nrg oncology nrg-br002
critical organ dose-volume limits

Composite dose distributions of organs at risk are critical to understand toxicity following SBRT. Composite dose plans including all treated metastases and organs at risk must be submitted, as well as individual SBRT plans, to evaluate protocol compliance. To facilitate composite planning, dose to all metastases should be calculated on a single CT scan simultaneously with in-plane resolution of at least 2 x 2 x 3mm. If this is not possible, composite plans should be generated incorporating the dose from each metastasis treated. The composite doses to critical normal tissues will be used to evaluate plan compliance. Tables 5-7, 5-8 and 5-9 list maximum dose limits to a point or volume within several critical organs based on the dose fractionation schema (one, three or five fractions) assigned based on metastatic tumor location. NOTE: If a point (0.03 cc) inside an OAR has > 5 Gy total dose contribution on the composite plan from multiple treatment sites, it is strongly suggested that the same dose scheme be used to treat all sites. NOTE: If different dose schemes are used in a given patient, dose limits to OAR receiving > 1 Gy contribution from treatment of individual metastases will be evaluated according to the table with the lowest number of treatment fractions (e.g., Table 5-7 for a single fraction will be used to assess OAR limits when a patient is treated with 1 and 5 fraction dose schemes). Planning priorities for Organs at Risk:
The spinal cord doses are absolute limits, and treatment delivery that exceeds these limits will constitute an unacceptable deviation. However, some OAR (i.e., the esophagus, trachea, bronchi and heart within the lung) may be situated adjacent to the treated GTV/PTV. As such, there is no specified limit as tumors that are immediately adjacent to that organ will not be able to be treated to the prescription doses without irradiating a small volume of that organ to the prescribed dose. In such a case, the planning must be accomplished so that there is no hot spot within that organ, even if that organ is part of the GTV/PTV, i.e., that no part of any serial OAR receives more than 105% of the prescribed dose (deviation unacceptable). In addition, the volume of the OAR in question needs to be minimized, both in length and in the width (i.e., circumference), with efforts made to reduce the dose to the contralateral wall of the organ. For parallel OAR, exceeding the doses in the tables (5-7, 5-8, 5-9) by more than 110% of the prescribed dose will be considered an unacceptable deviation. For non-spinal cord OAR with known sensitivity to high doses of radiation (including the bowel, esophagus, and stomach) included within a PTV or immediately adjacent to PTVs, a prescription dose at the lower end of acceptable variation should be used. Additionally, every effort should be made to cover the GTV with the prescription dose while ensuring rapid falloff to the organ at risk. Coverage of a section of PTV including or immediately adjacent to the OAR may be as low as 70% of the prescription dose ONLY in this situation. Every effort should be made to cover 100% of the GTV by the prescription dose at the lower end of acceptable variation. Since the tumor and normal tissue may not allow strict avoidance, the larger volume limits will not be scored as unacceptable deviations if exceeded. The total allowable doses over either a 1, 3, or 5 fraction treatment regimen are based on the schema assigned and are listed in Tables 5-7, 5-8 and 5-9. For tumors that are not immediately adjacent to any OAR, centers are encouraged to observe prudent treatment planning principles in avoiding unnecessary radiation exposure to critical normal structures; we expect that the OAR doses will be as low as achievable (ideally, < 6 Gy/fraction). NOTE: No studies of OAR limits for multiple metastases have been reported in the literature. Thus, organ limits from previously developed protocols, as shown in Tables 5-7, 5-8 and 5-9 below, will be utilized.  
Table 5-7 OAR Per Protocol Dose Limits for Single Fraction SBRT  
| Volume                |                  |                      |                                 |
|-----------------------|------------------|----------------------|---------------------------------|
| Serial Organ          | Volume           | Dose  (Gy)           | Avoidance Endpoint  (Reference) |
| Spinal Cord           | <0.35 cc         | 10                   | Myelitis                        |
| (RTOG 0915/Timmerman) |                  |                      |                                 |
|                       | <10%  partial    |                      |                                 |
| spinal cord           | 10               | Myelitis (RTOG 0631) |                                 |
|                       | <1.2 cc          | 8                    | Myelitis                        |
| (Timmerman)           |                  |                      |                                 |
|                       | <0.03 cc         | 14                   | Myelitis                        |
| (0915/Timmerman)      |                  |                      |                                 |
| Ipsilateral Brachial  | <0.03 cc         | 17.5                 | Neuropathy                      |
| Plexus                | (0915/Timmerman) |                      |                                 |
|                       | <3 cc            | 14                   | Neuropathy                      |
| (0915/Timmerman)      |                  |                      |                                 |
| Cauda Equina          | <0.03 cc         | 16                   | Neuritis                        |
| (RTOG 0631/Timmerman) |                  |                      |                                 |
|                       | <5 cc            | 14                   | Neuritis                        |
| (RTOG 0631/Timmerman) |                  |                      |                                 |
| Sacral Plexus         | <0.03 cc         | 18                   | Neuropathy                      |  
| (RTOG 0631)                       |                  |                                 |                                 |
|-----------------------------------|------------------|---------------------------------|---------------------------------|
|                                   | <5 cc            | 14.4                            | Neuropathy                      |
| (RTOG 0631/Timmerman)             |                  |                                 |                                 |
| Trachea and Ipsilateral           | <0.03 cc         | 20.2                            | Stenosis/Fistula                |
| Bronchus*                         | (0915/Timmerman) |                                 |                                 |
|                                   | <4cc             | 17.4                            | Stenosis/Fistula  (Timmerman)   |
| Esophagus*                        | <0.03 cc         | 15.4                            | Stenosis/Fistula  (RTOG 0631)   |
| < 5 cc                            | 11.9             | Stenosis/Fistula                |                                 |
| (RTOG 0915/ RTOG 0631/ Timmerman) |                  |                                 |                                 |
| Heart/Pericardium                 | <0.03 cc         | 22                              | Pericarditis                    |
| (RTOG 0631/Timmerman)             |                  |                                 |                                 |
|                                   | <15 cc           | 16                              | Pericarditis                    |
| (RTOG 0631/Timmerman)             |                  |                                 |                                 |
| Great vessels                     | <0.03 cc         | 37                              | Aneurysm                        |
| (RTOG 0915/RTOG 0631/ Timmerman)  |                  |                                 |                                 |
| <10 cc                            | 31               | Aneurysm                        |                                 |
| (RTOG 0915/RTOG 0631/ Timmerman)  |                  |                                 |                                 |
| Skin                              | <0.03 cc         | 27.5                            | Ulceration                      |
| (Timmerman)                       |                  |                                 |                                 |
| < 10 cc                           | 25.5             | Ulceration                      |                                 |
| (Timmerman)                       |                  |                                 |                                 |
| Stomach                           | <0.03 cc         | 22                              | Ulceration/fistula  (Timmerman) |
| < 5cc                             | 17.4             | Ulceration/fistula  (Timmerman) |                                 |
| Duodenum*                         | <0.03 cc         | 17                              | Ulceration                      |
| (Timmerman)                       |                  |                                 |                                 |
|                                   | <5 cc            | 11.2                            | Ulceration                      |
| (RTOG 0631/Timmerman)             |                  |                                 |                                 |
| <10 cc                            | 9                | Ulceration                      |                                 |
| (Timmerman)                       |                  |                                 |                                 |
| Bowel*                            | <0.03 cc         | 29.2                            | Colitis/Fistula  (Timmerman)    |
| <20 cc                            | 18               | Colitis/Fistula  (Timmerman)    |                                 |
| Rectum*                           | <0.03 cc         | 44.2                            | Proctitis/Fistula  (Timmerman)  |
| <3.5 cc                           | 39               | Proctitis/Fistula  (Timmerman)  |                                 |  
| <20 cc                                                                          | 22          | Proctitis/Fistula  (Timmerman)   |                                    |
|---------------------------------------------------------------------------------|-------------|----------------------------------|------------------------------------|
| Bladder                                                                         | <0.03 cc    | 25                               | Cystitis/Fistula  (Timmerman)      |
| <15 cc                                                                          | 12          | Cystitis/Fistula  (Timmerman)    |                                    |
| Ureter                                                                          | <0.03 cc    | 35                               | Stenosis                           |
| (Timmerman)                                                                     |             |                                  |                                    |
| Penile bulb                                                                     | <3 cc       | 16                               | Impotence                          |
| (Timmerman)                                                                     |             |                                  |                                    |
| Femoral heads                                                                   | <10 cc      | 15                               | Necrosis                           |
| (Timmerman)                                                                     |             |                                  |                                    |
| Bile duct                                                                       | <0.03 cc    | 30                               | Stenosis                           |
| (Timmerman)                                                                     |             |                                  |                                    |
| Renal Hilum/vascular                                                            | <15 cc      | 14                               | Malignant Hypertension (Timmerman) |
| trunk  Rib                                                                      | <0.03 cc    | 33                               | Pain or Fracture  (Timmerman)      |
| <5 cc                                                                           | 28          | Pain or Fracture  (Timmerman)    |                                    |
| Parallel Organ                                                                  | Volume      |                                  |                                    |
| Volume                                                                          | Dose  (Gy)  | Avoidance Endpoint  (Reference)  |                                    |
| Lung (total)                                                                    | <37% lung   | 8                                | Pneumonitis                        |
| volume                                                                          | (Timmerman) |                                  |                                    |
| <1500 cc                                                                        | 7           | Basic lung function  (Timmerman) |                                    |
| <1000 cc                                                                        | 7.6         | Basic lung function  (Timmerman) |                                    |
| Total kidney                                                                    | <200 cc     | 9.5                              | Basic Renal Function  (Timmerman)  |
| Liver                                                                           | <700 cc     | 11                               | Liver function  (Timmerman)        |
| NOTE: Doses to serial OAR up to and including105% of the dose prescribed to the |             |                                  |                                    |  
<1500 cc 7 Basic lung function  
(Timmerman)  
<1000 cc 7.6 Basic lung function  
(Timmerman)  
Total kidney <200 cc 9.5 Basic Renal Function  
(Timmerman)  
Liver <700 cc 11 Liver function  
(Timmerman)  
NOTE: Doses to serial OAR up to and including105% of the dose prescribed to the  
PTV will be scored as Variation Acceptable. Doses to parallel OAR up to 110% of the values listed in the table will be score as Variation Acceptable. Doses above these values will be scored as Deviation Unacceptable.  
Table 5-8 **OAR Dose Limits for 3 fraction SBRT**  
Serial Organ Volume Volume Dose  
(Gy)  
Avoidance Endpoint  
(Reference)  
| Table 5-8 OAR Dose Limits for 3 fraction SBRT   |             |             |                    |
|-------------------------------------------------|-------------|-------------|--------------------|
| Serial Organ                                    | Volume      | Volume Dose | Avoidance Endpoint |
| (Gy)                                            | (Reference) |             |                    |
| Spinal Cord                                     | <0.03 cc    | 22.5        | Myelitis           |
| (Timmerman)                                     |             |             |                    |  
| <1.2 cc                      | 13        | Myelitis                         |                                  |
|------------------------------|-----------|----------------------------------|----------------------------------|
| (Timmerman)                  |           |                                  |                                  |
| Ipsilateral Brachial Plexus  | < 0.03 cc | 26                               | Brachial Plexopathy  (Timmerman) |
| <3 cc                        | 22        | Brachial Plexopathy  (Timmerman) |                                  |
| Cauda Equina                 | <0.03 cc  | 25.5                             | Neuritis                         |
| (Timmerman)                  |           |                                  |                                  |
| <5 cc                        | 21.9      | Neuritis                         |                                  |
| (AAPM TG-101)                |           |                                  |                                  |
| Sacral Plexus                | <0.03 cc  | 24                               | Neuropathy                       |
| (AAPM TG-101)                |           |                                  |                                  |
| <5 cc                        | 22.5      | Neuropathy                       |                                  |
| (AAPM TG-101)                |           |                                  |                                  |
| Trachea and Ipsilateral      | <0.03 cc  | 30                               | Stenosis/Fistula                 |
| Bronchus*                    | (Z4099)   |                                  |                                  |
| <5cc                         | 25.8      | Stenosis/Fistula  (Timmerman)    |                                  |
| Esophagus*                   | <0.03 cc  | 27                               | Stenosis/Fistula                 |
| (Timmerman 2006  /RTOG 0618) |           |                                  |                                  |
| <5cc                         | 17.7      | Stenosis/Fistula  (Z4099)        |                                  |
| Heart/Pericardium            | <0.03cc   | 30                               | Pericarditis  (Z4099)            |
| <15 cc                       | 24        | Pericarditis  (Z4099)            |                                  |
| Great vessels                | <0.03cc   | 45                               | Aneurysm  (Z4099)                |
| <10 cc                       | 39        | Aneurysm  (Z4099)                |                                  |
| Skin                         | <0.03cc   | 33                               | Ulceration  (Z4099)              |
| <10cc                        | 31        | Ulceration                       |                                  |
| (Timmerman)                  |           |                                  |                                  |
| Stomach                      | <0.03cc   | 30                               | Ulceration/Fistula  (Timmerman)  |
| <10cc                        | 22.5      | Ulceration/Fistula  (Timmerman)  |                                  |
| Duodenum*                    | <0.03cc   | 24                               | Ulceration                       |
| (Timmerman 2006)             |           |                                  |                                  |
| <10cc                        | 15        | Ulceration                       |                                  |
| (Timmerman 2006)             |           |                                  |                                  |  
| Bowel*                     | <0.03 cc    | 34.5                            | Ulceration                          |
|----------------------------|-------------|---------------------------------|-------------------------------------|
| (Timmerman)                |             |                                 |                                     |
| <20cc                      | 24          | Colitis/Fistula (Z4099)         |                                     |
| Rectum*                    | <0.03 cc    | 49.5                            | Ulceration                          |
| (Timmerman)                |             |                                 |                                     |
| <3.5 cc                    | 45          | Proctitis/Fistula  (Timmerman)  |                                     |
| < 20 cc                    | 27.5        | Proctitis/Fistula  (Timmerman)  |                                     |
| Bladder                    | 0.03cc      | 33                              | Cystitis/Fistula  (Timmerman)       |
| <15 cc                     | 16.8        | Cystitis/Fistula  (AAPM TG-101) |                                     |
| Ureter                     | <0.03 cc    | 40                              | Stenosis                            |
| (Timmerman)                |             |                                 |                                     |
| Penile bulb                | < 3cc       | 25                              | Impotence                           |
| (Timmerman)                |             |                                 |                                     |
| Femoral heads              | <10 cc      | 24                              | Necrosis                            |
| (Timmerman)                |             |                                 |                                     |
| Bile duct                  | < 0.03 cc   | 36                              | Stenosis                            |
| (Timmerman)                |             |                                 |                                     |
| Renal hilum/vascular trunk | <15 cc      | 19.5                            | Malignant Hypertension  (Timmerman) |
| Rib                        | < 0.03 cc   | 50                              | Pain or Fracture  (Timmerman        |
| <5 cc                      | 40          | Pain or Fracture  (Timmerman    |                                     |
| Parallel Organ             | Volume      | Volume Dose                     | Avoidance Endpoint                  |
| (Gy)                       | (Reference) |                                 |                                     |
| Lung (total)               | <15% lung   | 20                              | Pneumonitis/Lung                    |
| volume                     | Function    |                                 |                                     |
| (RTOG 0618)                |             |                                 |                                     |
| < 37% lung                 | 11          | Pneumonitis                     |                                     |
| volume                     | (Timmerman) |                                 |                                     |
| <1500 cc                   | 10.5        | Basic Lung Function  (Z4099)    |                                     |
| <1000 cc                   | 11.4        | Pneumonitis  (Z4099)            |                                     |
| Total Kidney               | <200cc      | 15                              | Basic Renal Function  (Timmerman)   |
| Liver                      | <700 cc     | 17.1                            | Basic Liver function  (Timmerman    |  
*NOTE: Every effort should be made to avoid circumferential irradiation. NOTE: Doses to serial OAR up to and including 105% of the dose prescribed to the PTV will be scored as Variation Acceptable. Doses to parallel OAR up to 110% of the values listed in the table will be score as Variation Acceptable. Doses above these values will be scored as Deviation Unacceptable  
|                             | Table 5-9 OAR Dose Limits for 5 fraction SBRT Serial Organ Volume   | Volume Dose                      | Avoidance Endpoint               |
|-----------------------------|---------------------------------------------------------------------|----------------------------------|----------------------------------|
| (Gy)                        | (Reference)                                                         |                                  |                                  |
| Spinal Cord                 | <0.03 cc                                                            | 28                               | Myelitis                         |
| (Timmerman)                 |                                                                     |                                  |                                  |
|                             | <0.35 cc                                                            | 22                               | Myelitis                         |
| (Timmerman)                 |                                                                     |                                  |                                  |
|                             | <1.2 cc                                                             | 15.6                             | Myelitis                         |
| (Timmerman)                 |                                                                     |                                  |                                  |
| Ipsilateral Brachial Plexus | < 0.03 cc                                                           | 32                               | Brachial Plexopathy  (RTOG 0813) |
| <3 cc                       | 30                                                                  | Brachial Plexopathy  (RTOG 0813) |                                  |
| Cauda Equina                | <0.03 cc                                                            | 32                               | Neuritis                         |
| (AAPM TG-101)               |                                                                     |                                  |                                  |
|                             | <5 cc                                                               | 30                               | Neuritis                         |
| (AAPM TG-101)               |                                                                     |                                  |                                  |
| Sacral Plexus               | <0.03 cc                                                            | 32                               | Neuropathy                       |
| (AAPM TG-101)               |                                                                     |                                  |                                  |
|                             | <5 cc                                                               | 30                               | Neuropathy                       |
| (AAPM TG-101)               |                                                                     |                                  |                                  |
| Trachea and Ipsilateral     | <0.03cc                                                             | 40                               | Stenosis/Fistula                 |
| Bronchus*                   | (Timmerman)                                                         |                                  |                                  |
|                             | <5cc                                                                | 32                               | Stenosis/Fistula  (RTOG 0813)    |
| Esophagus*                  | <0.03cc                                                             | 35                               | Stenosis/Fistula  (Timmerman)    |
|                             | <5 cc                                                               | 27.5                             | Stenosis/Fistula  (RTOG 0813)    |
| Heart/Pericardium           | <0.03 cc                                                            | 38                               | Pericarditis                     |
| (Timmerman)                 |                                                                     |                                  |                                  |
|                             | <15 cc                                                              | 32                               | Pericarditis                     |
| (RTOG 0813)                 |                                                                     |                                  |                                  |
| Great vessels               | <0.03 cc                                                            | 53                               | Aneurysm                         |
| (Timmerman)                 |                                                                     |                                  |                                  |
|                             | <10 cc                                                              | 47                               | Aneurysm                         |
| (RTOG 0813)                 |                                                                     |                                  |                                  |  
| Skin                       | < 0.03cc    | 38.5                             | Ulceration                          |
|----------------------------|-------------|----------------------------------|-------------------------------------|
| (Timmerman)                |             |                                  |                                     |
|                            | < 10cc      | 36.5                             | Ulceration                          |
| (Timmerman)                |             |                                  |                                     |
| Stomach                    | < 0.5cc     | 35                               | Ulceration/Fistula  (Timmerman)     |
|                            | < 5cc       | 26.5                             | Ulceration/Fistula  (Timmerman)     |
| Duodenum*                  | < 0.5 cc    | 30                               | Ulceration                          |
| (RTOG 1112)                |             |                                  |                                     |
| < 5 cc                     | 18.3        | Ulceration                       |                                     |
| (Timmerman 2006)           |             |                                  |                                     |
| Bowel*                     | < 0.03 cc   | 40                               | Ulceration                          |
| (Timmerman)                |             |                                  |                                     |
|                            | <20 cc      | 28.5                             | Colitis/Fistula  (Timmerman)        |
| Rectum*                    | <0.03 cc    | 55                               | Ulceration                          |
| (Timmerman)                |             |                                  |                                     |
|                            | <3.5 cc     | 50                               | Proctitis/Fistula  (Timmerman)      |
|                            | <20 cc      | 32.5                             | Proctitis/Fistula  (Timmerman       |
| Bladder                    | < 0.03      | 38                               | Cystitis/Fistula  (Timmerman)       |
|                            | <15 cc      | 20                               | Cystitis/Fistula  (Timmerman)       |
| Ureter                     | < 0.03 cc   | 45                               | Stenosis                            |
| (Timmerman)                |             |                                  |                                     |
| Penile Bulb                | <3 cc       | 30                               | Impotence                           |
| (Timmerman)                |             |                                  |                                     |
| Femoral head               | <10 cc      | 30                               | Necrosis                            |
| (Timmerman)                |             |                                  |                                     |
| Bile Duct                  | <0.03 cc    | 41                               | Stenosis                            |
| (Timmerman)                |             |                                  |                                     |
| Renal hilum/Vascular Trunk | <15 cc      | 23                               | Malignant Hypertension  (Timmerman) |
| Rib                        | <0.03 cc    | 57                               | Pain or Fracture  (Timmerman)       |
| <5 cc                      | 45          | Pain or Fracture  (Timmerman)    |                                     |
| Parallel Organ             | Volume      | Volume Dose                      | Avoidance Endpoint                  |
| (Gy)                       | (Reference) |                                  |                                     |
| Lung (total)               | < 37% lung  | 13.5                             | Pneumonitis                         |
| volume                     | (Timmerman) |                                  |                                     |
| < 1500 cc                  | 12.5        | Basic Lung Function  (RTOG 0813) |                                     |  
< 1000 cc 13.5 Pneumonitis  
(RTOG 0813)  
Total Kidney < 200cc 18 Basic Renal Function  
(Timmerman)  
Liver <700 cc 21 Basic Liver Function  
(Timmerman)  
***NOTE**: Every effort should be made to avoid circumferential irradiation.  
NOTE: Doses to serial OAR up to and including 105% of the dose prescribed to the PTV will be scored as Variation Acceptable. Doses to parallel OAR up to 110% of the values listed in the table will be score as Variation Acceptable. Doses above these values will be scored as Deviation Unacceptable.
nrg oncology nrg-br002
rib/chest wall dose constraints

