A Randomized Phase II/III Study Comparing Stereotactic Body Radiotherapy(SBRT) Versus Conventional Palliative Radiotherapy (CRT) for Patients With Spinal Metastases
Phase: NA
Conditions: Spinal Metastases
Sponsor: Canadian Cancer Trials Group

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
AMENDMENT #1: 2017-FEB-02 
 
AMENDMENT #2: 2018-APR-03 
 
 
AMENDMENT #3: 2018-OCT-31 
 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCTG) 
 
A RANDOMIZED PHASE II/III STUDY COMPARING STEREOTACTIC BODY RADIOTHERAPY 
(SBRT) VERSUS CONVENTIONAL PALLIATIVE RADIOTHERAPY (CRT) FOR PATIENTS WITH 
SPINAL METASTASES  
 
CCTG Protocol Number: SC.24 
 
 
STUDY CHAIR: 
Arjun Sahgal 
 
 
TRIAL COMMITTEE: 
Mitchel Liu, Edward Chow, 
 
 
Rebecca Wong, Jim Butler,  
 
 
Jeffrey Greenspoon,  Michael Fehlings, 
 
 
Laura Masucci, Shankar Siva, Matthew Foote  
 
 
SENIOR INVESTIGATOR: 
Wendy Parulekar 
 
 
BIOSTATISTICIAN: 
Keyue Ding 
 
 
QUALITY OF LIFE COORDINATOR: 
Michael Brundage 
 
CORRELATIVE STUDIES COORDINATOR:  
Stanley Liu 
 
 
HEALTH ECONOMICS COORDINATOR: 
Marc Kerba 
 
 
RADIATION ONCOLOGY  
 
QUALITY ASSURANCE:  
Sten Myrehaug, Young Lee 
 
 
RADIOLOGY COORDINATOR: 
Pejman Maralani 
 
 
STUDY COORDINATOR: 
Maaike Hum 
 
 
REGULATORY SPONSOR: 
Canada: CCTG 
 
 
Australia: TROG 
 
(For contact information of study personnel see Final Page.) 
 

 
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TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) .................................................................................. 1 
 
TREATMENT SCHEMA ..................................................................................................................................... 2 
1.0 
OBJECTIVES ......................................................................................................................................... 3 
1.1 
Primary Objective ................................................................................................................................... 3 
1.2 
Secondary Objectives .............................................................................................................................. 3 
1.3 
Tertiary Objective ................................................................................................................................... 3 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ...................................................................... 4 
2.1 
Spinal Metastases .................................................................................................................................... 4 
2.2  
SBRT for Spinal Metastases ................................................................................................................... 4 
2.3 
Rationale for Current Study .................................................................................................................... 5 
2.4 
Health-Related Quality of Life ................................................................................................................ 8 
2.5 
Economic Analysis .................................................................................................................................. 8 
2.6 
Correlative Studies .................................................................................................................................. 9 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION.......................................................................... 11 
3.1 
Radiotherapy ......................................................................................................................................... 11 
 
4.0 
TRIAL DESIGN ................................................................................................................................... 13 
4.1 
Stratification .......................................................................................................................................... 13 
4.2 
Randomization ...................................................................................................................................... 13 
 
5.0 
STUDY POPULATION ....................................................................................................................... 14 
5.1 
Eligibility Criteria ................................................................................................................................. 14 
5.2 
Ineligibility Criteria ............................................................................................................................... 15 
6.0 
PRE-TREATMENT EVALUATION ................................................................................................... 17 
 
7.0 
ENTRY/RANDOMIZATION PROCEDURES .................................................................................... 18 
7.1 
Entry Procedures ................................................................................................................................... 18 
7.2 
Stratification .......................................................................................................................................... 18 
7.3 
Randomization ...................................................................................................................................... 18 
 
8.0 
TREATMENT PLAN ........................................................................................................................... 20 
8.1 
Treatment Plan ...................................................................................................................................... 20 
8.2 
Radiation Treatment Plan for CRT (ARM 1) ........................................................................................ 21 
8.3 
Radiation Treatment Plan for SBRT (ARM 2) ..................................................................................... 24 
8.4 
Radiotherapy Quality Assurance ........................................................................................................... 30 
8.5 
Submission of QA Documents for Review ........................................................................................... 30 
 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT .............................................. 31 
9.1 
Evaluation During and After Protocol Treatment ................................................................................. 31 
 
10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ......................................................... 32 
10.1 
Evaluability ........................................................................................................................................... 32 
10.2 
Definitions ............................................................................................................................................. 33 
 
11.0 
SERIOUS ADVERSE EVENT REPORTING ..................................................................................... 35 
11.1 
Definition of a Reportable Serious Adverse Event ............................................................................... 35 
11.2 
Serious Adverse Event Reporting Instructions ..................................................................................... 35 
11.3 
Other Protocol Reportable Events – Pregnancy Reporting ................................................................... 36 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health ............................................... 37 
 
 

 
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12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 38 
12.1 
Criteria for Discontinuing Protocol Treatment ..................................................................................... 38 
12.2 
Therapy After Protocol Treatment is Stopped ...................................................................................... 38 
12.3 
Follow-up Off Protocol Treatment ........................................................................................................ 38 
 
13.0 
CENTRAL REVIEW PROCEDURES AND SPECIMEN COLLECTION ......................................... 39 
13.1 
Radiotherapy Quality Assurance (RTQA) ............................................................................................ 39 
13.2 
Central Radiology Review .................................................................................................................... 39 
13.3 
Central Pathology Review ..................................................................................................................... 39 
13.4 
Specimen Collection ............................................................................................................................. 39 
 
14.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 40 
14.1 
Objectives and Design ........................................................................................................................... 40 
14.2 
Primary Endpoints and Analysis ........................................................................................................... 40 
14.3 
Sample Size and Duration of Study ...................................................................................................... 41 
14.4 
Safety Monitoring ................................................................................................................................. 42 
14.5 
Interim Analysis .................................................................................................................................... 42 
14.6 
Secondary Endpoint and Analysis ......................................................................................................... 42 
14.7 
Quality of Life Analysis ........................................................................................................................ 43 
14.8 
Economic Analysis ................................................................................................................................ 44 
 
15.0 
PUBLICATION POLICY ..................................................................................................................... 45 
15.1 
Authorship of Papers, Meeting Abstracts, Etc. ..................................................................................... 45 
15.2 
Responsibility for Publication ............................................................................................................... 45 
15.3 
Submission of Material for Presentation or Publication ........................................................................ 45 
 
16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ...................................................... 46 
16.1 
Regulatory Considerations .................................................................................................................... 46 
16.2 
Inclusivity in Research .......................................................................................................................... 46 
16.3 
Obtaining Informed Consent ................................................................................................................. 47 
16.4 
Discontinuation of the Trial .................................................................................................................. 48 
16.5 
Retention of Patient Records and Study Files ....................................................................................... 48 
16.6 
Centre Performance Monitoring ............................................................................................................ 48 
16.7 
On-Site Monitoring/Auditing ................................................................................................................ 49 
16.8 
Case Report Forms ................................................................................................................................ 49 
 
17.0 
REFERENCES ...................................................................................................................................... 50 
 
APPENDIX I -  
PATIENT EVALUATION FLOW SHEET......................................................................... 54 
APPENDIX II -  PERFORMANCE STATUS SCALES/SCORES ................................................................ 55 
APPENDIX III -  SPINAL INSTABILITY NEOPLASTIC SCORE (SINS) SCORESHEET ........................ 56 
APPENDIX IV -  DOCUMENTATION FOR STUDY .................................................................................... 57 
APPENDIX V -  NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ...................... 59 
APPENDIX VI - HEALTH-RELATED QUALITY OF LIFE ASSESSMENT AND ECONOMIC 
ANALYSIS .......................................................................................................................... 60 
APPENDIX VII - PATIENT DIARY .............................................................................................................. 72 
APPENDIX VIII - CTV DELINEATION .......................................................................................................... 81 
 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 

 
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AMEND #1: 2017-FEB-02 
STUDY ACKNOWLEDGMENT/DISCLOSURE (SA/D) 
 
I understand that this protocol contains information that is confidential and proprietary to CCTG. 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, and according to Good Clinical Practice and any 
applicable local regulations. I will make a reasonable effort to complete the study within the time 
designated. I confirm that I and study personnel participating under my supervision have adequate resource 
to fulfill their responsibilities as outlined in this protocol. I will maintain documentation of any investigator 
responsibilities assigned to participating study personnel. I confirm that all data will be submitted in a timely 
manner and will be accurate, complete and supported by source documents. I will complete any protocol 
specific training required by the sponsor and that I understand the requirement to inform additional site 
personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG to study personnel 
under my supervision. I will discuss this material with them to ensure that they are fully informed about the 
investigational product and the study.  
 
I understand that this trial will be registered on a public trial registry and that my contact information and 
site name will be included in the registry listing. 
 
