Phase III Randomized Controlled Trial and Economic Evaluation of Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic (1-3 Metastases) Cancer (SABR-COMET-3)
Phase: NA
Conditions: Metastatic Tumors
Sponsor: British Columbia Cancer Agency

  
 
 
 
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Protocol Title: Phase III Randomized Controlled Trial and Economic Evaluation of Stereotactic 
Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic (1-3 
metastases) cancer: SABR-COMET-3 
Protocol Number: 
Version Number and Date:  13.0; 15 May 2024 
Study Phase: III 
Short Title: SABR-COMET-3 
Sponsor Name: BC Cancer – Prince George 
 
Version 1.0: 06 Aug 2018 
Version 2.0: 22 Feb 2019  
Version 3.0: 18 Sept 2019 
Version 4.0: 04 Oct 2019 
Version 5.0: 24 Feb 2020 
Version 6.0: 07 Aug 2020 
Version 7.0: 14 Jul 2021 
Version 8.0; 08 Oct 2021 
Version 9.0; 04 Jan 2022 
Version 10.0; 11 Mar 2022 
Version 11.0; 01 Jun 2022 
Version 12.0; 01 May 2023 
 
 
 

  
 
 
 
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Table of Contents 
 
Table of Contents ...........................................................................................................................2 
I. 
Signature of Principal Investigator ...............................................................................5 
1. 
Protocol Summary ..........................................................................................................9 
1.1. 
Synopsis ............................................................................................................................9 
2. 
Introduction ...................................................................................................................16 
2.1. 
Trial Rationale and Background .....................................................................................16 
2.2. 
Radiation Treatment Overview .......................................................................................18 
 
Radiation therapy – Standard of Care (SOC) Arm (Arm 1) ...........................................18 
 
Radiation therapy – Experimental Arm – SABR (Arm 2) ..............................................18 
 
Sample Collection Schedule ...........................................................................................20 
2.3. 
Study Population .............................................................................................................20 
3. 
Trial Design ...................................................................................................................21 
3.1. 
Study Objectives and Endpoints .....................................................................................21 
3.2. 
Entry Procedures .............................................................................................................22 
a) 
Randomization ................................................................................................................24 
b) 
Blinded/Unblinded ..........................................................................................................24 
3.3. 
Study Duration ................................................................................................................24 
4. 
Eligibility........................................................................................................................25 
4.1. 
Inclusion Criteria ............................................................................................................25 
4.2. 
Exclusion Criteria ...........................................................................................................26 
4.3. 
Subject Withdrawal Criteria ...........................................................................................27 
 
Informed Consent............................................................................................................27 
4.4. 
Screen Failures ................................................................................................................28 
4.5. 
Availability for follow up ...............................................................................................28 
4.6. 
Ability to tolerate current treatment................................................................................28 
4.7. 
Biopsy/ Blood banking ...................................................................................................28 
4.8 
Schedule of Activities .....................................................................................................30 
4.8.1 
Investigations Prior to Randomization/Study Entry, During Trial 
and Follow-up .................................................................................................................31 
5. 
Subject Treatment Plan................................................................................................34 
5.1. 
Trial Treatment Summary ...............................................................................................34 
 
Standard Arm (ARM 1) ..................................................................................................34 
 
Experimental – SABR (ARM 2) .....................................................................................34 
5.1.3 
Duration of Study ............................................................................................................39 
5.2 
Data Handling and Recordkeeping .................................................................................39 
5.2.1 
Subject Reported Outcomes – Questionnaires ................................................................40 

  
 
 
 
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5.2.2 
Records Retention ...........................................................................................................41 
5.3 
Lifestyle Considerations, Prohibited Food and Additional 
Restrictions .....................................................................................................................41 
5.3.1 
Required Therapy............................................................................................................41 
5.3.2 
Permitted Concomitant Therapy .....................................................................................41 
5.3.3 
Prohibited Concomitant Therapy ....................................................................................41 
5.3.4 
Herbal Therapies .............................................................................................................41 
5.3.5 
Data Records for Concomitant Medications ...................................................................41 
5.4 
Co-enrolment ..................................................................................................................42 
5.5 
Subject Compliance/Deviations ......................................................................................42 
6.  
Dose Modifications ........................................................................................................43 
6.1 
General Toxicity Management .......................................................................................43 
6.2 
Interruptions (Arm 1 and Arm 2) ....................................................................................43 
6.3 
Missed Doses (Arm 2 (SABR))  .....................................................................................43 
7. 
Assessment of Efficacy..................................................................................................44 
8. 
Assessment of Safety .....................................................................................................46 
8.1 
Specification of Safety Parameters .................................................................................46 
8.2 
Recording and Reporting of Adverse Events (Aes)........................................................46 
8.2.1 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................46 
8.2.2 
Method for Detecting Aes and SAEs ..............................................................................46 
8.4 
Pregnancy........................................................................................................................49 
9. 
Statistics ..........................................................................................................................50 
9.1 
Statistical Methods ..........................................................................................................50 
9.2 
Planned Subjects Enrolled ..............................................................................................53 
9.3 
Procedures for Reporting Deviations from the Statistical Plan ......................................53 
10. 
Measurement of Study Endpoints ...............................................................................54 
10.1 
Definitions ......................................................................................................................54 
10.1.1 
Overall (OS) and Progression-Free Survival (PFS) ........................................................54 
10.1.2 
QOL measurement after treatment..................................................................................55 
10.1.3 
Toxicity ...........................................................................................................................55 
10.1.4 
Resource Utilization........................................................................................................55 
10.1.5 
Biomarkers ......................................................................................................................55 
10.2 
Evidence of Disease Recurrence.....................................................................................55 
10.3 
Dating of First Recurrence ..............................................................................................56 
10.4 
Management Following Recurrence ...............................................................................56 
11. 
Discontinuation of Trial and Subject 
Discontinuation/Withdrawal........................................................................................57 
11.1 
End of Study Definition ..................................................................................................57 

  
 
 
 
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11.2 
Discontinuation of trial ...................................................................................................57 
11.3 
Subject Discontinuation/Withdrawal from the Study .....................................................57 
11.4 
Post-Trial Follow-up .......................................................................................................57 
11.5 
Lost to Follow up ............................................................................................................57 
12. 
Regulatory, Ethical, and Study Oversight Considerations .......................................59 
12.1. 
Regulatory and Ethical Considerations...........................................................................59 
12.1.1 
Approvals for Protocols ..................................................................................................59 
12.1.2  Protocol Deviations.........................................................................................................59 
12.2. 
Informed Consent Process ..............................................................................................60 
12.3. 
Data Protection ...............................................................................................................61 
12.4. 
Committees Structure .....................................................................................................61 
12.5. 
Study and Site Start and Closure ....................................................................................61 
12.6. 
Premature Termination or Suspension of Study .............................................................62 
12.7. 
Publication Policy ...........................................................................................................62 
12.8. 
Financial Support ............................................................................................................62 
12.9. 
Trial Management ...........................................................................................................62 
13. 
References ......................................................................................................................64 
 
 
 
 
 
 
 
 

  
 
 
 
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I. 
Signature of Principal Investigator  
I agree to the terms of this clinical trial protocol and all amendments.  I will conduct the trial in 
compliance with all stipulations of the protocol, according to the principles of ICH Good Clinical 
Practice (GCP) and any applicable local regulations. 
 
 
See electronic signature 
Dr. Robert Olson 
 
 
Date 
 
 
 
 
 
 
 
 
 
 

  
 
 
 
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I. 
Contact Details of Key Personnel  
 
Study Principal Investigator: 
Dr. Robert Olson (Radiation Oncologist) 
BC Cancer – Prince George 
250-645-7325 
 
Primary Contact and Lead for study management: 
Lindsay Mathews (Study Coordinator) 
BC Cancer – Prince George 
250-645-7300 ext. 687427 
 
 

  
 
 
 
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II. 
LIST OF ABBREVIATIONS  
Abbreviations 
Description of Abbreviations 
AE 
Adverse event 
BPI 
Brief Pain Inventory 
CRF 
Case report form 
CI 
Confidence Interval 
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 
EORTC 
European Organisation for Research and Treatment of Cancer. 
EQ-5D-5L 
EuroQol-5 Dimension-5 Level 
FACT 
Functional Assessment of Cancer Therapy 
GCP 
Good Clinical Practice 
GTV 
Gross Tumour Volume 
Gy 
Gray 
HCP 
Health Care Provider 
HRQoL 
Health-Related Quality of Life 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
OAR 
Organs at Risk 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression free survival 
PRO 
Patient Reported Outcomes 

  
 
 
 
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PTV 
Planning Target Volume 
QALYS 
Quality-Adjusted Life Year 
QoL 
Quality of Life 
REB 
Research Ethics Board 
RECIST 
Response evaluation criteria in solid tumors 
RT 
Radiation therapy 
SABR 
Stereotactic Ablative Radiotherapy 
SAE 
Serious adverse event 
SOP 
Standard Operating Procedure 
SPI 
Study Principal Investigator 

  
 
 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Date and Version # of Protocol: 
  15 May 2024, Version 13.0 
Sponsor: BC Cancer 
 
Name of Study Method: 
Randomized Controlled Trial 
Phase of Development: 
III 
Title of Study: 
Phase III Randomized Controlled Trial and Economic Evaluation of Stereotactic Ablative 
Radiotherapy (SABR) for Comprehensive Treatment of Oligometastatic (1-3 metastases) 
cancer: SABR-COMET-3 
Study Design Overview/Rationale: 
This is a study assessing the impact of SABR, compared to standard of care treatment, on 
overall survival, oncologic outcomes, and quality of life in *patients with 1-3 metastatic 
lesions. 
*Note: the terms patients and subjects are used interchangeably in this protocol 
Trial Design and Schema 
 
Radiation Treatment Plan Arm 1: Standard of Care (SOC) 
Table 1. Dose and Fractionation - SOC 
Dose (Gy) 
Fractions 
Dose/Fractionation 
8 Gy 
1 
8Gy 
20 Gy 
5 
4Gy 
30 Gy 
10 
3Gy 

  
 
 
 
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Radiation Treatment Plan (Arm 2):  
Table 2 Dose and fractionations by site with [secondary options in square brackets] 
 Location 
Dose (Gy) 
Fractions 
Dose per fraction 
(Gy) 
Frequency 
Lung  
 
Tumors 5 cm or less 
surrounded by lung 
parenchyma  
48 Gy [54 Gy] 
 
4 [3] 
12 Gy [18 Gy] 
Daily, or Every 
second day 
Within 2 cm of mediastinum 
or brachial plexus  
60 Gy 
8 
7.5 Gy 
Daily 
Bone  
Any bone 
35 Gy [24] 
5 [2] 
7 Gy [12 Gy] 
Daily  
Brain 
Stereotactic lesions 
(no whole brain 
Radiation Therapy 
[RT]) 
< 2cm 
20-24 Gy 
1 
20-24 Gy 
Once 
2-3 cm 
18 Gy 
1 
18 Gy 
Once 
Metastases only  
35 Gy  
5 
7 Gy to PTV  
Daily  
Whole brain + Metastases  
35 Gy to 
metastases  
20 Gy whole brain  
5 
7 Gy to PTV 
4 Gy WBRT  
Daily  
Liver  
54 Gy 
3 
18 Gy 
Every second 
day  
Adrenal / Pancreas 
40 Gy [35 Gy] 
5 
8 Gy [7 Gy] 
Daily  
Lymph Node/Soft Tissue  
40 Gy  
5 
8 Gy 
Daily  
*Either bone or positron emission tomography (PET) scan is required. If PET is done, bone scan is not 
required (or vice versa) 
 
Disease Assessment: 
▪ 
Eastern Cooperative Oncology Group (ECOG) performance status 
▪ 
Overall Survival 
▪ 
Progression Free Survival 
▪ 
Patient Reported Outcomes (i.e. Quality of life assessment, questionnaires, etc.) 
▪ 
Provider Reported Toxicity (as per Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0) 
▪ 
Health Related Quality of Life 
▪ 
Correlation between candidate biomarkers and oncologic outcomes 
Study Population 
Patients diagnosed with 1 controlled primary tumour and 1-3 current metastatic lesions, and maximum 
of 8 lifetime metastatic lesions, as evidenced by imaging, meeting all eligibility criteria 

  
 
 
 
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Study Objectives: 
Primary Objective 
To compare the effect of SABR and Standard of Care (SOC), relative to SOC alone, on overall survival 
(OS) in patients with controlled primary solid tumors and 1-3 current metastatic cancer lesions. 
Secondary Objectives: 
Secondary Objectives: 
• 
To compare side effects, in terms of the occurrence of grade 2 or higher adverse events 
• 
To compare changes in progress-free survival (PFS) 
• 
To compare changes in patient-reported quality of life (QoL) 
• 
To estimate the cost-effectiveness of SABR versus SOC 
• 
To assess the correlation between candidate biomarkers of oligometastatic disease (blood- derived) 
and oncologic outcomes, including response to SABR, disease progression, and overall survival 
 