Recent reports have highlighted that the rib and chest wall in proximity to the treated lesion may represent an organ at risk for complication. Tumor location, particularly when located peripherally, will enhance the potential risk for chest wall toxicity. While target coverage should not be compromised to limit dose to the rib/chest wall, every effort should be made to minimize dose to this OAR.
nrg oncology nrg-br002
5.2.7 documentation requirements treatment interruptions

In general, treatment interruptions should be avoided by preventative medical measures and supportive therapies. Treatment breaks, including indications, must be clearly documented on the treatment record. Sites will record dose-volume values for all required structures on this datasheet. The datasheet must be completed and submitted with the digital RT data via TRIAD for review.  
5.2.8 Compliance Criteria Treatment Duration Treatment Duration will be defined per metastasis Per Protocol:
Single Fraction Treatment: SBRT should be completed within 6 weeks of randomization/registration 3 fraction treatment: All 3 fractions of SBRT should be completed within 3 weeks of first SBRT dose and within 6 weeks of randomization/registration 5 fraction treatment: All five fractions of SBRT should be completed within 3 weeks of first SBRT dose and within 6 weeks of randomization/registration Acceptable Variation: Treatment completing > 3 but < 4 weeks Unacceptable Deviation: Treatment completed > 4 weeks
nrg oncology nrg-br002
ptv dosimetry compliance

Tables 5-1 and 5-2 describe acceptable variations in the protocol prescription dose (dose covering 95% of the PTV). These criteria should be evaluated for each metastasis independently (i.e., while suppressing dose from all other metastases), particularly for metastases treated on separate days. This may not be possible for metastases treated on the same day using a single plan (e.g., VMAT). Prescription doses outside of the variation acceptable range will be scored as Deviation Unacceptable. Scoring of PTV coverage will be: acceptable if ≥ 95%, variation acceptable if 70-95%, deviation unacceptable if < 70%.
nrg oncology nrg-br002
organ at risk dosimetry compliance

Critical structure doses should be based on composite dose distribution when more than one met is treated (as stated in Section 5.2.6). Respect spinal cord, cauda equina, sacral plexus and brachial plexus dose constraints. Any dose to spinal cord, cauda equina, sacral plexus above that listed in Tables 5-7, 5-8, and 5-9 will be considered an unacceptable deviation. For all other OAR, when OAR dose criteria provided in Section 5.2.6 cannot be accomplished by following planning priorities outlined in Section 5.2.5, doses to serial OAR of more than 105% of the dose prescribed to the PTV will be scored as Deviations Unacceptable. Doses to parallel OAR exceeding 110% of the dose prescribed to the PTV will be scored as unacceptable deviations. Doses in the range between the numbers in the tables and unacceptable deviation will be considered acceptable variations.
nrg oncology nrg-br002
5.2.9 radiation therapy adverse events

