Phase II Non-randomized Trial of Stereotactic Ablative Radiotherapy (SABR) for Oligometastases
Phase: NA
Conditions: Metastatic Tumors
Sponsor: British Columbia Cancer Agency

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 1 of 65 
Protocol Title: Phase II non-randomized Trial of Stereotactic Ablative Radiotherapy (SABR) 
for Oligometastases 
Protocol Number: N/A 
Version Number: 10.0 
Study Phase: Phase II 
Short Title: SABR-5 
Sponsor Name: Dr. Robert Olson, MD (Radiation Oncologist) 
[BC Cancer – Centre for the North] 
 
 
Version 1.0: 07 Nov 2016  
Version 2.0: 05 Dec 2016  
Version 3.0: 06 Feb 2017  
Version 4.0: 31 Mar 2017 
Version 5.0: 17 Apr 2018 
Version 6.0: 09 Oct 2018 
Version 7.0: 20 Jun 2019 
Version 8.0: 20 Apr 2020  
Version 9.0: 17 Aug 2020 
Version 10.0: 22 Aug 2022 
 
 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 2 of 65 
Table of Contents 
Contents 
Table of Contents ...........................................................................................................................2 
I. 
Signature of Principal Investigator ...............................................................................5 
1. 
Protocol Summary ..........................................................................................................9 
1.1. 
Synopsis ............................................................................................................................9 
2. 
Introduction ...................................................................................................................15 
2.1. 
Trial Rationale and Background .....................................................................................15 
2.2. 
Radiation Treatment Overview .......................................................................................16 
 
Stereotactic Ablative Radiotherapy (SABR) ..................................................................16 
2.3. 
Study Population .............................................................................................................17 
3. 
Trial Design ...................................................................................................................18 
3.1. 
Study Objectives and Endpoints .....................................................................................18 
 
Objectives .......................................................................................................................18 
 
Endpoints ........................................................................................................................18 
3.2. 
Entry Procedures .............................................................................................................18 
a) 
Randomization ................................................................................................................20 
b) 
Blinded/Unblinded ..........................................................................................................20 
3.3. 
Study Duration ................................................................................................................20 
4. 
Eligibility........................................................................................................................21 
4.1. 
Inclusion Criteria ............................................................................................................21 
4.2. 
Exclusion Criteria ...........................................................................................................22 
4.3. 
Subject Withdrawal Criteria ...........................................................................................23 
 
Informed Consent............................................................................................................23 
4.4. 
Screen Failures ................................................................................................................24 
4.5. 
Availability for follow up ...............................................................................................24 
4.6. 
Ability to tolerate current treatment................................................................................24 
4.7. 
Biopsy/Tissue/Blood banking .........................................................................................24 
4.8. 
Schedule of Activities (revise schedule as needed) ........................................................25 
 
Investigations Prior to Randomization/Study Entry, During Trial 
and Follow-up .................................................................................................................25 
5. 
Subject Treatment Plan................................................................................................28 
5.1. 
Trial Treatment Summary ...............................................................................................28 
 
Stereotactic Ablative Radiotherapy ................................................................................28 
5.2. 
Data Handling and Recordkeeping .................................................................................31 
5.3. 
Lifestyle Considerations, Prohibited Food and Additional 
Restrictions .....................................................................................................................33 
 
Required Therapy............................................................................................................33 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 3 of 65 
 
Permitted Concomitant Therapy .....................................................................................33 
 
Prohibited Concomitant Therapy ....................................................................................33 
 
Herbal Therapies .............................................................................................................33 
 
Data Records for Concomitant Medications ...................................................................33 
5.4. 
Co-enrolment ..................................................................................................................34 
5.5. 
Subject Compliance/Deviations ......................................................................................34 
6. 
Dose Modifications ........................................................................................................35 
6.1. 
General Toxicity Management .......................................................................................35 
6.2. 
Treatment Modifications.................................................................................................35 
7. 
Assessment of Efficacy..................................................................................................36 
7.1. 
Schedule ..........................................................................................................................36 
7.2 
 Patient Reported Outcomes ...........................................................................................36 
7.3  
Physician/RN/Other Reported Outcomes .......................................................................36 
7.4 
Measurement of Response ..............................................................................................37 
8. 
Assessment of Safety .....................................................................................................38 
8.1. 
Specification of Safety Parameters .................................................................................38 
8.2. 
Recording and Reporting of Adverse Events .................................................................41 
 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................41 
 
Method of Detecting AEs and SAEs ..............................................................................42 
8.3. 
Follow-up of Subjects after Adverse Events ..................................................................45 
8.4. 
Pregnancy........................................................................................................................45 
9.0.          Statistics ........................................................................................................................46 
9.1 
Statistical Methods ..........................................................................................................46 
9.2.  Planned Subjects Enrolled .....................................................................................................46 
9.3. Procedures for Reporting Deviations from the Statistical Plan ..............................................46 
10. Measurement of Study Endpoints ........................................................................................47 
10.1 
Definitions ......................................................................................................................47 
10.1.1 
Survival outcomes ...........................................................................................................47 
10.1.2 
Lesion control rate ..........................................................................................................47 
10.1.3 
Toxicity ...........................................................................................................................47 
10.1.4 
Quality of Life.................................................................................................................47 
10.2 
Evidence of Disease Recurrence.....................................................................................47 
10.3 
Dating of First Recurrence ..............................................................................................47 
10.4 
Management Following Recurrence ...............................................................................47 
11 
Discontinuation of Trial and Subject 
Discontinuation/Withdrawal........................................................................................49 
11.1 
End of Study Definition ..................................................................................................49 
11.2 
Discontinuation of trial ...................................................................................................49 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 4 of 65 
11.3 
Subject Discontinuation/Withdrawal from the Study .....................................................49 
11.4 
Post-Trial Follow-up .......................................................................................................50 
11.5 
Lost to Follow up ............................................................................................................50 
12 
Regulatory, Ethical, and Study Oversight Considerations .......................................51 
12.1 
Regulatory and Ethical Considerations...........................................................................51 
12.1.1 
REB (Research Ethics Board) Approvals for Protocols .................................................51 
12.1.2 
Protocol Deviations .........................................................................................................51 
12.1.3 
Informed Consent Process ..............................................................................................52 
12.1.4 
Data Protection................................................................................................................53 
12.1.5 
Committees Structure......................................................................................................53 
12.5 
Study and Site Start and Closure ....................................................................................53 
12.6 
Publication Policy ...........................................................................................................54 
13 
References ......................................................................................................................55 
APPENDIX A - ELIGIBILITY CHECKLIST .........................................................................57 
APPENDIX B - PATIENT-REPORTED QUALITY OF LIFE – POSI .................................59 
APPENDIX C - RADIATION VOLUMES and DOSES .........................................................61 
APPENDIX D- SABR ORGAN-AT-RISK (OAR) CONSTRAINTS ......................................62 
 
 
 
 
 
 
 
 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 6 of 65 
I. 
Contact Details of Key Personnel  
 
Principal Investigator: 
Dr. Robert Olson (Radiation Oncologist) 
BC Cancer – Prince George, Centre for the North 
Email: rolson2@bccancer.bc.ca  
Tel: 250-645-7325 
 
Primary Contact and Lead for study management: 
Hadassah Abraham (Study Coordinator) 
BC Cancer – Prince George, Centre for the North 
Email: hadassah.abraham@bccancer.bc.ca 
Tel: 250-645-7300 x687438 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 7 of 65 
 
 
II. 
LIST OF ABBREVIATIONS 
Abbreviations 
Description of Abbreviations 
AE 
Adverse event 
CBCT 
Cone beam computed tomography 
CI 
Confidence Interval 
CR 
Complete response 
CT 
Computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical target volume  
DSMC 
Data Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
GCP 
Good Clinical Practice 
GTV 
Gross tumor volume 
Gy 
Gray (unit) 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IMRT 
Intensity-Modulated Radiation Therapy 
KV 
Kilo voltage 
LFT 
 Liver function test 
LN 
Lymph node 
MRI 
Magnetic Resonance Imaging 
MV 
Mega voltage 
OS 
Overall Survival 
PBT 
Proximal bronchial tree 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 8 of 65 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression free survival 
PFT 
Pulmonary Function Test 
PI 
Principal Investigator 
PSMA 
Prostate Specific Membrane Antigen  
POSI 
Positive Outcomes and Support Initiative 
PR 
Partial response 
PTV 
Planning target volume  
QoL 
Quality of Life 
REB 
Research Ethics Board 
RECIST 
Response evaluation criteria in solid tumors 
RFA 
Radiofrequency ablation 
RO 
Radiation Oncologist 
SABR 
Stereotactic Ablative Radiotherapy 
SAE 
Serious adverse event 
SOP 
Standard Operating Procedure 
SPI 
Study Principal Investigator 
Tx 
Treatment  
VMAT 
Volumetric-modulated arc therapy 
4D 
4-dimensional 
 
 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 9 of 65 
1. 
Protocol Summary 
1.1. 
Synopsis 
Date and Version # of Protocol: 
17 Aug 2020, Version 9.0 
Sponsor: BC Cancer 
Protocol Number: n/a 
Name of Study Method: 
Clinical Trial 
Phase of Development:  
Phase II 
Title of Study: 
Phase II Non-randomized Trial of Stereotactic Ablative Radiotherapy (SABR) for 
Oligometastases  
Study Design Overview/Rationale: 
This is a Phase II trial assessing quality of life and side effects in patients/subjects* with up to 5 
newly diagnosed or progressing metastatic cancer lesions treated with a comprehensive 
oligometastatic SABR treatment program. Secondarily we will document the disease free and 
overall survival. 
*Note that patients and subjects are used interchangeably in this document. 
Trial Design: 
This is a non-randomized phase II trial where all subjects will receive experimental SABR to 
5 newly diagnosed or progressing sites of metastatic disease. We will accrue 400 subjects to 
assess toxicity associated with this experimental treatment. 
 
Radiation Treatment Plan 
 
Eligibility 
Appendix A: Eligibility Checklist 
Staging 
Oligometastases Entry/Registration Form (Staging) 
 
Brain CT or MRI within 14 weeks of subject registration for sites with propensity for brain metastases 
 
Body Imaging within 14 weeks of subject registration 
o 
CT scan of chest/abdomen/pelvis, with or without bone scan (at discretion of study doctor), if no 
PET/CT is performed 
o 
PET/CT for PET+ tumors or PSMA-PET 
o 
MRI spine for patients with vertebral or paraspinal metastases 
 
Bloodwork as per standard of care 
 
Pregnancy test for women of child bearing potential  
Assessment 
 Oligometastases Entry/Registration form (Assessment) 
 
ECOG Status                                                        ●   Number of progressing metastases (max 5) 
●     Documentation of site(s) of disease 
 
●   Prior Chemotherapy history documented 
 
Able to treat all active sites with ablative intent        

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 10 of 65 
Appendix B:  PATIENT-REPORTED QUALITY OF LIFE – POSI 
Treatment Volumes 
GTV= gross disease on CT, MRI, or PET/CT 
CTV not generally used. Exceptions: 1) liver = GTV + 5mm 2) spine per provincial SABR spine protocol 
PTV= GTV (or CTV where applicable) + 2-5 mm; 2 mm for spinal and brain tumours, 5 mm for all other sites 
Pre-Tx Simulation Imaging 
 
4D CT should be acquired for moving tumors.  
 
If 4DCT is not possible, 3DCT is acceptable. 
 
Planning CT slice thickness <= 2.5 mm. (exception: spine SABR – slice thickness = 1.25 mm) 
 
Intravenous contrast could be used at the discretion of the treating radiation oncologist. 
 
Fiducial markers could be used at the discretion of the treating radiation oncologist. 
Prescription Isodose 
PTV:  V100% = 95% 
PTV:  V 90% > 99% 
 
 
 
 
Dose and Fractionation: 
Location 
Dose (Gy) 
Fractions 
Frequency 
Peripheral Lung 
48 or 54 
4 or 3 
Daily or every other day 
Central Lung 
-within 2 cm of PBT 
60 
8 
Daily 
Bone (including spine primary or 
retreatment) 
35 or 24 
5 or 2 
Daily 
Liver 
54 
3 
Every other day 
Adrenal 
40 or 60 
5 or 8 
Daily 
LN/Soft Tissue 
40 
5 
Daily 
Brain 
BC Cancer Stereotactic radiosurgery protocol 
Verification Imaging 
Frequency 
Purpose 
Pre-Tx CBCT 
Daily 
Move to match 
Post-Tx CBCT 
Day 1 or at RO discretion 
Assess intra-fraction movement 
 
Immobilization 
 Immobilization devices need to be approved by the practicing Radiation Oncologist(s) 
and SABR physics and dosimetry staff within the particular institution.   
 It is left at the discretion of the treating RO/Medical Physicist to determine which 
immobilization device is to be used based on their centre/department specific policy. 
 