Number of Subjects/Sample Size Calculations  
330 subjects will be accrued 
The results of the original SABR-COMET phase II trial demonstrated median OS of 28 months in the 
standard arm, 41 months in the experimental arm, and a 22% improvement in 5-year OS. Based on 
these results, this phase III trial initially aimed to detect a Hazard Ratio of death of 0.66 in the 
experimental arm compared to the standard arm (i.e. a 40% reduction in the hazard rate of death). A 5-
year OS of 20% had been assumed for the standard arm; the HR of 0.66 represents a 15% improvement 
in OS, smaller than the effect observed in the phase II trial. In order to detect this difference, with 80% 
power, alpha of 0.05, and an 8% dropout rate, assuming 5 years of accrual and a total trial time of 8 
years, 297 patients would be required (i.e. 99 in Arm 1 and 198 in Arm 2).  
Amendment June 2022: 
Study sample size was increased to 330 (110 in Arm 1 and 220 in Arm 2). This sample size will 
provide 80% power to detect an improvement in median OS from 16 months to 27 months allowing for 
5% dropout. This assumes 5 years of accrual and 1 year of additional follow-up.  
Planned Study Period: 
Anticipated length of study is 11 years 
Inclusion Criteria: 
Subjects must meet all of the following criteria to be eligible for participation in this study: 
• 
Total number of 1-3 current metastases, and a maximum 8 lifetime metastases 
• 
Age 18 or older 
• 
Able to provide informed consent 
• 
Life expectancy >6 months 

  
 
 
 
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• 
Histologically confirmed malignancy with metastatic disease detected on imaging. Biopsy of 
metastasis is preferred, but not required. 
• 
ECOG performance status 0 – 2 
• 
Controlled primary tumor 
▪ 
defined as at least 3 months since original tumor treated definitively, with no progression 
at primary site (can be considered controlled if no evidence of the primary tumour on 
imaging) 
• 
A history and physical exam, including ECOG performance status, performed within 6 weeks 
prior to trial enrollment 
• 
Not suitable for resection at all sites or declined surgery 
• Subject has had a CT chest, abdomen and pelvis or PET-CT within 8 weeks prior to 
enrollment, and with 12 weeks of treatment. CT neck as clinically indicated. 
• 
Patient has had a nuclear bone scan (if no PET-CT) within 8 weeks prior to enrollment, and 
within 12 weeks prior to treatment (if randomized to SABR) 
• 
If solitary lung nodule for which biopsy is unsuccessful or not possible, patient has had an 
FDG (fluorodeoxyglucose) PET scan or CT (chest, abdomen, pelvis) and bone scan within 8 
weeks prior to enrollment, and with 12 weeks prior to treatment (if randomized to SABR).  CT 
neck as clinically indicated. 
• 
If colorectal primary with rising Carcinoembryonic antigen (CEA), but equivocal imaging, 
patient has had an FDG PET scan within 8 weeks prior to enrollment, and with 12 weeks prior 
to treatment (if randomized to SABR) 
• 
Patient has had CT or MRI brain imaging if primary has a propensity for CNS metastasis 
within 8 weeks prior to enrollment, and with 12 weeks prior to treatment (if randomized to 
SABR) 
• 
Patient is judged able to: 
• 
Maintain a stable position during therapy  
• 
Tolerate immobilization device(s) that may be required to deliver SABR safely 
• 
Negative pregnancy test for Women of Child-Bearing Potential (WOCBP) within 4 weeks of 
RT start date  
• 
Patient is able and willing to complete the quality of life questionnaires, 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) 
Waivers to inclusion criteria will NOT be allowed. 
 
Exclusion Criteria: 
• 
Lesion in femoral bone requiring surgical fixation 
• 
Chemotherapy agents (cytotoxic, or molecularly targeted agents) used within the period of time 
commencing 2 weeks prior to radiation, lasting until 1 week after the last fraction for patients 
randomized to SABR. 
• 
Serious medical comorbidities precluding radiotherapy. These include interstitial lung disease 
in patients requiring thoracic radiation, Crohn’s disease in patients where the GI tract will 
receive radiotherapy, and connective tissue disorders such as lupus or scleroderma. 

  
 
 
 
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• 
Substantial overlap with a previously treated radiation volume. Prior radiotherapy in general is 
allowed, as long as the composite plan meets dose constraints herein. For patients treated with 
radiation previously, biological effective dose calculations should be used to equate previous 
doses to the tolerance doses listed below. All such cases should be discussed with the local and 
study PIs. 
• 
Concurrent malignant cancer, or history of malignant cancers within the past 5 years 
• 
Malignant pleural effusion 
• 
History of poor lung function (if treating near lung) 
• 
History of poor liver function (if treating near liver) 
• 
Inability to treat all sites of disease 
• 
Maximum size of 5 cm for lesions outside the brain, except: 
o Bone metastases over 5 cm may be included, if in the opinion of the local PI it can be 
treated safely (e.g. rib, scapula, pelvis) 
o Any brain metastasis >3 cm in size or a total volume of brain metastases greater than 
30 cc 
• 
Clinical or radiologic evidence of spinal cord compression, or epidural tumor within <2 mm of 
the spinal cord. Patients can be eligible if surgical resection has been performed, but the 
surgical site counts toward the total of up to 8 lifetime metastases (see section 3.2). 
• 
Dominant brain metastasis requiring surgical decompression 
• 
Pregnant or breastfeeding women 
Waivers to exclusion criteria will NOT be allowed. 
 
Concomitant Medication Restrictions or Requirements: 
Required / Permitted:  
Previous systemic, radiation, and hormone therapy is permitted. Hormone therapy is allowed during 
treatment. 
All cancer-specific concomitant medications that the subject is using should be recorded. 
 
Restrictions (for patients randomized to SABR):  
• 
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, 
adriamycin/doxorubicin, bevacizumab) are discouraged within the first month after radiation.  
Schedule of Study Assessments and Procedures: 
For Schedule of Assessments refer to Section 4.8. 

  
 
 
 
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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 record15. Grade 2 or 
higher toxicities that are possibly, probably, or definitely related to any cancer treatment must be 
documented and reported as AEs/SAEs for both arms. 
 
All Grade 3 or higher toxicities, related or not to cancer treatment, must also be documented, though 
start and stop dates do not need to be collected for toxicities considered to be unrelated or unlikely 
related to cancer treatment 
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 as per REB and institutional reporting guidelines.  
Conditions that are NOT considered a SAE will not be included in this protocol, e.g., hospitalizations 
for routine procedures, disease progression, death due to disease progression. 
Formal Stopping Rules: 
Accruing 330 subjects will increase confidence in the safety of SABR treatment (i.e. less grade 4 or 5 
toxicity, etc.). 
There will be 3 interim analyses. The data and safety monitoring committee (DSMC) will conduct the 
first interim analysis once 50 patients are accrued. For this analysis, the DSMC will be blinded to the 
identity of each treatment arm, but OS data will be presented for each arm, and treatment doses and 
volumes will be presented for SAEs reviewed. There are two planned interim analyses for efficacy in 
addition to the final analysis. The two interim analyses are expected to be carried out when the total 
number of observed study deaths reaches 40 and 65, thus treatment details will be reviewed to 
determine plausible causation of toxicities. As such, interim efficacy analyses will not be blinded.  The 
DSMC will recommend stopping the trial if there is an OS difference that is statistically significant 
with a threshold of p<0.001 using the log-rank test. The final analysis is expected to be carried out 3 
years after the enrollment of the last subject.  
Statistical Evaluations:  
Patients will be analyzed in the groups to which they are assigned (intention-to-treat).  
Survival Endpoints 
Progression-Free Survival (PFS) and Overall Survival (OS) will be calculated using the Kaplan-Meier 
method with differences compared using the stratified log-rank test. Pre-planned subgroup analysis will 
occur based on the stratification factors, and also based on the use of immunotherapy vs. non-
immunotherapy systemic agents. A Cox multivariable regression analysis will be used to determine 

  
 
 
 
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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. 
Secondary Endpoints 
Quality of life at 6 months will be measured using FACT, Cancer Specific Questionnaires, and EQ-5D-
5L scores, with differences between groups tested using the Student’s t-test.  Differences in rates of 
grade 2 or higher toxicity between groups will be tested using the Fisher’s Exact Test. EQ-5D-5L 
scores will be converted to quality -adjusted life years (QALYS) and combined with resource 
utilization data for the cost utility analysis (restricted to Canada). 
Endpoints for Evaluation: 
Overall Survival 
Progression-Free Survival 
Toxicity 
Quality of Life  
Health-Related Quality of Life 
Resource Utilization 
Correlation between candidate biomarkers of oligometastatic disease (blood-derived) and oncologic 
outcomes 

  
 
 
 
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2. 
Introduction 
2.1. 
Trial Rationale and Background 
The oligometastatic state refers to a stage of disease where a cancer has spread beyond the site 
of the primary tumour, but is not yet widely metastatic.1 In patients with a limited 
oligometastatic burden, emerging evidence suggests that treatment of all sites of disease with 
ablative therapies (such as surgery or stereotactic radiation) can improve patient outcomes, 
including overall- and progression-free survival. 
Historically, evidence to support the oligometastatic state has consisted of single-arm, non-
randomized studies without controls2,3. One classic study reported on over 5000 patients with 
lung metastases from a variety of primary tumours. In patients who achieved a complete 
resection of their lung metastases, 5-year overall survival (OS) was 36%, better than might be 
expected for a cohort of patients with metastatic disease.2 Similarly, after radiation, a recent 
pooled analysis of 361 patients with oligometastatic lesions treated with radiation demonstrated a 
3-year OS of 56%.3 
It has been suggested the long-term survivals achieved in patients with oligometastases after 
ablative therapies is merely due to the selection of very fit patients with slow growing tumours, 
since randomized evidence to support the oligometastatic paradigm has been lacking.4,5 
However, at least four recent randomized phase II trials now provide some supporting, though 
non-conclusive, evidence.  
 
Randomized Evidence Supporting the Oligometastatic State 
Two of these trials supporting the use of oligometastatic treatment were done in the setting of 
oligometastatic non-small cell lung cancer. In both, patients presented with a primary lung 
tumour and a limited number of metastatic lesions (1-3 in one trial, 1-5 in the other), and after 
initial systemic therapy, patients were randomly assigned to standard palliative treatments vs. 
consolidative ablative treatments to all sites of disease. Both trials were stopped early due to 
evidence of efficacy, with the ablative treatments achieving a ~3-fold improvement in 
progression-free survival (PFS)5,6. No OS data was reported in these trials but based on their 
results, the phase III NRG LU-002 trial is assessing the impact of consolidative ablative 
therapies on OS.   
A third trial, EORTC 40004, examined the impact of an ablative therapy (radiofrequency 
ablation [RFA]) in patients with colorectal cancer metastatic to the liver. In this trial, patients 
with a controlled primary tumour and fewer than 10 hepatic metastases not amenable to 
resection, and with no extra-hepatic disease, were randomized to systemic therapy +/- RFA to all 
sites of disease67,. When initially reported, the trial showed no difference in OS between arms, 
but with long-term follow-up (median 9.7 years), a significant difference in OS emerged, with an 
8-year OS of 36% in the RFA arm and only 9% in the systemic therapy arm7,8.  

  
 
 
 
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The fourth trial, Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of 
Oligometastatic Disease (SABR-COMET) enrolled 99 patients who had controlled primary solid 
tumours and up to 5 metastatic lesions7. Patients were randomized in a 1:2 ratio between 
standard of care (SOC) palliative treatments (Arm 1) vs. SOC + SABR to all sites of disease 
(Arm 2).9 The primary endpoint was OS, and the trial employed a randomized phase II screening 
design, with an alpha of 0.2, in order to provide an initial comparison between arms. More than 
90% of patients enrolled had 1-3 metastases7. OS was 28 months in Arm 1 and 41 months in 
Arm 2 (p=0.09), meeting the primary endpoint of the trial. PFS was doubled: 6 months in Arm 1 
and 12 months in Arm 2 (p=0.001). SABR was generally well tolerated, with a 29% rate of grade 
2 or higher toxicity, although the rate of treatment-related grade 5 toxicity was 4.5%9. 
The results of SABR-COMET met the pre-specified primary endpoint, with a trend toward 
improved OS with SABR, and have informed the design of this phase III randomized trial. This 
phase III trial will focus specifically on patients with 1-3 metastases, which comprised 92% of 
the patients on the SABR-COMET trial, as there was reluctance to accrue patients with 4-5 
metastases, and theoretically survival benefit is hypothesized to be greatest in those with 1-3 
metastases. This phase III trial incorporates stratification by histology and disease-free interval, 
as well as both economic and translational aims. 
 
