, the results will not be reported, but rather will be 
interpreted as a “Go Signal” for continuation on to the full accrual of the Ph III portion of 
the trial. If there is not a signal of an improvement in PFS, then the results will be 
interpreted as a “No-Go Signal,” accrual will be stopped, and the trial will be reported. 
 
Ph III Portion 
This major analysis will occur after at least 231 OS failure events (deaths) have been 
observed. It will include: 
 tabulation of all cases entered and those excluded from the analyses with the reasons 
for exclusion given 
 distributions of important prognostic baseline variables  
 the frequencies and severity of adverse events by treatment arm 
 compliance rate of treatment delivery 
 observed results with respect to the primary and secondary endpoints 
 
All eligible patients randomized will be included in the comparison and will be grouped by 
assigned treatment in the analysis. The primary hypothesis of treatment benefit will be 
tested using the log-rank statistic with a 1-sided significance level of 0.025. Additional 
analyses of treatment effect will be performed using the Cox proportional hazard model 
with the stratification factors included as fixed covariates, as well as any factors that show 
an imbalance between the arms (e.g. age, gender, race, etc.). Where feasible, treatment 
comparisons with respect to the primary endpoint (OS) will be compared within each ethnic 
and racial category. 
 
14.3.3 Sample Size and Power Calculations:  
 
Justification for selected PFS and OS Estimates  
For Arm I, the PFS and OS estimates are derived from a number of studies employing 
single or poly agent chemotherapy. Studies were selected that defined the number of 
metastatic lesions as to best approximate the population proposed in this trial, as shown in 
Table 2-1.  
 
For Arm II, the effect of metastasis-directed ablative therapy (either surgery or 
radiotherapy) on the progression-free and overall survival of breast cancer patients was 
estimated based on available series, as shown in Table 14-1. As can be seen in these 
series the median PFS is reported to be at least 14 months, and the 5-year overall survival 
for those with limited metastases (Greenberg 1996, Albain 2009) is >40%.  These effect 
sizes are selected based on the available literature. A large effect must be seen in order to 
integrate the finding of this trial into the standard practice for patients with limited 
metastatic breast cancer.  
 
Table 14-1  Selected Retrospective Studies of Ablative Metastasis-Directed Therapy in 
Breast Cancer Patients 
Study 
Number 
of 
patients 
Metastasis 
Directed 
Therapy 
ER/PR 
Positive 
Her 2 
Neu 
Positive 
≤ 2 
Metastases 
Median 
PFS 
Median 
OS 
5 
year 
OS 

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Type 
(Location) 
(months) 
(months) 
Milano et 
al.(2009) 
40 
SBRT 
(all body 
sites) 
63% 
Not 
Stated 
71% 
23 
Not 
Reached 
59% 
Abbott et 
al.(2012) 
86 
Surgery 
(liver) 
69% 
37% 
62% 
solitary 
14.2 
57 
43.6% 
Adam et 
al.(2006) 
85 
Surgery 
(liver) 
82% 
Not 
Stated 
Median=2 
(37% 
solitary) 
20 months 
(no 
extrahepatic 
disease) 
46 
41% 
Friedel et 
al. 
(all 
patients) 
(2002) 
467 
Surgery 
(lung) 
Not 
Stated 
Not 
Stated 
66% 
solitary 
Not Stated 
35 
35% 
Friedel et 
al. 
(1 
metastasis) 
(2002) 
308 
Surgery 
(lung) 
Not 
Stated 
Not 
Stated 
100% 
Not Stated 
42 
44% 
Planchard 
et 
al.(2004) 
125 
Surgery 
(lung) 
45% 
(of those 
available 
Not 
Stated 
Median=1 
Not Stated 
50 
 
45% 
 
Phase II-R Portion 
One-hundred and sixteen evaluable patients will provide 92% power to detect a signal for 
improved median PFS from 10.5 months to 19 months (HR=0.55), with a 1-sided type I 
error of 0.15. To adjust for ineligible/lost patients, a total of 128 patients will be required 
for the Ph II-R portion of the study.  
 
Phase III Portion 
An additional 208 evaluable patients, for a total of 324 evaluable patients, will be 
required to definitively determine if ablative therapy improves 5-year overall survival 
from 28% to 42.5% (HR=0.67), with 85% power and a one-sided type I error of 0.025. 
To adjust for ineligible/lost patients in the Ph III portion, the total accrual to the trial (to 
address the Ph III question) will be 360 patients (including the 128 that were already 
accrued in the Ph II-R portion). 
 
This integrated phase II/III design has 78% power for the overall survival analysis under 
the global alternative hypothesis, while having 0.025 (1-sided) probability of concluding 
a positive effect on overall survival under the global null hypothesis. 
 
