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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
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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   | 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   |
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| 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 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 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              | 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                                                         |
nrg oncology nrg-br002
coordinating center nrg oncology

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  
| 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   |
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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 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  
| 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   |
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Wendy Bergantz, RN
NRG Oncology 50 South 16th Street, Suite 2800 Philadelphia, PA 19102 215-574-3230 bergantzw@nrgoncology.org  
| 412-383-2554/Fax: 412-383-1387  bandosh@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
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 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.  
| 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      |
nrg oncology nrg-br002
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
nrg oncology nrg-br002
contact information (21-sep-2022)

| For regulatory requirements:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | For patient enrollments:                                                                                                                                                                                                | For data submission:                                                                                                                                                |
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| 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.)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | 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. | Data collection for this  study will be done  exclusively through  Medidata Rave. Refer to  the data submission  section of the protocol for  further instructions. |
| 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 Help Desk with  any OPEN related questions by  phone or email: 1-888-823-5923, or  ctsucontact@westat.com                                                                                              |                                                                                                                                                                     |
| Contact the CTSU Regulatory Help Desk  at 1-866-651-CTSU (2878) for regulatory  assistance.  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 Triadhelp.acr.org TRIAD Software Installation: https://triadinstall.acr.org/triadclient/
nrg oncology nrg-br002
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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nrg oncology nrg-br002
table of contents

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  
  
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.
nrg oncology nrg-br002
1. objectives 1.1 primary objectives

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
nrg oncology nrg-br002
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)
nrg oncology nrg-br002
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.
nrg oncology nrg-br002
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.
nrg oncology nrg-br002
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.
nrg oncology nrg-br002
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 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 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 firstline 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.  
| limited number of metastatic sites who appear potentially eligible for ablative therapy.  ≤ 2 met  Author/  Study Phase n ER/PR +  (%) HER2+  sites  (%)  ≤ 4 Met  Arms PFS  Sites  (Mo.)  (%)  1. Gem +  Albain 2008 599 32 - 57 91  Paclitaxel  2. Paclitaxel  9.89  8.4  1 Sunitinib+  Bergh 2012 593 72 Pos. 52 -  Docetaxel  2. Docetaxel  8.6  8.3  Tawfik  2013 II 30 77 Neg. 50 - 1. Vinorelbine,  capecitabine 8.6*  1. Trastuz +  Hurvitz  2013 IIR 137 54 Pos 49.3 -  Docetaxel  2. T-DM1  9.2  14.2  1. Docetaxel+  Trastuz  2. Docet + Tras +  BEV  Gianni  III  AVEREL 424 51 Pos 50 -  2013  13.7  16.5  1. Doxorubicin  2. Paclitaxel  3. Doxorubicin +  Paclitaxel  6*  6.3*  8.2*  Sledge  III  E1193 739 45 - 49 -  2003   |                  |
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|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | *Time To Failure |
nrg oncology nrg-br002
2.1 nrg-br002 rationale and trial

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 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.
nrg oncology nrg-br002
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 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.
nrg oncology nrg-br002
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.
nrg oncology nrg-br002
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 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 nonmetastatic (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                                                |            |      |                    |            |
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table 2-3

| 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        |
| * 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; AlixPanabieres 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 colocating 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 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.
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3. patient selection eligibility and

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.
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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. 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 s*ynchronous 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
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3.3 ineligibility criteria (14-jun-2018) patients

3.3.1 Pathologic evidence of active primary disease or local/regional breast tumor recurrence at the time of registration; 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