Translational Studies: Background & Rationale 
At the present time, there are no biomarkers that define the oligometastatic state.  The closest to a 
defining biological feature is tumour histology, of which breast, kidney, and prostate are associated 
with improved OS in patients with clinical oligometastatic disease10. Key clinical characteristics - 
colloquially termed ‘The Four Aces’10 - help to identify a patient sub-population with metastatic 
cancer that is most likely to benefit from ablation of all sites of disease. 
Even within this group, however, outcomes can be variable: while some patients exhibit long 
disease-free intervals and better-than-expected overall survival following ablation of metastases, 
others progress rapidly and extensively with poor survival outcomes12. Elucidating the biological 
mediators underlying a more indolent, sequential pattern of progression (i.e., oligometastasis) 
versus rapid, “poly-metastatic” progression will allow for more accurate selection of patients 
whose intrinsic natural history of disease make them more likely to benefit from ablation. 
Specific biological characteristics of oligometastatic disease could provide important predictive 
biomarkers in this setting, but have thus far remained elusive.  Studies up to this point have focused 
on micro-RNA (ribonucleic acid) profiling, but unfortunately these studies have not identified an 
miRNA (microRNA) expression signature that consistently defines patients with few metastases13-
15. No other studies to our knowledge have sought to identify specific biomarkers of 
oligometastasis. While a wide array of pre-clinical analyses have identified genetic and epigenetic 
alterations associated with metastasis in general,16 it remains to be determined which of these 
features represent useful biomarkers in differentiating rapid and widely metastatic cancer from an 

  
 
 
 
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oligometastatic natural history.  As such, the purpose of the translational arm of this trial is to 
assess the correlation between candidate biomarkers of oligometastatic disease (blood- 
derived) and oncologic outcomes including response to SABR, disease progression, and 
overall survival.  
 
2.2. 
Radiation Treatment Overview 
 
 
 Radiation therapy – Standard of Care (SOC) Arm (Arm 1) 
Arm 1 (SOC): Radiotherapy (RT) for patients in the standard arm will follow the principles of 
palliative RT, with the goal of alleviating symptoms or preventing imminent complications. RT 
given should be to palliate symptoms rather than ablate tumours (exceptions exist such as brain 
metastases). Chemotherapy, hormonal agents, and targeted anti-cancer systemic therapy may be 
used at the discretion of the patients’ treating oncologist and will not be mandated by the trial, 
but will be prospectively collected to inform the cost-effectiveness analysis. If palliative RT is 
indicated, treatment planning is to be done using computed tomography (CT) simulation or 
conventional simulation (fluoroscopy) as per individual institutional practice. Simple beam 
arrangements (e.g. parallel opposed beams), are favored wherever possible, and doses should be 
limited to 8 Gy in 1 fraction, 20 Gy in 5 fractions, or 30 Gy in 10 fractions, though on 
subsequent progression, SABR may be used per institutional policy, though not encouraged. 
 
 
Radiation therapy - Experimental Arm – SABR + SOC (Arm 2) 
For Arm 2 (SABR), all treatments in this study are based on our phase II SABRCOMET trial, 
further refined per recent evidence of normal tissue tolerance, the toxicities observed in that trial, 
and emerging relative contraindications to SABR1. The guiding principle for RT is to achieve 
disease control and minimize any potential adverse impact on quality of life (QoL).  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. Hormone therapy is permitted. Prior surgery to a 
metastatic site is permitted, but it will be counted towards the total of 8 lifetime metastases. 
Doses and fractionations by tumour site are shown in Table 2 (Section 5.1.2). Treatment will be 
setup using reproducible positioning, verified using an on-line protocol, for all patients in this 
study. 
 
All patients in Arm 2 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 

  
 
 
 
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target volume (CTV) expansion will be limited to vertebral and some bone lesions17,18. 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 3 (Appendix). Planning detail 
parameters will be similar to the phase II trial, and will be well outlined for planners. 
 
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 pain, 
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 pain, 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 abdominal pain, 
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.  
• 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  

  
 
 
 
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▪ 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 
 
Sample Collection Schedule (participating sites only) 
The translational component of this trial is not mandatory, however has been designed to minimize 
the impact on patients while addressing important research questions around the oligometastatic 
state. Specifically, the increased requirements, beyond standard of care testing, consist of drawing 
3 tubes of blood at 3 time periods (Figure 1): at randomization (baseline), 3-months post-treatment, 
and at progression. In patients who do not progress, the final sample will be drawn at study 
completion (5-years post randomization).   
 
 
2.3. 
Study Population 
Patients with 1 controlled primary solid tumour and 1-3 current metastatic cancer lesions, and 
maximum 8 lifetime metastatic lesions (e.g. could have had 5 brain lesions treated with 
fractionated stereotactic radiotherapy previously, but 3 current lesions), as evidenced by imaging, 
meeting all eligibility criteria. 
 

  
 
 
 
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3. 
Trial Design 
This study is a phase III multicentre randomized trial. Patients will be randomized in a 1:2 ratio 
between current standard of care treatment (Arm 1) vs. standard of care treatment + SABR (Arm 
2) to sites of known disease. 
 
Patients will be stratified by two of the strongest prognostic factors, based on a large multi-
institutional analysis18: histology (Group 1: prostate, breast, or renal; Group 2: all others), and 
disease-free interval (defined as time from diagnosis of primary tumour until first detection of 
the metastases being treated on this trial; divided as ≤2 years vs >2 years).  
 
 
 
3.1. 
Study Objectives and Endpoints  
3.1.1 Objectives 
Primary Objective 
To compare the effect of SABR and SOC, relative to SOC alone, on overall survival in patients 
with controlled primary solid tumours and 1-3 current metastatic cancer lesions 
Secondary Objective(s) 
• To compare side effects, in terms of the occurrence of grade 2 or higher adverse events 
• To compare changes in progress-free survival (PFS) 
• To compare changes in patient-reported quality of life (QoL) 
• To estimate the cost-effectiveness of SABR versus SOC 
• To assess the correlation between candidate biomarkers of oligometastatic disease (blood- 
derived) and oncologic outcomes, including response to SABR, disease progression, and 
overall survival 
 
 

  
 
 
 
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3.1.2 Endpoints 
Primary Endpoint:  
• Overall Survival 
 
Secondary Endpoint(s):  
• Progression-Free Survival 
• Toxicity 
• Quality of Life 
• Health-Related Quality of Life 
• Resource Utilization 
• Correlation between candidate biomarkers of oligometastatic disease (blood-derived) and 
oncologic outcomes 
 
 
3.2. 
Entry Procedures 
• History and Physical Examination within 6 weeks of study accrual (No exceptions to 
timelines):  
▪ Including prior cancer therapies and cancer-specific concomitant medications (for 
example, systemic therapy such as immunotherapy, hormone therapy and/or 
chemotherapy drugs and regular/supporting medications such as anti-emetics). 
 
• Restaging within 8 weeks prior to randomization, and with 12 weeks of treatment for 
patients randomized to SABR (No exceptions to timelines): 
▪ Brain: CT or MRI for tumour sites with propensity for brain metastasis. All patients with 
brain metastases at enrollment or previously require an MRI. 
▪ Body: 18-FDG PET/CT imaging is strongly recommended, except for tumours where 
FDG update is not expected (e.g. prostate, renal cell carcinoma). PSMA-PET or choline-
PET is recommended for prostate cancer. In situations where a PET scan is unavailable, 
or for tumours that do not take up radiotracer, CT chest/abdomen/pelvis with bone scan is 
required. CT Neck as clinically indicated. 
• Spine: MRI required for patients with vertebral or paraspinal metastases, though the MRI 
can be limited to the involved segment, including at least the involved vertebral body(ies) 
plus 2 vertebral bodies above and below, where applicable. 
 
• Pregnancy test for women of child-bearing potential within 4 weeks of RT start date (No 
exceptions to timeline) 
• Complete Blood Count (CBC) within 8 weeks prior to randomization 

  
 
 
 
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• Pulmonary function tests, if previously documented poor lung function, treating near lung, 
and at discretion of investigator 
• Liver function tests, if poor liver function, treating near liver, and at discretion of 
investigator 
 
Defining number of metastases: 
Patients are eligible if there are a maximum of 1-3 current metastatic lesions present. Each 
discrete lesion is counted separately. For patients with lymph node metastases, each node is 
counted as one site of metastasis. All known metastatic lesions must be targetable on planning 
CT. For patients where the lesion is only detectable on MRI, fusion of the MRI with the planning 
CT is required.  
 
Patients with prior metastases that have been treated with ablative/RT therapies (e.g. SABR, 
surgery, radiofrequency ablation) are eligible, as long as those metastases are controlled on 
imaging, and the total number of previously treated and current metastases does not exceed 8. 
(Brain metastases have to have been treated, or will be treated, with ablative technique (surgery 
SRS, or SRT)). In addition, if the previous lesions are treated with SABR, SRT, or SRS, there 
must be repeat imaging >/= 3 months after treatment showing disease stability or shrinkage. 
 
When patients have small indeterminate nodules (e.g. a 2 mm lung nodule) it can be difficult to 
determine whether these are benign or whether they represent metastasis. Any such lesion that is 
‘new’ is automatically considered a metastasis unless there are >2 months of documented 
stability without systemic therapy.  
 
Brain Metastases at Presentation 
If a patient presents with 1-2 brain metastases and ablation of those metastases (with surgery or 
radiation) is judged to be clinically required regardless of the treatment of extracranial 
metastases, ablative treatment is permitted. Those treated metastases count within the total 
number of 3 lesions. The patient would then be randomized to treatment of the extracranial 
disease. For example, a patient with a solitary brain metastasis and two lung metastases could 
receive an ablative technique to the brain (e.g. surgery, stereotactic radiosurgery [SRS], or 
fractionated stereotactic radiotherapy [FSRT]), and then be randomized to SABR vs SOC for the 
two lung metastases.  
 
Patients Already Receiving Systemic Therapy 
If a patient is already receiving systemic therapy, they are still eligible for enrolment. For 
example, if a patient with 2 metastases has been on systemic therapy for a year and is planning to 
continue, they can still be randomized, and if allocated to the standard arm would continue to 
receive systemic therapy, though on the experimental arm will receive SABR between cycles, 
and may require a short treatment break. 
 

  
 
 
 
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a) Randomization 
The study will employ a 1:2 randomization between Arm 1:Arm 2, with further stratification 
between 1) histology (Group 1: prostate, breast, or renal; Group 2: all others), and 2) disease-free 
interval (defined as time from diagnosis of primary tumour until first detection of the metastases 
being treated on this trial; divided as ≤2 years vs >2 years).  
 
Permuted block randomization will be used to reduce selection bias, promote allocation 
concealment, and improve balance across groups over the trial period. Patients will be 
randomized based on a permuted block design using a block size based on a multiple of 3 (with 
block size known only to statistician until analysis is completed, per ICH E9)20. The 
Coordinating Centre and trial statistician will be responsible for configuring the module within 
the electronic data capture (EDC) system that will be used to randomize participants. 
 
b) Blinded/Unblinded  
This is an open-label randomized controlled study design; however, during interim and final 
analyses, outcomes assessors and data analysts will be blinded to the identity of each treatment 
arm, however treatment doses and volumes will be presented for SAEs reviewed.  
 
 
3.3. 
Study Duration 
Study duration is expected to be 11 years, per activities listed below: 
Trial Activities 
Start date 
Expected End 
date 
Database setup, CRF Development  
31-Dec-18 
30-Sep-19 
Ethics/Site Approval and Clinical Trial Registration  
31-Dec-18 
27-Feb-19 
Site Training / Initiations 
1-May-19 
31-Oct-20 
Patient Recruitment 
1-Nov-19 
30-Jun-25 
Patient Follow-up 
1-Dec-19 
30-Jun-30 
Interim Data Analysis (est) 
1-Jul-21 
1-Jul-22 
Interim Data Analysis (est) 
1-Jul-22 
31-Dec-24 
Interim Data Analysis (est) 
1-Jan-24 
30-Jun-25 
Database Lock / Final Analyses / Knowledge 
Translation 
1-Aug-29 
31-Dec-30 
 

  
 
 
 
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4. 
Eligibility 
Waivers to eligibility criteria are not permitted. 
See Eligibility Checklist (Subject Registration Form) 
4.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for participation in this study: 
• Total number of 1-3 current metastases, and a maximum of 8 lifetime metastases 
• Age 18 or older 
• Able to provide informed consent 
• ECOG performance status 0 – 2 
• Life expectancy >6 months 
• Histologically confirmed malignancy with metastatic disease detected on imaging. 
Biopsy of metastasis is preferred, but not required. 
• Controlled primary tumour 
• 
defined as: at least 3 months since original tumour treated definitively, with no 
progression at primary site (can be considered controlled if no evidence of primary 
tumour on imaging)    
• 
A history and physical exam including performance status performed within 6 weeks 
prior to trial enrollment 
• Not suitable for resection at all sites or declined surgery 
• Patient has had a CT chest, abdomen and pelvis or PET-CT within 8 weeks prior to 
enrollment, and within 12 weeks prior to treatment if randomized to SABR. CT Neck as 
clinically indicated. 
• Patient has had a nuclear bone scan (if no PET-CT) within 8 weeks prior to enrollment, 
and within 12 weeks prior to treatment if randomized to SABR, 
• 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 within 8 weeks prior to 
enrollment, and within 12 weeks prior to treatment if randomized to SABR. CT Neck as 
clinically indicated. 
• If colorectal primary with rising CEA, but equivocal imaging, patient has had an FDG 
PET scan within 8 weeks prior to enrollment, and within 12 weeks prior to treatment if 
randomized to SABR, 
• Patient has had CT or MRI brain imaging if primary has a propensity for CNS metastasis 
within 8 weeks prior to enrollment, and within 12 weeks prior to treatment if randomized 
to SABR, 
• Patient is judged able to: 
▪ Maintain a stable position during therapy  
▪ Tolerate immobilization device(s) that may be required to deliver SABR safely 