Disease Assessment:  
 Patient Reported Quality of Life 
 
Toxicity (as per Common Terminology Criteria for Adverse Events (CTCAE) v.4) 
 
Overall Survival 
 
Disease-free Survival 
 
Study Population 
Patients with up to 5 newly diagnosed or progressing metastatic cancer lesions  

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 11 of 65 
Study Objective(s):  
 
Primary Objective: To assess quality of life and side effects in patients with up to 5 newly 
diagnosed or progressing metastatic cancer lesions treated with a comprehensive oligometastatic 
SABR treatment program  
 
Secondary Objective: To document disease free and overall survival 
Number of Subjects/Sample Size Calculations  
400 subjects will be accrued.  
Planned Study Period: 
Anticipated length of study is 8 years. Anticipated recruitment end date: 30 June 2020. 
Anticipated end date for all follow-up: 30 September 2025. 
Inclusion Criteria: 
Subjects must meet all of the following criteria to be eligible for participation in this study: 
 
Age 18 or older 
 
Able to provide informed consent 
 
Histologically confirmed malignancy with metastatic disease detected on imaging. 
- 
Biopsy of metastasis is preferred, but not required. 
 
Primary tumour treated radically or controlled by prior palliative radiotherapy or systemic therapy 
 
Maximum 5 metastases eligible for SABR (either 5 in total or 5 not controlled by prior treatment) 
 
Standard of care tests prior to SABR CT simulation within 14 weeks of patient’s registration date: 
- 
Brain CT or MRI imaging (for tumour sites with propensity for brain metastasis) 
- 
Body imaging:  
 CT chest/abdomen/pelvis, with or without bone scan (at discretion of study doctor), required 
if no PET-CT is performed 
 PET-CT or PSMA-PET is only required for specific evidence-based indications, and in such 
cases the CT neck/chest/abdomen/pelvis and bone scan are not required: 
 MRI spine for patients with vertebral or paraspinal metastases 
- 
For other indications, at the discretion of the treating oncologists, e.g. PET-CT scans may be 
done but are not required. 
- 
Blood tests as per standard of care 
- 
Negative pregnancy test (urinalysis) for women of child-bearing potential within 4 weeks of 
RT start date 
 
ECOG performance status 0-2 
 
All sites of progressive disease can be safely treated based on criteria below: 
 
For non-brainstem metastases, maximum size of 3cm if using single fraction radiosurgery. 
- 
If size is from 3.1 to 4cm, 25-35Gy/5 can be considered  
 
All brain metastases cases need approval from Stereotactic Radiosurgery (SRS) rounds 
- 
Maximum size of 6 cm for lesions outside the brain, except: 
 
Bone metastases over 6 cm may be included, if in the opinion of the local PI it can be treated 
safely (e.g. rib, scapula, pelvis) 
 
Life expectancy > 6 months 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 12 of 65 
- 
In many scenarios, this is best estimated by a multidisciplinary opinion from disease site 
experts, often obtained by presentation at multidisciplinary tumours rounds.  
 
Not a candidate for surgical resection at all sites: surgery to all sites not recommended by 
multidisciplinary team, or unfit or declining surgery. 
 
No chemotherapy agents (cytotoxic, or molecularly targeted agents) will be used within the 
period of time commencing 2 weeks prior to radiation, lasting until 1 week after the last fraction. 
Certain chemotherapy agents may require a longer break prior to or after SABR if protocols 
dictate. Hormonal therapy during SABR is allowed. 
 
Patients with metastases that have been previously treated may be eligible for this SABR 
protocol:  
- 
If the previous treatment was systemic therapy, the patient may be eligible, if the metastases 
have demonstrated a complete radiologic response  
- 
If the previous treatment was by a local non-radiation means (e.g. prior resection, RFA or 
microwave ablation), then SABR may be considered for residual/recurrent disease 
- 
If the previous treatment was SABR, the patient is not eligible unless the new site(s) 
was/were not previously treated 
 
If the previous treatment was conventional RT, SABR could be considered if it can be delivered 
safely. In such a circumstance it must be presented in a multidisciplinary setting for approval. 
 
Review and consensus by 3 disease site experts, or tumour group conference, for 
eligibility/prognosis  
 
Patient is able and willing to complete quality of life questionnaires in English, and other 
assessments that are a part of this study, via paper or online using REDCap (if email address 
is provided by participant on the informed consent) 
 
Note: The potential treating SABR radiation oncologist reserves the right to require a 
multidisciplinary note documenting life expectancy, other treatment options and suitability for 
SABR. 
 
Waivers to the inclusion criteria will NOT be allowed. 
 
 
 
Exclusion Criteria: 
 
Serious medical co-morbidities precluding radiotherapy 
 
Bone metastasis in a femoral bone if risk of pending fracture is high 
 
Patients with 1-3 brain metastasis and no disease elsewhere (these patients should not be accrued 
but  treated with stereotactic radiotherapy as per results of published randomized trials)  
 
Complete response to first-line chemotherapy (i.e. no measurable target for SABR) 
 
Persistent malignant pleural effusion 
 
Inability to treat all sites of progressing disease with ablative intent 
 
Clinical or radiological evidence of spinal cord compression  
 
Dominant brain metastasis requiring surgical decompression 
 
A candidate for an open randomized clinical trial comparing SABR to a standard treatment 
 
Pregnant or lactating women 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 13 of 65 
Waivers to the exclusion criteria will NOT be allowed. 
 
Concomitant Medication Restrictions or Requirements: 
 
Requirements:  
Previous systemic, radiation, and hormone therapy is permitted. Hormone therapy is allowed during 
SABR treatment. 
All cancer-specific concomitant medications that the subject is using should be recorded. 
 
Restrictions:  
No chemotherapy agents (cytotoxic, or molecularly targeted agents) will be used within the period of time 
commencing 2 weeks prior to radiation, lasting until 1 week after the last fraction. Certain chemotherapy 
agents may require a longer break prior to or after SABR if protocols dictate.  
 
Schedule of Study Assessments and Procedures: 
For Schedule of Assessments refer to Section 4.8. 
 
Adverse Events Determination and Reporting: 
Grade 1 toxicities such as mild fatigue, nausea, vomiting, skin irritation, pain, loss of appetite and some 
physical function are common and expected side effects of radiation therapy and therefore should not be 
reported as adverse events, if the event is documented in the subject’s medical record16.  
Only Grade 2 or higher toxicities that are possibly, probably, or definitely related to SABR will be 
documented and reported as adverse events (AEs)/serious adverse events (SAEs). 
Any Grade 4 or 5 adverse event that is definitely, probably, or possibly the result of protocol treatment 
must be reported to the Study Principal Investigator within 24 hours of discovery, and to the approving 
research ethics board (REB) as per their reporting guidelines. 
Local and non-local SAEs will be reported to the applicable REB as per their reporting guidelines.  
NOTE: Conditions that are NOT considered a SAE in this protocol are not included in reporting 
requirements, e.g., hospitalizations for routine procedures, disease progression, or death from disease 
progression  
Formal Stopping Rules: 
 
If any Grade 5 Serious Adverse Events (SAEs) definitely, probably, or possibly related to protocol 
treatment occur, all co-investigators will be made aware within 1 week of reporting to the principal 
investigator (PI), and a SABR-5 Toxicity Committee meeting will be held within one month of the event. 
During this time, any other patients on treatment to the same body site where the Grade 5 toxicity was 
interpreted to originate, (e.g. adrenal metastases) will have their plan reviewed by the PI to determine if 
that patients’ treatment should be put on hold prior to SABR-5 Toxicity Committee meeting. 
 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 14 of 65 
If 3 or more Grade 5 SAEs meet the definition of unanticipated problem (i.e. unexpected, related and 
involving greater risk occur during this study, as defined in Section 8.0)), the study will be temporarily 
put on hold in order to organize a SABR-5 Toxicity Committee meeting and initiate conversations with 
the BC Cancer/UBC REB. Depending on the results of these meetings, the study may be permanently 
closed or significant modifications may be made and re-reviewed by the REB (e.g. remove treatments of 
adrenal metastases from the study, or reduce the dose, if toxicity was from this body part treatment with 
SABR). 
 
Statistical Evaluations: 
 
Quality of Life: Descriptive statistics - changes in patient-reported QOL before and after treatment 
 
Toxicity: Prevalence of various SAE graded events at different time intervals for a patient (ex. at 1 
year, 2 years). Cumulative incidence will be used to capture multiple episodes of an SAE.  
 
Survival outcomes: Overall survival will be measured as time until death from any cause, and 
progression-free survival as time to either progression or death, whichever occurs first. 
 
Lesion control rate will be assessed retrospectively as RECIST criteria have not been validated in 
the setting of SABR, and is costly to implement in a prospective cohort. 
Endpoints for Evaluation: 
 
Primary Endpoints 
 
Patient Reported Outcomes (quality of life and side effects) 
 
Toxicity Assessed by the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 
4 
Secondary endpoints:  
 
Disease-free survival  
 
Time from SABR treatment to disease progression at any site or death 
 
Overall survival 
 
Lesional control rate, defined as lack of further progression 
 
Time to starting or re-starting chemotherapy for current cancer 
 
Number of cycles of further systemic therapy for current cancer 
 
 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 15 of 65 
2. 
Introduction 
2.1. 
Trial Rationale and Background 
The oligometastatic state was first defined in 1995 and refers to a stage of disease where 
cancer has spread beyond the site of origin, but is not yet widely metastatic.1 In such a state of 
limited metastatic disease, it is hypothesized that eradication of all sites of metastatic disease 
could result in long-term survival, or even cure, in some patients.2 Ablation of metastatic 
deposits can be achieved through several techniques, including surgery, radiofrequency ablation 
(RFA), or through Stereotactic ablative body radiotherapy (SABR), a new radiotherapy 
technology that delivers very large, hypofractionated doses of radiotherapy to small tumour 
targets, with high rates of local control.  
Clinical evidence to support the presence of an oligometastatic state is controversial. 
However, there is emerging low quality evidence in both the surgical and SABR literature that 
this state may exist. In a study of over 5200 patients with lung metastases who underwent 
surgical resection, a 5-year survival of 36% was reported in patients who achieved a complete 
resection, much higher than would be expected for stage IV disease.3 Similarly, in patients 
treated with SABR for 1-3 lung metastases from a variety of primary tumours, local control 
with SABR was 96% at 2-years, and 2-year survival was 39%.4 Long-term survival has been 
demonstrated in patients treated for oligometastases with surgery or SABR at several other 
tumour sites, including liver, brain, bone, and adrenal metastases.2,5-8 The risk of further 
metastases after ablative treatment is up to 60-80% in some studies.4,5 SABR can also be used 
for further salvage at newly progressive sites (oligoprogression).9   
Despite the apparent achievement of long-term survival with ablative treatment for 
oligometastatic disease, the level of evidence to support such treatments is weak, often based 
on single-arm studies without appropriate controls.10 Patients included in such reports are 
highly selected, based on good performance status and slow pace of tumour progression. It has 
been suggested that the long-term survival achieved with treatment of oligometastases is a 
result of the selection of fit patients with very slow-growing tumours, rather than the result of 
treatment intervention. 11 
Randomized trials are therefore necessary to establish the utility of ablative treatment of 
oligometastatic disease,10,12 and therefore the BC Cancer oligometastatic SABR group 
recommends that patients be offered a randomized control trial, if available, rather than 
being offered SABR on this current trial. BC Cancer has decided that given the limited 
evidence for SABR in this setting, it will not be offered off trial. The main focus of this trial 
is to assess the side effects and quality of life post SABR. This trial aims to provide a clear 
informed consent process, including the limited evidence for SABR off trial and potential harm 
from SABR (see section 2.2.1 and ICF for summary of risks and benefits) for patients opting 
to pursue SABR for oligometastases. 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 16 of 65 
 
2.2. 
Radiation Treatment Overview 
 
 Stereotactic Ablative Radiotherapy (SABR) 
The guiding principle for SABR is to achieve disease control and minimize any potential adverse 
impact on QoL. Doses and fractionations by tumour site are shown in Table 1 (Appendix D).  
All patients will undergo planning CT simulation. 4-dimensional CT will be used for tumours in 
the lungs or upper abdomen. Axial CT images will be obtained throughout the region of interest. 
For all lesions, the gross tumour volume (GTV) will be defined as the visible tumour on CT 
and/or MRI imaging +/- PET. Consistent with international consensus guidelines, clinical target 
volume (CTV) expansion will be limited to vertebral and some bone lesions7. For mobile 
tumours, tumour tracking or gating can be employed at the discretion of the institution. 
Alternatively, an internal target volume (ITV) can be created which encompasses all tumour 
motion from the 4D CT scan. For all CTVs or ITVs, a Planning Target Volume (PTV) margin of 
2-5 mm will be added depending on site of disease, immobilization, and institutional set-up 
accuracy: 2 mm margins may be used for spinal stereotactic treatments, 2 mm for brain tumours, 
and 5 mm for other sites. Organs at risk visible in the planning CT scan will be contoured. 
Constraints and references to their source are shown in Table 2 (Appendix D). 
Potential side effects from SABR will depend on the area being treated.  The side effects listed 
below are for SABR:  
 Radiation treatments to the head and neck area or brain may commonly cause headache, 
hair loss, mild sunburn of the skin, decreased hearing or irritation of the ears, dryness or 
irritation of the eyes and dry or sore mouth or throat or loss of taste during radiation 
treatments. Common delayed (more than 6 months after treatment) side effects from 
radiation treatments to the head and neck area may include persistent dry mouth 
(common) as well as changes in thinking or memory (rare and only if the brain is 
treated).  
 Radiation treatments to the chest area may commonly cause dry cough, sore throat or 
difficulty swallowing as well as mild sunburn of the skin. Delayed (late, more than 
6months post treatment) side effects from radiation treatments to the chest area may 
rarely cause new or persistent difficulties with swallowing; shortness of breath or cough.  
 Radiation treatments to the abdomen or pelvic area commonly include diarrhea or 
cramping of the bowels, discomfort or frequency of urination and possibly nausea. 
Rarely, delayed (late, more than 6months post treatment) side effects from radiation 
treatments may occur including persistent cramping, diarrhea or bleeding from the bowel; 
frequency or discomfort with urination or bleeding from the bladder.  
 Radiation treatments to bone can be associated with increased pain, redness of the skin, 
and a risk of a broken bone.  