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s) 
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of 
this protocol may not be used in any other clinical trial and may not be disclosed to any other person or 
entity without the prior written permission of CCTG. The foregoing shall not apply to disclosure required 
by governmental regulations or laws; however, I will give prompt notice CCTG of any such disclosure. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study may 
be terminated at any time by CCTG with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
CCTG and must be kept in confidence in the same manner as the contents of this protocol. 
 
 
________________________________________________ 
_________________________ 
Qualified Investigator 
Date 
(printed name and signature) 
 
 
Protocol Number: CCTG SC.24 
 
CENTRE: ___________________________________________ 

 
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AMEND #1: 2017-FEB-02; AMEND #2: 2018-APR-03; AMEND #3: 2018-OCT-31 
TREATMENT SCHEMA 
 
This is a randomized, non-blinded multicentre phase II/III study in patients with spinal metastases. 
 
Stratification 
1. Histology (radioresistant♦ vs. radiosensitive♦) 
2.  “Mass”* on imaging (present vs. absent) 
3.  Centre 
♦  radioresistant are renal cell carcinoma, melanoma, sarcoma and gastro-intestinal; radiosensitive are all other types 
* refers to tumour that involves the paraspinal tissues or presence of epidural disease (extra osseous disease extension) 
 
Patients with tumours (excluding seminoma, 
small cell lung cancer and metastases from 
hematologic malignancies - e.g. lymphoma, 
myeloma) who have MRI-documented spinal 
metastases, suitable for receiving radiation 
therapy, and fulfill the following criteria: 
• 
Pain secondary to spinal metastases 
requiring treatment 
• 
<3 consecutive spinal segments involved by 
tumour to be included in the target volume  

R 
A 
N 
D 
O 
M 
I 
Z 
A 
T 
I 
O 
N 
 
ARM 1 
Standard Conventional Radiotherapy 
(CRT)**  
20 Gy in 5 fractions 
 
 
 
ARM 2 
Stereotactic Body Radiotherapy 
(SBRT)*** 
24 Gy in 2 fractions 
**  Standard Conventional Radiotherapy will be referred to as “CRT” throughout this protocol. 
***  Stereotactic Body Radiotherapy will be referred to as “SBRT” throughout this protocol. 
 
Primary Endpoint - Phase II 
The ability to accrue 54 patients over a 18 month period to a study that randomizes patients with spinal 
metastases to Stereotactic Body Radiotherapy (SBRT) or Standard Conventional Radiotherapy (CRT) 
within a Canadian multicentre setting. 
 
Primary Endpoint - Phase III 
The primary objective of the phase III study is to assess complete pain response in the treatment area at 3 
months post-radiation. 
 
Secondary Endpoints 
• 
Complete pain response in the treatment area at 6 months post-radiation 
• 
Radiation site progression-free survival (RSS PFS) at 3 and 6 months 
• 
Spinal Instability Neoplastic Score at 3 and 6 months 
• 
Overall Survival 
• 
Adverse event profile 
• 
Health–Related Quality of Life  
• 
Economic Analysis 
• 
Radiotherapy Quality Assurance (RTQA) compliance 
 
Tertiary Endpoint 
• 
Radiomics 
• 
Biobanking for future correlative studies 

 
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AMEND #1: 2017-FEB-02; AMEND #2: 2018-APR-03; AMEND #3: 2018-OCT-31 
1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
Phase II Study 
 
The primary objective of the phase II feasibility study is to assess the ability of Canadian 
investigators from multiple institutions to randomize 54 patients with spinal metastases to SBRT 
or CRT over an 18 month period.  
 
Phase III Study 
 
The primary objective of the phase III study is to assess complete pain response in the treatment 
area at 3 months post-radiation. 
 
1.2 
Secondary Objectives 
 
To assess both treatment arms with respect to: 
• 
Complete pain response in the treatment area at 6 months post-radiation, based on the 
International Bone Metastases Consensus Working Party Criteria. 
• 
Radiation site progression-free survival (RSS PFS) at 3 and 6 months, using MRI imaging. 
• 
Spinal instability as measured by the Spinal Instability Neoplastic Score at 3 and 6 months.  
• 
Overall survival. 
• 
Adverse event profile, using the Common Terminology Criteria for Adverse Events version 
4.0 (CTCAE v 4.0). 
• 
Health–Related Quality of Life as measured by the EORTC QLQ-C30 and QLQ-BM22 
instruments. 
• 
Economic analysis as measured by the EuroQol EQ-5D-5L instrument. 
• 
Radiotherapy Quality Assurance (RTQA) compliance, using prospectively-defined protocol-
specified quality assurance measures. 
 
1.3 
Tertiary Objective 
 
• 
Radiomics analysis of collected MR images to identify predictive and prognostic biomarkers. 
• 
Biobanking for future correlative studies. 

 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
2.1 
Spinal Metastases 
 
Spinal metastases occur in up to 40% of cancer patients. Given more than 177,000 cancer diagnoses 
in Canada per year, 53,000 people are expected to develop spinal metastases annually [Canadian 
Cancer Statistics 2011]. Patients with spine metastases experience escalating pain with disease 
progression leading to pathological fractures and spinal cord compression [Rades 2007; Rades 2010]. 
These complications cause tremendous suffering and compromise quality of life. Management has 
been traditionally limited to the use of low-dose “locally palliative” CRT aimed at initial and 
temporary symptom control, but not necessarily durable tumour and pain control [Rades 2010; Zeng 
2012]. Although initial pain relief is expected following CRT, rates of complete pain relief (or 
“complete response”) are quite poor; when using standardized pain relief endpoints/criteria, rates 
of complete response range from 0-20% at 3 months post-treatment [Zeng 2012; Nguyen 2011; Chow 
2007]. Furthermore, image-based local control rates are disappointing for bulky tumours, and have 
been reported to be approximately 45% at one year [Mizumoto 2011]. As progressive spinal metastases 
can be devastating, including the potential for malignant epidural spinal cord compression leading 
to paralysis and requirements for emergency surgery and/or further RT, improved therapies are a 
high priority. 
 
2.2  
SBRT for Spinal Metastases 
 
With innovative radiotherapy technology and modern imaging capabilities, it is now possible to 
change the treatment paradigm for patients with spinal metastases. Rather than treating with low 
dose CRT, SBRT technology can be applied to the spine and deliver 2-6 times the biologically 
equivalent dose as compared with CRT. Stereotactic body radiotherapy has been defined by the 
Canadian Association of Radiation Oncology (CARO) SBRT Task Force as "The precise delivery 
of highly conformal and image-guided hypofractionated external beam radiotherapy, delivered in 
a single or few fraction(s), to an extra-cranial body target with doses at least biologically 
equivalent to a radical course when given over a protracted conventionally (1.8-3.0 Gy/fraction) 
fractionated schedule."[Sahgal 2011] The intent of SBRT for spinal metastases is to safely deliver 
higher doses of radiotherapy, which will provide superior pain and local tumour control [Sahgal 2008; 
Sahgal 2011]. However, there is currently no evidence from randomized controlled trials or even 
high-quality multi-institutional cohort trials demonstrating that SBRT is superior to existing 
standards [Sahgal 2008; Sahgal 2011]. Furthermore, there may be potential for adverse events in the 
form of vertebral compression fracture which may be related to the SBRT as opposed to the natural 
history of the spinal metastases [Sahgal 2013a].  
 
Current evidence is limited to a few single-institution, single-arm, cohort studies reporting local 
control rates of ~80% [Sahgal 2008; Sahgal 2011; Wang 2012; Al-Omair 2013; Thibault 2014] and complete 
pain response rates of ~50% at 3 months [Wang 2012; Nguyen 2009]. These outcomes represent 
potential for major therapeutic gains to support the use of SBRT as opposed to CRT; however, at 
this time there are no high quality multi-centre clinical trial outcome data reported to understand 
the full implications of this treatment. 
 
Despite the lack of high-quality evidence, spine SBRT is increasingly practiced in the United 
States, with ~60% of surveyed American radiation oncologists administering this treatment [Pan 
2011]. In Canada, adoption of this technology has been more limited; only 6 of 41 radiation 
oncology centres currently provide spine SBRT[Lund 2011] with additional centres exploring its 
feasibility. Therefore, we are in the right environment to study spine SBRT in the form of a clinical 
trial. 

 
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2.3 
Rationale for Current Study 
 
The current standard of care in the management of patients with spinal metastases is to deliver CRT 
with palliative intent. Therapeutic goals are to preserve neurologic function and spine stability and 
to treat (and prevent) pain. For those with neurologic compromise or spinal instability, surgery 
followed by radiotherapy is a common treatment. The proposed trial does not address this 
population. Instead, we address the more common clinical problem associated with considerable 
patient suffering, in which spinal metastases cause debilitating pain. This clinical scenario may be 
a harbinger of neurologic compromise or spinal instability; radiotherapy, along with other standard 
components of palliative management, is the mainstay of management. 
 