  
 
 
 
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• Negative pregnancy test for Women of Child-Bearing Potential (WOCBP) within 4 
weeks of RT start date 
• Patient is able and willing to complete the quality of life questionnaires, and other 
assessments that are a part of this study, via paper or online using REDCap (if email is 
provided by participant on informed consent) 
4.2. 
Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply: 
• Lesion in femoral bone requiring surgical fixation 
• Chemotherapy agents (cytotoxic, or molecularly targeted agents) used within the period 
of time commencing 2 weeks prior to radiation, lasting until 1 week after the last fraction 
for patients randomized to SABR.  
• Serious medical comorbidities precluding radiotherapy. These include interstitial lung 
disease in patients requiring thoracic radiation, Crohn’s disease in patients where the GI 
tract will receive radiotherapy, and connective tissue disorders such as lupus or 
scleroderma. 
• Substantial overlap with a previously treated radiation volume. Prior radiotherapy in 
general is allowed, as long as the composite plan meets dose constraints herein. For 
patients treated with radiation previously, biological effective dose calculations should be 
used to equate previous doses to the tolerance doses listed below. All such cases should 
be discussed with the local and study PI. 
• 
Concurrent malignant cancer, or history of malignant cancers within the past 5 years 
• Malignant pleural effusion 
• Inability to treat all sites of disease 
• Maximum size of 5 cm for lesions outside the brain, except: 
▪ Bone metastases over 5 cm may be included, if in the opinion of the local PI it can 
be treated safely (e.g. rib, scapula, pelvis) 
▪ Any brain metastasis >3 cm in size or a total volume of brain metastases greater than 
30 cc 
• Clinical or radiologic evidence of spinal cord compression, or epidural tumour within <2 
mm of the spinal cord. Patients can be eligible if surgical resection has been performed, 
but the surgical site counts toward the total of up to 8 lifetime metastases (see section 
3.2). 
• Dominant brain metastasis requiring surgical decompression 
• Pregnant or breastfeeding women 
 
 

  
 
 
 
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4.3. 
Subject Withdrawal Criteria 
Subjects may voluntarily discontinue participation in the study at any time.  
If a subject is removed or withdrawn from the study, the clinical and laboratory assessments and 
evaluations that would have been performed at the Study Completion/Early Termination Visit 
(see Section 4.8) should be obtained, if possible.  The Study Termination and Participant 
Withdrawal forms must also be completed in REDCap. 
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. 
Subjects withdrawn or discontinued can be replaced at the discretion of the sponsor-
investigator/Study Principal Investigator. 
 
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 or delegate is responsible for obtaining written informed consent from each 
subject, or if the subject is unable to provide informed consent, from the subject’s legally 
acceptable representative, prior to beginning any study procedures and treatment(s). The 
investigator or delegate should inform the subject, or the subject’s legally acceptable 
representative, of all aspects of the study, including the potential risks and benefits involved.  
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 
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 12.2 for detailed information on 
informed consent process and documentation. 
 

  
 
 
 
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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/serious 
adverse events, and follow-up. 
4.6. 
Ability to tolerate current treatment 
Patients 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. 
4.7. 
Biopsy/ Blood banking 
As per the eligibility criteria, a biopsy of metastasis is preferred, but not required. 
Biospecimen Collection (participating sites only) 
Blood sample collection for the translational aim must take place on Monday, Tuesday, 
Wednesday or Thursday such that biospecimens requiring immediate overnight shipping 
(Circulating Tumour Cells) can be received and processed quickly, without samples sitting 
unprocessed over a weekend.  
Biospecimen requirements are summarized in Table 3. 
Table 3:  Specimens Required for Biomarker Studies 
Specimen 
Sample 
Type 
Timing 
Specimen Collection Details 
Shipping 
Peripheral 
blood 
CTCs 
3 time-points 
Collected in CellSave® tubes for immediate 
(within 24h) shipping. Stable at room 
temperature during transport. 
Overnight shipment to 
LHSC 
PBMCs 
3 time-points 
Collected in Cell-Free DNA BCT ®tubes. 
Once PBMC extracted, stored at 
participating institution (-80°C). 
Annual batch-
shipment on dry ice to 
Amsterdam UMC 
ctDNA 
3 time-points 
Collected in Cell-Free DNA BCT ® tubes 
for immediate plasma separation. Once 
extracted, plasma stored at participating 
institution (-80°C). 
Annual batch-ship on 
dry ice to Molecular 
Genetics Lab, LHSC 
CTC, circulating tumour cell; PBMC, peripheral blood mononuclear cell; ctDNA, circulating tumour deoxyribose nucleic acid; LHSC, 
London Health Sciences Centre; PaLM, Pathology and Laboratory Medicine;   
 
 

  
 
 
 
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Laboratory Support and Shipping 
Each participating institution will require an on-site laboratory for peripheral blood sample 
processing.  This laboratory must also have freezer storage (-80°C and liquid nitrogen). The 
protocols for collection and processing of peripheral blood, including required equipment and 
reagents, are provided in the SABR-COMET-3 Laboratory Manual.  All shipping costs will be 
covered by the lead translational aim site (London Health Sciences Centre), and an additional small 
stipend will be provided to cover laboratory time.  A ‘biomarker studies kit’ containing collection 
tubes and pre-paid shipping labels will be sent to each participating institution to be retained by 
the personnel responsible for biospecimen collection (Figure 2).  
 
 
 
 

  
 
 
 
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4.8 
Schedule of Activities  
PRE-TREATMENT (BASELINE) EVALUATION (NO EXCEPTIONS TO TIMELINES) 
• History and Physical Examination within 6 weeks prior to study enrollment 
o Including prior cancer therapies and cancer-specific concomitant medications (for 
example, systemic therapy such as immunotherapy, hormone therapy and/or 
chemotherapy drugs and regular/supporting medications such as anti-emetics). 
• Restaging within 8 weeks prior to randomization, and within 12 weeks prior to 
treatment if randomized to SABR: 
o Brain: CT or MRI for tumour sites with propensity for brain metastasis. All patients with 
brain metastases at enrollment, or previously, require an MRI. 
o Body: 18-FDG PET/CT imaging is strongly recommended, except for tumours where 
FDG update is not expected (e.g. prostate, renal cell carcinoma). PSMA-PET or choline-
PET is recommended for prostate cancer. In situations where a PET scan is unavailable, 
or for tumours that do not take up radiotracer, CT chest/abdomen/pelvis with bone scan is 
required at baseline. CT Neck as clinically indicated. 
o Spine: MRI required for patients with vertebral or paraspinal metastases, though the MRI 
can be limited to the involved segment, including at least the involved vertebral body(ies) 
plus 2 vertebral bodies above and below, where applicable. 
• Pregnancy test for women of child-bearing potential within 4 weeks of RT start date 
• Complete Blood Count (CBC) within 8 weeks prior to randomization 
• Pulmonary function tests, if previously documented poor lung function, treating near lung, 
and at discretion of investigator 
• Liver function tests, if poor liver function, treating near liver, and at discretion of investigator 
 
 

  
 
 
 
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4.8.1 
Investigations Prior to Randomization/Study Entry, During Trial and Follow-up 
Assessment 
Screening/ 
Baseline Staging 
Investigations  
Enrollment/ 
Randomization 
 
Treatment  
€Follow-Up  
6 Week 
(+/- 3 Weeks) 
Follow-Up  
3 Month 
(+/- 3 weeks 
Follow-Up  
6 Month  
(+/- 6 weeks) 
Follow-Up  
12 Month 
(+/- 6 weeks) 
Follow-Up  
18 Month 
(+/- 6 weeks) 
Follow-Up  
24 Month 
(+/- 6 weeks) 
Follow-Up  
36 Month 
(+/- 6 weeks) 
Follow-Up 
48 Month 
(+/- 6weeks) 
Follow-up  
60 Month 
(+/- 6 weeks)  
or Early 
Termination 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology (CBC, 
and PFTS, LFTS, if 
applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
¥Pregnancy Test  
X 
£X 
 
 
 
 
 
 
 
 
 
 
Medical Imaging  
X* 
(see annotations 
below and refer to 
sections 3.2 and 4.8) 
£X 
 
 
X** 
(see annotations below and refer to section 7.0) 
Enrollment/ 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QoL (BPI, FACT-G 
or FACT subscale 
scoring (see table)) 
All Sites  
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
Canadian Sites 
Only 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Provider-Reported 
Resource Utilization 
All Sites 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Reported 
Resource Utilization  
Canadian Sites 
Only 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 

  
 
 
 
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Assessment 
Screening/ 
Baseline Staging 
Investigations  
Enrollment/ 
Randomization 
 
Treatment  
€Follow-Up  
6 Week 
(+/- 3 Weeks) 
Follow-Up  
3 Month 
(+/- 3 weeks 
Follow-Up  
6 Month  
(+/- 6 weeks) 
Follow-Up  
12 Month 
(+/- 6 weeks) 
Follow-Up  
18 Month 
(+/- 6 weeks) 
Follow-Up  
24 Month 
(+/- 6 weeks) 
Follow-Up  
36 Month 
(+/- 6 weeks) 
Follow-Up 
48 Month 
(+/- 6weeks) 
Follow-up  
60 Month 
(+/- 6 weeks)  
or Early 
Termination 
Specimen 
Collection 
(Participating sites 
only) 
 
X 
(prior to treatment) 
 
 
X 
 
 
 
 
 
 
X 
(or at progression) 
CT Planning 
 
X 
 
 
 
 
 
 
 
 
 
 
Quality Assurance/ 
Peer Review of 
Contours 
 
X 
 
 
 
 
 
 
 
 
 
 
Radiation 
Treatment 
 
 
X 
 
 
 
 
 
 
 
 
 
Toxicity 
Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* At baseline a CT C/A/P + Bone scan should be ordered for staging if PET is not carried out. CT neck at baseline may be done as clinically indicated. 
**During follow-up extra imaging outside of study schedule is allowed per discretion of the study doctor. Either CT C/A/P or PET is required. If PET is done, CT C/A/P is not 
required (or vice versa). Bone scans for follow-up visits are to be ordered as clinically indicated (ex. for patients with bone mets) and as per discretion of the oncologist. CT neck in 
follow-up is optional and based on the oncologist’s discretion. Follow-up MRI is required only for anatomical sites which required MRI for study entry (see section 3.2). All 
imaging is optional for prostate cancer patients with PSA < 5 for follow-up visits. If patient develops disease progression, post-progression imaging will be per standard of care. 
See also section 7 for follow-up imaging requirements. 
£Repeat scan/test only if initial scan/test is outside valid timelines listed below 
€At discretion of study doctor for patients randomized to Arm 1 (SOC) 
¥ Urinalysis or serology – per institutional guidelines. 
 
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 +/- 6 weeks, from target follow-up date, in order to align with scans used 
to assess response to systemic therapy. 
 
Physical and Medical History will be valid within 6 weeks prior to enrollment. 
Imaging and test results will be valid for 8 weeks prior to enrollment, and 12 weeks prior to treatment for patients randomized to SABR.  
Pregnancy test results will be valid for 4 weeks prior to treatment. 

  
 
 
 
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QoL Questionnaires Per Metastatic Site 
 
Site 
Questionnaires 
Adrenal / Pancreas 
FACIT-Abdominal 
Bone / Spine 
FACT-General + BPI 
Brain 
FACT-Brain 
Liver 
FACT-Hep/Liver (Hepatobiliary) 
Lung 
FACT-Lung 
Lymph Node/Soft Tissue Abdominal area 
FACIT-Abdominal  
Lymph Node/Soft Tissue Head & Neck area 
FACT-Head & Neck 
Lymph Node/Soft Tissue Male Pelvis area 
FACT-Prostate  
Lymph Node/Soft Tissue Female Pelvis area 
FACT-Cervix 
Lymph Node/Soft Tissue Chest/Lungs 
FACT-Lung 
Other 
FACT-General 
 

  
 
 
 
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5. 
Subject Treatment Plan 
 
5.1. 
Trial Treatment Summary 
 
 
Standard Arm (ARM 1) 
Radiotherapy for patients in the standard arm should follow the principles of palliative 
radiotherapy as per the individual institution, with the goal of alleviating symptoms or preventing 
imminent complications. Patients in this arm should not receive stereotactic doses or 
radiotherapy boosts. Recommended dose fractionations in this arm will include 8 Gy in 1 
fraction, 20 Gy in 5 fractions, and 30 Gy in 10 fractions. Patients who decline or who do not 
receive palliative RT should still be followed and complete all quality of life questionnaires. 
 