All Radiation Therapy AEs will be scored according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4. Adverse events related to SBRT for the treatment of metastases are dependent on the location of the metastases treated, as well as from exposure of surrounding normal tissues. For all treated metastases, fatigue is likely to occur and should be transient, lasting < 8 weeks. Other adverse events are likely to be related to the specific metastatic location receiving SBRT.
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lung (central and peripheral) mediastinal/cervical

Although cardiac and pericardial injury is uncommon in the conventionally fractionated course of RT, with large doses per fraction of SBRT a number of possible side-effects can be seen.
nrg oncology nrg-br002
gastrointestinal/esophageal injury

The radiation effects on the esophagus can be acute: esophagitis (i.e., dysphagia, causing pain on swallowing, typically relatively soon after RT course is completed, and typically resolves on its own within days to a week or longer), or chronic, typically manifesting with dysphagia due to stenosis, or esophageal ulceration, with perforation in the extreme cases. Central Airway/Bronchial Injury This bronchial injury with subsequent focal collapse of lung may impair overall pulmonary status. It also makes further assessment of tumor response more difficult as the collapsed lung approximates the treated tumor. Because atelectatic lung and tumor have similar imaging characteristics, radiology reports will often describe the overall process as progressive disease, while the actual tumor may be stable or shrinking. The consequences of bronchial toxicity, e.g., cough, dyspnea, hypoxia, impairment of pulmonary function test parameters, pleural effusion or pleuritic pain (associated with collapse), should all be graded according to the Common Terminology Criteria for Adverse Events (CTCAE), v. 4; MedDRA, v. 12.0.
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lung injury

Radiation pneumonitis is a subacute (weeks to months from treatment) inflammation of the end bronchioles and alveoli. Radiation fibrosis is a late manifestation of radiation injury to the irradiated lung. Given the small amount of lung that is typically included in the SBRT portals, lung toxicity has not been as dose-limiting as in conventionally fractionated, large-field RT, but it is nevertheless seen, can be symptomatic, and may be confused with other causes of respiratory deterioration, including infections, and tumor recurrence. Given that larger volumes of lung may be irradiated in this protocol compared to SBRT for primary tumors, it is very important that a Radiation Oncologist participate in the care of the patient, as the clinical picture may be very similar to acute bacterial pneumonia, with fatigue, fever, shortness of breath, nonproductive cough, and a pulmonary infiltrate on chest x-ray. The infiltrate on chest x-ray should include the area treated to high dose, but may extend outside of these regions. The infiltrates may be characteristically "geometric" corresponding to the radiation portal, but may also be ill defined. Patients reporting symptoms as above will be promptly evaluated and treated. Mild radiation pneumonitis may be treated with nonsteroidal anti-inflammatory agents or steroid inhalers. More significant pneumonitis will be treated with systemic steroids, bronchodilators, and pulmonary hygiene. Supra- and concurrent infections should be treated with antibiotics. Consideration of prophylaxis of opportunistic infections should be considered in immunocompromised patients.
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liver/abdominal-pelvic metastases

Very likely (80-90%): Patients may experience fatigue (which generally goes away after the radiation therapy is completed), skin irritation, redness, itchiness, discomfort, temporary changes in blood work (decrease in blood counts, increase in liver enzymes), without symptoms. Less likely (30%): Patients may experience nausea, vomiting (during therapy) - more common if stomach or gastrointestinal tract irradiated, gastric, esophagus, small bowel or large bowel irritation/ulceration, bleeding, fistula, obstruction or changes in motility following therapy (may require medications or surgery) (<10% permanent changes), chest wall pain, and rib fracture (< 10%). Less likely, but serious (<20%): Patients may experience radiation-induced liver disease (RILD) (<5%). Classic RILD is a clinical diagnosis of anicteric ascites, hepatomegaly and elevation of alkaline phosphatase relative to other transaminases that may occur 2 weeks to 3 months following radiation to the Liver; non-classic RILD includes elevation of liver enzymes and/or any decline in liver function within 12 weeks from start of therapy (~20%). RILD can lead to liver failure that could lead to death. There is an increased risk of liver toxicity in patients with large tumors and in patients with preexisting liver disease. In addition, permanent thrombocytopenia (<1%) may lead to bleeding, and kidney injury (<1%) may lead to changes on imaging and more rarely the need for medication.
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spinal metastases radiation myelitis

Given the proximity and position of the spinal cord in relation to the radiosurgery target, every effort should be made to minimize the radiation dose to the spinal cord. Radiation myelitis is a subacute or chronic clinical syndrome after radiation. The symptoms may include paresthesia, sensory changes, and motor weakness including paralysis. There is no active treatment for radiation myelitis; therefore, it is important to prevent any injury to the spinal cord. Corticosteroids are used when clinical symptoms develop.
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radiation esophagitis

Patients with thoracic spine treatment will likely develop esophageal mucositis within the first 2 weeks. These symptoms subside with time; however, adequate symptomatic treatment including hydration is advised. There are no long-term adverse events reported with spine radiosurgery. However, it is prudent to minimize the radiation spillage in the normal esophagus. The consequences of esophageal toxicity, e.g., swallowing difficulty, dysphagia, cough, dehydration, and fistula, should be documented.
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radiation laryngitis or pharyngitis

Patients with cervical spine treatment will likely develop laryngopharyngeal mucositis within the first 2 weeks. These symptoms subside with time; however, adequate symptomatic treatment including hydration is advised. No long-term laryngopharyngeal toxicity has been reported with spine radiosurgery. However, it is prudent to minimize the radiation spillage in the normal larynx and pharynx. The consequences of toxicity, e.g., swallowing difficulty, dysphagia, cough, dysphonia dehydration, and fistula, should be documented.
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tracheal injury

Although no cases of tracheal injury have been reported with spine radiosurgery, it is prudent to minimize the radiation spillage in the normal trachea. The consequences of tracheobronchial toxicity, e.g., cough, dyspnea, hypoxia, impairment of pulmonary function test parameters, pleural effusion or pleuritic pain (associated with collapse), should be documented. Radiation Pneumonitis There have been no reported cases of symptomatic radiation pneumonitis with spine radiosurgery. However, it is prudent to minimize the radiation spillage in the lung tissue. It is strongly recommended to use radiation beams directed from the posterior to avoid passage of radiation through the lungs. Patients with symptoms of pneumonitis will be promptly evaluated and treated. Mild radiation pneumonitis may be treated with nonsteroidal anti-inflammatory agents or steroid inhalers. More significant pneumonitis will be treated with systemic steroids, bronchodilators, and pulmonary hygiene. Supra- and concurrent infections should be treated with antibiotics. Consideration of prophylaxis of opportunistic infections should be considered in immunocompromised patients. Compression Fracture of Treated Vertebra Radiation doses in excess of 19 Gy for a single fraction are associated with higher rates of vertebral body compression (Saghal 2013). In this protocol, doses per fraction this high are not used, so that the estimated rate of vertebral body compression fracture following spinal metastases treatment should be approximately 10%.
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other adverse events

Short-term or long-term injury to the kidney or upper airway has not been reported. If other severe adverse events occur, details should be documented.
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osseous

Erythema, desquamation and alopecia are common side effects from radiation therapy for osseous metastases; other effects are determinate on location of metastasis, and may include pain, edema and neuralgia.
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5.3 surgery (arm 2) for

5.3.1 Technique, timing, other Breast cancer metastases must be proven pathologically prior to surgical resection. All surgical resections will be approached with intent of an R0 resection (rendering the patient with no evidence of measureable disease and pathologic negative margin). If surgical resection of a given metastasis is incomplete with gross or microscopic residual (i.e. positive margins) the treating team is encouraged to deliver additional therapy including completion resection, conventionally fractionated radiation therapy, or systemic therapy as appropriate. Given the lack of data in the post-operative setting SBRT should NOT be delivered to the incomplete resection site. If a metastases undergoes a biopsy only at the time of surgery, SBRT would be allowed per protocol. Approach to surgery will be based upon the treating surgeon. An open, laparoscopic, or thorascopic approach is acceptable. Surgery that may result in major morbidity and/or mortality is discouraged, i.e. major pancreatic resection or pneumonectomy. If at time of surgery, an R1 resection is the best outcome, then if possible the surgery should be aborted. Standard pre-operative and post-operative evaluation is required.  
5.3.2 Surgery Adverse Events Surgical morbidity and mortality must be recorded and reported. Any adverse event from surgery within 30-days must be reported. Morbidities include, but are not limited to hemorrhage, re-operation, infection, bile leak, persistent air leak, anastomotic leak/dehiscence, and poor wound healing.
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5.4 general concomitant medication and

5.4.1 Permitted Systemic Therapy Experimental therapeutics need to have a wash out period and must be discontinued 30 days prior to SBRT therapy being administered or surgery performed. Participants may receive continuing standard of care systemic therapy management for their disease as follows: All hormonal therapy and bone supportive therapy may be continued during SBRT and around surgical procedures with interruption only as needed for routine surgical care [ie: NPO]. Tamoxifen is recommended to be held for 1 week before and after any major surgical procedure due to the increased thrombosis risk. The ongoing use of biologic therapy with trastuzumab, pertuzumab, and lapatinib is permitted concurrent with SBRT and around surgical procedures with interruptions only as needed for routine surgical care. Administration of ado-trastuzumab emantasine, palbociclib and everolimus should follow the chemotherapy guideline listed in Section 5.4.3.
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5.4.2 permitted supportive therapy

All supportive therapy for optimal medical care will be given during the study period at the discretion of the attending physician(s) within the parameters of the protocol and documented on each site's source documents as concomitant medication.  
Anticonvulsants if indicated for reasons other than brain metastasis. For patients with liver and/or abdominal-pelvic metastases (as well as any other patient at the discretion of the treating oncologist) anti-emetics may be given prior to each fraction of SBRT to prevent nausea.  
For patients with lung (central or peripheral) and/or mediastinal/cervical lymph node metastases to be treated with radiation, corticosteroid premedication can be used at the discretion of the treating oncologist (in which case, its use needs to be reported.  
Anticoagulants as indicated for thrombotic disease. These must be held or bridged for patients undergoing surgical ablation according to routine surgical practice.  
Antidiarrheal as indicated by symptomatic diarrhea. Routine post-operative bowel regimens. Analgesic premedication to avoid general discomfort during simulation and treatment is recommended when appropriate.  
Routine anesthetics and post-surgical pain management. Hematopoietic growth factors should not be used during SBRT protocol therapy.  
G-CSF or pegylated G-CSF may have been given as part of prior chemotherapy as indicated by standard parameters, but ANC must be recovered to entrance values for the protocol without ongoing support.  
Herbal products are at the treating physicians' discretion and should be captured on the concomitant medication forms.  
Nutritional supplementation may be administered per standard indications and should be captured on the concomitant medication forms.  
Highly active antiretroviral therapy (HAART) is permitted for HIV affected individuals.  
Aspirin, non-steroidal anti-inflammatory, or other medications known to affect bleeding risks should be held for one week prior to any surgical study procedures, according to routine surgical guidelines.  
Routine use of blood products in the peri-operative time frame is permitted according to standard procedures.
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5.4.3 prohibited systemic therapy

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

Not applicable. Standard of care therapy will be given as appropriate for the patient's disease subtype at the discretion of the treating physician.
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7.2 adverse events and serious

7.2.1 The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for all AE reporting, CTEP-AERS, and case report forms. CTCAE version 5.0 will be utilized for CTEP-AERS reporting beginning April 1, 2018; all study case report forms will continue to use CTCAE version 4.0. All appropriate treatment areas should have access to a copy of CTCAE versions 4.0 and 5.0, which can be downloaded from the CTEP web site (https://ctep.cancer.gov/ protocolDevelopment/electronic_applications/ctc.htm).
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7.2.2 definition of an adverse

Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or definite). (International Conference on Harmonisation [ICH], E2A, E6). For multi-modality trials, adverse event reporting encompasses all aspects of protocol treatment including radiation therapy, surgery, device, and drug.  
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the pregnancy of a study participant must be reported via CTEP-AERS in an expedited manner.
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7.3 expedited reporting of adverse