Successful radiotherapy is based on existence of a differential effect of radiation to induce death of 
tumour cells while avoiding injury to normal cells. These differential effects can result from 
intrinsic differences of tumour and host cell radiosensitivity and/or differential exposures of the 
tumour and host cells to radiation. Dose-response relations between radiation dose and tumour or 
host cell injury exist and can be predicted based on the dose of radiation exposure, referred to as 
the biologically effective dose (BED). A mechanism to maximize differential effects of radiation 
on the tumour while minimizing host cell injury is to ensure different BEDs are delivered to these 
respective tissues. 
 
The radiobiologic rationale for SBRT is based on two principles. First, ultra-high doses per fraction 
administered in only a few fractions enhance tumour cell-kill by inducing greater tumour-cell death 
directly through apoptotic mechanisms, and indirectly through tumour vessel endothelial cell injury 
[Balagamwala 2012; Garcia-Barros 2003]. Second, with technologic advances, including computer 
software, modern CT and MR imaging can be directly fused with 3-dimensional radiotherapy 
planning and dose delivery. This capacity, coupled with new abilities to shape radiotherapy beams 
with use of multileaf collimator (MLC) systems located within the linear accelerator (linac) and 
the incorporation of image-guidance into the treatment process, mean that tumours can be precisely 
targeted with less normal tissue residing in the RT target volume, and lower BEDs directed at 
normal tissues immediately adjacent to the tumour [Sahgal 2008; Sahgal 2011]. As the potential benefit 
vs. harm of RT for patients with spinal metastases is determined by the differential BEDs that are 
directed at the tumour, as opposed to the adjacent spinal cord, these two principles of enhanced 
dosing to the tumour, including its administration in ultra-high doses per fraction, and sparing of 
normal tissue generate the hypothesis that SBRT will be a superior treatment and safe. 
 
High dose-per-fraction stereotactic radiotherapy has been applied to treat for brain metastases since 
the 1980’s [Sahgal 2008b]; initial testing in this clinical situation was made possible through abilities 
to immobilize the head using invasive surgical head frames. Five randomized controlled trials and 
a recent meta-analysis demonstrate that treating brain metastases with stereotactic radiotherapy is 
effective, safe and less neuro-toxic as compared with previous whole brain RT approaches [Tsao 
2011]. As technologies became available to target body tumours with this same precision, and with 
the use of non-invasive body frames and modern linac delivery systems, a natural evolution was to 
apply these principles to body tumours and, hence, the genesis of SBRT. Initial development of 
SBRT involved testing in patients with lung cancer as a means to deliver ultra-high BEDs to 
improve local tumour control, given that outcomes with CRT were very poor. Based on outstanding 
results of a large phase 2 trial evaluating inoperable patients [Timmerman 2010], SBRT has been 
adopted as a standard of care for these patients and 3-year local control rates of ~80% are seen 
[Timmerman 2010; Taremi 2012]; these rates are approximately double that expected with CRT and have 
promoted evaluation of SBRT as treatment for other cancers, including hepatocellular, prostate, 
pancreatic, and selected primary spinal tumours [Lo 2010]. 
 
 

 
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The developmental data associated with SBRT as treatment for patients with spinal metastases has 
been systematically evaluated. Available evidence consists of retrospective and prospective case 
series. The earliest review [Sahgal 2008] summarized the results of published series reporting the 
palliative and local control and benefits of SBRT in patients who had received no prior 
radiotherapy, were previously irradiated, were postoperative or were a mixed population. Only 
three studies provided data for complete pain relief; these ranged from 33 to 75%. These data are 
compromised by use of various measurement instruments and inconsistent durations of follow-up. 
Favourable rates of some degree of pain relief ranged from 67% to 100%. Crude local control data 
suggest excellent results, although with variable follow-up periods interpretations are limited. 
Local control was observed in 67/77 (87%) of those who had not previously received radiotherapy, 
23/24 (96%) previously irradiated, 49/52 (94%) postoperative patients and in 568/655 (87%) of 
those included in reports assessing mixed populations. The technical, simulation and treatment 
details associated with SBRT development at the University of Toronto have been described [Foote 
2011, Hyde 2012]. The initial treatment consisted of 24 Gy delivered in 3 fractions and preliminary 
results in a population predominantly pre-treated with radiation and chemotherapy yielded results 
consistent with published literature [Massuci 2011]. With greater experience, the dose-per-fraction 
was escalated and since 2011 treatment the standard of care at the University of Toronto has been 
24 Gy in 2 fractions - the SBRT prescription for this randomized controlled feasibility study. 
Recent publications with this approach [Al-Omair 2013; Thibault 2014] have been reported by Sahgal’s 
group showing consistent local control results and a risk of vertebral compression fracture that is 
clinically reasonable at ~10% [Cunha 2012; Sahgal 2013a]. This VCF rate is of significant importance 
as the use of the more aggressive single fraction dose of 24 Gy in 1, as advocated by some 
American Centers, has been shown to be associated with a 40% risk of VCF which is clinically 
unacceptable. This dose fractionation is also being increasingly adopted by the Japanese and UK 
radiation oncology community as their standard of care. 
 
The importance of clearly establishing SBRT as superior treatment for patients with spinal 
metastases is evident when implications associated with its adoption are considered. For patients, 
technical processes of radiotherapy simulation and delivery are more arduous than with CRT. 
Treatment with SBRT requires that radiotherapy be delivered to the target with a precision of 1-2 
mm. Very specific planning is thus performed, which includes simulation processes in which 
patients are immobilized for 30-60 minutes and may suffer from claustrophobia and incorporation 
of MR imaging into both treatment planning and follow-up. Balanced against these concerns is the 
potential for superior efficacy and a need to receive fewer treatment fractions. Thus, in addition to 
the need to clearly understand the efficacy benefits and adverse effect risks associated with SBRT, 
it is important to understand the patient experience associated with its administration. 
 
For radiation oncologists, special training in SBRT is required. The recent CARO task force on 
SBRT advocated training in disease site-specific SBRT practices before treatment is undertaken, 
including through course work, mentorship programs or participation in clinical trials that include 
rigorous RTQA processes. Similar supports are required for the entire radiation oncology team, 
which includes radiation planners, physicists and technologists. For institutions and funders, 
adoption of SBRT may be associated with new capital expenditures and operational implications, 
including trade-offs associated with abilities to treat three or four patients with CRT in the time 
span required for SBRT. Clear understandings of efficacy, effectiveness and cost-effectiveness are 
needed to inform processes of health service planning. 
 
 

 
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AMEND #1: 2017-FEB-02; AMEND #3: 2018-OCT-31 
Data from randomized phase II trial by Sprave et al (2018) evaluated the impact of SBRT (24Gy/1 
fr to 3D CRT 30 Gy/10 fr) on pain relief as defined by a 2-point reduction of self reported pain, 
using a visual analogue scale and measured within the treated area at 3 months post radiotherapy. 
No significant difference was seen between treatment arms for pain relief at 3 months (p=0.13) but 
there was a trend towards greater complete pain response at 3 months favouring the experimental 
arm: 43.5 (SBRT) versus 17.4% (CRT) p=0.057.  These results provide further justification for the 
conduct of the current study and inform the estimates for complete pain response in the CRT and 
SBRT arms (see Section 14.3). 
 
We are aware of one other ongoing randomized controlled trial addressing this issue: the Radiation 
Therapy Oncology Group (RTOG) continues its slow accrual onto RTOG-0631 (NCT00922974), 
which compares CRT 8 Gy in 1 fraction with SBRT 16-18 Gy in 1 fraction. Investigators based 
within CCTG, including those who are international leaders in investigating the treatment of bone 
metastases have considered this protocol and concluded that two important limitations of this trial 
exist. First, the standard arm CRT is not considered a Canadian standard for patients with spine 
metastases and an expected survival or more than 3 months [Chow 2007], as higher-dose fractionated 
treatment is preferred for those who are the primary candidates for SBRT. Second, we believe that 
the evolving experience with SBRT as treatment for spinal metastases suggests that higher doses 
given over 2 fractions as compared to one fraction will be more efficacious and safer. 
 
In summary, the hypothesis that SBRT will provide palliation that is superior to CRT for patients 
with spinal metastases is based on a strong radiobiologic rationale, promising data associated with 
its adoption for other tumour sites, and highly suggestive developmental data obtained from 
prospective single-arm evaluations of treating patients with spinal metastases. However, there are 
important risks and incompletely understood implications associated with its premature adoption 
given the current absence of data from a randomized controlled trial.  
 
As SBRT is complex and costly because it requires new technical resources, rigorous quality 
assurance, expertise in treatment planning, and adequate consent of patients regarding side effects, 
better evidence from a properly designed and conducted randomized controlled trial is needed 
before widespread adoption of spinal SBRT can be justified. Given universal patient access to 
provincially-organized Canadian cancer care delivery systems and as Canadian radiation 
oncologists have a strong investigative track record and are internationally recognized for their 
evaluation of radiotherapy practices for patients with bone metastases [Zeng 2012; Chow 2007; Sahgal 
2008; Sahgal 2011; Chow 2011; Chow 2002; Nguyen 2011; Sahgal 2009; Sahgal 2010], CCTG is well positioned 
to conduct such a randomized control trial. 
 