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 17 of 65 
 Fatigue during and following radiation treatments to any of these areas is common  
 Radiation treatments are associated with a small risk of serious injury to tissues or organs 
that are included in the area being treated. This injury may show up months to years post 
treatment. In very rare instances, these side effects may result in death. Some of these 
side effects include (depending on whether these areas are being treated):  
 Brain injury resulting in loss of strength, sensation or thinking ability  
 Spinal cord injury resulting in paraplegia  
 Lung injury resulting in shortness of breath  
 Esophagus injury resulting in difficulty swallowing  
 Heart injury resulting in a heart attack or fluid collection on the heart  
 Bone injury resulting in a broken bone  
 Rectal or bowel injury resulting in bleeding or perforation (hole) or fistula (abnormal 
connection between the bowel and another organ) 
 Bladder injury resulting in bleeding or perforation (hole) or fistula (abnormal 
connection between the bowel and another organ)  
 Adrenal dysfunction resulting in adrenal insufficiency 
 Tissue injury resulting in avascular necrosis 
 
There may or may not be a direct benefit to the patient. The cancer may shrink but these things 
cannot be predicted.  The information learned from this study may or may not help other 
participants with metastatic cancer and oligo-metastatic disease in the future. The potential 
benefits of SABR in this setting are that it could reduce side effects and/or improve the chance of 
controlling the cancer by more accurately treating the cancer and by giving higher doses of 
radiation.  
 
2.3. 
Study Population 
This study will be offered to patients with up to 5 newly diagnosed or progressing metastatic 
cancer lesions, meeting all eligibility criteria as described in sections 4.1 and 4.2, respectively. 
 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 18 of 65 
3. 
Trial Design 
This is a non-randomized phase II trial where all patients will receive experimental SABR for 
up to 5 newly diagnosed or progressing sites metastatic disease. We will accrue 400 patients 
to assess toxicity associated with this experimental treatment. 
3.1. 
Study Objectives and Endpoints  
 
Objectives 
Primary Objective: To assess quality of life and side effects in patients with up to 5 newly 
diagnosed or progressing metastatic cancer lesions treated with a comprehensive oligometastatic 
SABR treatment program.  
Secondary Objective: to document disease free and overall survival. 
 
Endpoints  
Primary Endpoints 
 Patient Reported Outcomes,  quality of life and side effects 
 Toxicity Assessed by the National Cancer Institute Common Toxicity Criteria (NCI-CTC) 
version 4 
Secondary Endpoints:  
 Progression-free survival  
 Time from SABR treatment to disease progression at any site or death 
 Overall survival 
 Lesional control rate, defined as lack of further progression 
 Time to starting or re-starting chemotherapy for current cancer 
 Number of cycles of further systemic therapy for current cancer 
 
400 patients will be accrued in order to adequately capture these endpoints. 
 
3.2. 
Entry Procedures 
 
PRE-TREATMENT STAGING/ ASSESSMENTS 
 
Staging/Testing within 14 weeks of patient registration date (no exceptions to timelines) 
 
 
 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 19 of 65 
Imaging/Staging: 
 Brain CT or MRI imaging (for tumour sites with propensity for brain metastasis) 
 Body imaging:  
 CT neck/chest/abdomen/pelvis, with or without bone scan (at discretion of study 
doctor), required if no PET-CT is performed 
 PET-CT is only required for specific evidence-based indications, and in such cases 
the CT neck/chest/abdomen/pelvis and bone scan are not required 
 MRI spine for patients with vertebral or paraspinal metastases 
 
Pre-Tx Simulation Imaging 
 4DCT should be acquired for moving tumours.  
 If 4DCT is not possible, 3DCT is acceptable. 
 Planning CT slice thickness <= 2.5 mm. (exception: spine SABR – slice thickness = 
1.25 mm) 
 Intravenous contrast could be used at the discretion of the treating radiation 
oncologist. 
 Fiducial markers could be used at the discretion of the treating radiation oncologist. 
 
Prescription Isodose 
 PTV:  V100% = 95% 
 PTV:  V 90% > 99% 
 
Treatment Volumes 
 GTV= gross disease on CT, MRI, or PET/CT 
 CTV not generally used. Exceptions: 1) liver = GTV + 5mm 2) spine per provincial 
SABR spine protocol 
 PTV= GTV (or CTV where applicable) + 2-5 mm; 2 mm for spinal and brain 
tumours, 5 mm for all other sites 
 
Testing: 
 Pulmonary function tests for lung metastases, if previously documented poor lung 
function, treating near lung, and at discretion of investigator 
 Liver function tests for liver metastases, if previously documented if poor liver function, 
treating near liver, and at discretion of investigator 
 Blood tests as per standard of care 
 Urine pregnancy test for women of child-bearing age within 4 weeks prior to RT start 
date 
 
Assessments 
 Eligibility Assessment (inclusion/exclusion criteria [see Eligibility Checklist – Appendix 
A]) 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 20 of 65 
 Oligometastases Entry/Registration Form 
 ECOG Status                                                         
 Number of total metastases (max 5) 
 Documentation of site(s) of disease 
 Prior Chemotherapy history documented 
 Able to treat all active sites with ablative intent  
 Concomitant medications 
 Quality Assurance Review of Contours (SABR Quality Assurance Review) 
 Quality of Life POSI Questionnaires (Appendix B)-POSI questionnaires -should be 
completed before treatment (ex. at time of patient registration or at CT-Simulation) 
 Provider Reported Toxicity, Grade 2 or higher, as per CTCAE v.4 
 
a) Randomization 
N/A 
b) Blinded/Unblinded 
N/A 
3.3. 
Study Duration 
Anticipated length of study is 8 years. Anticipated end date for recruitment: 30 June 2020. 
Anticipated end date for completion of all follow-up activities: 30 September 2025 
 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 21 of 65 
4. 
Eligibility 
Treatment will be offered to patients with up to 5 newly diagnosed or progressing metastatic cancer 
lesions meeting inclusion and exclusion criteria  
Waivers to eligibility criteria are not permitted. 
See Eligibility Checklist (Appendix A) 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for participation in this study: 
 Age 18 or older 
 Able to provide informed consent 
 Histologically confirmed malignancy with metastatic disease detected on imaging. 
- 
Biopsy of metastasis is preferred, but not required. 
 Primary tumour treated radically or controlled by prior palliative radiotherapy or systemic 
therapy 
 Maximum 5 metastases eligible for SABR (either 5 in total or 5 not controlled by prior 
treatment) 
 Standard of care tests prior to SABR CT simulation within 14 weeks: 
- 
Brain CT or MRI imaging (for tumour sites with propensity for brain metastasis) 
- 
Body imaging:  
 CT chest/abdomen/pelvis, with or without bone scan (at discretion of study doctor), 
required if no PET-CT is performed 
 PET-CT or PSMA-PET is only required for specific evidence-based indications, and 
in such cases the CT neck/chest/abdomen/pelvis and bone scan are not required: 
 MRI spine for patients with vertebral or paraspinal metastases 
- 
For other indications, at the discretion of the treating oncologists, e.g. PET-CT scans 
may be done but are not required.  
- 
Blood tests as per standard of care 
- 
Pregnancy test for women of child-bearing age 
 ECOG performance status 0-2 
 All sites of progressive disease can be safely treated based on criteria below 
 For non-brainstem mets, maximum size of 3cm if using single fraction radiosurgery. 
- 
If size is from 3.1 to 4cm, 25-35Gy/5 can be considered  
 All brain metastases cases need approval from Stereotactic Radiosurgery (SRS) rounds 
- 
Maximum size of 6 cm for lesions outside the brain, except: 
 Bone metastases over 6 cm may be included, if in the opinion of the local PI it can be 
treated safely (e.g. rib, scapula, pelvis) 
 Life expectancy > 6 months 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 22 of 65 
- 
In many scenarios, this is best estimated by a multidisciplinary opinion from disease 
site experts, often obtained by presentation at multidisciplinary tumours rounds.  
 Not a candidate for surgical resection at all sites: surgery to all sites not recommended by 
multidisciplinary team, or unfit or declining surgery. 
 No chemotherapy agents (cytotoxic, or molecularly targeted agents) will be used within 
the period of time commencing 2 weeks prior to radiation, lasting until 1 week after the 
last fraction. Certain chemotherapy agents may require a longer break prior to or after 
SABR if protocols dictate. Hormonal therapy during SABR is allowed. 
 Patients with metastases that have been previously treated may be eligible for this SABR 
protocol:  
- 
If the previous treatment was systemic therapy, the patient may be eligible, if the 
metastases have demonstrated a complete radiologic response  
- 
If the previous treatment was by a local non-radiation means (e.g. prior resection, RFA 
or microwave ablation), then SABR may be considered for residual/recurrent disease 
- 
If the previous treatment was SABR, the patient is not eligible unless the new site(s) 
was/were not previously treated 
 If the previous treatment was conventional RT, SABR could be considered if it can be 
delivered safely. In such a circumstance it must be presented in a multidisciplinary setting 
for approval. 
 Review and consensus by 3 disease site experts, or tumour group conference, for 
eligibility/prognosis 
Patients must be able and willing to complete  quality of life questionnaires in English, and 
other assessments that are a part of this study, via paper or online using REDCap (if email 
address is provided by participant on the informed consent)  
Note: The potential treating SABR radiation oncologist reserves the right to require a 
multidisciplinary note documenting life expectancy, other treatment options and suitability for 
SABR. 
4.2. 
Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply: 
 Serious medical co-morbidities precluding radiotherapy 
 Bone metastasis in a femoral bone if risk of pending fracture is high 
 Patients with 1-3 brain metastasis and no disease elsewhere (these patients should not be 
accrued but treated with stereotactic radiotherapy as per results of published randomized 
trials)  
 Complete response to first-line chemotherapy (i.e. no measurable target for SABR) 
 Persistent malignant pleural effusion 
 Inability to treat all sites of progressing disease with ablative intent 
 Clinical or radiological evidence of spinal cord compression  
 Dominant brain metastasis requiring surgical decompression 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 23 of 65 
 A candidate for an open randomized clinical trial comparing SABR to a standard treatment 
 Pregnant or lactating women 
 
4.3. 
Subject Withdrawal Criteria 
Subjects may voluntarily discontinue participation in the study at any time.  
If a subject is withdrawn from the study, the assessments and evaluations that would have 
been performed at the Study Completion/Early Termination (see Section 4.8) should be 
obtained.  The Study Termination Form should be completed in REDCap. 
Subjects withdrawn or discontinued can be replaced at the discretion of the sponsor-
investigator/Study Principal Investigator. Subjects can be withdrawn from the study at the 
instigation of the investigator if exclusion/inclusion criteria have been violated during the 
course of treatment ex. Disease progression does not allow for safe treatment of metastatic 
sites; safety reasons etc.  
If a subject is removed because of an adverse or serious event, they should remain under 
medical observation as long as deemed appropriate by the treating physician, and follow 
recording and reporting requirements listed in Section 8.2. 
 
 
Informed Consent 
Voluntary, written, dated and signed informed consent for participation in the study must be 
obtained prior to performing any study-related procedures (including screening evaluations). 
The written informed consent form must be approved by the IRB/REB and adhere to ICH GCP 
and the ethical principles that have their origin in the Declaration of Helsinki.   
The investigator is responsible for obtaining written informed consent from each subject, or if 
the subject is unable to provide informed consent, the subject’s legally acceptable representative, 
prior to beginning any study procedures and treatment(s). The investigator should inform the 
subject, or the subject’s legally acceptable representative, of all aspects of the study, including 
the potential risks and benefits involved. The potential risks and benefits are described in section 
2.2.1 and in the ICF.  
All screening evaluations must be completed and reviewed to confirm that subjects meet all 
eligibility criteria prior to study enrollment. A screening log will be maintained to record details 
of all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
The subject should be given ample time and opportunity to ask questions prior to deciding about 
participating in the study and be informed that participation in the study is voluntary and that 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 24 of 65 
they are completely free to refuse to enter the study or to withdraw from it at any time, for any 
reason. The informed consent must be signed and dated by the subject, or the subject’s legally 
acceptable representative, and by the person who conducted the informed consent discussion. A 
copy of the signed and dated written informed consent form should be given to the subject or the 
subject’s legally acceptable representative. The process of obtaining informed consent should be 
documented in the patient source documents. See Section 12.1.3 for detailed information on 
informed consent process and documentation. 
4.4. 
Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened Subjects should be assigned the same subject number as for the initial 
screening. 
4.5. 
Availability for follow up 
Patients must be accessible for treatment and follow-up. Investigators must assure themselves the 
patients on this trial will be available for complete documentation of treatment, adverse events, 
and follow-up. 
4.6. 
Ability to tolerate current treatment 
Patient must be able to maintain a stable position during therapy and be able to tolerate 
immobilization device(s) that may be required to deliver SABR safely. 
Review and consensus must be made by 3 disease site experts, or tumour group conference, for 
eligibility/prognosis (including patient’s ability to tolerate SABR).  
4.7. 
Biopsy/Tissue/Blood banking 
As per the eligibility criteria, a biopsy of metastasis is preferred, but not required.