All serious adverse events that meet expedited reporting criteria defined in the reporting table below will be reported via the CTEP Adverse Event Reporting System, CTEPAERS, accessed via the CTEP web site, https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 Submitting a report via CTEP-AERS serves as notification to the NRG Biostatistical/Data Management Center and satisfies NRG requirements for expedited adverse event reporting. CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only pathway. In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to NRG Oncology by phone, 1-215-574-3191. An electronic report must be submitted immediately upon re-establishment of the Internet connection.
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7.3.1 expedited reporting methods

CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification is electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 24-hour notification must be followed by a complete report within 5 days.  
Supporting source documentation is requested by NRG as needed to complete adverse event review. Supporting source documentation should include the protocol number, patient ID number, and CTEP-AERS ticket number on each page. For instructions to submit supporting documentation, contact NRG Oncology at 1-215574-3191.  
A serious adverse event that meets expedited reporting criteria outlined in the AE
Reporting Tables but is assessed by the CTEP-AERS as "an action not recommended" must still be reported to fulfill NRG safety reporting obligations. Sites must bypass the "NOT recommended" assessment; the CTEP-AERS allows submission of all reports regardless of the results of the assessment.
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7.3.2 expedited reporting requirements for

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

FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators **MUST** immediately report to the sponsor **ANY** Serious Adverse Events, whether or not they are considered  
  
  
  
  
 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria **MUST** be immediately reported to the NCI via CTEP-AERS within the timeframes detailed in the table below.  
| Grade 4                                                                                                                                                                                                                                                                        | Grade 5    |            |            |          |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|------------|------------|----------|
| Attribution                                                                                                                                                                                                                                                                    | Unexpected | Expected   | Unexpected | Expected |
| Unrelated  Unlikely                                                                                                                                                                                                                                                            | 10 day     | 10 day     |            |          |
| Possible  Probable                                                                                                                                                                                                                                                             | 24-h/5 day | 24-h/5 day | 24-h/5 day |          |
| Definite Expedited AE reporting timelines are defined as: o "24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of learning of  the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. |            |            |            |          |  
Expedited AE reporting timelines are defined as:
o "24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report.  
o "10 Calendar Days" - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE.
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an attribution of **possible, probable, or definite** require reporting as follows:
Expedited 24-hour notification followed by complete report within 5 calendar days for:
Unexpected Grade 4 and all Grade 5 AEs
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additional protocol-specific instructions or exceptions

7.3.3 Reporting to the Site IRB/REB
Investigators will report serious adverse events to the local Institutional Review Board (IRB) or Research Ethics Board (REB) responsible for oversight of the patient according to institutional policy.  
7.3.4 Secondary Malignancy A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm. CTEP requires all secondary malignancies that occur during or subsequent to treatment with an agent under an NCI IND/IDE be reported via CTEP-AERS . In addition, secondary malignancies following radiation therapy must be reported via CTEP-AERS. Three options are available to describe the event: Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia
[AML])
Myelodysplastic syndrome (MDS) Treatment-related secondary malignancy Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol.
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second malignancy

A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis from the initial malignancy). Second malignancies require ONLY routine reporting via CDUS unless otherwise specified.
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7.4 routine reporting requirements for

All Adverse Events **must** be reported in routine study data submissions. AEs reported expeditiously through CTEP-AERS must also be reported in routine study data submissions.
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8. registration and study entry

Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all individuals contributing to NCI-sponsored trials to register and renew their registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual registration using CTEP's web-based Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr. RCR utilizes five person registration types:
IVR - MD, DO, or international equivalent; NPIVR - advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., PhD);
AP - clinical site staff (e.g., RN or CRA) with data entry access to CTSU
applications such as the Roster Update Management System [RUMS], OPEN, Rave, acting as a primary site contact, or with consenting privileges; Associate (A) - other clinical site staff involved in the conduct of NCIsponsored trials; and Associate Basic (AB) - individuals (e.g., pharmaceutical company employees)
with limited access to NCI-supported systems.  
| RCR requires the following registration documents:  Documentation Required   | IVR   | NPIVR   | AP   | A   | AB   |
|------------------------------------------------------------------------------|-------|---------|------|-----|------|
| FDA Form 1572                                                                | ✔     | ✔       |      |     |      |
| Financial Disclosure Form                                                    | ✔     | ✔       | ✔    |     |      |
| NCI Biosketch (education, training, employment, license,                     | ✔     | ✔       | ✔    |     |      |
| and certification)  GCP training                                             | ✔     | ✔       | ✔    |     |      |
| Agent Shipment Form (if applicable)                                          | ✔     |         |      |     |      |
| CV (optional)                                                                | ✔     | ✔       | ✔    |     |      |  
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their practice sites on the FDA Form 1572 in RCR to allow the following:
Added to a site roster; Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN;
Act as the site-protocol Principal Investigator (PI) on the IRB approval.  
In addition, all investigators acting as the site-protocol PI (investigator listed on the IRB approval), consenting/treating/drug shipment investigator in OPEN must be rostered at the enrolling site with a participating organization. Additional information is located on the CTEP website at https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR **Help Desk** by email at RCRHelpDesk@nih.gov.  
8.1 Cancer Trials Support Unit Registration Procedures (21-SEP-2022)
This study is supported by the NCI Cancer Trials Support Unit (CTSU).
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irb approval

For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB review will continue to be accepted for studies that are not reviewed by the CIRB, or if the study was previously open at the site under the local IRB. International sites should continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office following country-specific regulations. Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) for Local Context to the CIRB using IRBManager to indicate their intent to open the study locally. The NCI CIRB's approval of the SSW is automatically communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB approvals across their Signatory Network. Site preferences can be set at the network or protocol level. Questions about establishing site preferences can be addressed to the CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). In addition, the site-protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB approval) must meet the following criteria in order for the processing of the IRB/REB approval record to be completed:
Holds an active CTEP status; Active status at the site(s) on the IRB/REB approval on at least one participating organization's roster; If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB
Signatory Institution(s) record; Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR profile; Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the RCR profile; and Holds the appropriate CTEP registration type for the protocol.
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additional requirements

Additional site requirements to obtain an approved site registration status include:
An active Federal Wide Assurance (FWA) number; An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating Organization (PO);
An active roster affiliation with the NCI CIRB roster under at least one CIRB
Signatory Institution (US sites only); and Compliance with all protocol-specific requirements (PSRs).  
IRB/REB Approved Informed Consent (International sites only: English and native language versions*) *Note: International and Canadian Institutions must provide certification/verification of IRB/REB IEC consent translation to NRG Oncology (described below).
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downloading site registration documents

Download the site registration forms from the protocol-specific page located on the CTSU members' website. Permission to view and download this protocol and its supporting documents is restricted to institutions and its associated investigators and staff on a participating roster. Log in to the CTSU members' website (https://www.ctsu.org) using your CTEP-IAM username and password; Click on *Protocols* in the upper left of the screen o Enter the protocol number in the search field at the top of the protocol tree; or o Click on the By Lead Organization folder to expand, then select NRG, and protocol number *NRG-BR002*.
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protocol-specific requirements for protocol nrg-br002

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

Submit required forms and documents to the CTSU Regulatory Officeusing the Regulatory Submission Portal on the CTSU website. To access the Regulatory Submission Porta,l log in to the CTSU members' website, go to the Regulatory section and select Regulatory Submission. Institutions with patients waiting that are unable to use the Regulatory Submission Portal should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651- CTSU (2878), or CTSURegHelp@coccg.org in order to receive further instruction and support.
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checking site's registration status

Site registration status may be verified on the CTSU members' website.  
Click on *Regulatory* at the top of the screen; Click on *Site Registration*; and Enter the site's 5-character CTEP Institution Code and click on Go.  
o Additional filters are available to sort by Protocol, Registration Status, Protocol Status, and/or IRB Type.  
Note: The status shown only reflects institutional compliance with site registration requirements as outlined within the protocol. It does not reflect compliance with protocol requirements for individuals participating on the protocol or the enrolling investigator's status with NCI or their affiliated networks.
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8.2 rt-specific pre-registration requirements (21-sep-2022)

For detailed information on the specific technology requirement required for this study, please refer to the table below and utilize the web link provided for detailed instructions. The check marks under the treatment modality columns indicate whether that specific credentialing requirement is required for this study. Specific credentialing components may require you to work with various QA centers; however, the IROC Houston QA Center will notify your institution and NRG Oncology when all credentialing requirements have been met and the institution is RT credentialed to enter patients onto this study. This document must be uploaded by the site to the CTSU Regulatory Submission Portal for RSS to be updated. IROC will automatically send the approval to the Regulatory Support System (RSS) to comply with the protocol-specific requirement, unless otherwise noted at the bottom of the IROC Credentialing Approval notification.  
| RT                          |                                                                                                                 |
|-----------------------------|-----------------------------------------------------------------------------------------------------------------|
| Credentialing  Requirements | Web Link for Procedures and Instructions: http//irochouston.mdanderson.org  Treatment  Modality Key Information |  
| SBRT                     | IMRT                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | The IROC Houston electronic facility questionnaire (FQ) should be  completed or updated with the most recent information about your  institution. To access this FQ go to  http://irochouston.mdanderson.org/questionnaires/   |                                                                                                                                                                                                                                                                                                                                                                                                              |
|--------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Facility                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                              |
| Questionnaire            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                               | To determine whether your institution needs to complete any further  credentialing requirements, please complete the "Credentialing  Status Inquiry Form" found under credentialing on the IROC  Houston QA Center website (http://irochouston.mdanderson.org)                                                                                                                                               |
| Credentialing  Status    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                              |
| Inquiry Form             | An IROC Houston anthropomorphic phantom must be successfully  completed (if the institution has not previously met this  credentialing requirement)if the institution plans to deliver SBRT  with IMRT. Credentialing for IMRT allows the institution to also  use 3D-CRT SBRT, but credentialing for 3D-CRT SBRT does not  allow the institution to use IMRT. Flattening-filter-free (FFF)  photon beam delivery, Tomotherapy and Cyberknife treatment  delivery modalities must be credentialed individually. Instructions  for requesting and irradiating the phantom are available on the  IROC Houston website under credentialing  (http//irochouston.mdanderson.org), |                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                              |
| Phantom  Irradiation     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                               | Submit a series of daily treatment images along with a spreadsheet  of IGRT data from 2 anonymized cancer patients treated with SBRT  to the appropriate site (1. lung/liver and 2. spine). The anonymized  data must come from a patient treated with an identical motion  management strategy (i.e., gating, breath-hold, abdominal  compression, motion tracking), as used with the phantom  irradiation. |
|                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                              |
| IGRT                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                              |
| Verification  Study      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                              |
| Credentialing Issued to: | IROC Houston QA Center will notify the institution and NRG  Headquarters that all desired credentialing requirements have been  met.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                              |
| Institution              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                              |  
NRG does not have a single, specific credentialing method for stereotactic body radiotherapy (SBRT). SBRT credentialing consists of a combination of other existing credentialing steps. SBRT requires the use of image-guided radiotherapy (IGRT) with its associated credentialing requirement. **Therefore, IGRT credentialing is also required** for this protocol . Since SBRT can be used for various sites in the body, treatment technique credentialing must include some method of addressing motion when lesions in or near the thorax are treated. Credentialing of individual treatment modalities is required for this
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protocol.