| PRE-TREATMENT ASSESSMENTS (14-JUN-2018)                                                                      |                                                                                                                      |                    |    |    |
|--------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|--------------------|----|----|
| Assessments                                                                                                  | Prior to Registration                                                                                                | Prior to Treatment |    |    |
| (calendar days)                                                                                              | (calendar days)                                                                                                      |                    |    |    |
| Initial diagnosis of metastatic                                                                              | ≤ 365 days                                                                                                           |                    |    |    |
| breast cancer 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                                                                               | ≤ 14 days                                                                                                            |                    |    |    |
| applicable)  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                                                                                          |                    |    |    |  
Adverse event evaluation X X X X
ASSESSMENTS IN FOLLOW UP: Arm 1 (14-JUN-2018)  
| Assessment                                                                                                                                                | Timepoints   |                |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|----------------|
| 3 mos after                                                                                                                                               |              |                |
| randomization  and every 3  months to 24  months                                                                                                          | Yearly       | At progression |
| thereafter                                                                                                                                                |              |                |
| Physical                                                                                                                                                  | X            | X              |
| examination  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                                                                                                                                             | X            | X              |
| evaluation  Optional studies*:  CTC Collection,  Plasma (ctDNA)                                                                                           | X            | X              |
| Tissue (optional)                                                                                                                                         | X            |                |
| Imaging studies**                                                                                                                                         | X            | X              |  
*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.  
| Assessments                                                                                                                               | Timepoints   |                |    |
|-------------------------------------------------------------------------------------------------------------------------------------------|--------------|----------------|----|
| 25-35 d  post  ablation                                                                                                                   | 3 mos  after |                |    |
| randomization  and every  3 months  to 24  months                                                                                                                                           | Yearly       | At progression |    |
| thereafter                                                                                                                                |              |                |    |
| 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              |    |
|                                                                                                                                           | X            |                |    |
| (If SBRT  delivered  to the  liver)                                                                                                       | X            |                |    |
| (If SBRT  delivered  to the  liver)                                                                                                       |              |                |    |
| ALT, AST  Adverse event evaluation                                                                                                        | X            | X              |    |
| Optional studies:  CTC Collection,  Plasma (ctDNA)                                                                                        | X            | X              |    |
| Tissue (Optional)                                                                                                                         | X            |                |    |
| Imaging studies**                                                                                                                         | X            | X              |    |
| **Note: We strongly encourage the use of PET/CT to follow patients for disease progression in patients                                    |              |                |    |  
**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.
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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. 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.
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arm 2 metastases treated with

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).
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4.2 disease progression and subsequent

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.
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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

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)
Dosing schemes are in general divided between patients with osseous and nonosseous 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                                                                                                                                 | 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                                                                                                             | 30 Gy               | 28 - 30.3 Gy         |
| be limited to peripheral lung  and single liver metastases)  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         |  
Note: Doses outside the range of Per Protocol and Variation Acceptable will be scored as Deviation Unacceptable.  
| 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                                                                | 30 Gy             | 27 - 30.3 Gy         |
| (Preferred for non-spinal  metastases)  5  (Preferred for        | 35 Gy             | 30 - 35.4 Gy         |
| thoracic/cervical spine)                                         |                   |                      |  
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.
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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)

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.
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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.
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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 nonisocentric. 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 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.
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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.
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5.2.3 localization simulation and 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.
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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. Highresolution 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 discretion of the treating oncologist, but every effort should be made to obtain a composite distribution.
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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)
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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. 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.
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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, |                            |                    |  
****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 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)
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5.2.4 target volumes metastasis location