Sample Size Consideration for Translational Research 
 
Primary Objective 
It is expected that 80% of the trial population will have signed consent to participate in 

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the tissue/specimen component of the study and will have usable baseline material based 
on collection from RTOG 10-14. Based on the SWOG 0500 data and the differences in 
patient selection in this trial excluding those who progress on standard chemotherapy, we 
expect that among patients with available specimens, 75% will have <5 CTCs per 7.5ml 
of blood at baseline. Based on the proposed PFS event rates in two treatment arms and 
the results from Cristofanilli (2004), the projected monthly event rates for patients with 
<5 CTCs per 7.5ml of blood and ≥5 CTCs per 7.5ml of blood at baseline are 0.0368 and 
0.0943 correspondingly. Under other general assumptions of the main trial (accrual time, 
total follow-up time) and assuming a two-sided probability of type I error of 0.05, the 
sample size of 116 evaluable patients, accrued in the Phase II-R portion, will be sufficient 
to  detect such a difference with a statistical power of 88%. Similarly, based on the 
proposed OS event rates in two treatment arms and the results from Cristofanilli (2004) 
the projected monthly event rates for patients with <5 CTCs per 7.5ml of blood and ≥5 
CTCs per 7.5ml of blood at baseline are 0.0148 and 0.0265 correspondingly. The total 
sample size of 324 evaluable patients will be sufficient to provide a statistical power of at 
least 93% to detect such a difference. The estimation is based on the simple unstratified 
log-rank test and provides the conservative approximation for the purpose of the primary 
analysis for the transactional susbstudy (Akazawa, 1997; Schoenfeld, 1983) 
 
Selected Secondary Objectives 
To evaluate whether <5 CTCs per 7.5ml of blood is a predictive marker for improved 
PFS (OS), a statistical test for interaction between baseline CTCs and treatment will be 
performed. Table 14-2 provides the statistical power to detect a presence of interaction 
under previously described assumptions except for the different effect of treatment in the 
<5 and ≥ 5 CTCs per 7.5ml of blood subgroups. We assume a two-sided test is performed 
at the alpha = 0.05 level.  
 
Table 14-2 Statistical power to evaluate whether <5 CTCs per 7.5ml of blood at baseline 
is a predictive marker for improved PFS and OS  
 
Endpoint 
The effect of treatment (HR)  
Interaction effect size  
(HR <5 CTCs / 
HR ≥5 CTCs) 
Power 
<5 CTCs 
≥5 CTCs 
 
 
 
 
 
PFS 
0.20 
0.96 
0.21 
0.64 
 
0.25 
0.91 
0.28 
0.50 
 
0.30 
0.85 
0.35 
0.37 
 
0.35 
0.79 
0.44 
0.25 
 
0.40 
0.73 
0.55 
0.16 
 
 
 
 
 
OS 
0.50 
0.97 
0.52 
0.53 
 
0.53 
0.92 
0.58 
0.40 
 
0.55 
0.88 
0.62 
0.31 
 
0.57 
0.85 
0.67 
0.24 
 
0.60 
0.80 
0.75 
0.14 

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Non-Compliance with Randomized Treatment 
Treatment other than the treatment arm to which the patient was randomized is not 
permitted per the protocol and will be considered non-compliant. However, as this will not 
prevent treatment crossovers (patients receiving the treatment to which they were not 
randomized) from occurring and the primary endpoint analyses will be done based on the 
arm to which the patient was randomized, the rate of treatment crossovers will be closely 
monitored.   
 
Tables 14-3a and 14-3b show the impact for 5% and 10% crossover from the control arm 
to the experimental arm for the Ph II-R and Ph III portions respectively.  If the crossover 
rate falls between 5% and 10%, NRG Oncology will discuss with NCI the potential of 
amending the trial in order to adjust for this crossover, so as to maintain the original 
study parameters.  If the crossover rate reaches or exceeds 10%, NRG Oncology will 
discuss with NCI the feasibility of continuing the trial. 
 
 
Table 14-3a: Impact of Crossover from Control Arm to Experimental Arm for Ph II-R  
 
 
 
Crossover 
Rate 
Adjusted 
Experimental 
Median PFS 
Rate 
Power 
Given 
Crossover 
(95%  by 
Design) 
Increase in Accrual 
Time to Maintain 
Original Parameters 
 
 
5% 
18.3 
93% 
2.5 mths 
 
 
10% 
17.6 
91% 
6 mths 
 
 
Table 14-3b: Impact of Crossover from Control Arm to Experimental Arm for Ph III  
 
 
 
Crossover 
Rate 
Adjusted 
Experimental 
5-yr OS Rate 
Power 
Given 
Crossover 
(85%) 
Increase in Accrual 
Time to Maintain 
Original Parameters 
 
 
5% 
41.6% 
81% 
6.5 mths 
 
 
10% 
40.8% 
76% 
15 mths 
 
 
14.4 
Study Monitoring of Primary Objectives (9/16/16) 
Interim Analysis to Monitor the Study Progress   
Interim reports with statistical analyses will be prepared twice per year until the initial 
treatment results have been presented/published. In general, the interim reports will contain 
the following information: 
 patient accrual rate with a projected completion date (while the study is still accruing) 
 total patients accrued  
 distributions of important pre-treatment and prognostic baseline variables  

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 the frequencies and severity of adverse events by treatment arm 
 
The interim reports will not contain the results from the treatment comparisons with respect 
to the primary endpoints, PFS/OS, or any secondary endpoints, with the exception of 
reporting of adverse events. 
 