However, institutions need to credential for only the most complex modality they intend to use. The increasing complexity level for treatment modalities is threedimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy
(IMRT), and volumetric arc therapy (VMAT). Treating with flattening-filter-free (FFF) photon beam, Tomotherapy or the CyberKnife requires separate credentialing. The selected treatment technique(s) have to be coupled with the motion management technique that will be used by the institution. Taken together, the various required credentialing steps can be considerable. However, the number of steps can be reduced through a process of "grandfathering" institutions with appropriate previous credentialing. Please contact the Imaging and Radiation Oncology Core (IROC) Houston for more information. NOTE: If the institution wishes to utilize a single isocenter setup to treat multiple lesions, which is discouraged (see Section 5.2.2) for lesions more than 10cm away, the SBRT credentialing must be performed with two lesions (lung and spine) in the lung SBRT phantom provided by IROC Houston. Furthermore the phantom must be irradiated in the same manner (i.e., utilizing a single isocenter to treat both the lung and spine metastases concurrently) and with appropriate motion management.  
8.2.1 Digital Radiation Therapy Data Submission Using Transfer of Images, and Data Transfer of Images and Data (TRIAD) is the American College of Radiology's (ACR) image exchange application. TRIAD provides sites participating in clinical trials a secure method to transmit images. TRIAD anonymizes and validates the images as they are transferred.
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triad access requirements a valid

Registration type of: Associate (A), Associate Plus (AP), Non-Physician Investigator (NPIVR), or Investigator (IVR) registration type. Refer to the CTEP Registration Procedures section for instructions on how to request a CTEP-IAM account and complete registration in RCR.  
TRIAD Site User role on an NCTN or ETCTN roster.  
All individuals on the Imaging and Radiation Oncology Core provider roster have access to TRIAD and may submit images for credentialing purposes, or for enrollments to which the provider is linked in OPEN.
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triad installations

To submit images, the individual holding the TRIAD Site User role will need to install the TRIAD application on their workstation. TRIAD installation documentation is available at https://triadinstall.acr.org/triadclient/. This process can be done in parallel to obtaining your CTEP-IAM account and For questions, contact TRIAD Technical Support staff via email TRIADSupport@acr.org or 1-703-390-9858.
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8.3 patient enrollment (12-aug-2021)

Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria have been met, and the study site is listed as 'approved' in the CTSU RSS. Patients must have signed and dated all applicable consents and authorization forms.
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8.3.1 oncology patient enrollment network

The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs registration/randomization systems or the Theradex Interactive Web Response System (IWRS) for retrieval of patient registration/randomization assignment. OPEN will populate the patient enrollment data in NCI's clinical data management system, Medidata Rave. Requirements for OPEN access:
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a valid ctep-iam account

To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN corresponding roster, or participating organization roster with the role of Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration type; If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold the OPEN Registrar task on the DTL for the site; and Have an approved site registration for the protocol prior to patient enrollment.  
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site's IRB
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. Prior to accessing OPEN, site staff should verify the following:
Patient has met all eligibility criteria within the protocol stated timeframes; and All patients have signed an appropriate consent form and HIPAA
authorization form (if applicable).  
Note: The OPEN system will provide the site with a printable confirmation of registration and treatment information. You may print this confirmation for your records. Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members' website. Further instructional information is in the OPEN section of the CTSU website at https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
9. DRUG INFORMATION
Not applicable to this study
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10. pathology/biospecimen (11-jul-2018)

See detailed specimen collection/processing/shipping instructions on the NRG-BR002 protocol page of the CTSU website. Instructions are also provided with all kits. Patients must be offered the opportunity to consent to optional specimen collections. If the patient consents to participate, the site is required to submit the patient's specimens as specified in the protocol. Sites are not permitted to delete the specimen component from the protocol or from the sample consent. Funding for the following studies has been generously provided from two sources: Ralph R. Weichselbaum, MD Daniel K. Ludwig Distinguished Service Professor & Chair Director, Ludwig Center for Metastasis Research Ludwig Center for Metastasis Research 924 E. 57th Street Chicago IL 60637-5419 And Peter Kuhn 3430 S. Vermont Suite \#106 Los Angeles, CA 90089 Optional Study \#1: Whole Blood Collection for Translational Research:
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circulating tumor cells (ctcs)

See the NRG-BR002 protocol page of the CTSU website for further details on collection logistics. Consenting patients will have 7.5 ml of whole blood drawn by phlebotomy or through a central venous access device into a "CellSave" tube (included with NRG-BR002 kits) to collect and quantify CTCs (see below for collection timepoints). Because the analytes for this study degrade rapidly, only specimens drawn Mon-Wed, and shipped overnight no later than Thursday to MD Anderson Cancer Center will be accepted (see address below). NOTE: Samples for CTC analysis must be drawn on a Monday, Tuesday or a Wednesday in "CellSave" blood collection tubes containing EDTA and a stabilizer (Immunicon Corporation), must be clearly labeled with patient study number, type of sample, and date collected, and it must be shipped to UT MD Anderson Cancer Center overnight no later than Thursday so samples can be received and processed by Friday of the same week. Specimens are being collected to determine whether a blood test could predict who will benefit from ablation of metastatic disease, and to better understand the biology that drives metastases.  
(see Section 2.2 for further details).  
Required Forms: ST form. CTC tubes, kits and special CTC shipping supplies will be supplied with the Banking Kits (optional Study\#3) from the NRG Oncology Biospecimen BankSan Francisco (NRGBB-SF). Please allow 5-10 days for delivery as kits are shipped to sites by Fed Ex ground Shipping days: Monday-Wednesday (U.S. sites); Monday-Tuesday (Canada and Non-North American).  
Shipping costs: Sites will receive BR002 specific Fed Ex account and reference number in the kits provided with instructions from the NRBB-SF. Please contact wwoodward@mdanderson.org; 713-563-2363 with any questions regarding this process
Submit Cell Save tube materials by FedEx priority overnight for CTC analysis (**labeled** NRG-BR002) directly to:
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dr. carol hall

UT MD Anderson Cancer Center Dept of Surgical Oncology 1515 Holcombe Blvd CRB T4.3932 Houston , TX 77030 713-563-8898/FAX 713-794-4830 Notify both Dr. Carol Hall (cshall@mdanderson.org) and Dr. Wendy Woodward (wwoodward@mdanderson.org) by e-mail on the day of submission with the following information: (1) that a sample is being submitted with the NRG case number; (2) the overnight shipping carrier and tracking number, and (3) e-mail and phone number of contact person. For questions regarding Kits, contact: NRG Oncology Biospecimen Bank- San Francisco  
| 415-476-7864/FAX 415-476-5271  NRGBB@ucsf.edu Specimen Type Collection Time                                                      | Collection                                                                                                             |                     |         |
|----------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|---------------------|---------|
| Points                                                                                                                           | Information and  Requirements                                                                                          | Shipping            |         |
| Whole Blood for  CTCs: 7.5ml whole  blood in a  "CellSave"   tube  (Drawn Mon-Wed  only)                                         | (1)Pre-treatment                                                                                                       | Single tube at room | Ambient |
| temperature                                                                                                                      | temperature via  overnight carrier no  later than Thursday  Ship to UT MD  Anderson; contact  the lab before  shipping |                     |         |
| (2) Post treatment:  Arm 2:4 wks. post  SBRT OR Arm  1:3 months post  registration  (3) At disease  progression (if  applicable) |                                                                                                                        |                     |         |  
| Optional Study #2: Plasma Collection for Translational Research: ctDNA analysis  See the NRG-BR002 protocol page of the CTSU website for further details on  collection logistics. A special plasma tube manufactured by Streck (tiger lid, 7-10 mL) will be drawn at the  same time points as the CTC collection into a "Streck" tube (provided by NRG  Oncology Biospecimen Bank-SF with special NRG-BR002 kits) for eventual ctDNA  cell-free analysis, high-content single cell liquid biopsy (HD-SCA), and mathematical  correlation to clinical data.  This tube must be filled in after the "CellSave" tube in Optional Study #1. If no other  tube is collected at the time points of CTC collection, then the first 2 mL of blood must  be drawn into another tube (not "Streck") and discarded. Then, proceed to draw blood  into the "Streck" tube.  The "Streck" tube should be shipped to The Kuhn-Hicks Laboratory at USC (see  address below).   Required Forms: ST form.   Streck tubes will be supplied with the special Streck shipping kit from the  NRG Oncology Biospecimen Bank-SF. Each kit is for one timepoint. Please  allow 5-10 days for delivery as kits are shipped to sites by Fed Ex ground   Shipping days: Monday-Wednesday (U.S. sites); Monday-Tuesday (Canada  and Non-North American).  Shipping costs: Fed ex account information will be provided with each special  Streck kit instruction packet from the NRGBB-SF. Contact the Kuhn lab at  (kuhnlab@usc.edu) for Streck kit collection or shipping information.   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Submit "Streck" tube ctDNA materials (**labeled NRG-BR002**) directly to:
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peter kuhn

c/o USC Michelson Hall Kuhn-Hicks Laboratory 1002 Childs Way, MCB 310 Los Angeles, CA 90089-3502 Notify Dr. Wendy Woodward (wwoodward@mdanderson.org) and Dr. Peter Kuhn's lab (kuhnlab@usc.edu) by e-mail on the day of submission with the following information: (1) that a sample is being submitted with the NRG case number; (2) date/time of draw; (3) the shipping carrier and tracking number, and (4) e-mail and phone number of contact person.  
For questions call Xiomara Villasenor at 213-740-9614 (xvillase@usc.edu) or the Kuhn Lab (213-740-9945, kuhnlab@usc.edu); Or Dr. Woodward (713-563-2363) to coordinate labels addressed to USC.  
NOTE: Guidelines for the shipment of ctDNA/"Streck" tube: The Biospecimen bank kit will include instructions with Fed Ex account information and a special shipping container for shipping the Streck tube. This includes a white, two part "cassette" to hold the blood tube, an air pillow bag, a Paksense probe for temperature monitoring, and a blue shipping cardboard box.  
Open the blue shipping box to extract a silver air pillow bag that contains the white cassette. Open the white cassette and extract a 2-layer plastic tube holder.  
Place the filled ambient Streck tube inside the smaller plastic holder, place the lid. Insert smaller plastic holder into the larger plastic holder, place the lid.  
Prepare the Paksense temperature monitoring probe: Peel off the plastic cover over the back of the glue dot that is found in the back of the Paksense probe. Place the Paksense, glue dot down in the insert inside one side of the white cassette. Activate the Paksense probe by pressing the Start button for 2 seconds, then release. A green light should now be blinking.  
Place the 2-layer plastic tube holder containing the specimen inside the white cassette and snap the two halves together.  
Place the white cassette inside the air pillow bag. It will be a tight fit. Place the air pillow bag into the blue cardboard shipping box with the ST Form.  
No need to use the sticky seal; just fold it over.  
Verify the FedEx label is addressed to the Kuhn lab at USC and Biohazard label is visible. Contact your local Fed-Ex representative for pick-up.  
Send shipment notification email to kuhnlab@usc.edu.  
Specimen Type Collection Time Points Collection Information and Requirements  
PLASMA (ctDNA): 7-10 mL  
(1)Pre-treatment Collect blood in  
special Streck tube.  
Blood in special Streck tube sent in  
| Collection  Information and  Requirements   | Shipping  Blood in special   |
|---------------------------------------------|------------------------------|
| special Streck tube.                        | Streck tube sent in          |  
| of anticoagulated  whole blood in tiger  lid "Streck" tube   | (2) Post treatment:  Arm 2:4 wks. post  SBRT OR Arm  1:3 months post  registration   | Do not process.   | ambient  temperature  controlled special  shipper via  overnight carrier  for 10:30am  delivery  (Ship to Kuhn Lab  at USC by  overnight couriercontact Kuhn lab  before shipping)   |
|--------------------------------------------------------------|--------------------------------------------------------------------------------------|-------------------|---|
| (3) At disease  progression (if  applicable)                 |                                                                                      |                   |   |  
Optional Study \#3: Specimen Collection for Tissue Banking See the NRG-BR002 protocol page of the CTSU website for further details on collection logistics. Patients must be offered the opportunity to consent to optional specimen collection. If the patient consents to participate, the site is required to submit the patient's previously collected diagnostic specimens as specified in the protocol. Sites are not permitted to delete the specimen component from the protocol or from the sample consent. Specimens are being collected for future translational research projects and being submitted to the NRG Oncology Biospecimen Bank- San Francisco for banking  
Required Forms: ST form, pathology reports. All forms must be completely filled out with an NRG Label including the Study \#, Case \#, NRG Institution number or Institution NCI ID, and patient initials. The pathology accession number must remain visible on the pathology report but all other PHI information must be redacted/removed.  
Kits are available for Frozen biospecimens from the NRG Oncology Biospecimen Bank-San Francisco Detailed Processing and shipping instructions are provided on the protocol webpage Shipping days for Frozen Specimens: Monday-Wednesday (U.S. sites);
Monday-Tuesday (Canada and Non-North American). We are unable to accept shipments on Saturdays or holidays.  
Shipping costs: One Prepaid Fed Ex label is provided for batch shipping the Frozen biospecimens for banking specimens for each case in the kits.  
Ship all Biospecimens for Optional Study \#3 for banking to:
NRG Oncology Biospecimen Bank- San Francisco UCSF Dept of Radiation Oncology 2340 Sutter Street- Room S341 San Francisco, CA 94115 415-476-7864  
| NRGBB@ucsf.edu  415-476-7864/FAX 415-476-5271  Specimen Type Collection Time   | Collection                                                           |                                                                                                |                                         |
|--------------------------------------------------------------------------------|----------------------------------------------------------------------|------------------------------------------------------------------------------------------------|-----------------------------------------|
| Points                                                                         | Information and  Requirements                                        | Shipping                                                                                       |                                         |
| Representative  H&E stained slides  of the primary  tumor                      | Pre-treatment:  obtained as part of  routine diagnostic  procedures. | H&E stained slide.  Can be a duplicate  cut slide, does not  have to be the  diagnostic slide. | Slide shipped  ambient to the  NRGBB-SF |
| A paraffin-                                                                    | Pre-treatment:                                                       | Paraffin-embedded                                                                              | Block or punch                          |  
| embedded tissue  block or one 3mm  punch from the  block of the  primary tumor  taken before  initiation of  treatment   | obtained as part of  routine diagnostic  procedures.                     | tissue block or  punch. Must match  the H&E being  submitted.                                                        | block shipped  ambient to the  NRGBB-SF. Ship  with a cold pack  during warmer  weather to avoid  wax from melting                 |
|--------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------|
| Representative  H&E stained slides  of the metastatic  tumor                                                             | Pre-treatment:  obtained as part of  routine diagnostic  procedures.     | H&E stained slide.  Can be a duplicate  cut slide, does not  have to be the  diagnostic slide                        | Slide shipped  ambient to the  NRGBB-SF                                                                                            |
| A paraffinembedded tissue  block or one 3mm  punch from the  block of the  metastatic tumor  taken before  initiation of  treatment when  available                                                                                                                          | Pre-treatment:  obtained as part of  routine diagnostic  procedures.     | Paraffin-embedded  tissue block or  punch from block  must match the  same tissue block as  the H&E being  submitted | Block or punch  block shipped  ambient to the  NRGBB-SF. Ship  with a cold pack  during warmer  weather to avoid  wax from melting |
| Representative  H&E stained slides  of the metastatic  tumor                                                             | At Progression:  obtained as part of  routine diagnostic  procedures.    | H&E stained slide.  Can be a duplicate  cut slide, does not  have to be the  diagnostic slide                        | Slide shipped  ambient to the  NRGBB-SF                                                                                            |
| A paraffinembedded tissue  block or one 3mm  punch of the  metastatic tumor  taken at the time of  progression if  available                                                                                                                          | At progression: if  obtained as part of  routine diagnostic  procedures. | Paraffin-embedded  tissue block or  punch from block                                                                 | Block or punch  block shipped  ambient to the  NRGBB-SF. Ship  with a cold pack  during warmer  weather to avoid  wax from melting |
| SERUM: 5-10 mL  of whole blood in 1  red-top tube and  centrifuge                                                        | Pre-treatment                                                            | Frozen serum  samples containing  a minimum of 0.5  mL per aliquot in 1  mL cryovials (five)                         | Serum sent frozen  on dry ice via  overnight carrier  to the NRGBB-SF                                                              |  
| PLASMA (for  banking): 5-10 mL  of anticoagulated  whole blood in  EDTA tube #1  (purple/ lavender  top) and centrifuge   | Pre-treatment                                                                                                                                                        | Frozen plasma  samples containing  a minimum of 0.5  mL per aliquot in 1  mL cryovials (five)   | Plasma sent frozen  on dry ice via  overnight carrier  to the NRGBB-SF       |
|---------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|
| Whole blood for  DNA: 5-10 mL of  anticoagulated  whole blood in  EDTA tube #3  (purple/lavender  top) and mix            | Pre-treatment;  note: If site missed  this collection time  point they may  collect whole blood  for DNA at a later  time point but must  note this on the ST  Form. | Frozen whole blood  samples containing  1.5-2 ml per aliquot  in 2ml cryovials (3)              | Whole blood sent  frozen on dry ice  via overnight  carrier to the  NRGBB-SF |
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11. special studies (non-tissue) none