Before embarking on a phase III trial, enabling data were needed to obtain information about the 
endpoints (timing, point estimates, standard deviations) and trial conduct compliance (accrual, 
Radiotherapy Quality Assurance [RTQA]). 
 
We thus proposed to first conduct a randomized, non-blinded multicentre phase II feasibility study 
to obtain these enabling data and then embark on a phase III study should the essential trial metrics 
be supportive. 
 
 

 
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AMEND #1: 2017-FEB-02; AMEND #2: 2018-APR-03 
2.4 
Health-Related Quality of Life 
 
The main patient-reported outcome (PRO) of interest in this study is the secondary endpoint: worst 
pain scores analyzed according to the a-priori defined response categories of the International Bone 
Metastases Consensus Working Party Criteria. These assessments and analyses are described 
further in sections 10 and 14. In addition to pain scores, patients allocated to both treatment arms 
will complete the EORTC QLQ-C30 (core) and the QLQ-BM22 (bone metastases module) quality 
of life instruments. 
 
The EORTC QLQ-C30 is the core quality-of-life questionnaire of the EORTC quality of life 
evaluation system [Bottomlay 2007]. It has been validated [Aaronson 1993] in both English and French 
and is used on several CCTG studies. The EORTC QLC-C30 consists of 30 items organized into 
five function domains (physical, emotional, cognitive, role, and social functioning), three symptom 
scales (fatigue, pain and nausea), six single item scales (sleep disturbance, constipation, diarrhea, 
dyspnea, appetite loss, and financial issues), and a two item global health status scale. The QLQ-
BM-22 module also has been validated specifically in patients with bone metastases and is designed 
to be used in conjunction with the EORTC QLQ-C30 core questionnaire [Chow 2009, Zeng 2012b]. 
The QLQ-BM22 module consists of 22 items, divided into four sub scales, namely: descriptions of 
painful sites, painful characteristics, functional interference, and psychosocial aspects. All items 
are rated from 1 (“not at all”) to 4 (“very much”) in response to item stems (e.g.; “have you had 
pain while sitting?”). Items on both the core questionnaire and BM-22 module are scored according 
to published manuals of the EORTC as routinely used by the CCTG.  
 
The rationale for collecting quality-of-life data on this study, however, is based on two key issues. 
In the phase III study, quality-of-life information will be used to determine relative benefits of each 
treatment approach in terms of detectable improvements in pain scores, interference scores, and 
associated improvements in patients’ functional scores. Quality-of-life outcomes will also inform 
the detection and interpretation of potential adverse effects of treatment such as the impact of 
vertebral fractures or other adverse effects on Patient Reported Outcomes (PROs). Second, the 
feasibility of collecting these data using an electronic data capture strategy will be assessed. The 
feasibility of collecting a typical PRO “battery” (in this case the core questionnaire and module) 
will inform the design of data collection strategies in future clinical trials conducted by CCTG. The 
electronic data capture aspect of the protocol is discussed further in Appendix VI. 
 
2.5 
Economic Analysis 
 
Spinal bone metastases are a common complication of cancer and often present with spinal bone 
pain. Progressive disease can lead to soft tissue or bone compressing the adjacent neurological 
structures, leading to a variety of adverse sequelae. In an effort to improve both clinical outcomes 
and quality of life over CRT, SBRT has emerged as an innovative treatment option for patients 
with spinal metastases. Despite the upfront costs associated with planning and delivery of SBRT, 
the potential benefits include improved quality of life by reducing pain or averting 
neurological/surgical events.  However, there is limited information on the health system costs and 
outcomes comparing SBRT and CRT in the context of a publically funded health care system 
 
The objective of the economic analysis of the SC.24 CCTG protocol is to compare the costs and 
utility values of treating spinal bone metastases with SBRT and CRT.  The economic analysis will 
examine efficacy outcomes, health system resource utilization and utility values captured by the 
study from the publicly funded health system perspective. 
 
 

 
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Secondary study objectives include: to describe the utility health preference values associated with 
spinal bone metastases and associated outcomes; to describe and cost the health system resource 
encounters across both treatment modalities; to describe utilization of analgesics. 
 
2.6 
Correlative Studies 
 
Tissue Based Correlative Studies: 
 
Although it has been long established that ionizing radiation (IR) directly kills tumour cells through 
the induction of DNA double-stranded breaks, it is becoming clear that IR effects on the tumor 
microenvironment can also influence tumour kill [Fokas 2012]. Irradiation of tumours with single 
high doses of more than 8 Gy result in activation of endothelial cell acid sphingomyelinase 
(ASMase), and membrane release of the second messenger ceramide, which then initiates 
endothelial cell apoptosis leading to microvascular dysfunction or ablation [Fuks 2005; Garcia-Barros 
2003]; ablation of the vasculature can result in secondary tumour cell death. In contrast, lower 
fractionated doses of IR are not believed to induce significant endothelial apoptosis. Early clinical 
support for induction of apoptotic mediators by high dose IR is provided by Sathishkumar et al. 
[Sathishkumar 2005], who demonstrated that elevated ceramide or sphingomyelinase levels in sera 
correlated with tumour response to high dose irradiation. Ceramide can be metabolized to 
sphingosine-1-phosphate (S1P), which is a potent pro-survival sphingolipid that can inhibit 
endothelial apoptosis [Bonnaud 2007]. Thus, the balance between pro-apoptotic (ASMase and 
ceramide), and anti-apoptotic (S1P) factors are intimately involved in regulating endothelial 
response to high dose IR.  
 
Based on the above, we hypothesize that serum levels of ASMase and S1P will serve as predictive 
biomarkers for vascular and tumour response to SBRT. To test this, blood will be collected from 
consenting patients at baseline (prior to first fraction of radiotherapy) and immediately after the 
second fraction of radiotherapy, and serum and plasma stored. We will assay serum levels of 
ASMase and S1P, and correlate their levels with clinical response to SBRT. This will lead to the 
future development and validation of novel serum biomarkers predictive of response to SBRT, 
which are currently lacking. This may allow for improved stratification of patients in future trials 
and also support future investigations of novel strategies to biologically enhance tumour response 
to SBRT. 
 
Image based correlative studies: Radiomics Analysis 
 
Human tumours display substantial inter- and intra-tumoural heterogeneity, on both a genetic and 
phentotypic level, leading to considerable differences in angiogenic, proliferative, immunogenetic 
and metastatic potential [Marusyk 2010]. Heterogenetic tumours are associated with poorer prognosis 
in a variety of tumours [Ganeshan2012a; Ganeshan 2012b; Vujasinovic 2015], but is difficult to assess as a 
biopsy may not be representative of the whole tumour.  
 
With the advent of advanced imaging techniques, radiomics - which refers to the variety of 
quantitative techniques to evaluate tumour heterogeneity—has emerged as a leading candidate in 
the evaluation of tumour heterogeneity. Radiomics maximizes the clinical information gathered 
from imaging, using mathematical methods to evaluate gray-level intensity, pixel inter-
relationships, and spectral properties of an image to derive “texture features” which may be 
imperceptible to the human visual system [Davnall 2012]. As it is based on post-processed imaging, 
the whole tumour can be captured with no need for additional acquisitions. The techniques can also 
be applied retrospectively, allowing for large cohorts to be studied.  
 
 

 
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Several different models have been developed, including statistical-, model-, and transform-based 
methods [Davnall 2012; Kassner 2010]. Statistical-based techniques have been most commonly applied 
and describe the distribution and relationships of gray level values in the image. Statistical-based 
radiomics include three orders of parameter: first-order statistics relate to gray-level frequency 
distribution within the region of interest, which can be obtained from the histogram of pixel 
intensities. Second-order statistics are co-occurrence measurements calculated using spatial gray 
level dependence matrices and depend on the interaction of its pixel with the neighboring pixels. 
Higher-order statistics use neighborhood gray-tone-difference matrices, which examine the spatial 
relationship among three or more pixels and are thought to closely resemble the human perception 
of the image. Model-based approaches utilizes complex techniques such as fractal analysis to 
analyse texture features. Lastly, transform-based methods include Fourier, Gabor, and wavelet 
transports to analyse texture in a frequency or the scale space. The various methods and numerous 
variables which can be used to extract texture features results in potentially hundreds of values that 
can be examined.  
 