Systemic therapy will be pre-specified based on the standard of care approach for that patient, 
and it may include systemic therapy (cytotoxic, targeted, hormonal, or immunotherapy) or 
observation. See section 5.2.1.6 for the timing of systemic therapy. 
 
 
Experimental – SABR (ARM 2) 
Table 1 presents the dose and fractionations to be used in delivery of SABR.  All doses are 
prescribed to the periphery of the planning target volume (PTV). 
Table 2 Dose and fractionations by site [secondary options in square brackets] 
Tumour 
Location 
Description 
Total Dose 
(Gy) 
Number of 
fractions 
Dose per 
fraction 
(Gy) 
Frequency 
Lung  
Tumours 5 cm or less 
surrounded by lung parenchyma 
48 Gy [54 Gy] 
4 [3] 
12 Gy [18 
Gy] 
Daily, or 
Every second 
day 
Within 2 cm of mediastinum or 
brachial plexus 
60 Gy 
8 
7.5 Gy 
Daily 
Bone  
Any bone 
35 Gy [24 Gy] 
5 [2] 
7 Gy [12 
Gy] 
Daily 
Brain 
 
 
Stereotactic lesions (no 
whole brain RT) 
< 2cm 
20-24 Gy 
1 
20-24 Gy 
Once 
2-3 cm 
18 Gy 
1 
18 Gy 
Once 
Metastases only 
35 Gy 
5 
7 Gy to PTV 
Daily 
 
Whole brain + Metastases 
35 Gy to 
metastases  
20 Gy whole 
brain 
5 
7 Gy to PTV 
4 Gy WBRT 
Daily 
Liver  
 54 Gy 
3 
18 Gy 
Every second 
day 
Adrenal / Pancreas 
40 Gy [35 Gy] 
5 
8 Gy [7 Gy] 
Daily 
Lymph Node/Soft Tissue 
40 Gy 
5 
8 Gy 
Daily 
 
 
 

  
 
 
 
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5.1.2.1 Immobilization 
Treatment will be set up using reproducible positioning and verified using an on-line protocol for 
all patients in this study. Immobilization may include a custom immobilization device, such as 
thermoplastic shell or vacuum bag, as per individual institutional practice when delivering SABR. 
Some centers do not use immobilization devices and have demonstrated high degrees of accuracy; 
this is acceptable in this study. 
 
5.1.2.2 Imaging/Localization/Registration 
All patients in Arm 2 will undergo planning CT simulation. 4-dimensional CT will be used for 
tumours in the lungs, liver, or adrenals. Axial CT images will be obtained throughout the region 
of interest. For centres using stereotactic radiosurgery platforms, real-time tumour tracking 
and orthogonal imaging systems are permitted. 
 
5.1.2.3 4D-CT Procedures 
For patients undergoing 4D-CT, medical physics will review the 4D-CT images and will perform 
the following quality assurance procedures according to institutional guidelines: 
i) Ensure all end inspiration (0%) tags exist and are in the right place. This ensures image 
integrity. 
ii) If the quality of the 4D-CT images is not sufficient (determined by Physics), then standard 
3D-CT will be performed on the fast helical CT or Untagged Average CT. 
iii) Motion measurements in all 3 directions are performed: 
1) If the motion is less than or equal to 7 mm and the good quality images exist, then 
treatment planning may be performed on the Untagged Average CT with the 50% or 
60% phase (End Expiration) and the 0% phase being fused to it. This will define the 
IGTV. 
2) If the motion is greater than 7 mm in any one direction, then respiratory-gated 
radiotherapy can be considered. In this case, treatment planning will be performed on 
a subset average CT dataset (usually labeled either 30%-60% Avg CT or 40%-70% 
Avg CT) generated by Physics. This is an average CT over the intended gated 
interval. Therefore, the GTV that is delineated on this scan will incorporate residual 
motion in the intended gated interval. The 0% phase will also be fused to this dataset. 
The PTV for planning will include the GTV delineated on the subset average CT plus 
margins for microscopic extension (Physician’s discretion) and setup uncertainty. The 
GTV_0% should also be delineated and combined with the GTV delineated on the 
subset average CT to define an additional volume labeled IGTV_CBCT. This contour 
may be used for image registration with CBCT only. 
 
5.1.2.4 Volume Definitions (Arm 2) 
For all lesions, the gross tumour volume (GTV) will be defined as the visible tumour on CT 
and/or MRI imaging +/- PET. No additional margin will be added for microscopic spread of 
disease (i.e. Clinical Target Volume [CTV]=GTV). For bone lesions, CTV of 3-5mm will be 

  
 
 
 
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allowed. For vertebral lesions, anatomic approach will be taken as per International Spinal 
consortium guideline17,18. 
An anatomic approach is taken to the CTV based on where the disease within the spinal segment 
is located. The rules for CTV are as follows:  
 
1. If the vertebral body is involved with GTV then the entire vertebral body is taken as CTV.  
2. If the ipsilateral pedicle and/or transverse process has GTV then the entire ipsilateral 
posterior segment (pedicle, lamina and transverse process) ±the spinous process is taken into 
the CTV. The inclusion of the spinous process is per the discretion of the radiation 
oncologist. 
3. If the ipsilateral pedicle, lamina, and/or transverse process has GTV, then the entire 
ipsilateral posterior segment (pedicle, lamina, and transverse process) plus the spinous 
process is taken into the CTV  
4. If bilateral involvement of the pedicle and/or transverse process with GTV, then the posterior 
segment anatomy ± the spinous process is taken into the CTV. The inclusion of the spinous 
process is per the discretion of the radiation oncologist.  
5. If bilateral involvement of the pedicles and lamina, and/or transverse process with GTV, then 
the entire posterior segment anatomy is taken into the CTV, including the spinous process.  
6. If the spinous process is involved with GTV alone then the bilateral lamina ± pedicles are to 
be taken into the CTV.  
 
The International Spinal Consortium Guideline is a reference for CTV delineation and can be 
adhered to as described17,18.  
 
In the case of epidural disease, a 5 mm anatomic margin (excluding the spinal cord) beyond the 
GTV may be used within the epidural compartment including in the cranio-caudal direction. A 
circumferential CTV as per a donut-based CTV is allowed and encouraged in the case of 
epidural disease at the discretion of the treating radiation oncologist. If paraspinal disease 
present, a minimum 5 mm CTV margin may be applied beyond the GTV.  
A Planning Target Volume (PTV) margin of 2-5 mm will be added depending on site of disease, 
immobilization, and institutional set-up accuracy: 2-3 mm margins should be used for spinal 
stereotactic treatments, 0-2 mm for brain tumours, and 5 mm for other sites.  
Targets should be named based on the organ involved, and numbered from cranially to caudally. 
For example, in a patient with 3 lung lesions, there would be: GTV_lung_1, GTV_lung_2, and 
GTV_lung_3, and corresponding PTV_lung_1, PTV_lung_2_, and PTV_lung_3, representing 
the lesions from superior to inferior.  
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. Alternatively, the thecal sac may be used as the PRV. For radiosurgery 
platforms, a PRV margin of 1 mm is permitted for the spinal cord. 

  
 
 
 
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Organ At Risk (OAR) Doses 
OAR doses are listed in Appendix 1. OAR doses may not be exceeded except in the case of 
chestwall / ribs. In cases where the PTV coverage cannot be achieved without exceeding OAR 
doses, the PTV coverage is to be compromised. All serial OARs within 5 cm of the PTV must be 
contoured (partial organ contours allowed); for parallel organs (liver, lung, etc.) within 5cm of 
PTV, the whole organs need to be contoured. This should be tested for each PTV by creating a 5 
cm expansion to examine which OARs lie within that expansion. 
 
Treatment Planning 
Treatment can be delivered using static beams (either 3D-conformal radiotherapy or intensity-
modulated) or rotational therapy (volumetric modulated arc therapy, or tomotherapy). 
Dose constraints may not be exceeded (except chestwall/ribs). If a dose constraint cannot be 
achieved due to overlap of the target with an organ at risk, the fractionation can be increased or 
the target coverage compromised in order to meet the constraint. In cases where the target 
coverage or dose must be reduced, the priority for dose coverage is the GTV (e.g. attempt to 
cover as much of the GTV as possible with the prescription dose). All such cases of dose 
reduction or target coverage compromise must be approved by the local PI prior to 
treatment. For vertebral tumours, note that the spinal cord constraints apply to the PRV. 
For all targets, doses should be prescribed to 60-90% isodose line surrounding the PTV, and all 
hotspots should fall within the GTV. 95% of the PTV should be covered by 100% of the 
prescription dose, and 99% of the PTV should be covered by 90% of the prescription dose.  
Doses must be corrected for tissue in homogeneities. Several non-overlapping 6/10 MV beams 
(on the order of 7-11 beams) or 1-2 VMAT arcs combined possibly with a few non-coplanar 
beams should be utilized. Non-coplanar beams can be used to reduce 50% isodose volumes.   
The number of isocentres is at the discretion of the treating physician, physicists, and 
dosimetrists. Generally, metastases can be treated with separate isocenters if they are well-
separated.  
The scheduling and sequence of treating each metastasis is at the discretion of individual 
physicians, but in general should begin with the brain, due to risks associated with progression. 
Radiation schedule will depend on sites of tumour being treated, but generally daily or every 
other day for 1-3 weeks. 
 
As CNS SRS for brain mets is offered on either arm there are no planning constraints or 
dosimetric submissions required for brain treatment. 
 
 
5.1.2.5 Quality Assurance (Arm 2) 
In order to ensure patient safety and effective treatment delivery, a robust quality assurance 
protocol is incorporated. The following requirements must be completed for each patient: 
• Prior to treatment, each patient must be discussed at quality assurance (QA) rounds or be 
peer reviewed by a radiation oncologist with SABR expertise. 

  
 
 
 
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• All radiotherapy plans must meet target dose levels for organs at risk (except 
chestwall/ribs) (Appendix 1). Prior to plan approval, the dose to each organ at risk must 
be verified by the physicist or treating physician.  
• All dose delivery for intensity-modulated plans (including arc-based treatments) will be 
confirmed before treatment by physics staff. 
 
Peer review of contours may be done within centre and must follow institutional guidelines.  
Acceptable documentation of peer review and approval: 
• Certified copies of approvals within Radiation Therapy planning software,  
• COMET-3 Quality Assurance study forms, 
• Email. If email is used, all elements of the QA form must be addressed in the email, 
including final approval of contours.  
Certified copies of approvals, email, or QA forms must be uploaded to REDCap or saved at the 
site.  
 
DICOMs for SABR patients must be submitted to the Coordinating Centre before the end of the 
recruitment period.  
 
5.1.2.6 Systemic Therapy 
Patients treated with prior systemic therapy are eligible for this study, however, no chemotherapy 
agents (cytotoxic, or molecularly targeted agents) are allowed within the period of time 
commencing 2 weeks prior to radiation lasting until 1 week after the last fraction. Hormonal 
therapy is allowed. Use of chemotherapy schemes containing potent enhancers of radiation 
damage (e.g. gemcitabine, adriamycin/doxorubicin, bevacizumab) are discouraged within the 
first month after radiation. 
 
5.1.2.7 Further radiotherapy for progressive disease at new metastatic sites  
Patients in Arm 1 who develop new, untreated metastatic deposits should be treated with 
standard-of-care approaches. SABR to those sites is not permitted, except for unique scenarios 
where it would be considered standard of care (e.g. all disease controlled on systemic therapy 
with a newly developed brain metastasis). Apart from brain metastases, treatment of ‘oligo-
progression’ with SABR is not permitted. 
 
Patients in Arm 2 who develop new, untreated metastatic deposits should be considered for 
SABR at those sites, if such deposits can be treated safely with SABR, and if the treating 
institution offers SABR for that body site. If SABR is not possible, then palliative RT can be 
delivered as clinically appropriate. Data collection for progression at new sites is not required 
under this protocol 
 
 
 
 

  
 
 
 
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5.1.2.8 Quality Assurance for Centres Joining Study 
Prior to opening the study, each participating research centre will be required to send to the 
Study Principal Investigator a mock treatment plan for the anatomic sites that will be treated (e.g. 
Lung, brain, liver, adrenal), to ensure that the treatment plans are designed in compliance with 
the protocol. The local principal investigators will provide pertinent CT datasets. Each 
participating research centre can choose which tumour sites will be treated at their individual 
centre (i.e. some centres may only choose to treat a subset of the eligible metastatic sites). Sites 
that have prior accreditation for SABR through a clinical trial (e.g. SABR-COMET, or organ-
specific SABR trials) are exempt from this requirement for the organ sites that have been 
accredited in those trials.  
5.1.3 Duration of Study 
Per section 3.3, this study is expected to be 11 years in duration. 
 