Futility Testing at the Completion of the Ph II-R Accrual 
It is projected that at the time of the Ph II-R accrual completion, 74% of the 84 required Ph 
II-R primary endpoint (PFS) events will have occurred. At this time, a futility analysis will 
be performed.  If the HR (λablation/λstandard of care) is < 1 then accrual will continue during the 
additional time needed for the full Ph II-R analysis; otherwise, accrual will be stopped, 
pending the results of the full Ph II-R analysis. 
 
Significance Testing for Early Termination and/or Reporting of the Primary Endpoint 
(OS) of the Ph III Portion of the Trial 
Assuming that the trial continues on to the full Ph III portion, two interim significance tests 
of treatment difference are planned, using the Haybittle-Peto (Lan 1983; O’Brien 1979) 
rule for efficacy and the Freidlin-Korn (Freidlin 2002) rule C for futility. The timing of the 
interim analyses will be based on OS failure events, as described in Section 14.2.1.  The 
maximum number of OS events required for the study is 231. Under the alternative 
hypothesis that ablative therapy will increase 5-year OS from 28% to 42.5%, the projected 
number of events and the nominal significance levels for rejecting the H0 or the H1 for the 
interim analyses are shown in the table below:   
 
Table 14-4: Nominal Significance Levels for Interim Analyses 
 
Interim 
Analysis 
Number of 
Events 
Efficacy: 
Reject H0 
if 
p (H0) ≤ 
Futility: 
Reject H1 
if 
Z (H1) ≤ 
#1 
69 
≤ 0.001 
-0.92 
#2 
173 
≤ 0.001 
0.05 
 
At each planned interim analysis, the one-sided p-value from the log-rank test assessing 
treatment efficacy with respect to OS will be compared to the nominal significance level 
in Table 14-4 above.  If the computed p-value is less than or equal to the nominal 
significance level boundary for rejecting the H0 (efficacy), then accrual to the trial will be 
stopped (if applicable) and it will be concluded that the OS with ablative therapy (Arm 2) 
is significantly higher than palliative standard of care (Arm 1) and the results will be 
reported.  If the Z-score is less than or equal to the nominal critical value for rejecting the 
H1 (futility), then accrual to the trial will be stopped (if applicable) and the fact that it 
cannot be concluded that the OS with ablative therapy (Arm 2) is significantly higher than 
palliative standard of care (Arm 1) will be reported. Otherwise, if neither boundary is 
crossed, accrual to the trial and/or follow-up (as applicable) will continue to the next 
scheduled analysis.    
 

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In addition to accrual, distributions of pretreatment characteristics, frequency and severity 
of adverse events, and compliance with protocol treatment blinded efficacy results will be 
reported to the NRG Oncology DMC, following the required number of events for the 
planned interim analysis. 
 
14.5 
Accrual Considerations (14-JUN-2018) 
14.5.1 Accrual Rate 
Patient accrual is projected to be 4 cases per month. Assessment of accrual compliance 
will be based on the NCI Ph II-R and Ph III accrual rules and will be monitored by the 
NRG Oncology DMC. It is projected that approximately 11 months of follow-up post the 
Ph II-R accrual will be required to reach the number of events in order to assess the Ph II-
R endpoint of PFS and determine if the trial will continue to the full Ph III accrual. Given 
the number of patients required for the Ph III portion of the trial and the fact that the 
projected monthly accrual is only 4, accrual will not be halted following accrual to the Ph 
II-R portion of the trial. A futility analysis will be performed at the completion of the Ph 
II-R accrual, as described in Section 14.4.  Assuming that futility boundary is not crossed, 
full accrual to the Ph III portion of the trial will be determined following the results of the 
Ph II-R analysis, as described in Section 14.3.2. 
 
14.5.2 Accrual Goal 
 
Ph II-R: 128 
 
Ph III:    360 patients (including the 128 already accrued in the Ph II-R portion). 
 
14.5.3 Study Accrual Duration 
Ph II-R: Based on the projected accrual of 4 cases/month, the Ph II-R portion of the trial 
should complete accrual in ~ 2.5 years.  
 