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 25 of 65 
4.8. 
Schedule of Activities (revise schedule as needed) 
 
Investigations Prior to Randomization/Study Entry, During Trial and Follow-up 
Assessment 
Screening/ 
Baseline Staging 
Investigations 
Enrollment/ 
Randomization 
 
Treatment 
Follow-Up 
Week 6 -3 Month+/- 
3 Weeks) 
Follow-Up  
6 Month  
(+/- 8 weeks) 
Follow-Up every 6 months [12-month, 
18-month, 24-month, 30-month, 36-
month, 42-month, 48-month, 54-month] 
 
(+/- 8 weeks) 
Follow-up:  
60 Month 
(+/- 8 weeks) or Early Termination 
Informed Consent Form   
X 
 
 
 
 
 
 
 Inclusion/Exclusion Criteria  
X 
 
 
 
 
 
 
Medical History 
X 
 
 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
CT scans or MRI scan, or 
full body CT scan/ PET scan  
or PSMA PET 
X 
 
 
X 
 ^^ 
X 
 ^^ 
 
 
X 
^^ 
 
 
X 
^^ 
**Bone Scan or PET-CT scan 
(or PET-PSMA for prostate 
cancer***) 
X 
 
 
Optional 
Optional 
 
 
Optional 
 
 
Optional 
Hematology (PFTs LFTs if 
applicable) 
X 
 
 
 
 
 
 
Pregnancy Test (Urinalysis) 
X 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Quality of Life 
Questionnaires (POSI) 
 
X 
 
X 
X 
X 
X 
Planning CT 
 
X 
 
 
 
 
 
Quality Assurance Review 
of Contours 
 
X 
 
 
 
 
 
SABR Treatment 
 
 
X 
 
 
 
 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 26 of 65 
Assessment 
Screening/ 
Baseline Staging 
Investigations 
Enrollment/ 
Randomization 
 
Treatment 
Follow-Up 
Week 6 -3 Month+/- 
3 Weeks) 
Follow-Up  
6 Month  
(+/- 8 weeks) 
Follow-Up every 6 months [12-month, 
18-month, 24-month, 30-month, 36-
month, 42-month, 48-month, 54-month] 
 
(+/- 8 weeks) 
Follow-up:  
60 Month 
(+/- 8 weeks) or Early Termination 
Toxicity Assessment (HCP-
reported FU form)  
 
 
 
X 
X 
 
X 
 
X 
Adverse Events  
 
 
X 
X 
X 
X 
X 
*Extra imaging outside of study schedule is allowed per discretion of the study doctor 
**Imaging is optional for prostate cancer patients with PSA < 5 and is up to the discretion of the treating Radiation Oncologist. If 
patient develops disease progression, imaging will be per standard of care. 
***Follow-up appointments starting at week 6 post-treatment are with the study doctor, (or family doctor if appointment is over 
videolink/ phone and is requested by study doctor) and questionnaire is completed. 
^^ +/- PET, bone scan as clinically indicated; CT Head – Optional 
Imaging/Staging: 
 Brain CT or MRI imaging (for tumour sites with propensity for brain metastasis) 
 Body imaging:  
 CT neck/chest/abdomen/pelvis, with or without bone scan (at discretion of study doctor), required if no PET-CT is 
performed 
 PET-CT is only required for specific evidence-based indications, and in such cases the CT neck/chest/abdomen/pelvis and 
bone scan are not required 
MRI spine for patients with vertebral or paraspinal metastases 
Imaging and blood test results will be valid for 14 weeks prior to enrollment/registration.  
Pregnancy test results will be valid for 4 weeks prior to treatment. 
 

  
 
 
 
Protocol: SABR-5 
 
 
CONFIDENTIAL 
 
Page 27 of 65 
Since many patients will be receiving systemic therapy and separately-timed imaging may be required to assess response, attempts 
should be made to avoid duplication of scans. The follow-up imaging requirements herein may be adjusted by +/- 8 weeks, from 
target follow-up date, in order to align with scans used to assess response to systemic therapy. 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 28 of 65  
5. 
Subject Treatment Plan 
5.1. 
Trial Treatment Summary 
 
Stereotactic Ablative Radiotherapy 
Treatment Planning 
Dose / Fractionation / Prescription 
PTV:  V100% = 95% (The Volume of the PTV receiving 100% of the prescription dose is equal 
to 95%) 
PTV:  V 90% > 99% (The Volume of the PTV receiving 90% of the prescription dose is greater 
than 99%) 
PTV coverage is secondary to organs at risk (OAR) constraints based on clinical judgement. 
PTV coverage can be decreased in order to meet OAR constraints. If the PTV coverage by 100% 
is <50% of the PTV volume, then patients will not be included in the study. Minimum dose to 
PTV should be >50% of prescribed dose. 
 
Dose and 
Fractionation: Location 
Dose (Gy) 
Fractions 
Frequency 
Peripheral Lung 
48 [54]* 
4 [3]* 
Daily or every 
other day 
Central Lung 
 - within 2cm of  PBT  
60 
8 
daily 
Spine (primary) 
24 [35]* 
2 [5]* 
 
daily 
Spine (retreatment) 
35 [24]* 
5 [2]* 
daily 
Bone (non-spine) 
35 or 24 
5 or 2 
daily 
Liver 
54 
3 
Every other 
day 
Adrenal 
40 or 60 
5 or 8 
daily 
LN/Soft Tissue 
40 
5 
daily 
Brain 
BC Cancer Stereotactic radiosurgery protocol 
*preferred dose or fractionation listed first, while dose or fractions in [square brackets] are the secondary 
option. 
 
Immobilization 
 Immobilization devices need to be approved by the practicing Radiation Oncologist(s) 
and SABR physics and dosimetry staff within the particular institution.   
 It is left at the discretion of the treating Radiation Oncologist/Medical Physicist to 
determine which immobilization device is to be used based on their centre/department 
specific policy. 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 29 of 65  
Pre-Treatment Simulation 
 4D CT should be acquired for tumours which are likely to move from respiratory 
motion, such and lung, liver and adrenal sites.  
 If 4DCT is not possible, 3DCT is acceptable 
 Planning CT slice thickness: CT slices thickness should be no greater than 3mm, and pixel 
sizes should be no greater than 1x1 mm. For Spine SABR, the CT slice thickness should 
be no greater than 2 mm (e.g. 1.25 mm)  
 Intravenous contrast may be used at the discretion of the treating Radiation Oncologist. 
 Fiducial markers may be used at the discretion of the treating Radiation Oncologist. 
 When available, 4DCT images should be sent to Treatment Planning System:    
 
-  All phases 0 – 90  
 
-  MIP (Maximum Intensity Projection)  
 
-  MIN (Minimum Intensity: for bony lesions) 
 
-  Average CT (if used for planning purposes) 
 
Treatment Volumes 
For all lesions, the gross tumour volume (GTV) will be defined as the visible tumour on CT 
and/or MRI imaging. When used for target definition, MRI and/or PET imaging should be 
registered with the planning CT 
 
For mobile lesions (e.g. Lung and Liver tumours) an internal GTV (IGTV) can be created as 
per site specific BC Cancer clinical protocols. 
 
A Clinical Target Volume (CTV) in general will not be used, except in liver and bone. For 
vertebral lesions, the CTV will be as per the BC Cancer spine SABR protocol. For bone, a 
CTV of 5 mm is optional. 
 
A PTV margin of 2-5 mm will be added depending on site of disease and local 
immobilization and image guidance practices: no less than a 2 mm margins may be used for 
spinal stereotactic treatments, 2 mm for brain tumours, and no less than a 5 mm margin for 
other sites. For radiosurgery platforms, a PTV margin of 0-1 mm is permitted. In situations 
where imaging or immobilization may be limited, > 5 mm margins may be considered for 
non-spinal bone metastases. 
 
Organs at risk visible in the planning CT scan (Appendix D) will be contoured.  
 
For spinal lesions, a pre-treatment MRI is required to assess the extent of disease and 
position of the cord. This must be fused with the planning CT scan. A Planning Organ at Risk 
Volume (PRV) expansion of no less than 2 mm will be added to the spinal cord, and dose 
constraints for the spinal cord apply to this PRV. For radiosurgery platforms, a PRV margin 
of 1 mm is permitted for the spinal cord. 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 30 of 65  
Relevant Organs at Risk (OAR) 
 The relevant OARs are dependent on the location of the target volume and should be 
outlined from the simulation CT.  
 As a general rule, critical structures within 5 cm of the PTV should be contoured.  
 Please refer to Appendix D for a list of structures that should be considered for different 
treatment sites. 
 
Treatment Planning / Technique 
 
Technique 
 
3DCRT or IMRT/VMAT delivery techniques are allowed. 
 
6MV megavoltage beams and 6 or 10 MV Flattening Filter Free (FFF) beams may be 
used. FFF beams are encouraged due to their high dose rate. 
 
Dose Calculation Algorithm: 
 Type II only (3D scatter correction dose algorithms, such as Eclipse AAA, Acuros, or 
Collapsed Cone)    
 Inhomogeneity Corrections = ON 
 Dose grid resolution should be approximately equal to the CT slice thickness, and no 
larger than 3mm with a higher resolution for Spine SABR  
 
PTV Prescription isodose: 
 The Volume of the PTV receiving 100% of the prescription dose is equal to 95% while 
the Volume of the PTV receiving 90% of the prescription dose is greater than 99%. 
 PTV coverage may be compromised to achieve dose constraints for critical OARs at the 
discretion of the Radiation Oncologist, but PTV coverage must be such that 50% 
isodose covers 95% of the PTV (V50%> 99% ). 
 Chest wall dose constraints can be exceeded in order to meet PTV coverage, at the 
discretion of the treating oncologist. 
 The hotspot should be in the PTV and not in the adjacent normal tissue. The hotspot 
should generally be less than 150% of the prescription dose. For lung lesions, the 
hotspot should not exceed 167% of the prescription dose.    
 
OAR and Normal Tissue Dose Constraints:  
 Please refer to Appendix D for the OAR dose constraints.  
 The dose distribution should conform to the PTV as much as possible. As a guideline 
for a single lung lesion, please refer to Appendix D for dose conformality indices. For 
multiple lung lesions, the specified dose conformality indices might not be achievable. 
 
 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 31 of 65  
Treatment Verification / Imaging 
 Collision Check:  Recommended for all plans containing non-coplanar beams 
 KV, MV or CBCT image guidance must be used for all fractions. It is strongly 
recommended that CBCT Image Guidance is used for all treatment fractions as 
indicated in the following table: 
 
Verification Imaging 
Frequency 
Purpose 
Pre-Tx CBCT 
Daily 
Move to match 
Post-Tx CBCT 
Day 1 or at RO discretion 
Assess intra-fraction movement 
 
 If treatment time is expected to exceed 45 minutes, mid-tx position verification should 
be performed. 
 
Quality Assurance 
The contours of the GTV, IGTV, PTV and all relevant OAR will be evaluated and approved 
upon review by a second Radiation Oncologist (See Quality Assurance (QA) forms. E-
approval is acceptable if all elements on QA forms are addressed in e-communications, 
including final approval of contours). 
 
 Dose volume histogram parameters will be evaluated by the planning dosimetrist(s), 
physicist(s) and Radiation Oncologist(s). 
 
 Institutional quality assurance rounds may also evaluate the radiation plans and delivery 
of oligometastases SABR. 
 
 All plans must be independently verified with measurements and/or with quality 
assurance software used in the verification of SABR plans. 
 
5.2. 
Data Handling and Recordkeeping 
 
All subject data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 
The investigator must permit study-related monitoring, audits, REB review, and 
regulatory agency inspections and provide direct access to source data documents. 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 32 of 65  
 
The Sponsor-Investigator/Study PI or designee is responsible for the data management 
of this study including quality checking of the data. 
 
The Sponsor-Investigator/Study PI assumes accountability for actions delegated to other 
individuals  
 
Study monitor will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of Subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion. No records 
may be destroyed during the trial and/or retention period. No records may be transferred 
to another location or party without written notification to the sponsor. 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 33 of 65  
5.3. 
Lifestyle Considerations, Prohibited Food and Additional 
Restrictions 
 
Required Therapy 
None 
 
Permitted Concomitant Therapy 
All cancer-specific concomitant medications that the subject is using should be recorded at each 
visit.  
Previous systemic, radiation, and hormone therapy is permitted. Hormone therapy is allowed 
during treatment. All concomitant medications should be continued throughout the trial unless 
the responsible investigator (ie. Treating Radiation Oncologist) decides otherwise. 
 
Prohibited Concomitant Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
  The use of systemic therapy agents that are cytotoxic, immunotherapeutic, or molecularly 
targeted agents are NOT allowed within the period of time commencing 2 weeks prior to 
radiation, lasting until 1 week after the last fraction.  
Use of chemotherapy schemes containing potent enhancers of radiation damage (e.g. 
gemcitabine, doxorubicin, bevacizumab, adriamycin) are discouraged within the first month after 
radiation.  
 
Herbal Therapies 
Concomitant herbal therapies that the subject is using do not need to be recorded. 
 