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.
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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
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 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
(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 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                                                                                                                                                       | Lung        | Lung             |                       |             |                                     |                                 |                                 |
| Parameter                                                                                                                                                      | Central     | Periphera l      | Liver                 | Abdominalpelvic             | Mediastinal/ Cervical  Lymph  Nodes | Osseous                         | Spinal                          |
| CT                                                                                                                                                             | Pulmonary/  | Pulmonar         |                       |             |                                     |                                 |                                 |
| window/level                                                                                                                                                   | Mediastinal | y/  Mediastin al | Hepatic               | Soft tissue | Pulmonary/                          | Bone/soft                       | Bone/soft                       |
| Mediastinal                                                                                                                                                    | tissue      | tissue           |                       |             |                                     |                                 |                                 |
| Additional                                                                                                                                                     | PET/CT      | PET/CT           | PET/CT                | PET/CT      | PET/CT                              | PET/CT                          | PET/CT                          |
| Studies                                                                                                                                                        | MRI         | MRI              | MRI                   | MRI         |                                     |                                 |                                 |
| Multiphase                                                                                                                                                     | N/A         | N/A              | N/A                   | Yes         | N/A                                 | N/A                             | N/A                             |
| CT                                                                                                                                                             |             |                  |                       |             |                                     |                                 |                                 |
| Anatomy of  focus for  multimodality  fusion                                                                                                                                                                | Bony        | Bony             | Liver                 | Bony        | Bony                                | Bony                            | Bony                            |
| Anatomy                                                                                                                                                        | Anatomy     | Anatomy          | Anatomy               | Anatomy     | Anatomy                             |                                 |                                 |
| GTV                                                                                                                                                            | Metastasis  | Metastasis       | Metastasis            | Metastasis  | Metastasis                          | Metastasis                      | Metastasis                      |
| definition  CTV                                                                                                                                                | =           | =                |                       |             |                                     |                                 |                                 |
| definition                                                                                                                                                     | GTV/ITV*    | GTV/ITV *        | =  GTV/ITV *          | =GTV/ITV*   | =GTV/ITV                            | = GTV                           | = GTV                           |
| *+                                                                                                                                                             |             |                  |                       |             |                                     |                                 |                                 |
| PTV axial                                                                                                                                                      | = CTV +     | = CTV +          | = CTV +               | = CTV +     | = CTV +                             | = CTV +                         | = PTV in                        |
| expansion                                                                                                                                                      | 5mm**       | 5mm**            | 5mm**                 | 5mm**       | 5mm**                               | 5mm**                           | RTOG  0631**  (see Figure  5-2) |
| PTV  craniocaudal  expansion                                                                                                                                   | = CTV +     | = CTV +          | = CTV +               | = CTV +     | = CTV +                             | = CTV +                         | = PTV in                        |
| 7mm**                                                                                                                                                          | 7mm**       | 7mm**            | 7mm**                 | 7mm**       | 7mm**                               | 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 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.
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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
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.  
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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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
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 nonspinal 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.
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5.2.6 critical structures note all

|                                                      | 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                                                                                                                                                |               |  
| 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                                                                                                                                                                      | | 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 | Description                                                                                                                                                                       |
| Node  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                                                                                                                                                                       |  
| 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 | For spinal/paraspinal tumors. |
| GTV_3500_5  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                                                                                                                                          |            |    |                               |  
| 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    | For non-spinal osseous tumors.                                                     |
| _6  GTV_2000_6 or GTV_3000 _6 or GTV_3500 | For non-spinal osseous tumors.                                                     |
| _6  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,           |  
| 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                                                                      | Description                                                                        |
| (lymph node/adrenal gland) 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                                                                       |  
| Kidney_L   | Left Kidney           |
|------------|-----------------------|
| Kidneys    | Total kidneys         |
| Femurs     | Both Femurs           |
| Duodenum   | Duodenum              |
| Bladder    | Bladder               |
| Liver      | Liver                 |
| BileDuct   | Bile duct             |
| Bowel      | Large and Small Bowel |
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planning sbrt near prior radiotherapy

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).
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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  
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.
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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:
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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.
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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.
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sacral plexus

Include the nerve roots from L5 to S3 on each side from the neuroforamina to the coalescing of the nerves at the obturator internus muscle.
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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.
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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.
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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.
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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.
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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 right middle lobe bronchus, the lingular bronchus, and the right and left lower 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."
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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.
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proximal bronchial tree plus 2

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.
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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).
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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.
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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. 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.
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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.
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bowel (large/small)

The bowel should be contoured from the ileocecal area to include the ascending, transverse, descending, and sigmoid colon as one structure.
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rectum

The entire rectum with contents from the peritoneal reflection of the sigmoid to the anus should be contoured.
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bladder

This organ will be contoured as bladder wall exclusive of urinary contents.
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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.
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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).
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femoral heads

The ball of the head and socket joint should be contoured.
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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).
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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 structure should be constructed as a single contour that is 2 cm larger than the PTV.
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other structures

The constraints tables above contain other structures. These are required if the structure is within 3 cm of the PTV.