Studies on radiomics has largely focused on breast, lung, liver and prostate cancer. The results of 
these works have demonstrated that radiomics can assist with the prediction of disease prognosis 
[Segal 2007; Grove 2015] and treatment selection [Kuo 2007; Teruel 2014]. In addition, data has shown 
that certain radiomic features correlate with molecular processes and genomic expression [Segal 
2007; Diehn 2008]. However, there is currently little to no literature regarding the texture features of 
spinal metastases prior to, or after radiation treatment, especially in a randomized controlled trial. 
SC.24 provides a unique opportunity to explore the use of radiomics in this population to identify 
prognostic and predictive biomarkers for pain and tumour responses after radiation treatments.  

 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
3.1 
Radiotherapy 
 
3.1.1 
Standard Conventional Radiotherapy (CRT) 
 
CRT refers to the delivery of radiation to the treatment area with two opposed fields (anterior-
posterior parallel opposed pair), and a dose of 20 Gy in 5 fractions. Typically, one to two vertebral 
bodies above and below the target disease is included to account for technical uncertainties and 
beam penumbra. This technique does not tissue spare and the entire portal is exposed to the 
prescribed dose. Standard portals and technology are used and no intensity modulation permitted. 
This technique and approach represents current Canadian standard of care for radiation of spine 
metastases. 
 
3.1.1.1 Adverse Events (CRT) 
 
The adverse event profile of radiotherapy in general is related to irradiation of normal tissue within 
the treatment field as well as tumour-specific effects. The most common adverse events include 
fatigue, soreness, pain flare, skin redness in the irradiated area and damage to other organs within 
the irradiation field (e.g. dry throat). Less likely adverse events include changes in how temperature 
is experienced, weakness and clumsiness on one or both sides of the body and episodes of pain or 
electric shock sensations in the back and legs. Rare but serious side effects include compression 
fractures and radiation myelopathy which may lead to paralysis or loss to bowel and bladder 
functions.  
 
3.1.2 
Stereotactic Body Radiotherapy (SBRT) 
 
This technique has been defined by the Canadian Association of Radiation Oncology (CARO) 
SBRT Task Force as "The precise delivery of highly conformal and image-guided hypofractionated 
external beam radiotherapy, delivered in a single or few fraction(s), to an extra-cranial body target 
with doses at least biologically equivalent to a radical course when given over a protracted 
conventionally (1.8-3.0 Gy/fraction) fractionated schedule."[Sahgal 2012]. Essentially, spine 
metastases are treated with SBRT by applying modern radiation technology, image-guidance and 
intensity modulation or robotic arc based delivery. The aim is to dose escalate the tumour volume 
as compared to CRT, while still maintaining safety on the critical organs-at-risk (OAR) by 
differentially dosing. The dose applied is 24 Gy and delivered in 2 daily fractions. This dose has 
been reported in series by the study chair and found to be tolerable and efficacious. The intent of 
spine SBRT is to improve upon the historic CRT rates of complete pain relief and local tumour 
control. 

 
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3.1.2.1 Adverse Events (SBRT) 
 
The adverse events anticipated for SBRT are generally the same as for CRT with the exception of 
radiation myelopathy, pain flare and fracture. Theoretical additional risks associated with SBRT 
include more intense radiation reactions (e.g. skin, mucosa), which depend upon the radiotherapy 
field. The most serious risk of spinal SBRT is the occurrence of radiation myelopathy, which can 
result in permanent paralysis. Recent published guidelines provide safe SBRT dosing to the spinal 
cord and minimizes this risk to under 5% [Sahgal 2010; Sahgal 2013b]; the choice of the experimental 
arm of this study will account for these. Outcome data utilizing this technique and the published 
guidelines from the University of Toronto demonstrate good tolerability with no cases of radiation 
myelopathy [Sahgal 2013b]. Single institution experience of the study Chair [personal communication A 
Sahgal] has resulted in no cases of radiation myelopathy in over 1000 treated patients. The second 
most serious risk is new or progressive vertebral compression fracture (VCF). While this is a known 
complication of treating bone metastases, its incidence may be greater with SBRT, and has a 
reported incidence of approximately10% with the treatment regimen of 24 Gy in 2 fractions. 
Although VCF is diagnosed post-SBRT, still less than half of all patients require an intervention 
and, in those that did, a minimally invasive cement augmentation procedure has been applied as 
opposed to an open spinal surgery. Pain flare may also be more intense with this treatment 
compared to conventional CRT [Chiang 2013] and may be treated with prophylactic dexamethasone 
or rescue dexamethasone upon occurrence.  

 
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4.0 
TRIAL DESIGN 
 
4.1 
Stratification 
 
Patients will be stratified by: 
1.  Histology (radioresistant♦ vs. radiosensitive♦) 
2.  “Mass”* on imaging (present vs. absent) 
3.  Centre 
 
♦  
radioresistant are renal cell carcinoma, melanoma, sarcoma and gastro-intestinal; radiosensitive are all 
other types  
* 
refers to tumour that involves the paraspinal tissues or presence of epidural disease (extra osseous disease 
extension) 
 
4.2 
Randomization 
 
Phase II: 
 
Patients will be randomized to receive one of the following treatments below to a planned sample 
size of 54. 
 
Phase III: 
 
Patients will be randomized to receive one of the following treatments below to a planned sample 
size of 228. 
 
Arm 
Treatment(s) 
Dose 
Duration 
1 
Standard Conventional 
Radiotherapy (CRT) 
20 Gy in  
5 fractions 
1 fraction a day for 5 days,  
Monday to Friday excluding weekends 
(weekend treatments are permitted, if needed) 
2 
Stereotactic Body 
Radiotherapy (SBRT) 
24 Gy in  
2 fractions 
1 fraction a day for 2 days,  
Monday to Friday excluding weekends 
 

 
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5.0 
STUDY POPULATION 
 
The study population consists of patients who have MRI-documented spinal metastases and are 
suitable for receiving radiation therapy. 
 
This study is designed to include women and minorities as appropriate, but is not designed to 
measure differences in intervention effects. 
 
5.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. 
Questions about eligibility criteria should be addressed prior to calling for randomization. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates for 
this therapy. For the safety of the patients, as well as to ensure that the results of this study can be 
useful for making treatment decisions regarding other patients with similar diseases, it is important 
that no exceptions be made to these criteria for admission to the study. 
 
Patients must fulfill all of the following criteria to be eligible for admission to the study: 
 
5.1.1 
Histologic or cytologic diagnosis of cancer (excluding seminoma, small cell lung cancer and 
hematologic primaries). 
 
5.1.2 
Spinal metastasis documented with MRI and suitable for treatment with radiotherapy with the 
following characteristics:  
• 
Painful, as defined by a pain score > 2 for worst pain in the planned target treatment volume;  
• 
< 3 consecutive spinal segments involved by tumour to be included in the planned target 
volume. The patient may have other spinal metastases to be treated as per the radiation 
oncologist’s discretion, but the eligible spinal metastatic site for SC.24 has to be one where 
there is pain and no more than 3 consecutive segments to be included as clinical target volume 
and appropriate for either 20 Gy in 5 fractions or 24 Gy in 2 fractions per the randomization. 
 
5.1.3 
There is no plan to change the pain medication on the first day of protocol treatment with 
radiotherapy. 
 
5.1.4 
ECOG Performance Status 0-2. 
 
5.1.5 
Seen by a radiation oncologist and judged to be appropriate for participation in this study including 
ability to tolerate protocol radiotherapy (SBRT or CRT). 
 
5.1.6 
Age of 18 years or older. 
 
5.1.7 
Patient is able and willing to complete the Patient Diary (pain and analgesic use). 
 
 

 
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5.1.8 
Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life and economic 
analysis questionnaires in either English or French. The baseline assessment must be completed 
within required timelines, prior to randomization. Inability (illiteracy in English or French, loss of 
sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible 
for the study. However, ability but unwillingness to complete the questionnaires will make the 
patient ineligible. 
 
5.1.9 
Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrollment in the trial to document 
their willingness to participate. 
 
5.1.10 Patients must be accessible for treatment and follow-up. Investigators must assure themselves the 
patients randomized on this trial will be available for complete documentation of the treatment, 
adverse events, and follow-up. 
 
5.1.11 In accordance with CCTG policy, protocol treatment is to begin within 3 weeks of patient 
randomization. From the time of successful treatment planning, no more than 12 days can elapse 
before the first fraction of radiotherapy is delivered. 
 
5.1.12 Women/men of childbearing potential must have agreed to use a highly effective contraceptive 
method. A woman is considered to be of "childbearing potential" if she has had menses at any time 
in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective 
contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or 
with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or 
bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously 
celibate patient chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive 
measures. 
 
Women of childbearing potential will have a pregnancy test to determine eligibility as part of the 
Pre-Study Evaluation (see Appendix I); this may include an ultrasound to rule-out pregnancy if a 
false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and 
partner is vasectomized, it may be associated with tumour production of hCG, as seen with some 
cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy. 
 
5.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
5.2.1 
Patients who have a pacemaker, such that MRI cannot be performed or treatment cannot be 
delivered safely. 
 