A full 3D dosimetry plan PRE-TREATMENT REVIEW for the first patient registered for each disease site category treated at the institution on this protocol must be submitted to TRIAD for review PRIOR TO DELIVERY of radiation treatment. If the institution has previously treated patients with the same disease site on NRG-BR001 then a pretreatment review is not necessary. If the initial case at the institution treats a single metastasis with SBRT, the institution will also be required to submit their first multiple metastases case to be treated with SBRT for pre-treatment review PRIOR TO
DELIVERING ANY PROTOCOL TREATMENT. The plan(s) will be reviewed centrally by the PIs, and feedback regarding protocol compliance will be forwarded to the participating institution. Based on the results of any of the reviews described above, a request for additional pre-treatment reviews might be necessary. In general, the treatment plan for subsequent patients enrolled at a site will not be required to be centrally reviewed prior to treatment, but will be reviewed for protocol compliance at a later date.  
Allow 3 business days for the results of the pre-treatment review process. The pretreatment review process will not start until all required data is submitted to TRIAD.
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rt quality assurance review

The Radiation Oncology Co-Chairs will perform an RT Quality Assurance Review after complete data for the first 20 cases enrolled has been received at NRG Oncology. The Radiation Oncology Co-Chairs will perform ongoing reviews after complete data for each cohort of 20 enrolled cases has been received at NRG Oncology. These reviews will be on going.
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12.2 surgical quality assurance reviews

The Surgical Oncology Co-Chair, Nora Jaskowiak, M.D., will perform a Quality Assurance Review on a continuous basis for patients randomized to Arm 2 that receive surgery as part of their ablative treatment. After NRG Oncology Statistics and Data Management Center (SDMC) has received complete data for each Arm 2 case enrolled that receives surgery, Dr. Jaskowiak will perform a review. Documents reviewed will be the Pre-operative H&P, the Operative Report, the Pathology Report from the surgical procedure, and the Discharge Summary from the surgical admission. In addition, all surgical SAEs will be reported in an expedited manner and reviewed regularly by the Surgical PI. Dr. Jaskowiak will utilize the expertise of other surgical oncologists, thoracic surgeons, and Orthopedic oncologic surgeons (at the University of Chicago and Duke Medical Center) if sub-specialty quality issues arise. If concern arises about surgical quality upon review, Dr. Jaskowiak will directly communicate with both the PI and surgeon at the institution, with possible intervention, if deemed appropriate.
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13. data and records 13.1

Medidata Rave is a clinical data management system being used for data collection for this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role assignments. Requirements to access Rave via iMedidata:
A valid CTEP-IAM account; and Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA,
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements:
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus (AP) registration type; Rave Investigator role must be registered as an Non-Physician Investigator
(NPIVR) or Investigator (IVR); and Rave Read Only role must have at a minimum an Associates (A) registration type.  
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and documentation required. Upon initial site registration approval for the study in Regulatory Support System (RSS), all persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, site staff must log in to the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, and click on the "accept" link in the upper right-corner of the iMedidata page. Site staff will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (eLearnings) and can be accessed by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning is required and has not yet been taken, the link to the eLearning will appear under the study name in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has been recorded, access to the study in Rave will be granted, and a Rave EDC link will display under the study name. Site staff that have not previously activated their iMedidata/Rave account at the time of initial site registration approval for the study in RSS will receive a separate invitation from iMedidata to activate their account. Account activation instructions are located on the CTSU website in the Data Management section under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU members' website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888823-5923 or by e-mail at ctsucontact@westat.com.
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13.2 summary of data submission

Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during the trial using Medidata Rave®. Additionally, certain adverse events must be reported in an expedited manner for more timely monitoring of patient safety and care. See Sections 7.2 and 7.3. for information about expedited and routine reporting. For reporting of second primary cancers or other report forms available in Rave: Indicate form for reporting in Rave, timeframes, add if loading of the pathology report is required. Summary of Data Submission: Refer to the protocol-specific website. See Section 8.4.2 for TRIAD account access and installation instructions.
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13.3 data quality portal (21-sep-2022)

The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered queries and form delinquencies, monitor data quality and timeliness, generate reports, and review metrics. The DQP is located on the CTSU members' website under Data Management. The Rave Home section displays a table providing summary counts of Total Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP Reports modules are available to access details and reports of unanswered queries, delinquent forms, forms with current status and timeliness reports. Review the DQP modules on a regular basis to manage specified queries and delinquent forms. The DQP is accessible by site staff that are rostered to a site and have access to the CTSU website. Staff that have Rave study access can access the Rave study data using a direct link on the DQP. To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, DQP Queries, DQP Delinquent Forms. DQP Form Status, and DQP Reports modules 13. 4 Global Reporting/Monitoring This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31, and October 31.
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14. statistical considerations 14.1 study

Patients will be stratified before randomization with respect to the following: number of metastases (1 vs. > 1), hormone receptor status (ER and/or PR positive vs. ER and PR negative), Primary Breast HER2 Status (positive vs. negative), and First-line standard systemic therapy (Yes vs. No).
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14.1.2 randomization

This study will use a permuted-block randomization with a 1:1 allocation. The treatment allocation scheme described by Zelen (1974) will be used because it balances patient factors other than institution.  
14.1.3 Total Accrual Ph II-R: 128 Ph III: 360 patients (including the 128 already accrued in the Ph II-R portion). 14.1.4 Justification of Design: This study will be an integrated phase II/III interim analysis trial, proposed by Hunsberger et al (2009). This efficient design allows the patients from the Ph II-R portion of the trial to be included in the Ph III portion of the trial, given the Ph II-R results provide a go signal for continuation to the Ph III.
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14.2 study endpoints 14.2.1 primary

Ph II-R: Progression-free survival (failure: progression or death due to any cause) Ph III: Overall survival (failure: death due to any cause)
14.2.2 Secondary Endpoints Existing metastasis control Appearance of new metastases Adverse Events Evaluating impact of ablative therapy on circulating tumor cells (CTCs) in oligometastatic breast cancer patients Exploring clinically relevant technological parameters per Section 1.2
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14.3 primary objectives study design

The primary objectives for the study are to evaluate if ablation (through Stereotactic Body Radiotherapy (SBRT) or surgical resection of all known metastases) in oligometastatic breast cancer patients will (i) show a sufficient signal for improvement in progression-free survival (PFS) to warrant (ii) full accrual to a Phase III superiority trial with OS as the primary endpoint.
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phase ii-r portion

The primary endpoint hypothesis is that ablative therapy will provide a signal for improved PFS from 10.5 months to 19 months, corresponding to a hazard ratio (HR) of 0.55 (experimental/control).
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phase iii portion

The primary endpoint hypothesis is that ablative therapy will improve overall survival from 28% to 42.5% at 5-years, corresponding to a HR of 0.67 (experimental/control).  
14.3.2 Definitions of Primary Endpoints and How These Will Be Analyzed Progression-free survival (PFS) will be estimated by the Kaplan-Meier method (1958), with PFS failure defined as: progression of initial/treated metastases (see Section 4), appearance of new metastases, or death due to any cause. The distribution of PFS estimates between the two arms will be compared using the log rank test (Mantel 1966). PFS time will be measured from the date of randomization to the date of first PFS failure or last follow-up. Imaging will be every 3 months for 2 years or until progression. After 2 years, imaging will be lengthened to every 6 months or until progression. After 5 years without progression, imaging per best clinical practice is recommended. Overall survival (OS) will be estimated by the Kaplan-Meier method (1958). The distribution of OS estimates between the two arms will be compared using the log rank test (Mantel 1966). OS time will be measured from the date of randomization to the date of death or last follow-up. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with OS.
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analysis for reporting the initial

This major analysis will occur after at least 69 PFS failure events have been observed. It will include:
tabulation of all cases entered and those excluded from the analyses with the reasons for exclusion given distributions of important prognostic baseline variables the frequencies and severity of adverse events by treatment arm compliance rate of treatment delivery observed results with respect to the primary endpoint of PFS
All eligible patients randomized will be included in the comparison and will be grouped by assigned treatment in the analysis. The primary hypothesis of treatment benefit will be tested using the log-rank statistic with a 1-sided significance level of 0.15. If there is a signal of an improvement in PFS, the results will not be reported, but rather will be interpreted as a "Go Signal" for continuation on to the full accrual of the Ph III portion of the trial. If there is not a signal of an improvement in PFS, then the results will be interpreted as a "No-Go Signal," accrual will be stopped, and the trial will be reported.
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ph iii portion