Data Records for Concomitant Medications 
Cancer-specific concomitant medications must be recorded on the SABR-5 concomitant 
medication form, which is a cumulative form to be updated throughout the study.  
 
If no concomitant medications are being taken at the time of study visits, this can be indicated on 
a line on the form, with the following annotation: 
 
‘Confirmed no concomitant medications are being taken during study visit X [Date: DD MMM 
YYYY; INITIALS]’ 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 34 of 65  
5.4. 
Co-enrolment 
Enrolment in other studies may be permitted. Investigators must check with the Study Principal 
Investigator. 
5.5. 
Subject Compliance/Deviations 
Subject compliance, such as attending study visits and completing questionnaires, will be 
monitored via REDCap. If any visits are not completed, investigator or delegate must call and 
conduct follow-up over the telephone, or send questionnaires to patients via regular mail, to 
complete POSI questionnaires, and the HCP form for outcomes and toxicity. Missed visits must 
be documented in the deviation log. 
Deviations to eliminate immediate hazards to study subjects must be reported to the Study PI 
immediately upon discovery and to the REB within 7 calendar days. All other reportable 
deviations must be reported to the Study PI immediately, however to the REB within 15 calendar 
days. See section 12.1.2 Protocol Deviations for a list of deviations. 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 35 of 65  
6. 
Dose Modifications 
6.1. 
General Toxicity Management 
Dose modifications are not allowed; but PTV undercoverage is allowed and already described. 
6.2. 
Treatment Modifications 
Interruptions and missed doses are major deviations and must be recorded in the deviation log on 
paper and in REDCap. Major deviations must be reported to the Study PI immediately and may 
require an additional deviation report (see Section 12.1.2). 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 36 of 65  
7. 
Assessment of Efficacy 
Assessment of Response and Patient Follow-Up 
7.1. 
Schedule 
 
Clinical follow-up appointments will occur at 6 weeks-3 months, and then every 6 months (from 
treatment end date) for 5 years.  At each visit, a medical history including an examination of 
concurrent medication will be conducted by the oncologist or a delegated family physician (e.g. 
if patient is followed over videolink), and CTC-AE toxicities recorded. Quality of life 
questionnaires are to be completed at each visit and can be done remotely if needed (e.g. by 
phone, videolink, or mail), or the patient can complete these questionnaires at home (paper and 
mailed to investigator) or online using REDCap 
 
CT head (or MR head), CT chest, abdomen and pelvis, and bone scans will be repeated every 6 
months, (+/- PET-CT, bone scan as clinically indicated) until 5 years have elapsed. Head 
imaging can be omitted for histologies without a propensity for brain metastases (e.g. prostate). 
PET-CT scanning may be used in follow-up for patients who were staged with a PET-CT scan 
for trial entry. In such cases, the PET-CT replaces the CTs of the chest, abdomen, pelvis and the 
bone scan; brain imaging would still be required for histologies (definition of propensity for 
brain metastases to be left to the treating investigator) with a propensity for brain metastases. 
*Extra imaging outside of study schedule is allowed per discretion of the study doctor. Patients 
with prostate cancer who have a PSA below 5 may omit imaging requirements.  
 
Since many patients will be receiving systemic therapy and separately-timed imaging may be 
required to assess response, attempts should be made to avoid duplication of scans. The imaging 
requirements herein may be adjusted by +/- 8 weeks, from target follow-up date, in order to 
align with scans used to assess response to systemic therapy. 
 
 
7.2 
 Patient Reported Outcomes 
     See Appendix B   
 
Patient Reported Outcomes will be collected using the questionnaires chosen for BC 
Cancer’s Prospective Outcomes and Support Initiative (POSI: H14-00647) based on body 
site being treated (see Appendix B).  
 
7.3  
Physician/RN/Other Reported Outcomes 
 
See HCP-Reported Follow-Up (Outcomes and Toxicity)   
 ECOG performance status 
 Outcomes including recurrence, therapy since SABR, and toxicity 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 37 of 65  
 Next local therapy or chemotherapy/ targeted therapy start date 
 Date of relapse or new metastases 
 Date of Death 
 
CTCAE version 4.0 toxicity 
 
 
7.4 
Measurement of Response   
 
 Survival outcomes: Overall survival will be measured as time until death from any 
cause, and progression-free survival as time to either progression or death, 
whichever occurs first. 
 Lesion control rate will be assessed retrospectively as RECIST criteria have not 
been validated in the setting of SABR, and is costly to implement in a prospective 
cohort 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 38 of 65  
8. 
Assessment of Safety 
8.1. 
Specification of Safety Parameters 
STUDY ENDPOINTS AND STOPPING RULES 
The primary objective of this study is to measure quality of life and side effects (as determined 
by toxicity) associated with SABR. Thus, the larger the sample size the more confident we can 
be that adverse events are not common with SABR as prescribed and delivered on this protocol. 
We initially set the sample size at 200, but since accrual has been successful, and in order to have 
more confidence in the safety of SABR, we are doubling the sample size to 400. In addition, 
lymph node treatment with SABR is a particular interest, and thus increasing the sample size in 
order to accrue 50 patients will give us more confidence in a less than 10% incidence of grade 4 
toxicity (see below). Increasing the sample size to 400 patients gives us a 66% chance to accrue 
over 50 lymph node metastases, while increasing the sample size to 300 only gives us a <20% 
chance of accruing over 50 such patients. 
This study with an original sample size of 200 patients had limited power to detect an increased 
incidence of adverse events and complicates (see Tables below). For this reason, the trial’s 
power is augmented by aSABR-5 Toxicity Committee), which is bound by rules that require the 
suspension/termination of a trial accrual under certain events as outlined below. 
Probabilities for exact # of grade 4 toxicity events given true rate of grade 4 toxicities = 5%, 
4%, 3%, 2%, assuming sample size of 100 
 
# of grade 4 
toxicity events out 
of 100 samples 
Probability of exact # 
of grade 4 toxicity 
events given true rate 
of grade 4 toxicities = 
5% 
Probability of exact # 
of grade 4 toxicity 
events given true rate 
of grade 4 toxicities = 
4% 
Probability of exact # 
of grade 4 toxicity 
events given true rate 
of grade 4 toxicities = 
3% 
Probability of exact 
# of grade 4 toxicity 
events given true 
rate of grade 4 
toxicities = 2% 
0 
0.6% 
1.7% 
4.8% 
13.3% 
1 
3.1% 
7% 
14.7% 
27.1% 
2 
8.1% 
14.5% 
22.5% 
27.3% 
3 
14% 
19.7% 
22.7% 
18.2% 
4 
17.8% 
20% 
17.1% 
9% 
5 
18% 
16% 
10.1% 
3.5% 
6 
15% 
10.5% 
5% 
1.1% 
 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 39 of 65  
 
Probabilities for exact # of grade 4 toxicity events given true rate of grade 4 toxicities =5%, 
4%, 3%, 2% for a sample size = 200 
# of grade 4 
toxicity events out 
of a sample size 
=200  
Probability of exact # 
of grade 4 toxicity 
events given true rate 
of grade 4 toxicities = 
5% 
Probability of exact # 
of grade 4 toxicity 
events given true rate 
of grade 4 toxicities = 
4% 
Probability of exact # 
of grade 4 toxicity 
events given true rate 
of grade 4 toxicities = 
3% 
Probability of exact 
# of grade 4 toxicity 
events given true 
rate of grade 4 
toxicities = 2% 
0 
0.004% 
0.03% 
0.2% 
1.8% 
1 
0.04% 
0.2% 
1.4% 
7.2% 
2 
0.2% 
1% 
4.3% 
14.6% 
3 
0.7% 
2.7% 
8.8% 
19.6% 
4 
1.7% 
5.6% 
13.4% 
19.7% 
5 
3.6% 
9.1% 
16.2% 
15.8% 
6 
6.1% 
12.3% 
16.3% 
10.5% 
 
95% confidence interval for true rate of toxicities with sample size = 100 or 200 
# of grade 4 toxicity 
events  
Upper limits of one-sided 95% 
confidence interval for true 
rate of grade 4 toxicities 
(sample size=100)  
Upper limits of one-sided 95% 
confidence interval for true 
rate of grade 4 toxicities 
(sample size=200)  
0 
3% 
1.5% 
1 
4.7% 
2.3% 
2 
6.2% 
3.1% 
3 
7.6% 
3.8% 
4 
8.9% 
4.5% 
5 
10.2% 
5.2% 
6 
11.5% 
5.8% 
 
Additional Tables with sample size increase to 400: 
Probabilities for exact # of grade 4 toxicity events given true rate of grade 4 toxicities =5%, 
4%, 3%, 2% for a sample size = 400 
# of grade 4 
toxicity events 
out of a sample 
size =400  
Probability of exact 
# of grade 4 toxicity 
events given true 
rate of grade 4 
toxicities = 5% 
Probability of exact 
# of grade 4 toxicity 
events given true 
rate of grade 4 
toxicities = 4% 
Probability of exact 
# of grade 4 toxicity 
events given true 
rate of grade 4 
toxicities = 3% 
Probability of 
exact # of grade 4 
toxicity events 
given true rate of 
grade 4 toxicities 
= 2% 
0 
0.00000012% 
0.0000081% 
0.00051% 
0.031% 
1 
0.0000026% 
0.00014% 
0.0063% 
0.25% 
2 
0.000027% 
0.0011% 
0.039% 
1.03% 
3 
0.00019% 
0.0062% 
0.16% 
2.8% 
4 
0.0010% 
0.026% 
0.49% 
5.6% 
5 
0.0041% 
0.085% 
1.20% 
9.1% 
6 
0.014% 
0.23% 
2.45% 
12% 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 40 of 65  
 
Cumulative Probabilities grade 4 toxicity events given true rate of grade 4 toxicities =5%, 
4%, 3%, 2% for a sample size = 400 
# of grade 4 
toxicity events 
out of a sample 
size =400 
true rate of grade 4 
toxicities = 5% 
true rate of grade 4 
toxicities = 4% 
true rate of grade 4 
toxicities = 3% 
true rate of grade 
4 toxicities = 2% 
<=0 
0.00000012% 
0.0000081% 
0.00051% 
0.031% 
<=1 
0.0000027% 
0.00014% 
0.0068% 
0.28% 
<=2 
0.000030% 
0.0013% 
0.046% 
1.3% 
<=3 
0.00022% 
0.0075% 
0.21% 
4.1% 
<=4 
 
 0.0012% 
0.033% 
0.70% 
9.7% 
<=5 
0.0053% 
0.12% 
1.9% 
19% 
<=6 
0.020% 
0.35% 
4.4% 
31% 
 
95% one-sided confidence interval for true rate of grade 4 toxicities with sample size =400, 
50 
# of grade 4 
toxicity events  
Upper limits of one-
sided 95% confidence 
interval for true rate 
of grade 4 toxicities 
(sample size=400)  
Upper limits of one-
sided 95% 
confidence interval 
for true rate of grade 
4 toxicities (sample 
size=50) 
0 
0.75% 
5.8% 
1 
1.2% 
9.1% 
2 
1.6% 
12% 
3 
1.9% 
15% 
4 
2.3% 
17% 
5 
2.6% 
20% 
6 
2.9% 
22% 
 
The last table above also demonstrates our confidence of grade 4 toxicities within smaller subsets 
of SABR patients receiving lymph node SABR. With our larger sample size of 400, there is a 
66% chance we will accrue 50 lymph node metastases (based on the fact that we accrued 20 in 
the first 150 patients); if we detect 0 or 1 grade 4 toxicities, that will be associated with a 95% 
confidence that the true rate of grade 4 toxicity is below 10%. 
 
The primary objective of this study is to assess quality of life and toxicity post SABR for 
oligometastases. If any grade 5 SAEs definitely, probably, or possibly related to protocol 
treatment occur, all co-investigators at each site will be made aware within 1 week of reporting 
to the principal investigator (PI), and a SABR-5 Toxicity Committee meeting will be held within 
one month of the event. During this time, any other patients on treatment to the same body site 
where the grade 5 toxicity was interpreted to originate (e.g. adrenal metastases) will have their 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 41 of 65  
plan reviewed by the PI to determine if that patients’ treatment should be put on hold prior to 
SABR-5 Toxicity meeting. 
 
If 3 or more grade 5 SAEs meet the definition of unanticipated problem (i.e. unexpected, related 
and involving greater risk occur during this study), the study will be temporarily put on hold in 
order to organize a SABR-5 Toxicity Committee meeting and initiate conversations with the BC 
Cancer/UBC REB. Depending on the results of these meetings the study may be permanently 
closed or significant modifications may be made and re-reviewed by the REB (e.g. remove 
treatments of adrenal metastases from the study, or reducing the dose, if toxicity was from this 
body part treatment with SABR). 
 
For the purpose of reporting this study, we will define SABR for oligometatases to be reasonably 
safe with the following a priori endpoints. We will report the 95% confidence interval (see table 
above) that the upper confidence is equal to or lower than. In other words, 4 toxicities (with 
sample size of 200) we have 95% confidence the toxicity (whatever grade) is <5% or lower. 
Likewise, with 6 toxicities, we have 95% confidence the toxicity is less than 6%.  
 
 <5% grade 5 toxicity 
 <10% grade 4 toxicity 
 < 25% grade 3 toxicity 
 
8.2. 
Recording and Reporting of Adverse Events 
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the subject to discontinue study treatment or participation in the study. 
 