5.2.2 
Patients with prior treatment with any radionuclide within 30 days prior to randomization. 
 
5.2.3 
Patients with prior radiation to the spinal segment intended to be treated with protocol radiotherapy 
such that the protocol therapy cannot be delivered as intended. 
 
5.2.4 
Patients with prior surgery to the spinal segment intended to be treated with protocol radiotherapy. 
 
 

 
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5.2.5 
Patients who have received chemotherapy within 1 week prior to administration of protocol 
radiotherapy or who are expected/planned to receive chemotherapy within one week of completing 
protocol radiotherapy. Centre guidelines regarding administration of targeted non-cytotoxic 
therapy must be followed with the proviso that no systemic anticancer therapy should be 
administered within 24 hours prior to and post-radiotherapy. Endocrine therapy may be 
administered during radiotherapy as per the discretion of the treating physician. 
 
5.2.6 
Patients with spine instability as judged by a Spinal Instability Neoplastic Score (SINS) [Fisher 2010] 
of more than 12 (see Appendix III). 
 
5.2.7 
Patients with symptomatic spinal cord compression or cauda equina syndrome resulting from bony 
compression or epidural compression of the spinal cord and cauda equina, respectively. 
Symptomatic refers to neurologic deficit in the form of motor, bowel or bladder dysfunction 
 
5.2.8 
Pregnant or lactating women. 

 
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6.0 
PRE-TREATMENT EVALUATION 
(See Appendix I) 
 
Investigations 
Timing 
History and Physical 
Exam including: 
• Physical Examination 
• ECOG PS 
Within 4 weeks prior to 
randomization 
Radiology 
• MRI entire spine 
Within 8 weeks prior to 
randomization 
Pain / Analgesic 
Assessment 
• Patient Diary* 
Within 7 days prior to 
randomization 
 
ALSO: Repeat at Day 0♦♦ 
Adverse Events** 
Baseline adverse event evaluation (to document 
residual adverse event from previous therapy and 
baseline symptoms): events > grade 2 only 
Within 7 days prior to 
randomization 
Health-Related  
Quality of Life*** 
• EORTC QLQ-C30 and QLQ-BM22 
questionnaires  
Within 7 days prior to 
randomization 
 
ALSO: Repeat at Day 0♦♦ 
Economic Analysis*** 
• EQ-5D-5L questionnaire 
Within 7 days prior to 
randomization 
 
ALSO: Repeat at Day 0♦♦ 
Other Assessments 
• SINS score (use scoring sheet♦) 
Within 7 days prior to 
randomization 
• Pregnancy test (for women of child bearing 
potential only) 
Within 7 days prior to 
randomization 
Correlative Studies♦♦♦ 
• Optional, for consenting patients only: Plasma 
and Serum  
After randomization and prior to 
start of treatment 
* 
See Appendix VII. Worst Pain to be recorded only for the site included in the radiotherapy target volume. There must be no 
plan to change the pain medication on the first day of protocol treatment with radiotherapy (i.e. pain medication 
previously optimized). The diary MUST capture all medications that affect pain directly (e.g. opioids, non-opioid 
analgesics) or indirectly (e.g. steroids, co-analgesics). Other medications may also be listed. Site staff may assist the patient,  
with listing medication names /routes on the diary.  
**  
Report only Adverse Events > grade 2, using the CTCAE v 4.0. See Appendix V. 
***  
The Quality of Life and Economic Analysis questionnaires will be completed by the patient electronically. See Appendix VI.  
♦  
See Appendix III. 
♦♦  
Day 0 is defined as the day of the first fraction of radiotherapy, but prior to the administration of radiotherapy. 
♦♦♦  
See section 13 and the SC.24 Specimen Collection Manual posted on the SC.24 trial webpage. 

 
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7.0 
ENTRY/RANDOMIZATION PROCEDURES 
 
7.1 
Entry Procedures 
 
All randomizations will be done through the CCTG web-based, password-operated Electronic Data 
Capture (EDC) system. Complete details regarding obtaining a password, accessing the system and 
randomizing patients will be provided at the time of study activation and will also be included in 
the “EDC Data Management Guidebook”, posted on the SC.24 trial specific web-site. If sites 
experience difficulties accessing the system and/or randomizing patients please contact the help 
desk (link in EDC) or the SC.24 Study Coordinator. 
 
All eligible patients enrolled on the study by the participating treatment centre will be assigned a 
serial number which must be used on all documentation and correspondence with CCTG. 
 
The following information will be required: 
• 
trial code (CCTG SC.24) 
• 
name of investigator under whose name patient will be randomized 
• 
patient's initials (may be coded)  
• 
informed consent language, version date, date signed by patient, name of person conducting 
consent discussion and date signed by the person who conducted the consent form discussion 
• 
confirmation of the requirements listed in Section 5.0, including dates of essential tests  
• 
stratification factors  
 
7.2 
Stratification 
 
Subjects will be stratified by: 
1.  Histology (radioresistant♦ vs. radiosensitive♦) 
2.  “Mass”* on imaging (present vs. absent) 
3.  Centre 
♦  
radioresistant are renal cell carcinoma, melanoma, sarcoma and gastro-intestinal; radiosensitive are all 
other types 
* 
refers to tumour that involves the paraspinal tissues or epidural disease (extra-osseous extension) 
 
7.3 
Randomization 
 
Randomization will be provided electronically. 
 
Note: The validity of results of the trial depends on the authenticity of and the follow-up of all patients 
entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be 
withdrawn prior to final analysis, unless the participant withdraws from the trial and requests that 
data collection/submission cease from the point in time of withdrawal. 
 
All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting registration/randomization. 
 
 

 
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All eligible randomized patients will be followed according to the instructions on section 9.0 and 
Appendix IV for 6 months or until sites are informed by CCTG that further follow-up is no longer 
required. The follow-up requirements for ineligible patients are as follows: (1) ineligible patients 
who have received at least one dose of study radiotherapy will be followed the same way as eligible 
patients (see section 9.0 and Appendix IV); (2) ineligible patients who have received no protocol 
therapy should submit the Baseline Report plus the 4 week, 3 and 6 month Follow-Up Reports, the 
latter for the purposes of only reporting patient status and any other anti-cancer therapy received. 

 
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8.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of patients rests with the individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 3 weeks of patient 
randomization. From the time of successful treatment planning, no more than 12 days can elapse 
before the first fraction of radiotherapy is delivered. 
 
8.1 
Treatment Plan 
 
8.1.1 
Radiation Therapy 
 
Arm 
Treatment(s) 
Dose 
Duration 
1 
Standard Conventional 
Radiotherapy (CRT) 
20 Gy in  
5 fractions 
1 fraction a day for 5 days,  
Monday to Friday excluding weekends 
(weekend treatments are permitted if needed) 
2 
Stereotactic Body 
Radiotherapy (SBRT) 
24 Gy in  
2 fractions 
1 fraction a day for 2 days,  
Monday to Friday excluding weekends 
 
8.1.2 
Glossary 
 
CBCT -  ConeBeam Computed Tomography 
CT - 
Computed Tomography 
CTV - 
Clinical Target Volume 
DRR - 
Digitally Reconstructed Radiographs 
DVH - 
Dose Volume Histogram  
GTV - 
Gross Tumour Volume 
IMRT - Intensity Modulated Radiation Therapy 
MLC - 
Multileaf Collimators  
MRI - 
Magnetic Resonance Imaging 
OAR - 
Organs at Risk 
QA - 
Quality Assurance 
PRV - 
Planning organ at Risk Volume 
PTV - 
Planning Target Volume 
SRS - 
Stereotactic Radiosurgery 
VMAT - Volumetric Modulated Arc Therapy 

 
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8.2 
Radiation Treatment Plan for CRT (ARM 1) 
 
Patients will be simulated and treated with a conventional radiation technique and prescribed a total 
dose of 20 Gy given daily over 5 fractions, Monday to Friday, excluding weekends and statutory 
holidays (if the radiation oncologist wishes the patient to be treated over the weekend or statutory 
holiday, then this is permitted). The prescribed dose will be to the ICRU point, a prescription 
isodose or midplane depending on the institutional policy. The beam arrangement of an anterior-
posterior parallel opposed pair or a conformal technique using up to 4 beams is allowed at the 
discretion of the radiation oncologist if a more conformal dose distribution is required to minimize 
exposure to the normal tissues. No single direct posterior beam arrangement will be allowed nor 
intensity modulated radiotherapy (IMRT). The target vertebrae will be contoured as the clinical 
target volume and a 1 to 2 cm margin for PTV and a 1 to 2 cm margin for beam penumbra will be 
added beyond the PTV to define the field borders. Shielding with MLC or poured lead blocks are 
permitted and may compromise coverage of the PTV in order to spare the organs-at risk.  
 
8.2.1 
CRT Patient Evaluation 
 
Patients should be evaluated by the radiation oncologist for suitability for radiation prior to 
planning. Patients should be able to lie flat and judged able to tolerate treatment. All patients should 
be reviewed by the treating radiation oncologist weekly during treatment for assessment of toxicity 
and treatment response.  
 