 
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. Source data must be printed and retained in the subject’s 
research file/source documentation. 
• 
The investigator must permit study-related monitoring, audits, REB review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the SABR-COMET-3 Monitoring Plan. 
• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
• 
The 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. 
 
 
 

  
 
 
 
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Data Sharing 
Protocol Data from this study will be pooled with the pending EORTC trial OligoRARE, a 
randomized trial specifically looking at the impact of SABR in patients with oligometastases 
from less-common tumour histologies. Anonymized data from patients with non-breast, non-
prostate, non-lung and non-colorectal histologies will be shared with EORTC investigators.  
 
5.2.1 Subject Reported Outcomes – Questionnaires 
   
5.2.1.1 Functional Assessment of Cancer Therapy:  
General (FACT-G) / *FACT sub-scale (site specific) / Brief Pain Inventory (BPI): data will be 
used to measure patient reported Quality of life 
 
*FACT sub-scales: 
-FACIT-Abdominal Symptoms  
-FACT-Brain 
-FACT-Cervix 
-FACT-Head and Neck 
-FACT-Hepatobiliary (Liver) 
-FACT-Lung 
-FACT-Prostate 
 
Both paper and electronic versions are available. Subjects and Sites may use either or both 
collection methods as appropriate. 
 
5.2.1.2 EuroQol-5 Dimensions 5-Level (EQ-5D-5L) (Canadian sites only):  
Responses to the EQ-5D-5L will generate a measure of individual’s preference for a health state 
multiplied by the length of time in that health state to yield a QALY 21-23. QALYs will be 
combined with resource utilization for the cost utility analysis. Canadian weights for the EQ-5D-
5L will be applied24,25. 
Both paper and electronic versions are available. Subjects and Sites may use either or both 
collection methods as appropriate. 
 
5.2.1.3 Patient- and Provider-Reported Resource Utilization Forms:  
The Patient-Reported Resource Utilization Form (Canadian sites only) will capture the number 
of units of key resources reported by the subject from time of randomization to death or trial 
cessation, whichever occurs first. The Provider-Reported Resource Utilization Form (all sites) 
will capture units of key resources extracted from centre and trial administrative databases. Key 
resources include number of cycles of further chemotherapy/systemic therapy, targeted- and 
immune-therapies, number of Emergency Room visits, number of hospital admissions, and 
physics, radiation oncologist, radiation therapist, nurse, and treatment unit time. Direct medical 

  
 
 
 
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costs and costs per unit of resource consumption will be established using provincial fee 
schedules (e.g. BC Medical Services Plan (MSP), Ontario Health Insurance Plan (OHIP), Nova 
Scotia Pharmacare) and provincial program data (e.g. New Drug Funding Program and the 
Ontario Drug Benefit (ODB) Program and BC Cancer Provincial Systemic Therapy Program) 
Both paper and electronic versions are available. Subjects and Sites may use either or both 
collection methods as appropriate. 
5.2.2 Records Retention 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
 
5.3 
Lifestyle Considerations, Prohibited Food and Additional Restrictions 
5.3.1 
Required Therapy 
None 
 
5.3.2 Permitted Concomitant Therapy 
Previous systemic, radiation, and hormone therapy is permitted. Hormone therapy is allowed 
during treatment. 
 
All cancer-specific concomitant medications that the subject is using should be recorded. 
 
5.3.3 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, adriamycin/doxorubicin, bevacizumab) are discouraged within the first 
month after radiation.  
 
5.3.4 Herbal Therapies 
Concomitant herbal therapies that the subject is using do not need to be recorded. 
 
5.3.5 Data Records for Concomitant Medications 
Cancer-specific concomitant medications (i.e. medications prescribed by a physician to reduce 
side effects of cancer/treatments) must be documented at registration and at all study follow-up 
visits. 
 

  
 
 
 
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Concomitant medications must be recorded on the SABR-COMET-3 Concomitant Medication 
Form, which is a cumulative form to be updated throughout the study.  
 
5.4 
Co-enrolment 
Enrollment in other studies may be permitted. Investigators must check with 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. 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. 

  
 
 
 
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6.  
Dose Modifications 
6.1 
General Toxicity Management 
In general, dose modifications are not allowed, but PTV undercoverage is allowed and already 
described in 5.1.2.4 Volume Definitions (Arm 2) - Treatment Planning section. If a dose 
modification is thought to be required/necessary, the modification must be discussed and 
approved by both the local Site PI and the Study PI. 
6.2 
Interruptions (Arm 1 and Arm 2) 
Unscheduled treatment interruptions greater than 24 hours in duration will be considered minor 
deviations for either arm. Unscheduled treatment interruptions greater than 36 hours in duration 
will be considered major deviations in the intervention Arm 2. Both deviations must be reported 
to the Study PI immediately. 
6.3 
Missed Doses (Arm 2 (SABR))  
Missed doses, defined as omission of 1 or more fractionation(s), are major violations and not 
allowed for the intervention Arm 2. Missed doses must also be reported as deviations to the 
Study PI immediately.  

  
 
 
 
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7. Assessment of Efficacy 
 
Clinical follow-up appointments will occur at 6 weeks, 3 months, and then every 6 months (from 
treatment end date) for the first two years, and annually for years 3-5, and may be conducted via 
telephone or videolink. Follow-up visits for SABR patients should be scheduled from SABR 
treatment end date. Follow-up visits for all SOC patients, including those who do not receive any 
treatment, should be scheduled from randomization date. At each visit, a medical history will be 
conducted by the oncologist or a delegated family physician (e.g. if patient is followed over 
videolink), and CTCAE26 toxicities and Eastern Cooperative Oncology Group (ECOG) score 
recorded. The FACT-G or subscale, EQ-5D-5L Quality of life, and resource utilization 
questionnaires are to be completed at each visit, remotely (e.g. by phone, videolink, or mail), or 
the patient can complete these questionnaires at home (online using REDCap or on paper and 
mailed to investigator). 
 
Follow-Up Imaging should be ordered based on site(s) of metastasis(ses) and imaging ordered 
for staging. General guidelines: 
• 
CT Brain – as clinically indicated, if there is a propensity for brain metastases (if brain 
MRI not carried out) 
• MRI Brain – as clinically indicated, if there is a propensity for brain metastases (if brain 
CT not carried out) 
• MRI (sites other than head) – if MRI was required for study entry (and in addition to CT 
C/A/P or PET) 
• CT C/A/P– For all patients at all imaging FU timepoints (If PET not carried out) 
• Bone scan - as clinically indicated and as per discretion of the investigator (ex. follow-up 
of patient with a bone met) 
• PET – For all patients at all imaging FU timepoints if CT C/A/P not carried out.  
• CT neck - optional and based on the oncologist’s discretion. 
 
 
CT brain (or MR brain [as applicable]), MRI (as applicable), and/or CT chest, abdomen and 
pelvis (CT C/A/P) or PET will be carried out at 3 and 6 months and repeated every 6 months, for 
the first 2 years, then every 12 months until 5 years have elapsed. Bone scan as clinically 
indicated and as per discretion of oncologist. Brain imaging can be omitted for histologies 
without a propensity for brain metastases (e.g. prostate). CT neck in follow-up is optional and 
based on the oncologist’s discretion. 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, and pelvis (and neck where applicable); brain imaging would still be 
required for histologies with a propensity for brain metastases (definition of propensity for brain 
metastases to be left to the treating investigator). If PSMA-PET or PET-CT was used for staging, 
but is not available for follow-up, CT C/A/P can be ordered for follow-up assessments (i.e. 
prostate cancers). Patients with prostate cancer who have a PSA below 5 may omit all follow-
up imaging requirements, regardless of the location/number of metastases.  
 

  
 
 
 
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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 +/- 6 weeks, from target follow-up date, in order to 
align with scans used to assess response to systemic therapy. 
 
 
Biomarker Methodology: The Liquid Biopsy 
To evaluate potential biomarkers in a clinical setting, the use of a “liquid biopsy” is less invasive 
and more practical alternative to repeat biopsies.  A liquid biopsy refers to sampling of peripheral 
blood to isolate and characterize circulating tumour DNA (ctDNA), circulating tumour cells 
(CTCs), and/or circulating host immune cells, among others27.  Liquid biopsy is an ideal sampling 
technique in this clinical trial because biopsy of metastatic lesions is not always possible, and 
unlike metastectomy, SABR does not inherently yield tissue. Moreover, there is evidence that post-
SABR anti-tumour immune activation can be detected in the peripheral blood27 and that tumour 
necrosis (the immunogenic cell death mechanism associated with SABR) is associated with greater 
ctDNA concentrations, 30 thus making liquid biopsy a rational means by which to assess potential 
biomarkers longitudinally.  
 
Despite its many potential advantages, liquid biopsy does have some drawbacks, including the 
fact that discordance has been observed between genotyping via ctDNA versus tumour tissue; 
however, this may merely reflect clonal or temporal heterogeneity.27  

  
 
 
 
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8. Assessment of Safety 
8.1 Specification of Safety Parameters  
8.2 Recording and Reporting of Adverse Events (AEs) 
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 Serious Adverse Event (SAE) and remain 
responsible for following up on AEs that are serious, considered related to the study intervention 
or study procedures, or that caused the subject to discontinue the study treatment or participation 
in the study. 
8.2.1 Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from the start of intervention until completion of all follow-up visits. 
All SAEs will be collected from the start of intervention until completion of all follow-up visits. 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent must be recorded in the subject’s medical record. 
8.2.2  Method for Detecting AEs and SAEs 
 
Definitions 
An 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/treatment:  
 
• 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 (excluding 
hospital admissions for scheduled elective surgery and admissions for palliative or terminal care)  
• Is a congenital anomaly/birth defect 
 
 

  
 
 
 
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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.  
 
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 
participation in the research itself).  
 
Expected events are distinguished from unexpected events on a case-by-case basis, at the 
discretion of the radiation oncologist. 
 
Causality 
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. 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 
possibly related and 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 

  
 
 
 
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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. 
 
Severity 
The severity of adverse events will be evaluated using the Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0 grading scale26.  
 
Grade 1: 
 Mild  
Grade 2: 
 Moderate 
Grade 3: 
 Severe 
Grade 4: 
 Life-threatening or disabling 
Grade 5: 
 Death  
 
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 record33.  
 
Grade 2 or higher toxicities that are possibly, probably, or definitely related to any cancer 
treatment must be documented and reported as AEs/SAEs for both arms. 
 
All Grade 3 or higher toxicities, related or not to cancer treatment, must also be documented, 
though start and stop dates do not need to be collected for toxicities considered to be unrelated or 
unlikely related to cancer treatment. 
 
These toxicities must be documented in the AE log and SAE report form, entered in 
applicable REDCap forms, and follow REB and institutional reporting guidelines. 
 
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. 
 
 
 
 
 

  
 
 
 
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Immediately Reportable Serious/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, and 
further reported to the REB per institutional guidelines. 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 a SAE Report form and in REDCap as well. 
Unanticipated events are to be reported to the Study PI within 24 hours of discovery, and 
to the local REB as required. 
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 
 
8.3 
 Follow-up of Subjects after Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each 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).  
 
8.4  
Pregnancy 
Details of pregnancies will not be collected. 
 
 
 

  
 
 
 
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9. Statistics 
9.1 
 Statistical Methods 
 
Patients will be analyzed in the groups to which they are assigned (intention-to-treat).  
 
Survival Endpoints 
PFS and OS will be calculated using the Kaplan-Meier method with differences compared using 
the stratified log-rank test. Pre-planned subgroup analysis will occur based on the stratification 
factors, and also based on the use of immunotherapy vs. non-immunotherapy systemic agents. 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. 
 
Secondary Endpoints 
Quality of life at 6 months will be measured using FACT, Cancer Specific Questionnaires, and 
EQ-5D-5L scores, with differences between groups tested using the Student’s t-test21-24,35.  
Differences in rates of grade 2 or higher toxicity between groups will be tested using the Fisher’s 
Exact Test.  
 
Cost Utility Analysis (CUA)   
A CUA will be conducted in line with the Canadian Agency for Drugs and Technologies in 
Health (CADTH) Guidelines for the Economic Evaluation of Health Technologies36,37. Non-
parametric bootstrapping will be used to estimate the 95% confidence intervals and to construct a 
cost-effectiveness acceptability curve. Sensitivity analysis will be conducted by varying the 
major drivers of costs. All costs will be adjusted to a base year using the healthcare component 
of the Statistics Canada Consumer Price Index38 to adjust for price inflation over time. 
Subsequent incremental cost per unit of OS improvement using OS outcomes will be explored. 
Although Canada has a single-payer health insurance system, the provincial and territorial 
governments are responsible for health care administration and delivery. Our analyses will be 
undertaken from the perspectives of the BC and Ontario provincial Ministries of Health as we 
expect these provinces to accrue the highest number of patients. We will gain consent from all 
trial participants to prospectively assess their patient-level records pertaining to the frequency of 
hospital admissions and the use of targeted- and immunotherapies. We will use the resource 
costing method whereby utilization data are collected from existing data sources and then 
multiplied by unit costs. 
 