 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from the start of RT treatment until completion of all follow-up visits. 
All SAEs will be collected from the start of RT treatment until completion of all follow-up visits. 
Medical occurrences that begin before the start of study RT treatment but after obtaining 
informed consent will be recorded in the subject’s medical record.  
 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 42 of 65  
 
Method of Detecting AEs and SAEs 
 
 
Definitions 
 
Adverse Event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medical 
treatment or procedure that may or may not be considered related to the medical treatment 
or procedure. 
 
Serious Adverse Event (SAE) as defined in the ICH Guideline: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, E2A Section IIB 
includes any untoward medical occurrence that at any dose:  
 
 Results in death* 
 
Is life-threatening (refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe.) 
 Results in persistent or significant disability/incapacity  
 Requires in-patient hospitalization or prolongation of existing hospitalization  
 Is a congenital anomaly/birth defect 
 
*underlying cause of death must be investigated and confirmed by the PI to be reported as 
an SAE. If death is due to disease progression, this is reported using the Study 
Termination Form in REDCap. Deaths from disease progression are not to be recorded 
as SAEs. 
 
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization may be considered a serious adverse event, when, based upon medical 
and scientific judgment, they may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above.  
 
Causality (attribution) 
 
An adverse event is considered related to the research intervention if there is a reasonable 
possibility that the event may have been caused by the research intervention (i.e. a causal 
relationship between the event and the research intervention cannot be ruled out by the 
investigator(s)). The relationship of an AE to the study treatment (causality) will be 
described using the following definitions:  
 
Unrelated:  Any adverse event for which there is evidence that an alternative etiology 
exists or for which no timely relationship exists to the administration of the study 
treatment and the adverse event does not follow any previously documented pattern. 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 43 of 65  
The adverse event, after careful consideration by the investigator, is clearly and 
incontrovertibly due to causes other than the intervention. 
 
Unlikely:  Any adverse event for which the time relationship between the study treatment 
and the event suggests that a causal relationship is unlikely and/or the event is more 
likely due to the subject’s clinical condition or other therapies concomitantly 
administered to the subject. 
 
Possible:  Any adverse event occurring in a timely manner after the administration of the 
study treatment that follows a known pattern to the intervention and for which no 
other explanation is known. The adverse event, after careful consideration by the 
investigator, is considered to be unlikely related but cannot be ruled out with 
certainty. 
 
Probable:  Any adverse event occurring in a timely manner after the administration of the 
study treatment that follows a known pattern to the intervention and for which no 
other explanation is known. The adverse event, after careful consideration by the 
investigator, is believed with a high degree of certainty to be related to the 
intervention. 
 
Definitely Related: Any adverse event occurring within a timely manner after 
administration of the study treatment that is a known sequela of the intervention and 
follows a previously documented pattern but for which no other explanation is 
known. The adverse event is believed by the investigator to be incontrovertibly 
related to the intervention. 
 
 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 44 of 65  
 
Severity 
The severity of adverse events will be evaluated using the Common Terminology Criteria 
for Adverse Events (CTCAE) v4.0 grading scale (see (http://ctep.cancer.gov).  
 
Grade 1: 
 Mild  
Grade 2: 
 Moderate 
Grade 3: 
 Severe 
Grade 4: 
 Life-threatening or disabling  
Grade 5: 
 Death  
 
Note: The term “severe” is a measure of intensity: thus a severe adverse event is not 
necessarily serious. For example, nausea of several hours’ duration may be rated as severe, 
but may not be clinically serious. 
 
Grade 1 toxicities such as mild fatigue, nausea, vomiting, skin irritation, pain, loss of 
appetite and some physical function are common and expected side effects of radiation 
therapy and therefore should not be reported as adverse events if the event is documented 
in the subject’s medical record15.  
 
Only Grade 2 or higher toxicities that are possibly, probably, or definitely related to 
SABR treatment will be documented and reported as AEs/SAEs.  
These toxicities must be documented in the AE log and SAE report form, and entered in 
REDCap, and follow REB and BC Cancer reporting guidelines. 
 
Immediately Reportable Adverse Events 
 
Any Grade 4 or 5 serious adverse event that is definitely, probably, or possibly the result 
of protocol treatment must be reported to the Study PI within 24 hours of discovery. The 
follow-up/final report should be completed within an additional 8 days. All other SAEs 
(Grade 2-3) that are definitely, probably, or possibly related to treatment should be reported 
to the Study PI within 15 days. These should be documented in an SAE Report form and 
in REDCap as well. 
 
Unanticipated/unexpected events include events that are inconsistent with, or present a 
greater risk of harm, than the known or recognized risks or side effects of SABR treatment, 
as described in Section 2.2.1. Unanticipated events also include those events where there 
is a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research (i.e. possibly, probably, or definitely related to 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 45 of 65  
participation in the research itself). Unanticipated events are to be reported to the Study PI 
within 24 hours of discovery, and to the local REB as required. 
All local (internal) serious, unexpected adverse events will be reported to the applicable 
REB as per their reporting guidelines.  
NOTE: Conditions that are NOT considered a SAE in this protocol are not included in reporting 
requirements, e.g., hospitalizations for routine procedures, disease progression, or death from 
disease progression. 
 
 
8.3. 
Follow-up of Subjects after Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow the subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 11.5).  
 
Dissemination of Safety Events 
The Study PI will notify all participating sites of Grade 4 or 5 SAEs (as described above) within 
7 days of receipt of the report. Follow up information will be sent as it becomes available. 
Investigators will review and file these reports in their trial documentation, and submit the 
reports to their local REBs if required.  
 
8.4. 
Pregnancy  
Details of pregnancy will not be collected. 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 46 of 65  
9.0.          Statistics 
9.1  Statistical Methods 
 
 
Primary objective 
Quality of life at 6 months will be measured using FACIT, Cancer Specific Questionnaires, with 
differences between groups tested using the Student’s t-test17.  Differences in rates of grade 2 or 
higher toxicity between groups will be tested using the Fisher’s Exact Test.  
 
Survival Endpoints 
PFS and OS will be calculated using the Kaplan-Meier method with differences compared using 
the stratified log-rank test. A Cox multivariable regression analysis will be used to determine 
baseline factors predictive of survival endpoints. For the endpoint of time to new metastases, a 
Fine and Gray competing risk analysis will be used to account for competing risk of death 
9.2.  Planned Subjects Enrolled 
The primary objective of this study is to assess quality of life and determine the toxicity 
associated with SABR, thus the larger the sample size the more confident we can be that adverse 
events are not common with SABR as prescribed and delivered on this protocol. We initially set 
the sample size at 200, but since accrual has been successful, and in order to have more 
confidence in the safety of SABR, we are doubling the sample size to 400. In addition, lymph 
node treatment with SABR is a particular interest, and with 20 patients accrued to date, we must 
increase the sample size in order to accrue 50 patients, which gives us more confidence in a less 
than 10% incidence of grade 4 toxicity (see below). Increasing the sample size to 400 patients 
gives us a 66% chance to accrue over 50 lymph node metastases, while increasing the sample 
size to 300 only gives us a <20% chance of accruing over 50 such patients. 
9.3. Procedures for Reporting Deviations from the Statistical Plan 
Any deviations from the original statistical plan should be described and justified in progress 
and/or in the final report, as appropriate.  

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 47 of 65  
10. Measurement of Study Endpoints 
10.1    Definitions 
10.1.1 Survival outcomes 
Overall survival will be measured as time until death from any cause, and progression-free 
survival as time to either progression or death, whichever occurs first. 
10.1.2 Lesion control rate 
Lesion control rate will be assessed retrospectively as RECIST criteria have not been validated in 
the setting of SABR, and is costly to implement in a prospective cohort. 
10.1.3 Toxicity 
Toxicity will be measured using CTCAE v4.0. 
10.1.4 Quality of Life  
Responses to site-specific POSI questionnaires will be measured before and after treatment. 
 
10.2   Evidence of Disease Recurrence 
Disease recurrence/progression will be detected upon imaging, standard of care testing (e.g. 
biochemical recurrence as evidenced by increases in tumour-specific blood tests past normal 
values), and/or detected upon clinical examination during follow-up visits.  If there is 
progression outside of a SABR site, and it meets RECIST criteria, this may be considered distant 
recurrence, however should be reassessed and confirmed in a subsequent scan as scarring around 
SABR can mimic recurrence. 
10.3   Dating of First Recurrence 
Date of first recurrence will be the date of the scan showing new or progressive growth of 
lesion(s), or the date of laboratory tests showing tumour-specific blood tests increased past 
normal parameters.  
Date of first occurrence must be captured on the HCP-Reported FU form and in REDCap. 
10.4   Management Following Recurrence 
 
Progressive disease 
A primary objective of this study is to assess toxicity, specifically Grade 2 or higher toxicity, of 
SABR used on this study, not overall survival, and therefore strict control of subsequent 
treatments is outside the mandate of this trial. If patients develop new, untreated metastatic 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 48 of 65  
deposits, treatment decisions are up to treating oncologist within the constraints of provincial 
and regional guidelines. The subsequent treatment is not mandated by this study, nor are the 
outcomes recorded for subsequent treatments, but original SABR toxicity on trial should be 
followed as long as feasible for the patient. Patients could be considered for SABR at 
subsequent sites, if such deposits, or progression at previously stable sites, can be treated safely 
with SABR, though ultimately this is a clinical decision outside the mandate of this trial. If 
SABR is not possible, then palliative RT can be delivered if indicated. If a patient progresses at 
the same site they were treated with SABR, then they should be treated with standard of care 
which may involve SABR as long as site can be safely treated, and at the discretion of the 
treating oncologist within the constraints of provincial and regional clinical treatment guidelines. 
 
Follow-up evaluations and questionnaire completions will still be based on schedule 4.8 for the 
original SABR treated sites on trial. However, if necessary, it can be changed at study doctor’s 
discretion if the patient is deteriorating and no longer able to complete questionnaires. The 
questionnaires may be done via mail or telephone call. 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 49 of 65  
11 Discontinuation of Trial and Subject Discontinuation/Withdrawal 
11.1 End of Study Definition 
A subject is considered to have completed the study if he/she has completed all phases of the 
study including the last scheduled procedure shown in the Schedule of Activities.  
The end of the study is defined as the date of the last scheduled procedure shown in the Schedule 
of Activities for the last subject in the trial globally. 
11.2 Discontinuation of trial 
If any Grade 5 Serious Adverse Events (SAEs) definitely, probably, or possibly related to 
protocol treatment occur, all site PIs will be made aware within 1 week of reporting to the 
Sponsor-Investigator/Study PI), and a Data Safety Monitoring Committee (DSMC) meeting will 
be held within one month of the event. During this time, any other patients on treatment to the 
same body site where the Grade 5 toxicity was interpreted to originate, (e.g. adrenal metastases) 
will have their plan reviewed by the PI to determine if that patients’ treatment should be put on 
hold prior to DSMC meeting. 
 
If 3 or more Grade 5 SAEs meet the definition of unanticipated problem (i.e. unexpected, related 
and involving greater risk occur during this study), the study will be temporarily put on hold in 
order to organize a DSMC meeting and initiate conversations with the BC Cancer/UBC REB. 
Depending on the results of these meetings, the study may be permanently closed or significant 
modifications may be made and re-reviewed by the REB (e.g. remove treatments of adrenal 
metastases from the study, or reduce the dose, if toxicity was from this body part treatment with 
SABR). 
 
11.3 Subject Discontinuation/Withdrawal from the Study 
 Subjects may voluntarily discontinue participation in the study at any time. If a subject is 
removed from the study, the clinical and laboratory evaluations that would have been 
performed at the end of the study should be obtained.  If a subject is removed because of 
an adverse event, they should remain under medical observation as long as deemed 
appropriate by the treating physician. A subject may be withdrawn from the study at the 
investigator’s discretion if any exclusion/inclusion criteria have been violated during the 
study, or for safety reasons, etc. 
 At the time of discontinuing from the study, if possible, an early discontinuation/termination 
visit should be conducted. See Section 4.8 for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
 The date and reason for Subject discontinuation must be recorded on the Study Termination 
form in REDCap. 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 50 of 65  
11.4 Post-Trial Follow-up 
There is no planned follow-up at the end of the study. Additional care to be provided to Subjects 
after they complete or discontinue the study will involve standard of care treatment for what is 
normally expected for their condition. 
11.5 Lost to Follow up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
 
Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record. 
 
Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 51 of 65  
12 Regulatory, Ethical, and Study Oversight Considerations  
The Principal Investigator will obtain ethical approval and clinical trial authorization by 
competent authorities according to local laws and regulations. 
12.1 Regulatory and Ethical Considerations 
12.1.1 REB (Research Ethics Board) Approvals for Protocols  
This study will be conducted in accordance with the protocol and with the following: 
 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
 
Applicable laws and regulations. 
The protocol (and any amendments), the informed consent form, and any other written 
information to be given to subjects will be reviewed and approved by a properly constituted 
Institutional Review Board (IRB)/Research Ethics Board (REB), operating in accordance with, 
ICH GCP and local regulatory requirements. A letter to the investigator documenting the date of 
the approval of the protocol and informed consent form will be obtained from the IRB/REB prior 
to initiating the study.  
Site Principal Investigators will be responsible for the following: 
 
Notifying the REB of SAEs and unanticipated problems or other significant safety findings 
as required by REB procedures 
 
Providing oversight of the conduct of the study at the site and adherence to requirements of 
ICH guidelines, the REB and all other applicable local regulations 
12.1.2 Protocol Deviations  
A protocol deviation occurs when the subject, investigator, or staff fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary endpoint 
criteria. Protocol deviations for this study include, but are not limited to, the following: 
 
Failure to meet inclusion/exclusion criteria 
 
Use of a prohibited concomitant medication 
 
Failure to comply with OAR constraints 
 
Failure to comply with treatment dose, fractionations, and/or frequency as specified in this 
protocol 
 
Failure to conduct study follow-up visits and/or to collect study-related data within the 
timeframes as specified in this protocol 
 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
deviation. The Study Principal Investigator will determine if a protocol deviation will result 
in withdrawal of a subject. 
 