8.2.2 
CRT Equipment and Treatment Delivery 
 
8.2.2.1 Equipment 
 
Treatment using a standard linear accelerator with beam energies ranging from 6 MV to 18 MV 
photons is acceptable. Verification of the fields with portal imaging or CBCT is acceptable. 
Shielding with a MLC or poured lead blocks as beam modifying devices is acceptable. Planning 
systems with capability for DICOM data transfer must be used.  
 
8.2.2.2 Treatment Delivery 
 
Standard fields with a parallel-opposed anterior-posterior beam arrangement and a conformal 
technique with up to 4 beams is acceptable. No direct posterior beam arrangements will be 
permitted. No inverse-planned intensity modulated radiotherapy (IMRT) or volumetric modulated 
arc radiotherapy (VMAT) is permitted.  
 
8.2.3 
CRT Positioning, Immobilization and Localization/Simulation 
 
8.2.3.1 Positioning 
 
Patients will be supine for simulation. 
 
8.2.3.2 Immobilization  
 
For spinal metastases below the 5th thoracic vertebrae (T5) no immobilization device is required. 
For patients with spinal metastases from the 1st cervical vertebrae (C1) to the 4th thoracic vertebrae 
(T4), a standard thermoplastic head and shoulder mask should be used for immobilization. 

 
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8.2.3.3 Localization Imaging/Simulation 
 
Thin slice CT simulation as a 3D treatment planning volumetric imaging study must be used to 
define the target volumes and organs-at-risk (OAR). CT slice thickness of ≤ 3mm is required (pixel 
size 512 x 512) and should encompass the target vertebrae, and the scan length should be at least 
10 cm cranially and caudally. No IV contrast or motion management is required.  
 
If artifacts are present, due to metal prostheses, the artifacts must be contoured and assigned a 
density of water. The metal implant must also be contoured and assigned an appropriate density. 
 
8.2.4 
CRT Volume Definitions  
 
8.2.4.1 Gross Tumour Volume (GTV) 
 
The GTV will be contoured as visible gross disease on CT. The baseline MRI can be used in the 
determination of the GTV. 
 
8.2.4.2 Clinical Target Volume (CTV) 
 
The CTV will encompass the GTV and include the entire spinal segment to be treated. If paraspinal 
disease is present then a 0.5 cm margin beyond any paraspinal soft tissue disease will be applied 
respecting anatomic boundaries. In cases where the adjacent vertebrae above and below needs to 
be included to achieve the therapeutic goals then a second CTV will be created that includes the 
target CTV of interest with those levels. No more than 3 spinal segments can be included in that 
CTV. For example, if T6 is the target vertebrae and the radiation oncologist needs to include T7 as 
disease is present and judgment made to treat then: a T6 CTV will be contoured and a T6-T7 CTV 
contoured with the latter considered the final CTV to place PTV margin upon and planned for 
treatment.  
 
8.2.4.3 Planning Target Volume (PTV) 
 
A uniform 1-2 cm PTV will be applied beyond the CTV. The PTV margin applied is based on 
institution practice. In the case where the target vertebrae includes adjacent levels (per 8.2.4.2) and 
the target vertebrae CTV drawn, a PTV margin must also be applied to the target vertebrae CTV in 
order to report dosimetric data; however, the PTV to be planned upon is the multilevel PTV. 
 
8.2.4.4 Organs at Risk (OAR) 
 
The spinal canal will be contoured at least 1 vertebral levels above and below the PTV. The only 
OAR to be contoured for lower thoracic and upper lumbar spinal tumours to be treated are the 
kidneys. 
 
8.2.4.5 Nomenclature 
 
The target CTV vertebrae to be treated and tracked will be named according to the vertebrae to be 
treated, for example for a T6 target the CTV will be named CTV_T6. The associated PTV will be 
named the PTV_T6. In cases where adjacent vertebrae (no more than 3 consecutive vertebrae can 
be included as CTV) is judged by the radiation oncologist to be encompassed in the CTV to achieve 
the goals of therapy due to adjacent disease, then a new CTV will be created encompassing the 
vertebrae to be treated. This CTV will be named according to the vertebral levels to be treated, for 
example if T6 and T7 are to be treated then the CTV will be named CTV_T6T7 and its PTV will 
be named PTV_T6T7. The treatment plan will be based on this final PTV, i.e. PTV_T6T7. 
However, a PTV will still be applied to the CTV_T6 and be named PTV_T6 for the purposes of 
tracking and data collection for the target vertebral segment under study. 
 
 

 
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8.2.5 
CRT Dose Specification  
 
8.2.5.1 Targets 
 
The total dose of 20 Gy will be delivered in 5 fractions, therefore, 4 Gy per fraction. The total dose 
will be prescribed to the ICRU reference point, midplane, or an isodose line based on the 
institutional practice. At least 99% of the PTV should be covered by at least 95% of the prescribed 
dose (V95%≥99%). A 115% maximum point of the prescription dose is permitted as long as it is 
not within the spinal canal. In situations where the kidneys require significant shielding, then 
compromises can be made such that coverage of the PTV by 85% of the prescribed dose is 
acceptable and the heterogeneity accepted also is adjusted such that we allow 15% to +15% of the 
prescribed dose. If the PTV extends outside of the external contour, it should be retracted from the 
external contour by no more than 5 mm for dose statistics. 
 
8.2.5.2 Organs at Risk 
 
The maximum dose to the spinal canal will be 22 Gy. 
 
If kidneys are in the field then 1/3 of the contoured kidney may be exposed to the prescribed dose 
otherwise 2/3 should be shielded by the beam modifying device. There are no other OAR required 
to be contoured. The spinal canal and kidney dose limits ate strict and as such there are no minor 
deviations. Any deviation beyond above for spinal canal and kidney are major deviations. 
 
8.2.5.3 Fractionation  
 
20 Gy in 5 fractions, therefore 4 Gy per fraction, will be delivered daily Monday to Friday 
excluding weekends and statutory holidays (if the radiation oncologist wishes the patient to be 
treated over the weekend or statutory holiday, then this is permitted). 
 
8.2.5.4 Corrections for Interruptions  
 
If delays occur in delivery there are no corrections to be applied to the radiation dose delivered. 
 
8.2.6 
CRT Treatment Planning 
 
8.2.6.1 Beam Energy 
 
6MV-18MV photons. 
 
8.2.6.2 Beam Arrangement 
 
The beam arrangement must be an anterior-posterior parallel-opposed pair or a conformal beam 
arrangement with no more than 4 beams. 
 
8.2.6.3 Beam Modifiers 
 
MLC or poured lead shielding are acceptable beam modifying devices. 
 
8.2.6.4 Planning Priorities 
 
Priorities for planning include: 1) OAR, 2) PTV coverage 
 
8.2.6.5 Inhomogeneity Corrections 
 
Inhomogeneity corrections are required when doing final dose calculations. 
 
 

 
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8.2.6.6 Acceptable Dose Heterogeneity 
 
A dose heterogeneity of -5% and +15% of the prescribed dose with the intent to cover at least 99% 
of the PTV by at least 95% of the prescribed dose is allowed. In situations where the kidneys require 
significant shielding, then compromises can be made such that coverage of the PTV by 85% of the 
prescribed dose is acceptable and the heterogeneity accepted also is adjusted such that we allow -
15% to +15% of the prescribed dose. 
 
8.2.6.7 Planning Technique 
 
Forward planning. 
 
8.2.6.8 Treatment Delivery Constraints 
 
Segments are permitted to decrease dose inhomogeneity. 
 
8.2.7 
CRT Verification 
 
8.2.7.1 Position Verification/Correction 
 
Portal images (EPID) or CBCT must be used to verify treatment position as per institutional 
protocol. 
 
8.2.7.2 Dose Verification (see ATC Guidelines 13) 
 
Independent monitor unit (MU) check for the total MU should be ≤ 3% (and for each beams also 
≤ 3%) different to the planned MU. 
 
8.3 
Radiation Treatment Plan for SBRT (ARM 2) 
 
8.3.1 
SBRT Patient Evaluation 
 
Patients should be evaluated for suitability of SBRT. Patients should be able to lie flat for at least 
60 minutes. In particular, if the pain is too severe when lying down then this may compromise the 
ability to tolerate SBRT, and if the patients’ breathing status is such that lying flat is not possible 
then the patient is not eligible. 
 
8.3.2 
SBRT Equipment and Treatment Delivery 
 
8.3.2.1 Equipment 
 
Treatment is to be delivered using photons and an energy ranging from 6 MV to 18 MV. 
Image-guidance based on CBCT imaging capabilities are required for linac-based delivery. 
 
Planning systems with capability for DICOM data transfer must be used. 
 
Cyberknife, which has a stereoscopic image guidance system and is a well-defined technology 
specifically for spine SBRT, is permitted in this trial. 
 