Interim Analyses  
There will be 3 interim analyses. The data and safety monitoring committee (DSMC) will conduct 
the first interim analysis once 50 patients are accrued. For this analysis, the DSMC will be blinded 
to the identity of each treatment arm, but OS data will be presented for each arm, and treatment 
doses and volumes will be presented for SAEs reviewed. There are two planned interim analyses 
for efficacy in addition to the final analysis. The two interim analyses are expected to be carried 

  
 
 
 
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out when the total number of observed study deaths reaches 40 and 65, thus treatment details will 
be reviewed to determine plausible causation of toxicities. As such, interim efficacy analyses will 
not be blinded.  The DSMC will recommend stopping the trial if there is an OS difference that is 
statistically significant with a threshold of p<0.001 using the log-rank test. The final analysis is 
expected to be carried out 3 years after the enrollment of the last subject.  
 
Circulating Tumour Cell Analysis 
Rationale 
Circulating tumour cells have repeatedly demonstrated their utility as a clinical prognostic metric.  
Prospective clinical studies have provided evidence that CTCs are prognostic in metastatic breast, 
prostate, and colorectal cancer, whereby increasing concentration correlates with oncologic 
outcomes such as treatment response and survival.27-30  Recently, the largest pooled CTC analysis 
to date revealed that CTC enumeration identifies an indolent subgroup of metastatic breast cancer 
patients (Stage IVindolent) with improved survival, independent of treatment or molecular subtype39.  
The role of CTCs in oligometastatic disease has not been studied, yet the sub-population with 
slowly-progressing natural history may overlap with the clinical definition of oligometastasis. 
Thus, CTCs may represent a useful prognostic and/or predictive biomarker and their evaluation in 
this setting is warranted. 
 
Analysis 
A peripheral blood sample will be collected at each participating institution into provided CellSave 
blood collection tubes (Menarini Silicon Biosystems; preferred) or Cell-Free DNA BCT® blood 
collection tubes (Streck) which stabilize CTCs for 96 h at room temperature. Samples will then be 
prepared for CTC analysis using the CellSearch system (Veridex, Inc.) in the London Health 
Sciences Centre (LHSC).  Participating institutions will ship samples within 24h to LHSC for 
processing and CellSearch analysis.    
 
Host Immune Cell Analysis 
Rationale 
The role of the host immune system in establishing a prohibitive or permissive microenvironment 
for metastatic colonization is increasingly well-established: while activation of cytotoxic T-
lymphocytes is thought to inhibit metastases, regulatory T-lymphocytes can conversely 
exhaust/de-activate anti-tumour immunity, thus having the opposite effect40. Additionally, recent 
evidence suggests that natural killer cells contribute to non-specific immune surveillance to create 
an inhospitable milieu for the establishment of metastatic colonies.31 Furthermore, as evidenced 
by the successful application of immune-checkpoint inhibition in treating metastatic cancer, the 
modulation of the host immune system can dramatically impact the extent of metastasis.  Finally, 
both pre-clinical and clinical data demonstrate that immune cell activity can also be modulated by 
SABR,41 an effect that can be monitored in peripheral blood via analysis of circulating immune 
cells following radiotherapy.28  SABR may also effect a so-called abscopal (out-of-field) response, 
thereby improving control of metastatic disease42.  Given the important role of immune 
surveillance for metastasis, its therapeutic modulation in the setting of metastatic disease, and its 

  
 
 
 
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interplay with SABR, evaluating the importance of host immunity in the context of oligometastasis 
ablation is warranted to explore useful predictive and/or prognostic biomarkers. 
 
Analysis 
We aim to analyze peripherally circulating immune cells for expression of surface antigens that 
are reflective of immune activation or exhaustion/suppression.  The analysis itself will be 
conducted by the Amsterdam UMC.  Samples will be collected and stored at each participating 
institution as per the Laboratory Manual and stored at -70 oC-80oC will subsequently be shipped, 
on an annual basis, on dry ice to VU Amsterdam for further processing and Fluorescence-activated 
cell sorting (FACS) analysis.  
 
Tumour DNA Analysis 
Rationale: 
Recent studies utilizing contemporary genomic analysis techniques have identified individual 
gene-level alterations (e.g., mutations and copy-number variations) as well as genome-scale 
metrics (e.g., tumour mutational burden and percent genomic copy-number alteration) that 
correlate with metastatic disease and poor outcomes30-33. Perhaps most informatively, multi-region 
sequencing of primary tumours and paired metastases has permitted phylogenetic analysis of 
metastasis evolution, shedding light on genetic alterations that correlate with patterns of metastatic 
dissemination; specifically, elect genetic alterations in the setting of renal cancer effectively 
differentiate a rapid, multi-site “poly-metastatic” progression from an attenuated, indolent 
metastatic disease course reminiscent of an oligometastatic natural historyhistory32.  These large-
scale studies have performed whole-genome sequencing in each patient, an approach that is not 
currently practical or cost-effective in the clinical setting.  However, curating the findings of these 
large-scale analyses to develop a targeted approach using a panel-based subset of frequently-
altered genetic loci will permit a more focused yet rationally-based evaluation of oligometastatic 
tumour DNA, akin to the approach taken by Abbosh et al. 30  
 
 
Analysis: 
The plasma fraction containing circulating tumour DNA (ctDNA) will be isolated from 
peripheral blood collected at the above-mentioned timepoints as per the protocol detailed in the 
Laboratory Manual. Once extracted, plasma samples will be frozen at -70 oC to -80oC. 
Concentration of ctDNA to gauge feasibility for subsequent analysis will be determined prior to 
freezing and storage.  Participating institutions will batch-ship frozen samples on dry ice to 
LHSC where all samples will be stored.   
 
 
 
 

  
 
 
 
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9.2 
Planned Subjects Enrolled 
Sample Size Calculation 
The results of the original SABR-COMET phase II trial demonstrated median OS of 28 months 
in the standard arm, 41 months in the experimental arm, and a 22% improvement in 5-year OS. 
Based on these results, this phase III trial initially aimed to detect a Hazard Ratio of death of 0.66 
in the experimental arm compared to the standard arm (i.e. a 40% reduction in the hazard rate of 
death). A 5-year OS of 20% had been assumed for the standard arm; the HR of 0.66 represents a 
15% improvement in OS, smaller than the effect observed in the phase II trial. In order to detect 
this difference, with 80% power, alpha of 0.05, and an 8% dropout rate, assuming 5 years of 
accrual and a total trial time of 8 years, 297 patients would be required (i.e. 99 in Arm 1 and 198 
in Arm 2). 
Amendment June 2022: 
Study sample size was increased to 330 ( in Arm 1 and 220 in Arm 2)This sample size will 
provide 80% power to detect an improvement in median OS from 16 months to 27 months 
allowing for 5% dropout. This assumes 5 years of accrual and 1 year of additional follow-up. 
 
9.3 
Procedures for Reporting Deviations from the Statistical Plan 
Any deviations from the original statistical plan will be described and justified in the progress 
and/or in the final report, as appropriate.  

  
 
 
 
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10.  Measurement of Study Endpoints 
Primary Outcome Measure: 
 
Overall survival: Time from randomization to death from any cause [Time Frame: At 
approximately end of year 5 (study completion)] 
 
Secondary Outcome Measures: 
• Side effects: Occurrences of grade 2 or higher adverse events assessed at 6 weeks, 3 
months, 6 months, and every 6 months post treatment for years 1 and 2. At approximately 
end of years 3, 4, and 5. 
• Progression-free survival (PFS): Time from randomization to disease progression at 
any site or death. [Assessment Time Frame: At 6 weeks, 3 months, 6 months, and every 6 
months post treatment for years 1 and 2. At approximately end of years 3, 4, and 5.] 
• Patient-reported quality of life (QoL): assessed via Functional Assessment of Cancer 
Therapy- General (FACT-G)/sub-scale questionnaires administered at baseline, 6 weeks, 
3 months, 6 months, and every 6 months post treatment for years 1 and 2. At 
approximately end of years 3, 4, and 5. 
• Health-related quality of life (HRQoL): assessed via EuroQOL Group EQ-5D-5L 
questionnaire administered at baseline, 3 months, 6 months, and every 6 months post 
treatment for years 1 and 2, and at approximately end of years 3, 4, and 5. 
• Resource Utilization: assessed via Patient- and Provider-Reported number of hospital 
admissions, ER visits, systemic or radiation therapy, collected at 3 months, 6 months, and 
every 6 months post treatment for years 1 and 2, and at approximately end of years 3, 4, 
and 5. 
• Correlation between candidate biomarkers of oligometastatic disease (blood- derived) 
and oncologic outcomes: assessed via CTC and ctDNA Enumeration/Detection at 
baseline, 3 months post-treatment, and at disease progression or study completion (Year 
5) 
 
10.1 
Definitions 
 
10.1.1 Overall (OS) and Progression-Free Survival (PFS) 
OS and PFS will be calculated using the Kaplan-Meier method with differences compared using 
the stratified log-rank test. Pre-planned subgroup analysis will occur based on the stratification 
factors, and also based on the use of immunotherapy vs. non-immunotherapy systemic agents. 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. 

  
 
 
 
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10.1.2 QOL measurement after treatment 
Quality of life at 6 months will be measured using FACT, Cancer Specific Questionnaires, and 
EQ-5D-5L scores (Health-Related Quality of Life), with differences between groups tested using 
the Student’s t-test21-24.  Differences in rates of grade 2 or higher toxicity between groups will be 
tested using the Fisher’s Exact Test. 
 
10.1.3 Toxicity 
Toxicity will be measured using CTCAE v5.026 
 
10.1.4 Resource Utilization 
Resource utilization will be measured using data recorded on the Patient-Reported Resource 
Utilization and Provider-Reported Resource Utilization forms (number of units of key resources 
reported by the subject from time of randomization to death or trial cessation, whichever occurs 
first, and units of key resources extracted from centre and trial administrative databases). Key 
resources include number of cycles of further chemotherapy/systemic therapy, targeted- and 
immune-therapies, number of Emergency Room visits, number of hospital admissions, and 
physics, radiation oncologist, radiation therapist, nurse, and treatment unit time. Direct medical 
costs and costs per unit of resource consumption will be established using provincial fee 
schedules (e.g. BC Medical Services Plan (MSP), Ontario Health Insurance Plan (OHIP), Nova 
Scotia Pharmacare) and provincial program data (e.g. New Drug Funding Program and the 
Ontario Drug Benefit (ODB) Program and BC Cancer Provincial Systemic Therapy 
Program)35,36. 
10.1.5 Biomarkers 
Circulating Tumour Cells (CTCs) will be detected/enumerated using the Food and Drug 
Administration (FDA)- and Health Canada approved CellSearch system (Menarini Silicon 
Biosystems) at the London Health Sciences Centre (LHSC).  
 
Flow cytometry will be used to detect expression of cell surface antigens on host immune cells, 
including cytotoxic and regulatory T-lymphocytes, that are reflective of immune activation or 
exhaustion/suppression (processing and analysis to be conducted by the Amsterdam University 
Medical Centre).  
 
Circulating tumour DNA (ctDNA) in plasma will be quantified and undergo targeted gene 
sequencing to assess for candidate genetic alterations related to metastatic disease. For each 
biological variable quantified, the appropriate statistical analysis will be used to correlate with 
clinical outcomes including progression-free survival and overall survival.  
 
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 

  
 
 
 
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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 On-Study Follow-Up form and in REDCap. 
 
10.4 Management Following Recurrence 
 
Follow-up After Progression 
After progression, for patients randomized to Arm 2 SABR will be encouraged for new sites at 
MRP discretion and institution approval, even if the number of new sites exceeds the maximum 
number of sites allowed at baseline.  
 
After progression, imaging, laboratory investigations, or additional treatment (e.g. further 
chemotherapy) should be carried out at the discretion of the oncologist. However, the patient will 
need to complete follow-up visits and quality of life and resource utilization questionnaires as 
per the trial protocol schedule. These may be done remotely (e.g. by phone or mail) to minimize 
visit burden for patients. Any additional visits outside of the protocol follow-up schedule are 
allowed at the oncologists’ discretion.  

  
 
 
 
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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. Please 
complete the REDCap Study Termination form for each participant completing the study. 
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 
The DSMC may stop the entire study if toxicity rates are excessive (>25% grade 3 toxicity, or 
>5% grade 4 or 5 toxicity), or if interim analysis indicates there is an OS difference that is 
statistically significant with a threshold of p < 0.001 using the log-rank test. 
 
11.3 Subject Discontinuation/Withdrawal from the Study 
• 
A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, etc. reasons.  
• 
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. 
 
11.4 Post-Trial Follow-up 
There is no planned follow-up at the end of the study. Additional care that will 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. 

  
 
 
 
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• 
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 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.  