When a protocol deviation occurs, it must be documented on the Protocol Deviation Log in 
REDCap. The deviation will be discussed with the investigator and a Protocol Deviation 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 52 of 65  
Report detailing the deviation may be requested. This form will be signed by the Sponsor and 
the Investigator.  The deviation may also require further reporting to the REB.  
 
12.1.3 Informed Consent Process 
The investigator is responsible for obtaining written informed consent from each subject, or if 
the subject is unable to provide informed consent, the subject’s legally acceptable representative, 
prior to beginning any study procedures and treatment(s). The investigator should inform the 
subject, or the subject’s legally acceptable representative, of all aspects of the study, including 
the potential risks and benefits involved.  
The subject should be given ample time and opportunity to ask questions prior to deciding about 
participating in the study and be informed that participation in the study is voluntary and that 
they are completely free to refuse to enter the study or to withdraw from it at any time, for any 
reason.  
The informed consent must be signed and dated by the subject, or the subject’s legally acceptable 
representative, and by the person who conducted the informed consent discussion 
The medical record must include a statement that written informed consent was obtained before 
the subject was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign and date the ICF. 
The process of obtaining informed consent must be documented in the subject’s source 
documents.   
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. 
 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 53 of 65  
12.1.4 Data Protection 
Confidentiality of Subject Records 
The names and personal information of study participants will be held in strict confidence.  All 
study records (case report forms, safety reports, correspondence, etc.) will only identify the 
subject by initials and the assigned study identification number.  The investigator will maintain a 
confidential subject identification list (Master List) during the course of the study.  Access to 
confidential information (i.e., source documents and patient records) is only permitted for direct 
subject management and for those involved in monitoring the conduct of the study (i.e., 
Sponsors, CROs, auditors, representatives of the IRB/REB, and regulatory agencies). The 
subject’s name will not be used in any public report of the study. Any subject records or datasets 
that are transferred to the sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred. 
The subject must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the subject who will be required to give consent for their data to be used as described in the 
informed consent  
12.1.5 Committees Structure 
There is no independent Data and Safety Monitoring Committee (DSMC) for this study. The 
SABR-5 Toxicity Committee will be made up of the study investigators. The committee will 
meet once or twice annually (as required) after study initiation to review toxicity outcomes. If 
any grade 3-5 toxicity is reported, the committee will review the case notes to determine if such 
toxicity is related to treatment. If the committee deems that toxicity rates are excessive (>25% 
grade 3 toxicity, or >10% grade 4 or >3% 5 toxicity), then the committee can, at its discretion, 
recommend cessation of the trial, dose adjustment, or exclusion of certain treatment sites that are 
deemed as high-risk for complications. 
12.5 
   Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
subjects. 
BC Cancer reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Study PI or investigator may include but are 
not limited to: 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 54 of 65  
 
Failure of the investigator to comply with the protocol, the requirements of the REB or 
local health authorities, the sponsor's procedures, or GCP guidelines 
 
Inadequate recruitment of Subjects by the investigator 
If the study is prematurely terminated or suspended, the Sponsor-Investigator/Study PI shall 
promptly inform the Investigators, the REBs, and regulatory authorities as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the subject and 
should assure appropriate subject therapy and/or follow-up 
12.6  
Publication Policy 
 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the Sponsor-Investigator/Study PI to protect proprietary 
information and to provide comments. 
 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor-Investigator/Study PI 
will generally support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 55 of 65  
13 References 
1. Hellman S, Weichselbaum R: Oligometastases. Journal of Clinical Oncology 13:8-10, 1995 
2. Macdermed DM, Weichselbaum RR, Salama JK: A rationale for the targeted treatment of 
oligometastases with radiotherapy. J Surg Oncol 98:202-6, 2008 
3. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. The 
International Registry of Lung Metastases. J Thorac Cardiovasc Surg 113:37-49, 1997 
4. Rusthoven KE, Kavanagh BD, Burri SH, et al: Multi-institutional phase I/II trial of 
stereotactic body radiation therapy for lung metastases. Journal of clinical oncology 27:1579-84, 
2009 
5. Rusthoven KE, Kavanagh BD, Cardenes H, et al: Multi-institutional phase I/II trial of 
stereotactic body radiation therapy for liver metastases. Journal of clinical oncology 27:1572-8, 
2009 
6. Louie AV, Rodrigues G, Yaremko B, et al: Management and prognosis in synchronous 
solitary resected brain metastasis from non-small-cell lung cancer. Clin Lung Cancer 10:174-9, 
2009 
7. Milano MT, Katz AW, Schell MC, et al: Descriptive analysis of oligometastatic lesions treated 
with curative-intent stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 72:1516-22, 
2008 
8. Inoue T, Katoh N, Aoyama H, et al: Clinical outcomes of stereotactic brain and/or body 
radiotherapy for patients with oligometastatic lesions. Jpn J Clin Oncol 40:788-94, 2010 
9. Milano MT, Philip A, Okunieff P: Analysis of patients with oligometastases undergoing two 
or more curative-intent stereotactic radiotherapy courses. Int J Radiat Oncol Biol Phys 73:832-7, 
2009 
10. Treasure T, Fallowfield L, Farewell V, et al: Pulmonary metastasectomy in colorectal cancer: 
Time for a trial. European Journal of Surgical Oncology (EJSO) 35:686-689, 2009 
11. Primrose J, Treasure T, Fiorentino F: Lung metastasectomy in colorectal cancer: is this 
surgery effective in prolonging life? Respirology 15:742-6, 2010 
12. Inoue T, Katoh N, Aoyama H, et al: Clinical Outcomes of Stereotactic Brain and/or Body 
Radiotherapy for Patients with Oligometastatic Lesions. Japanese Journal of Clinical Oncology 
40:788-794, 2010 
13. Timmerman RD: An Overview of Hypofractionation and Introduction to This Issue of 
Seminars in Radiation Oncology. Seminars in Radiation Oncology 18:215-222, 2008 
14. Olson RA, Daudt H, Stephen J, French J, Halperin R, Bahl G, Beckham W, Olivotto I. 
Feasibility of Population-Based Collection of Patient-Reported Outcome Measures in a 
Provincial Radiation Therapy Program. Int J Radiat Oncol Biol Phys 90(1);S718-9, 2014. 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 56 of 65  
15. American Cancer Society. (2015, June 30). A Guide to Radiation Therapy. 
16. Uppal A, Wightman SC, Mallon S, et al: 14q32-encoded microRNAs mediate an 
oligometastatic phenotype. Oncotarget 6:3540-52, 2015 
17. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, et al. The Functional 
Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin 
Oncol. 1993 Mar 1;11(3):570-9. 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 57 of 65  
APPENDIX A - ELIGIBILITY CHECKLIST 
 
Eligibility Checklist for Oligometastatic Disease 
 
You must be able to circle Y (Yes) or N/A to all of the following: 
Y/N: 5 or fewer progressing metastases 
Y/N: Age 18 or older 
Y/N:  Willing to provide informed consent 
Y/N: Patient must have histologically confirmed malignancy with a maximum of 5 
progressing metastatic deposits on imaging.  
Y/N: Not suitable for surgical resection at all sites or decline surgery 
Y/N: Patient has had a CT chest abdomen and pelvis or PET-CT 
Y/N or N/A: Patient has had a nuclear medicine bone scan (if no PET-CT) 
Y/N or N/A:  If solitary lung nodule for which biopsy is unsuccessful or not possible, 
patient has had an FDG PET scan or CT (chest, abdomen, pelvis) and bone 
scan 
Y/N or N/A:  If colorectal primary with rising CEA, but equivocal imaging, patient has had 
an FDG PET scan 
Y/N or N/A: Patient has had CT or MRI brain imaging if primary has a propensity for CNS 
metastases 
Y/N or N/A: Patient has had pulmonary function tests if treating lung lesion(s) and at 
discretion of treating radiation oncologist 
Y/N or N/A:   Patient has had liver function tests if treating liver lesion(s) and at discretion 
of treating radiation oncologist 
Y/N or N/A: Patient is judged able to: 
 
Maintain a stable position during therapy 
 
Tolerate immobilization device(s) that may be required to deliver SABR 
safely 
Y/N or N/A:  Negative pregnancy test for women of child-bearing potential within 4 weeks 
prior to treatment 
Y/N:   
ECOG performance status 0-2 
Y/N: 
Review and consensus by 3 disease site experts, or tumour group conference, 
for eligibility/prognosis (Brain mets must be reviewed by Stereotactic 
Radiosurgery (SRS) rounds) 
Y/N:  
Patient is able and willing to complete study questionnaires 
 
 
Exclusion Criteria 
You must be able to circle N (No) to all of the following: 
 
Y/N:  Previous SABR to the lesion(s) 
Y/N: Lesion in a femoral bone requiring surgical fixation 
Y/N: Persistent malignant pleural effusion 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 58 of 65  
Y/N: Comorbidities precluding radiotherapy 
Y/N: Chemotherapy/systemic therapy within the last 48 hours 
Y/N or N/A: Patients with 1-3 brain metastasis and no disease elsewhere (these patients 
should not be accrued but be treated with stereotactic radiotherapy off trial as per 
results of randomized trials)  
Y/N: Complete response to first-line chemotherapy (i.e. no measurable target for SABR)  
Y/N: Inability to treat all sites of progressing malignant disease  
Y/N: Clinical or radiologic evidence of spinal cord compression 
Y/N: Dominant brain metastasis requiring surgical decompression 
Y/N: A candidate for an open clinical trial at treating centre that randomizes between SABR 
and a standard treatment 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 59 of 65  
APPENDIX B - PATIENT-REPORTED QUALITY OF LIFE – POSI 
 
 
Bone metastases: POSI Brief Pain Inventory questionnaire 
 
Brain metastases: POSI CNS questionnaire 
 
Head & Neck metastases: POSI HN questionnaire, which includes MDASI-HN 
 
Lung metastases: POSI SABR Lung questionnaire, which include the FACT FLSI-12 
 
Abdominal/Adrenal metastases: FACIT AD Version 4 
 
Male Pelvis: SHIM and IPSS questionnaires 
 
Female Pelvis: POSI gyne questionnaire, which includes the EPIC Bowel 2, EPIC Urinary 2, 
PRO-CTAE GI Toxicity, EORTC QLQ CX-24, and EQ5DL 
 
 
 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 60 of 65  
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 61 of 65  
APPENDIX C - RADIATION VOLUMES and DOSES  
For all lesions, the gross tumour volume (GTV) will be defined as the visible tumour on CT 
and/or MRI imaging +/- PET.  
- 
CTV will be added at the discretion of the MRP but in general not needed except in liver 
(~5mm) and spine. 
 
For vertebral lesions, the CTV will be as practice per spine SABR protocol. A Planning Target 
Volume (PTV) margin of 2-5 mm will be added depending on site of disease, immobilization, 
and institutional set-up accuracy: 2 mm margins may be used for spinal stereotactic treatments, 
2 mm for brain tumours, and 5 mm for other sites. In situations where imaging or 
immobilization may be limited, > 5 mm margins may be considered for non-spinal bone 
metastases. 
 
Organs at risk visible in the planning CT scan (Appendix D) will be contoured. For 
radiosurgery platforms, a PTV margin of 0-1 mm is permitted. 
 
For spinal lesions, a pre-treatment MRI is required to assess the extent of disease and position 
of the cord. This must be fused with the planning CT scan. A Planning Organ at Risk Volume 
(PRV) expansion of 2 mm will be added to the spinal cord, and dose constraints for the spinal 
cord apply to this PRV. For radiosurgery platforms, a PRV margin of 1 mm is permitted for 
the spinal cord. 
 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 62 of 65  
APPENDIX D- SABR ORGAN-AT-RISK (OAR) CONSTRAINTS 
 
Dose constraints 
These are based on the AAPM TG 101, SABR-COMET, SC-24 trials as well as most updated references. If any 
structure is not listed, the constraints may be calculated using the linear quadratic formula from accepted 
QUANTEC doses, using an alpha-beta ratio of 3 (except neural structure: alpha-beta of 2) for late effects. 
 