Ph III: If the trial continues to the full Ph III accrual, that accrual should complete in ~4.5 
years from the end of the Ph II-R accrual. 
 
14.5.4 Estimated Duration for Completion of Primary Endpoint:  
Ph II-R: Approximately 1 year from completion of the Ph II-R accrual.  
 
Ph III: Approximately 6 years from determination of the Ph II-R results. 
 
14.6 
Secondary or Exploratory Elements (including correlative science aims) 
14.6.1 Statistical Analysis Plan for Translational Research 
Primary endpoint/analysis 
The prognostic effect of the initial presence of CTCs at baseline on PFS (OS) will be 
evaluated using the Cox proportional hazards model, controlling for treatment effect and 
stratification factors. The hypothesis tests will be two-sided and will use an alpha level of 
0.05 to determine significance. 
 
Secondary endpoints/analyses 
The interaction between treatment effect and the initial presence of CTCs at baseline on 
PFS (OS) will be evaluated in the Cox model, which will include an indicator for 

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treatment group, an indicator for presence of CTCs (൒5 per 7.5ml of blood), and their 
interaction term. The analysis will be adjusted for the stratification factors. 
 
The effect of change in CTC count from CTC ൒2 per 7.5ml of blood at baseline to 
CTC=0 at follow-up after initial treatment on PFS (OS) will be evaluated using the Cox 
proportional hazards model, controlling for treatment effect and stratification factors. The 
analyses will be conditional on a patient’s event-free survival up to post-treatment 
evaluation. The interaction between treatment effect and change in CTC count will be 
evaluated in the Cox model, which will include an indicator for treatment group, an 
indicator for change of CTCs, and their interaction term. The analysis will be adjusted for 
the stratification factors.  
 
For the analyses related to the circulating tumor DNA, the levels of ctDNA will be 
dichotomized at the median level. If at the time of the analysis the data published 
suggests alternative cutoffs to be more clinically relevant, we would revise our plan prior 
to analysis. The prognostic effect of dichotomized ctDNA on PFS (OS) will be evaluated 
using the Cox proportional hazards model, controlling for treatment effect and 
stratification factors. In addition, the presence of the interaction between treatment effect 
and dichotomized ctDNA will be evaluated (predictive effect). Spearman rank correlation 
coefficient will be used to correlate the levels of CTCs and ctDNA. 
 
All secondary analyses will be performed at 0.05 level. 
 
14.6.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
Treated Metastasis Progression: is the clearance and subsequent recurrence or the 
development of new metastases in the treated area. The rates of treated metastases control 
for the experimental arm will be reported overall and by the following factors: tumor 
receptor status (ER, PR, HER-2), use of chemotherapy, protocol treatment (surgery vs. 
SBRT), and number of metastases (solitary metastasis vs. 2 metastasis). 
 
Appearance of New Metastases 
Failure for this endpoint will be the appearance of any new metastases. The cumulative 
probability of new metastases in the presence of competing failure events will be estimated 
by the cumulative incidence method (Kalbfleish 1980). The cumulative incidence 
distributions between the two arms will be compared using Gray’s test (Gray 1988). The 
Cox proportional hazard regression model will be used to analyze the effects of factors, in 
addition to treatment, that may be associated with the incidence of new metastases, 
including tumor receptor status (ER, PR, HER-2), use of chemotherapy, protocol treatment 
(surgery vs. ablative therapy), and number of metastases (solitary metastasis vs. 2 
metastasis). 

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14.7 
Gender/Ethnicity/Race Distribution  (21-SEP-2022) 
Women of all races and ethnic groups are eligible for this study.  In conformance with the 
national Institutes of Health (NIH) Revitalization Act of 1993 with regard to inclusion of 
women and minorities in clinical research, possible interactions between race/ethnicity and 
treatment have been considered. The projected non-White and Hispanic/Latino accrual 
rates are too low for any meaningful treatment comparisons. 
DOMESTIC 
 
 
 
 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
 Male  
Female 
 Male  
American Indian or Alaska Native 
6 
0 
0 
0 
6 
Asian 
11 
0 
0 
0 
11 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
25 
0 
0 
0 
25 
White 
224 
0 
25 
0 
249 
More than one race 
10 
0 
5 
0 
15 
TOTAL 
276 
0 
30 
0 
306 
FOREIGN 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
 Male  
Female 
 Male  
American Indian or Alaska Native 
0 
0 
0 
0 
0 
Asian 
2 
0 
0 
0 
2 
Native Hawaiian or other Pacific Islander 
1 
0 
0 
0 
1 
Black or African American 
3 
0 
0 
0 
3 
White 
44 
0 
3 
0 
47 
More than one race 
1 
0 
0 
0 
1 
TOTAL 
51 
0 
3 
0 
54 
 
 
 
 
 
 
 
 
 
 

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