This major analysis will occur after at least 231 OS failure events (deaths) have been observed. It will include:
tabulation of all cases entered and those excluded from the analyses with the reasons for exclusion given distributions of important prognostic baseline variables the frequencies and severity of adverse events by treatment arm compliance rate of treatment delivery observed results with respect to the primary and secondary endpoints All eligible patients randomized will be included in the comparison and will be grouped by assigned treatment in the analysis. The primary hypothesis of treatment benefit will be tested using the log-rank statistic with a 1-sided significance level of 0.025. Additional analyses of treatment effect will be performed using the Cox proportional hazard model with the stratification factors included as fixed covariates, as well as any factors that show an imbalance between the arms (e.g. age, gender, race, etc.). Where feasible, treatment comparisons with respect to the primary endpoint (OS) will be compared within each ethnic and racial category.
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14.3.3 sample size and power

Justification for selected PFS and OS Estimates For Arm I, the PFS and OS estimates are derived from a number of studies employing single or poly agent chemotherapy. Studies were selected that defined the number of metastatic lesions as to best approximate the population proposed in this trial, as shown in Table 2-1.  
For Arm II, the effect of metastasis-directed ablative therapy (either surgery or radiotherapy) on the progression-free and overall survival of breast cancer patients was estimated based on available series, as shown in Table 14-1. As can be seen in these series the median PFS is reported to be at least 14 months, and the 5-year overall survival for those with limited metastases (Greenberg 1996, Albain 2009) is >40%. These effect sizes are selected based on the available literature. A large effect must be seen in order to integrate the finding of this trial into the standard practice for patients with limited metastatic breast cancer.  
| Study      | Number  of  patients   | Metastasis  Directed  Therapy   | ER/PR    | Her 2  Neu  Positive   | ≤ 2   | Median   | Median   | 5   |
|------------|------------------------|---------------------------------|----------|------------------------|-------|----------|----------|-----|
| Metastases | PFS                    | OS                              | year  OS |                        |       |          |          |     |
| Positive   |                        |                                 |          |                        |       |          |          |     |  
| Type                                     | (months)                               | (months)   |          |            |          |            |    |       |
|------------------------------------------|----------------------------------------|------------|----------|------------|----------|------------|----|-------|
| (Location)                               |                                        |            |          |            |          |            |    |       |
| Milano et                                | 40                                     | SBRT       |          |            |          |            |    |       |
| al.(2009)                                | (all body  sites)                      | 63%        | Not      | 71%        | 23       | Not        |    |       |
| Reached                                  | 59%                                    |            |          |            |          |            |    |       |
| Stated                                   |                                        |            |          |            |          |            |    |       |
| Abbott et                                | 86                                     | Surgery    | 69%      | 37%        | 62%      | 14.2       | 57 | 43.6% |
| al.(2012)                                | (liver)                                | solitary   |          |            |          |            |    |       |
| Adam et                                  | 85                                     | Surgery    | 82%      | Not        | Median=2 |            |    |       |
| al.(2006)                                | (liver)                                | Stated     | (37%     |            |          |            |    |       |
| solitary)                                | 20 months  (no  extrahepatic  disease) | 46         | 41%      |            |          |            |    |       |
| Friedel et  al.  (all  patients)  (2002) | 467                                    | Surgery    | Not      | Not        | 66%      | Not Stated | 35 | 35%   |
| (lung)                                   | Stated                                 | Stated     | solitary |            |          |            |    |       |
| Friedel et  al.  (1  metastasis)  (2002) | 308                                    | Surgery    | Not      | Not        | 100%     | Not Stated | 42 | 44%   |
| (lung)                                   | Stated                                 | Stated     |          |            |          |            |    |       |
| Planchard  et  al.(2004)                 | 125                                    | Surgery    | 45%      |            |          |            |    |       |
| (lung)                                   | (of those  available                   | Not        | Median=1 | Not Stated | 50       | 45%        |    |       |
| Stated                                   |                                        |            |          |            |          |            |    |       |
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phase ii-r portion

One-hundred and sixteen evaluable patients will provide 92% power to detect a signal for improved median PFS from 10.5 months to 19 months (HR=0.55), with a 1-sided type I error of 0.15. To adjust for ineligible/lost patients, a total of 128 patients will be required for the Ph II-R portion of the study.
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phase iii portion

An additional 208 evaluable patients, for a total of 324 evaluable patients, will be required to definitively determine if ablative therapy improves 5-year overall survival from 28% to 42.5% (HR=0.67), with 85% power and a one-sided type I error of 0.025. To adjust for ineligible/lost patients in the Ph III portion, the total accrual to the trial (to address the Ph III question) will be 360 patients (including the 128 that were already accrued in the Ph II-R portion). This integrated phase II/III design has 78% power for the overall survival analysis under the global alternative hypothesis, while having 0.025 (1-sided) probability of concluding a positive effect on overall survival under the global null hypothesis.
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sample size consideration for translational

Primary Objective It is expected that 80% of the trial population will have signed consent to participate in the tissue/specimen component of the study and will have usable baseline material based on collection from RTOG 10-14. Based on the SWOG 0500 data and the differences in patient selection in this trial excluding those who progress on standard chemotherapy, we expect that among patients with available specimens, 75% will have <5 CTCs per 7.5ml of blood at baseline. Based on the proposed PFS event rates in two treatment arms and the results from Cristofanilli (2004), the projected monthly event rates for patients with <5 CTCs per 7.5ml of blood and ≥5 CTCs per 7.5ml of blood at baseline are 0.0368 and 0.0943 correspondingly. Under other general assumptions of the main trial (accrual time, total follow-up time) and assuming a two-sided probability of type I error of 0.05, the sample size of 116 evaluable patients, accrued in the Phase II-R portion, will be sufficient to detect such a difference with a statistical power of 88%. Similarly, based on the proposed OS event rates in two treatment arms and the results from Cristofanilli (2004) the projected monthly event rates for patients with <5 CTCs per 7.5ml of blood and ≥5 CTCs per 7.5ml of blood at baseline are 0.0148 and 0.0265 correspondingly. The total sample size of 324 evaluable patients will be sufficient to provide a statistical power of at least 93% to detect such a difference. The estimation is based on the simple unstratified log-rank test and provides the conservative approximation for the purpose of the primary analysis for the transactional susbstudy (Akazawa, 1997; Schoenfeld, 1983)
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selected secondary objectives

To evaluate whether <5 CTCs per 7.5ml of blood is a predictive marker for improved PFS (OS), a statistical test for interaction between baseline CTCs and treatment will be performed. Table 14-2 provides the statistical power to detect a presence of interaction under previously described assumptions except for the different effect of treatment in the <5 and ≥ 5 CTCs per 7.5ml of blood subgroups. We assume a two-sided test is performed at the alpha = 0.05 level.  
| The effect of treatment (HR)   | Interaction effect size   |       |      |      |
|--------------------------------|---------------------------|-------|------|------|
| Endpoint                       | (HR <5 CTCs /             | Power |      |      |
| HR ≥5 CTCs)                    |                           |       |      |      |
| <5 CTCs                        | ≥5 CTCs                   |       |      |      |
| PFS                            | 0.20                      | 0.96  | 0.21 | 0.64 |
|                                | 0.25                      | 0.91  | 0.28 | 0.50 |
|                                | 0.30                      | 0.85  | 0.35 | 0.37 |
|                                | 0.35                      | 0.79  | 0.44 | 0.25 |
|                                | 0.40                      | 0.73  | 0.55 | 0.16 |
| OS                             | 0.50                      | 0.97  | 0.52 | 0.53 |
|                                | 0.53                      | 0.92  | 0.58 | 0.40 |
|                                | 0.55                      | 0.88  | 0.62 | 0.31 |
|                                | 0.57                      | 0.85  | 0.67 | 0.24 |
|                                | 0.60                      | 0.80  | 0.75 | 0.14 |  
Table 14-2 Statistical power to evaluate whether <5 CTCs per 7.5ml of blood at baseline is a predictive marker for improved PFS and OS
Non-Compliance with Randomized Treatment Treatment other than the treatment arm to which the patient was randomized is not permitted per the protocol and will be considered non-compliant. However, as this will not prevent treatment crossovers (patients receiving the treatment to which they were not randomized) from occurring and the primary endpoint analyses will be done based on the arm to which the patient was randomized, the rate of treatment crossovers will be closely monitored. Tables 14-3a and 14-3b show the impact for 5% and 10% crossover from the control arm to the experimental arm for the Ph II-R and Ph III portions respectively. If the crossover rate falls between 5% and 10%, NRG Oncology will discuss with NCI the potential of amending the trial in order to adjust for this crossover, so as to maintain the original study parameters. If the crossover rate reaches or exceeds 10%, NRG Oncology will discuss with NCI the feasibility of continuing the trial.  
Table 14-3a: Impact of Crossover from Control Arm to Experimental Arm for Ph II-R  
Crossover  
Rate  
Adjusted  
Experimental  
Median PFS  
Rate  
| Adjusted                    |                                                            |              |     |          |
|-----------------------------|------------------------------------------------------------|--------------|-----|----------|
| Rate                        | Experimental  Median PFS  Rate                             | Power  Given |     |          |
| Crossover  (95% by  Design) | Increase in Accrual  Time to Maintain  Original Parameters |              |     |          |
|                             | 5%                                                         | 18.3         | 93% | 2.5 mths |
|                             | 10%                                                        | 17.6         | 91% | 6 mths   |  
Table 14-3b: Impact of Crossover from Control Arm to Experimental Arm for Ph III  
Crossover  
Rate  
Adjusted  
Experimental  
5-yr OS Rate  
| Adjusted         |                                                            |              |     |          |
|------------------|------------------------------------------------------------|--------------|-----|----------|
| Rate             | Experimental  5-yr OS Rate                                 | Power  Given |     |          |
| Crossover  (85%) | Increase in Accrual  Time to Maintain  Original Parameters |              |     |          |
|                  | 5%                                                         | 41.6%        | 81% | 6.5 mths |
|                  | 10%                                                        | 40.8%        | 76% | 15 mths  |
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14.4 study monitoring of primary

Interim reports with statistical analyses will be prepared twice per year until the initial treatment results have been presented/published. In general, the interim reports will contain the following information:
patient accrual rate with a projected completion date (while the study is still accruing) total patients accrued distributions of important pre-treatment and prognostic baseline variables  
the frequencies and severity of adverse events by treatment arm The interim reports will not contain the results from the treatment comparisons with respect to the primary endpoints, PFS/OS, or any secondary endpoints, with the exception of reporting of adverse events.
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futility testing at the completion

It is projected that at the time of the Ph II-R accrual completion, 74% of the 84 required Ph II-R primary endpoint (PFS) events will have occurred. At this time, a futility analysis will be performed. If the HR (λablation/λstandard of care) is < 1 then accrual will continue during the additional time needed for the full Ph II-R analysis; otherwise, accrual will be stopped, pending the results of the full Ph II-R analysis.
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significance testing for early termination

Assuming that the trial continues on to the full Ph III portion, two interim significance tests of treatment difference are planned, using the Haybittle-Peto (Lan 1983; O'Brien 1979) rule for efficacy and the Freidlin-Korn (Freidlin 2002) rule C for futility. The timing of the interim analyses will be based on OS failure events, as described in Section 14.2.1. The maximum number of OS events required for the study is 231. Under the alternative hypothesis that ablative therapy will increase 5-year OS from 28% to 42.5%, the projected number of events and the nominal significance levels for rejecting the H0 or the H1 for the interim analyses are shown in the table below:  
| Interim   | Number of   | Efficacy:               |                                    |
|-----------|-------------|-------------------------|------------------------------------|
| Analysis  | Events      | Reject H0  if  p (H0) ≤ | Futility:  Reject H1  if  Z (H1) ≤ |
| #1        | 69          | ≤ 0.001                 | -0.92                              |
| #2        | 173         | ≤ 0.001                 | 0.05                               |  
Table 14-4: Nominal Significance Levels for Interim Analyses At each planned interim analysis, the one-sided p-value from the log-rank test assessing treatment efficacy with respect to OS will be compared to the nominal significance level in Table 14-4 above. If the computed p-value is less than or equal to the nominal significance level boundary for rejecting the H0 (efficacy), then accrual to the trial will be stopped (if applicable) and it will be concluded that the OS with ablative therapy (Arm 2) is significantly higher than palliative standard of care (Arm 1) and the results will be reported. If the Z-score is less than or equal to the nominal critical value for rejecting the H1 (futility), then accrual to the trial will be stopped (if applicable) and the fact that it cannot be concluded that the OS with ablative therapy (Arm 2) is significantly higher than palliative standard of care (Arm 1) will be reported. Otherwise, if neither boundary is crossed, accrual to the trial and/or follow-up (as applicable) will continue to the next scheduled analysis. In addition to accrual, distributions of pretreatment characteristics, frequency and severity of adverse events, and compliance with protocol treatment blinded efficacy results will be reported to the NRG Oncology DMC, following the required number of events for the planned interim analysis.
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14.5 accrual considerations (14-jun-2018)