Table 1. Dose and fractionations by site with [secondary options in square brackets] 
 
OAR 
SABR ORGAN-AT-RISK (OAR) CONSTRAINTS 
Dmax to  ≤=0.035cc for all OARs.  
Exception: Dmax to 0cc (hard max)  Spinal cord, Spinal cord PRV, Thecal sac/Cauda Equina 
Fractions 
2  
(for spine mets only as 
per CCTG SC24) 
3 
4 
5 
8 
Spinal Cord PRV  
(2mm on cord) 
(or Spinal Canal) 
Dmax ≤  17 Gy12 
 
Dmax ≤ 20.3 Gy13 
 
 
Dmax ≤ 23 Gy 13 
 
 
Dmax ≤ 25.3 Gy 13 
 
Dmax ≤ 30.6 Gy13 
Spinal Cord PRV 
/Thecal Sac 
(reirradiation) 
See Table 6 below11 
(NB: 1st row with 0 nBED not applicable, see above for 1st time spine treatment ) 
Thecal Sac /  
Cauda equina 
Dmax ≤ 17 Gy12 
 
Dmax ≤ 24 Gy1 
V21.9 Gy ≤ 5 cc1 
 
Dmax ≤ 29 Gy 1* 
V27 Gy ≤ 5 cc1* 
Dmax ≤ 32 Gy1 
V30 Gy ≤ 5 cc1 
Dmax ≤ 39 Gy1* 
V36 Gy ≤ 5 cc1* 
Sacral plexus 
Dmax ≤ 26 Gy12 
(+ nerve roots) 
Dmax ≤ 24 Gy1 
V22.5 Gy ≤ 5 cc1 
Dmax ≤ 29 Gy 1* 
V27 Gy ≤ 5 cc1* 
Dmax ≤ 32 Gy1 
V30 Gy ≤ 5 cc1 
Dmax ≤ 39 Gy1* 
V36 Gy ≤ 5 cc1* 
Brainstem 
 
NA 
(not medulla) 
Dmax ≤ 23.1 Gy1 
V18 Gy ≤ 0.5 cc1 
(not medulla) 
Dmax ≤ 28 Gy1* 
V21 Gy ≤ 0.5 cc1* 
(not medulla) 
Dmax ≤ 31 Gy 1 
V23 Gy ≤ 0.5 cc1 
 
NA 
 
Optic Pathway 
Dmax≤ 15.8 Gy17 
D0.2cc≤ 11.5Gy 17 
Dmax ≤ 19.5 Gy17 
D0.2cc ≤ 15.0 Gy17 
Dmax ≤ 22.5 Gy17 
D0.2cc ≤ 17.5Gy17 
Dmax ≤ 25 Gy17 
D0.2cc  ≤ 20 Gy17 
 
NA 
NA 
Cochlea 
Dmax ≤ 16.5 Gy18 
 
Dmax ≤ 20 Gy18 
 
 
Dmax ≤ 22.5 Gy18 
 
 
Dmax ≤ 25.0 Gy18 
 
 
NA 
Parotids (each) 
Mean ≤ 7 Gy12 
NA 
NA 
NA 
NA 
Pharynx 
Dmax ≤ 20Gy12 
Mean ≤ 9Gy12 
NA 
 
NA 
NA 
 
NA 
Larynx 
Dmax ≤ 20Gy12 
Mean ≤ 9Gy12 
NA 
NA 
NA 
NA 
PBT and PT    
(prox. bronch tree 
& prox. trachea) 
Dmax ≤ 20 Gy12 
 
Dmax ≤ 30 Gy 1 
 
Dmax ≤ 34.8 Gy3 
 
Dmax ≤ 40 Gy1 
 
Dmax ≤ 46.3 Gy3* 
 
 
Lungs-GTV 
 
 
NA 
>1500cc ≤ 11.6 Gy1 
V18 Gy ≤  10%3,8* 
Mean ≤ 5.5 Gy 8* 
1500cc≤ 11.6 Gy3 
V20 Gy ≤ 10%3,8 
Mean ≤ 6 Gy 8 
>1500cc  ≤12.5 Gy1 
V22 Gy ≤ 10%3,8* 
Mean ≤ 6.5 Gy 8* 
> 1500c ≤ 14 Gy3* 
V26Gy ≤ 10%3,8* 
Mean ≤ 7 Gy 8* 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 63 of 65  
OAR 
SABR ORGAN-AT-RISK (OAR) CONSTRAINTS 
 
Dmax to  ≤=0.035cc for all OARs.  
Exception: Dmax to 0cc (hard max)  Spinal cord, Spinal cord PRV, Thecal sac/Cauda Equina 
Fractions 
2  
(for spine mets only as 
per CCTG SC24) 
3 
4 
5 
8 
Each Lung 
V5 Gy ≤ 35%12 
V10 Gy ≤ 10%12 
V20 Gy ≤ 3%12 
Mean ≤ 5 Gy12 
NA 
NA 
NA 
NA 
Chest wall and Ribs: 
Dmax ≤ 36.5 Gy7* 
V25Gy < 30cc6* 
Dmax ≤ 44 Gy 7 
V30 Gy ≤ 30 cc6 
Dmax ≤ 50 Gy 7 
V34 Gy ≤ 30 cc6 
Dmax ≤ 55Gy 7 
V37 Gy ≤ 30cc6 
Dmax ≤ 68 Gy7 
V45 Gy ≤ 30 cc6 
Brachial Plexus 
NA 
Dmax ≤ 24 Gy 1 
V20.4 Gy ≤ 3cc1 
Dmax ≤ 26 Gy 4 
V23.6 Gy ≤ 3 cc 3 
Dmax ≤ 30.5 Gy 1 
V27 Gy ≤ 3 cc1 
Dmax ≤ 35 Gy 4 
Heart / Pericardium 
NA 
 
Dmax ≤ 30 Gy1 
V24 Gy ≤ 15 cc1 
 
Dmax ≤ 34 Gy 3 
V28 Gy ≤ 15 cc 3 
Dmax ≤ 38 Gy1 
V32 Gy ≤ 15 cc1 
Dmax ≤ 46 Gy  2 
V39 Gy ≤ 15 cc 2 
Great Vessels 
 
Dmax ≤ 40 Gy20 
 
Dmax ≤ 44 Gy20 
Dmax ≤ 49.0 Gy20 
Dmax ≤ 51.5 Gy20 
Dmax ≤ 65 Gy  2 
Skin 
 
Dmax < 26 Gy1* 
V24 Gy < 10 cc1* 
Dmax ≤ 33 Gy1 
V30Gy ≤ 10 cc1 
Dmax ≤ 36 Gy 3 
V33.2 Gy ≤ 10 cc 3 
Dmax ≤ 39.5 Gy1 
V36.5 Gy ≤ 10 cc1 
Dmax ≤ 48 Gy3* 
V44 Gy ≤ 10 cc3* 
Esophagus 
Dmax ≤ 20 Gy12 
 
Dmax ≤ 27.0 Gy21 
Dmax ≤ 30 Gy 3, 21 
Dmax ≤ 35 Gy1, 21 
Dmax ≤ 40 Gy 2 
Stomach 
 
Dmax ≤ 20 Gy12 
Dmax ≤ 22.2 Gy1 
 
(Dmax ≤25 Gy 
if PTV close by; MRP to 
specify14) 
Dmax ≤ 27  3 
Dmax ≤ 32 Gy1 
 
(Dmax ≤ 35 Gy 
if PTV close by ; 
MRP to specify14 ) 
Dmax ≤ 40 Gy 2 
Duodenum 
 
 
Dmax ≤ 20 Gy12 
 
 
Dmax ≤ 22.2 Gy1 
 
(Dmax ≤25 Gy 
f PTV close by ; MRP to 
specify14) 
Dmax ≤ 29.0 Gy1* 
 
Dmax ≤ 32 Gy1,22 
 
Dmax ≤ 35 Gy if PTV 
close by ; 
MRP to specify14 ) 
 
Dmax ≤ 39 Gy 2 
 
Small Bowel 
(Jejunum/ileum) 
Dmax ≤ 20 Gy12 
 
 
 
Dmax ≤ 25.2 Gy1, 23 
 
 
 
Dmax ≤ 28.5 Gy23 
 
 
 
Dmax ≤ 29.0 Gy23 
 
(Dmax ≤ 35 Gy1    
if PTV close by MRP to 
specify) 
Dmax ≤ 40 Gy 2 
 
 
 
Large Bowel 
(Colon, Rectum) 
Dmax ≤ 20 Gy12 
Dmax ≤ 28.2 Gy 1 
Dmax ≤ 34.5 Gy 1* 
Dmax ≤ 38 Gy 1 
Dmax ≤ 46 Gy1 
Kidneys (each) 
Dmax ≤ 26 Gy12 
Mean ≤ 6 Gy 12 
(*each kidney) 
NA 
NA 
NA 
NA 
Renal Cortex (Kidneys) 
(R & L combined) 
See  
“Kidneys (each)” 
> 200 cc ≤ 14.4 Gy2 
> 200 cc < 16.2Gy1* 
> 200cc ≤ 17.5 Gy1 
> 200 cc ≤ 21 Gy 2 
Liver 
(Liver minus GTV) 
 
Dmax ≤ 26 Gy12 
Mean ≤ 8 - 9 Gy12    
>700 cc ≤ 17 Gy1 
>700 cc ≤ 19 Gy 1* 
> 700 cc ≤ 21Gy1 
> 700 cc ≤ 22 Gy2 
Bladder Wall 
 
NA 
Dmax ≤ 28.2 Gy1 
Dmax ≤ 34.5 Gy 1* 
Dmax ≤ 38 Gy1 
 
NA 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 64 of 65  
           Penile Bulb 
 
 
NA 
Dmax ≤ 42 Gy 1 
V21.9 Gy ≤ 3 cc1 
NA 
Dmax ≤ 50 Gy1 
V30 Gy ≤ 3 cc1 
 
NA 
     Femoral Heads 
    (R & L combined) 
NA 
V21.9 Gy ≤ 10 cc1 
V27 Gy ≤ 10 cc 1* 
V30 Gy ≤ 10 cc1 
NA 
*Values are EQD2 conversion from stated reference 
 
 
1  Benedict SH et al., AAPM TG101, Med.Phys 37(9), 2010 (NB: max pt = 0.035cc) 
2   Palma et al., SABR-COMET Trial, Palma et al, v.1.9, Apr 2015   
3  RTOG 0915, http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0915. 
4  Forquer JA et al., Radiother Onc, 93:408-413,  2009  
          
 
5  Karlsson K et al., IJROBP, 87(3): 590-595, 2013 
6  Dunlap NE et al., IJROBP 76(3): 796-801, 2010 
 
 
  
 
7 Andolino DL et al., IJROBP 80(3): 692-697, 2011 
8  Baker R, IJROBP, 85(1):190-195, 2013   
 
 
         
9 Matsuo Yet al., IJROBP, 83(4): e545-549, 2012. 
10 Bongers EM et al., Radiother Onc, 109: 95-99, 2013 (VU EMC TO 2013)     
11 Sahgal A et al., IJROBP, 82(1):107-116, 2012 
 
12 Sahgal et al., NCIC CTG Protocol #SC.24. Feb 2, 2017 
13 Sahgal A et al., IJROBP, 85(2):341-7, 2013 ( Table 5; using 5% risk as per Sahgal ; personal communication Feb 2017 ) 
 
14 BCCA liver protocol 2011 
15 Velec M, et al, IJROBP (2017), doi: 10.1016/j.ijrobp.2017.01.221 
        
16 Grimm, et al, JACMP (2011), 12(2) 267 
17Hiniker, et al., Sem Radiat Oncol 26(2), 97-104, 2016.  DOI: (10.1016/j.semradonc.2015.11.008)  
18Rashid, et al., Sem Radiati Oncol 26(2) 105-111, 2016. DOI: (10.1016/j.semradonc.2015.11.004) 
19Kimsey et al., Sem Radiat Oncol 26(2), 129-134, 2016. DOI: (10.1016/j.semradonc.2015.11.003)  
20Xue et al, Sem Radiat Oncol 26(2), 135-139, 2016.  DOI: (10.1016/j.semradonc.2015.11.001) 
21Nuyttens et al., Sem Radiat Oncol 26(2), 120-128, 2016. DOI: (10.1016/j.semradonc.2015.11.006)  
22Goldsmith et al., Sem Radiat Oncol 26(2), 149-156, 2016. DOI: (10.1016/j.semradonc.2015.12.002)  
23 LaCouture et al., Sem Radiat Oncol 26(2), 157-164, 2016. DOI: (10.1016/j.semradonc.2015.11.009) 
 
 
 
 

  
 
 
 
Protocol: SABR-5 
 
CONFIDENTIAL 
 
Page 65 of 65  
PROTOCOL SIGNATURE PAGE 
 
Protocol Title:  Phase II non-randomized Trial of Stereotactic Ablative Radiotherapy (SABR) 
for Oligometastases 
 
Protocol Version/ Date: _________________________________ 
 
Sponsor/Study Principal Investigator Name: 
Dr. Robert Olson 
 
 
Site: _____________________ 
 
 
Declaration of Investigator 
 
I confirm that I have read the above-mentioned protocol and its attachments, and I agree to: 
 conduct the described trial in compliance with all stipulations of the protocol, with 
applicable regulatory requirement(s), and ICH E6 Guideline for Good Clinical Practice 
(GCP);  
 comply with procedures for data entry/recording/reporting as outlined in the data 
management plan;  
 permit monitoring, auditing and inspection; and  
 retain the trial related essential documents until Dr. Robert Olson (Study Principal 
Investigator) informs me that these documents are no longer needed. 
 
 
 
Site Principal Investigator Name:  ______________________________________ 
                                                            
 
Site Principal Investigator Signature:  ___________________________________ 
                                                            
 
Date:  __________________________________________