  
 
 
 
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12. 
Regulatory, Ethical, and Study Oversight Considerations  
The Principal Investigators 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 
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 
the current federal regulations 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. Any institution opening this study 
will obtain IRB/REB approval prior to local initiation and will be responsible for maintaining 
approval throughout the duration of the trial. Principal Investigators must provide evidence of 
IRB/REB approval on an annual basis. 
 
The Principal Investigators will be responsible for the following: 
• 
Obtaining local Institutional Review Board (IRB) / Research Ethics Board (REB) 
approval 
• 
Providing written summaries of the status of the study to the REB annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the REB 
• 
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 
Participating sites must receive pre-approval from the Study Principal Investigator for any 
amendments to the protocol. 
 
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 

  
 
 
 
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• 
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 
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 per BC Cancer 
and/or institutional SOPs. 
 
12.2. 
Informed Consent Process 
The investigator or delegate 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 investigator or delegate will explain the nature of the study to the subject or his/her legally 
authorized representative and answer all questions regarding the study. 
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines, and the REB or study center. 
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 patient source documents.   
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study as applicable. 

  
 
 
 
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A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative. 
 
12.3. 
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 
and their representatives, representatives of the IRB/REB, and regulatory agencies). The 
subject’s name will not be used in any public report of the study. 
Include all measures to be taken to comply with the applicable rules on protection of personal 
data and any relevant information on measures to be taken in case of a data security breach. 
Subjects will be assigned a unique identifier by the sponsor. 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 if any 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. 
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate REB 
members, and by inspectors from regulatory authorities. 
 
12.4. 
Committees Structure 
The Data Safety Monitoring Committee (DSMC) will review data relating to safety and efficacy, 
conduct and review interim analyses, and ensure the continued scientific validity and merit of the 
study. There will be 3 interim reviews conducted by the DSMC for the purpose of monitoring 
study conduct and assessing patient safety. See sections 1.1 Synopsis (Formal Stopping Rules) 
and Section 9.1 Statistical Methods for details regarding DSMC interim analyses. 
 
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 

  
 
 
 
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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 sponsor or investigator may include but are 
not limited to: 
• 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 
 
12.6. 
Premature Termination or Suspension of Study 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the REBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the subject and should assure 
appropriate subject therapy and/or follow-up. 
 
12.7. 
Publication Policy 
Upon completion of this project, the results will be published in a peer-reviewed journal and 
presented at one or more conferences. Investigators agree to submit all manuscripts or abstracts 
to the sponsor before submission. This allows the sponsor 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 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. Accrual at each center and the amount of 
individual contribution, including study design, patient accrual, and data analysis will also factor 
in to authorship. 
 
12.8. 
Financial Support 
This trial is funded by the BC Cancer Research Foundation, the Canadian Institutes for Health 
Research (CIHR), and Varian Medical Systems. The funding agencies are not directly involved 
in data collection or analysis.  
 
12.9. 
Trial Management 
The Coordinating Centre for this study will be BC Cancer-Prince George under leadership of Dr. 
Robert Olson as Study Principal Investigator. Dr. Olson and the Coordinating Centre will be 

  
 
 
 
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Page 63 of 71 
responsible for trial activities at all participating sites, including international sites. The 
Coordinating Centre will be responsible for randomization of participants using a randomization 
module in the REDCap Electronic Data Capture (EDC) system, which will be used for trial data 
collection. In conjunction with trial statistician and Site Principal Investigators, the Coordinating 
Centre will be responsible for storing and analyzing trial data. Designated Site Principal 
Investigators will be responsible for reviewing eligibility of participants at their centre. In 
addition to providing credentials, evidence of regulatory training, and evidence of IRB/REB 
approval, all sites will receive protocol training and data entry training prior to site initiations.  

  
 
 
 
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13. 
References 
 
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oligometastatic patients treated with ablative radiotherapy: A multi-institutional pooled 
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3. Pastorino U, Buyse M, Friedel G, Ginsberg RJ, Girard P, Goldstraw P, Johnston M, 
McCormack P, Pass H, Putnam Jr JB. Long-term results of lung metastasectomy: prognostic 
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1;113(1):37-49. 
4. Primrose, John, Tom Treasure, and Francesca Fiorentino. "Lung metastasectomy in 
colorectal cancer: is this surgery effective in prolonging life?." Respirology 15.5 (2010): 742-
746. 
5. Palma DA, Salama JK, Lo SS, Senan S, Treasure T, Govindan R, et al. The oligometastatic 
state—separating truth from wishful thinking. Nat Rev Clin Oncol. 2014 Sep;11(9):549 
6. Ashworth A, Rodrigues G, Boldt G, Palma D. Is there an oligometastatic state in non-small 
cell lung cancer? A systematic review of the literature. Lung cancer. 2013 Nov 1;82(2):197-
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7. Ruers T, Van Coevorden F, Punt CJ, et al: Local Treatment of Unresectable Colorectal Liver 
Metastases: Results of a Randomized Phase II Trial. J Natl Cancer Inst 109, 2017 
8. Ruers T, Punt C, Van Coevorden F, et al: Radiofrequency ablation combined with systemic 
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Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors 
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Dec;12(1):305. 
10. Palma D, Olson R, Harrow S, Gaede S, Louie A, Haasbeek C, et al. Stereotactic ablative 
radiotherapy versus standard-of-care palliative treatment in patients with oligometastatic 
cancer (SABR-COMET): a randomized, phase II, open-label trial. Lancet. 2019; 
393(10185;2051- 
11. Palma, David A., Alexander V. Louie, and George B. Rodrigues. "New strategies in 
stereotactic radiotherapy for oligometastases." Clinical Cancer Research 21.23 (2015): 5198-
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12. Correa RJ, Salama JK, Milano MT, et al: Stereotactic Body Radiotherapy for 
Oligometastasis: Opportunities for Biology to Guide Clinical Management. Cancer J 22:247-
56, 2016 
13. Lussier YA, Khodarev NN, Regan K, et al: Oligo- and polymetastatic progression in lung 
metastasis(es) patients is associated with specific microRNAs. PLoS One 7:e50141, 2012 

  
 
 
 
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14. Lussier YA, Xing HR, Salama JK, et al: MicroRNA expression characterizes 
oligometastasis(es). PLoS One 6:e28650, 2011 
15. Uppal A, Wightman SC, Mallon S, et al: 14q32-encoded microRNAs mediate an 
oligometastatic phenotype. Oncotarget 6:3540-52, 2015 
16. Lambert AW, Pattabiraman DR, Weinberg RA: Emerging Biological Principles of 
Metastasis. Cell 168:670-691, 2017 
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consensus guidelines for target volume definition in spinal stereotactic radiosurgery. Int J 
Radiat Oncol Biol Phys 83:597, 2012 
18. Redmond KJ, Robertson S, Lo SS, Soltys SG, Ryu S, McNutt T, et al. Consensus contouring 
guidelines for postoperative stereotactic body radiation therapy for metastatic solid tumor 
malignancies to the spine. Int J Radiat Oncol Biol Phys. 2017 Jan 1;97(1):64-74 
19. Hong JC, Ayala-Peacock DN, Lee J, et al: Classification for long-term survival in 
oligometastatic patients treated with ablative radiotherapy: A multi-institutional pooled 
analysis. PLoS One 13:e0195149, 2018 
20. Food and Drug Administration. E9: statistical principles for clinical trials. Federal Register. 
1998 Sep 16;63(179):49583-98. 
21. Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 
Dec 1;20(10):1727-36. 
22. Devlin NJ, Krabbe PFM: The Development of New Research Methods for the Valuation of 
EQ-5D-5L. Eur J Health Econ. 2013 Jul;14(S1–S3):1–3 
23. Rabin R, Charro FD. EQ-SD: a measure of health status from the EuroQol Group. Ann Med. 
2001 Jan 1;33(5):337-43. 
24. Pickard AS, Wilke CT, Lin HW, Lloyd A. Health utilities using the EQ-5D in studies of 
cancer. Pharmacoeconomics. 2007 May 1;25(5):365-84. 
25. National Institute for Clinical Excellence. Guide to the methods of technology appraisal. 
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nice.org.Uk/aboutnice/howwework/devnicetech/technologyappraisalprocessguides/guidetoth
emethodsoftechnologyappraisal. jsp. 2008. 
26. National Cancer Institute, 2017. Common terminology criteria for adverse events (CTCAE) 
v5.0. 
27. Alix-Panabières C, Pantel K. Clinical applications of circulating tumor cells and circulating 
tumor DNA as liquid biopsy. Cancer Discov. 2016 May 1;6(5):479-91. 
28. De Goeje PL, Smit EF, Waasdorp C, Schram MT, Kaijen-Lambers ME, Bezemer K, et al. 
Stereotactic Ablative Radiotherapy Induces Peripheral T-Cell Activation in Patients with 
Early-Stage Lung Cancer. Am J Respir Crit Care Med. 2017 Nov 1;196(9):1224-7. 
29. Merker JD, Oxnard GR, Compton C, et al: Circulating Tumor DNA Analysis in Patients 
With Cancer: American Society of Clinical Oncology and College of American Pathologists 
Joint Review. J Clin Oncol 36:1631-1641, 2018 
30. Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, 
Moore DA, Veeriah S, Rosenthal R, Marafioti T. Phylogenetic ctDNA analysis depicts early-
stage lung cancer evolution. Nature. 2017 May;545(7655):446 

  
 
 
 
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31. Lambert AW, Pattabiraman DR, Weinberg RA: Emerging Biological Principles of 
Metastasis. Cell 168:670-691, 2017 
32. Turajlic S, Xu H, Litchfield K, Rowan A, Chambers T, Lopez JI, Nicol D, O’Brien T, Larkin 
J, Horswell S, Stares M. Tracking cancer evolution reveals constrained routes to metastases: 
TRACERx Renal. Cell. 2018 Apr 19;173(3):581-94. 
33. Jamal-Hanjani M, Wilson GA, McGranahan N, et al: Tracking the Evolution of Non-Small-
Cell Lung Cancer. N Engl J Med 376:2109-2121, 2017 
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Assessment of Cancer Therapy scale: development and validation of the general measure. J 
Clin Oncol. 1993 Mar 1;11(3):570-9. 
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S, Krahn MD. Estimating the cost of cancer care in British Columbia and Ontario: a 
Canadian inter-provincial comparison. Healthcare Policy. 2017 Feb;12(3):95.23. National 
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37. Lee KM, McCarron CE, Bryan S. Guidelines for Economic Evaluation of Health 
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39. Davis AA, Pierga JY, Dirix LY, Michiels S, Rademaker A, Reuben JM, et al. The impact of 
circulating tumor cells (CTCs) detection in metastatic breast cancer (MBC): Implications of 
“indolent” stage IV disease (Stage IVindolent). J Clin Oncol. 2018 May 20;36(15):1019-
1019 
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Trends Cancer. 2016 Jun 1;2(6):286-94.41.  
42. Ngwa W, Irabor OC, Schoenfeld JD, Hesser J, Demaria S, Formenti SC. Using 
immunotherapy to boost the abscopal effect. Nature Reviews Cancer. 2018 May;18(5):313. 
 
 
 
 
 
 
 
 
 

  
 
 
 
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Appendix:  
 
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 4 SABR ORGAN-AT-RISK (OAR) CONSTRAINTS 
 
OAR 
SABR ORGAN-AT-RISK (OAR) CONSTRAINTS 
 
Dmax to  ≤=0.035cc for all OARs.  
Fractions 
2  
 
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* 
 
 

  
 
 
 
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OAR 
SABR ORGAN-AT-RISK (OAR) CONSTRAINTS 
 
Dmax to  ≤=0.035cc for all OARs.  
 
Fractions 
2  
 
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 
if 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 

  
 
 
 
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OAR 
SABR ORGAN-AT-RISK (OAR) CONSTRAINTS 
 
Dmax to  ≤=0.035cc for all OARs.  
 
Fractions 
2  
 
3 
4 
5 
8 
 
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) 

  
 
 
 
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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) 
 
 
 
 
Constraints for Dose Spillage and Conformality 
 
The R100 (ratio of size of prescription isodose volume to size of PTV) should be less than 1.2. 
Exceptions are allowed for small PTVs. The R50 (ratio of size of 50% prescription isodose 
volume to size of PTV) should be as low as possible and conform to the table below. Values for 
the maximum dose 2 cm or more away from the PTV (D2cm) is below.  
 
 
  
Source: NRG LU002 trial protocol 
 
 
 
 

  
 
 
 
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PROTOCOL SIGNATURE PAGE 
 
Protocol Title:  Phase III Randomized Controlled Trial and Economic Evaluation of Stereotactic 
Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic (1-3 metastases) cancer:  
SABR-COMET-3 
 
Protocol Version/ Date:  
  v13.0;  15 May 2024 
 
Sponsor-Investigator Name: 
Dr. Robert Olson 
 
 
Site: _____________________ 
 
 
Declaration of Investigator 
 
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:  __________________________________________