14.5.1 Accrual Rate Patient accrual is projected to be 4 cases per month. Assessment of accrual compliance will be based on the NCI Ph II-R and Ph III accrual rules and will be monitored by the NRG Oncology DMC. It is projected that approximately 11 months of follow-up post the Ph II-R accrual will be required to reach the number of events in order to assess the Ph IIR endpoint of PFS and determine if the trial will continue to the full Ph III accrual. Given the number of patients required for the Ph III portion of the trial and the fact that the projected monthly accrual is only 4, accrual will not be halted following accrual to the Ph II-R portion of the trial. A futility analysis will be performed at the completion of the Ph II-R accrual, as described in Section 14.4. Assuming that futility boundary is not crossed, full accrual to the Ph III portion of the trial will be determined following the results of the Ph II-R analysis, as described in Section 14.3.2.
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14.5.2 accrual goal ph ii-r

Ph III: 360 patients (including the 128 already accrued in the Ph II-R portion).
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14.5.3 study accrual duration

Ph II-R: Based on the projected accrual of 4 cases/month, the Ph II-R portion of the trial should complete accrual in ~ 2.5 years. Ph III: If the trial continues to the full Ph III accrual, that accrual should complete in ~4.5 years from the end of the Ph II-R accrual.  
14.5.4 Estimated Duration for Completion of Primary Endpoint:
Ph II-R: Approximately 1 year from completion of the Ph II-R accrual.  
Ph III: Approximately 6 years from determination of the Ph II-R results.
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14.6 secondary or exploratory elements

The prognostic effect of the initial presence of CTCs at baseline on PFS (OS) will be evaluated using the Cox proportional hazards model, controlling for treatment effect and stratification factors. The hypothesis tests will be two-sided and will use an alpha level of 0.05 to determine significance.
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secondary endpoints/analyses

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

Failure for this endpoint will be the appearance of any new metastases. The cumulative probability of new metastases in the presence of competing failure events will be estimated by the cumulative incidence method (Kalbfleish 1980). The cumulative incidence distributions between the two arms will be compared using Gray's test (Gray 1988). The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with the incidence of new metastases, including tumor receptor status (ER, PR, HER-2), use of chemotherapy, protocol treatment (surgery vs. ablative therapy), and number of metastases (solitary metastasis vs. 2 metastasis).
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14.7 gender/ethnicity/race distribution (21-sep-2022)

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

Abbott, D.E., et al., Resection of liver metastases from breast cancer: estrogen receptor status and response to chemotherapy before metastasectomy define outcome. *Surgery*, 2012. 151(5): p. 710-6.  
. Adam, R., et al., Is liver resection justified for patients with hepatic metastases from breast cancer? *Annals of surgery,* 2006. 244(6): p. 897-907; discussion 907-8. Akazawa, K., et al., Power of Logrank Test and Cox Regression Model in Clinical Trials with Heterogeneous Samples. *Statistics in Medicine*, 1997. 16: p. 583-597 Albain, K.S., et al., Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. *J Clin Oncol*, 2008. 26(24): p. 3950-7. Albain, K.S., et al., Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. *Lancet*, 2009. 374 (9707): p. 2055-63. Alix-Panabières, C. et al., Circulating tumor cells and circulating tumor DNA. *Annu Rev* Med, 2012. 63: p. 199-215. Bergh, J., et al., Clinical and pharmacokinetic study of sunitinib and docetaxel in women with advanced breast cancer. *Breast*, 2012. 21(4): p. 507-13. Bidard, FC., et al., Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma. *Int J Cancer*, 2014. 134(5): p. 1207-13. Cleeland C.S., et al. Pain Outcomes in Patients with Advances Breast Cancer and Bone Metastases. *Cancer*, 2013; 119: 832-838 Cristofanilli M, B.G., Ellis MJ, *et al* .Circulating Tumor Cells, Disease Progression and Survival in Metastatic Breast Cancer*. N Engl J Med* , 2004; 351, 781-791. Demaria, S., et al., Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. *Int J Radiat Oncol Biol Phys*, 2004. 58(3): p. 862-70. Dewas, S., et al., Stereotactic body radiation therapy for liver primary and metastases: the Lille experience. *Cancer Radiother*, 2012. 16(1): p. 58-69. Fisher, B. Laboratory and clinical research in breast cancer--a personal adventure: the David A. Karnofsky memorial lecture*. Cancer Res*. 1980; 40: 3863-3874. Fong, Y., et al., Liver resection for colorectal metastases. *J Clin Oncol*, 1997. 15(3): p. 938-46. Formenti, S., et al., Abscopal response in irradiated patients: results of a proof of priniciple trial. *Int J Radiat Oncol Biol Phys,* 2008. 72(S1): p. S6-7. Freidlin B, Korn EL. A comment on futility monitoring. *Controlled Clinical Trials*. 2002;23:355-366. Friedel, G., et al., Results of lung metastasectomy from breast cancer: prognostic criteria on the basis of 467 cases of the International Registry of Lung Metastases. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic *Surgery*, 2002. 22(3): p. 335-44. Fumagalli, I., et al., A single-institution study of stereotactic body radiotherapy for patients with unresectable visceral pulmonary or hepatic oligometastases. *Radiat Oncol*, 2012. 7: 164. Gianni, L., et al., *AVEREL:* Arandomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. *J Clin Oncol*, 2013. 31(14): p. 1719-25.  
Greenberg, P.A., et al., Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. *J Clin Oncol*: official journal of the American Society of Clinical Oncology, 1996. 14(8): p. 2197-205. Halsted, W.S., I. The Results of Radical Operations for the Cure of Carcinoma of the Breast. *Ann Surg*, 1907. 46(1): p. 1-19. Heitzer, E., et al., Circulating tumor cells and DNA as liquid biopsies. *Genome Med*, 2013. 5(8): p 73. Hellman, S. Karnofsky Memorial Lecture. Natural history of small breast cancers. *J Clin* Oncol. 1994; 12 :2229-2234. Hellman, S, Weichselbaum, RR. Oligometastases. *J Clin Oncol*. 1995; 13:8-10. Hunsberger S, Zhao Y,Simon R, et al. A comparison of phase II study strategies. Clin Cancer Res. 2009;15:5950-5955 Hurvitz, S.A., 0.0.0. A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy. *Breast Cancer Res Treat,* 2013. 141(3): p. 437-46. Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. *Ann Stat.* 16:1141-1154, 1988. Kalbfleish JD, Prentice RL: The statistical analysis of failure time data. New York, NY, John Wiley & Sons. 1980. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. *J Stat* Assoc. 1958;53: 457-81, Karnoub, A.E., et al., Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. *Nature*, 2007. 449(7162): p. 557-63.  
. Kocher, M., et al., Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol:official journal of the American Society of Clinical Oncology, 2011. 29(2): p. 134-41. Lan KKG, DeMets ER. Discrete sequential boundaries for clinical trials. *Biometrika*. 1983;70: 659-663. Lewis, S.L., et al., An International Survey of Definitive SABR for Extracranial Limited Metastases. *Int J Radiat Oncol Biol Phys*, 2013. 87(2): p. S605
. *Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases.*
International Registry of Lung Metastases. *J Thorac Cardiovasc Surg*, 1997. 113(1): p. 37-49.  
Maclean, J. et. al., Multi-disciplinary management for patients with oligometastases to the brain: results of a 5 year cohort study. *Radiat Oncol*, 2013. 8: 156.  
.  
Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. *Cancer Chemother. Rep* 1966:50: 163-70, McDonald, ML, Deschamps, C, Ilstrup, DM, et al. Pulmonary resection for metastatic breast cancer. *The Annals of thoracic surgery.* 1994. 58:1599-1602.  
Milano, M.T., et al., Oligometastases treated with stereotactic body radiotherapy: longterm follow-up of prospective study*. Int J Radiat Oncol Biol Phys*, 2012. 83(3): p. 87886. Milano, M.T., et al., Oligometastatic breast cancer treated with curative-intent stereotactic body radiation therapy. *Breast Cancer Res Treat*, 2009. 115(3): p. 601-8. Miller, G., et al., Outcomes after resection of synchronous or metachronous hepatic and pulmonary colorectal metastases. *J Am Coll Surg, 2007.* 205(2): p. 231-8. Muss, H.B., et al., Adjuvant chemotherapy in older women with early-stage breast cancer. *N Engl J Med*, 2009. 360(20): p. 2055-65. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. *Biometrics*. 1979;35:549-556. Planchard, D., et al., Uncertain benefit from surgery in patients with lung metastases from breast carcinoma. *Cancer*, 2004. 100(1): p. 28-35. Pockaj, B.A., et al., Metastasectomy and surgical resection of the primary tumor in patients with stage IV breast cancer: time for a second look? *Annals of surgical oncology*, 2010. 17(9): p. 2419-26. Postow, M.A., et al., Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med, 2012. 366(10): p. 925-31. Rusthoven, K.E., et al., Multi-Institutional Phase I/II Trial of Stereotactic Body Radiation Therapy for Lung Metastases. *J Clin Oncol,* 2009a. 27(10): p. 1579-84. Rusthoven, K.E., et al., Multi-Institutional Phase I/II Trial of Stereotactic Body Radiation Therapy for Lung Metastases. *J Clin Oncol*, 2009b. 27: p. 1572-1578 Salama, J.K., et al., Stereotactic body radiotherapy for multisite extracranial oligometastases: Final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease. *Cancer*, 2012. 118(11): p. 2962-70. Schoenfeld, D.A., Sample-Size Formula for the Proportional-Hazards Regression Model. Biometrics, 1983.39(2): p. 499-503 Simpson, R., et al., Pulmonary resection for metastaic breast cancer. *Aust NZ J Surg,* 1997. 67(10): p. 717-9.  
Stamell, E.F., et al., The Abscopal Effect Associated With a Systemic Anti-melanoma Immune Response. *Int J Radiat Oncol Biol Phys*, 2012.  
Staren, E.D., et al., Pulmonary resection for metastatic breast cancer. *Archives of surgery*,
1992. 127(11): p. 1282-4. Tanvetyanon, T., et al., Outcomes of adrenalectomy for isolated synchronous versus metachronous adrenal metastases in non-small-cell lung cancer: a systematic review and pooled analysis. *J Clin Oncol,* 2008. 26(7): p. 1142-7. Tawfik, H., Y. Rostom, and H. Elghazaly, All-oral combination of vinorelbine and capecitabine as first-line treatment in HER2/Neu-negative metastatic breast cancer. Cancer Chemother Pharmacol, 2013. 71(4): p. 913-9. Timmerman, R., et al., Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol, 2006. 24(30): p. 4833-9. Tree, A.C., et al., Stereotactic body radiotherapy for oligometastases. Lancet Oncol, 2013. 14(1): p. e28-37. Torok, J., et al., Stereotactic body radiation therapy for adrenal metastases: a retrospective review of a noninvasive therapeutic strategy. *Future oncology*, 2011. 7(1): p. 145-51. Valastyan, S., et al., A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. *Cell,* 2009. 137(6): p. 1032-46. Vlastos, G., et al., Long-term survival after an aggressive surgical approach in patients with breast cancer hepatic metastases. *Ann Surg Oncol*, 2004. 11(9): p. 869-74. Wronski, M., et al., Survival after surgical treatment of brain metastases from lung cancer: a follow-up study of 231 patients treated between 1976 and 1991. *J Neurosurg*, 1995. 83(4): p. 605-16. Zelen M. The randomization and stratification of patients to clinical trials. *J Chron Dis*. 1974: 27: 365-75,