8.3.2.2 Treatment Delivery 
 
For MLC-linac-based delivery, static MLC, dynamic MLC, compensator IMRT, or VMAT are 
allowed. 
 
 

 
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No motion management is required. 
 
For Cyberknife technology, either cone-based or MLC-based Cyberknife deliveries are allowed. 
 
8.3.3 
SBRT Positioning, Immobilization and Localization/Simulation 
 
8.3.3.1 Positioning 
 
Patients will be simulated and treated in the supine position. 
 
8.3.3.2 Immobilization  
 
Patients will be immobilized supine only. In a body immobilization device for tumours on and 
below the 5th thoracic (T5) vertebrae and in a thermoplastic head and neck immobilization mask 
system for tumours extending from the 1st cervical vertebrae (C1) to the 4th thoracic vertebrae (T4). 
 
The body immobilization device will be according to departmental policy as each center has an 
established clinical treatment program for spine SBRT, and should be specified in the Facility 
Questionnaire. In the case of Cyberknife treatments, body immobilization is not mandatory due to 
the near-real time image guidance verification system inherent to Cyberknife, but for MLC-linac 
based therapy immobilization is mandatory. 
 
8.3.3.3 Localization Imaging/Simulation 
 
Treatment planning CT slice thickness of ≤2.5 mm is required (pixel size 512x512), and the total 
scan length will encompass the target vertebrae and extend at least 10 cm cranially and caudally. 
No IV contrast or motion management is required. 
 
MR images for fusion to the planning CT can be obtained from diagnostic imaging without the 
patient in the simulation position or in the immobilization device. The sequences include a T1- and 
T2-weighted axial MRI and some centers may use a T1 post-gadolinium axial MRI at their 
discretion. The target will be contoured according to information on both the planning CT and MRI. 
The spinal cord will be delineated according to the MRI and the thecal sac delineated according to 
the MRI and the CT. 
 
If CT artifacts are present, due to metal prostheses, the artifacts must be contoured and assigned a 
density of water. The metal implant must also be contoured and assigned an appropriate density. 
 
8.3.4 
SBRT Volume Definitions 
 
8.3.4.1 Gross Tumour Volume (GTV) 
 
The GTV is the disease that is visible on the CT and the T1- and T2-weighted axial MR. 
 
8.3.4.2 Clinical Target Volume (CTV) 
 
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. 
 
 

 
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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. 
 
In addition, the International Spinal Consortium Guideline is a reference for CTV delineation [Cox 
2012] - see Appendix VIII and can be adhered to as described. 
 
In the case of epidural disease, a 5 mm anatomic margin (excluding the spinal cord) beyond the 
GTV is required 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 must be applied beyond the GTV. 
 
In the case of adjacent vertebral segments required to be included in the treatment volume to 
achieve the goals of care, up to 2 contiguous vertebral segments may be included as a 2nd CTV. 
For example, when the target vertebral segment for study purpose is C7 then the CTV is named 
CTV_C7; however, if the radiation oncologist deems it needed to include C6 and T1 then a CTV 
included the relevant anatomy within all three spinal segments is to be contoured as the treatment 
planning CTV and named CTV_C6C7T1. For the purposes of the study, the target CTV in this 
example is the CTV_C7 despite treating CTV_C6C7T1. It would be best to contour each CTV 
spinal segment separately and then join them to form the treatment CTV. 
 
8.3.4.3 Planning Target Volume (PTV) 
 
A uniform margin of 1 to 3 mm is required for PTV. The specific number of millimeters will be 
center/department policy specific but no more than 3 mm is permitted and no less than 1 mm. In 
the case where the target vertebrae includes adjacent levels (per 8.3.4.2) and the target vertebrae 
CTV drawn, a PTV margin must also be applied to the target vertebrae CTV in order to report 
dosimetric data; however, the PTV to be planned upon is the multilevel PTV. Based on the above 
example, a PTV_C7 would be generated, as would a PTV_C6C7T1. 
 
8.3.4.4 Organs at Risk (OAR) 
 
Each of the OAR limits are strict. There are no minor deviations and any deviation beyond these 
numbers are major deviations. Please note, in brackets are what the OAR should be called in the 
plans. This will allow easier analysis of the results. 
 
• 
Spinal cord (CORD): contoured based on T1 and/or T2 MRI fused to the planning CT. A 1.5-
2 mm margin for PRV is to be applied. The thecal sac can also be contoured. The maximum 
point dose to the spinal cord PRV and/or thecal sac is 17 Gy. This dose is to be strictly adhered 
to and treatment planning must be adjusted such that this spinal cord PRV/thecal sac dose met 
within -5%. The point maximum dose to the spinal cord PRV or thecal sac cannot exceed 17 
Gy under any circumstance. 
 
 

 
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• 
Cauda equine (CAUDA): The thecal sac must be contoured as the surrogate for the cauda 
equina. The maximum point dose limit of 17 Gy is to be applied to the thecal sac. In this 
situation no PRV is required. This dose is to be strictly adhered and treatment planning adjusted 
such that this thecal sac dose met within -5%. The point maximum dose to the thecal sac cannot 
exceed 17 Gy under any circumstance. 
• 
Kidneys (KIDNEY_RT, KIDNEY_LT): Each kidney will be contoured when relevant to the 
spinal segment to be treated based on the CT scan. The maximum point dose should be ≤ 26 Gy 
and the mean dose to each kidney should be ≤ 6 Gy. 
• 
The esophagus (ESOPHAGUS), stomach (STOMACH), rectum (RECTUM), small and large 
bowel (BOWEL) should be contoured based on the CT where relevant and the maximum point 
dose should be ≤ 20 Gy. 
• 
Trachea (TRACHEA) should be contoured where relevant on the CT and the maximum point 
dose should be ≤ 20 Gy. 
• 
The liver (LIVER) should be contoured according to the CT where relevant and the maximum 
point dose should be ≤ 26 Gy and mean dose should be ≤ 8-9 Gy. 
• 
Each lung (LUNG_RT, LUNG_LT) should be contoured where relevant. The dose limits for 
each lung are: V10 < 10%, V5 < 35%, and V20 < 3% and a mean dose of ≤ 5 Gy. 
• 
Pharynx (PHARYNX) maximum point dose should be ≤ 20 Gy and mean dose should be 
≤ 9 Gy.  
• 
Larynx (LARYNX) maximum point dose should be ≤ 20 Gy and mean dose should be ≤ 9 Gy. 
• 
Each parotids (PAROTIDS_RT, PAROTIDS_LT) mean dose should be ≤ 7 Gy. 
• 
For sacral tumours (S1-S5) nerve roots should be contoured and followed until the point they 
reach the abdominal contents. A maximum point dose of ≤ 26 Gy is permitted. 
 
8.3.4.5 Planning Organ at Risk Volume (PRV) 
 
PRV margin of 1.5-2 mm is required only for the spinal cord and the dose limit of 17 Gy applied 
to this structure. If the thecal sac is also contoured then the dose limit to the cord PRV is the dose 
limiting OAR. For cauda equina, the thecal sac is contoured and no PRV applied. 
 
8.3.4.6 Unspecified Tissue 
 
A volume known as unspecified tissue must be identified. This volume is defined as tissue 
contained within the skin but which is not included in any other contoured structure, i.e. external 
contour with all the target volumes and OAR subtracted. The volume should extend at least 1cm 
above and 1cm below the most cranial-caudal PTV. The dose should be minimized to this volume 
using it in the inverse planning objective. There is no constraint for this volume. 

 
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8.3.4.7 Nomenclature 
 
The CTV and PTV will be named according to the target vertebrae to be treated. For example, for 
a L1 vertebral segment to be treated, the GTV, CTV and PTV should be named GTV_L1, CTV_L1, 
and PTV_L1. In the case where non-target vertebrae are to be included in the target volume in order 
to achieve the goals of therapy, then that target volume includes the vertebral segment of interest 
plus the additional vertebral segments. That target volume will be named according to the target 
and the adjacent vertebral segments included (no more than three contiguous vertebral segments 
can be included). For example, in the case of a L1 vertebral segment to be treated and the T12 and 
L2 to be treated, then the CTV will be named CTV_T12L2, and the PTV named PTV_T12L2. 
However, a PTV will still be applied to the CTV_L1 and be named PTV_L1 for the purposes of 
tracking and data collection for the target vertebral segment under study. 
 
Note for organs at risk that are paired like the kidney then a ‘R’ or ‘L’ should precede the OAR 
name, representing right or left for bilateral organs, e.g. R_kidney where applicable. 
 
8.3.5 
SBRT Dose Specification  
 
8.3.5.1 Targets 
 
24Gy in 2 fractions with be prescribed to the ICRU reference point for the target PTV. Prescription 
can also be based on an isodose or to the median or mean dose to the PTV and recorded as such. 
 
8.3.5.2 Unspecified Normal Tissue Dose Limits 
 
No more than 1cc of unspecified tissue and other normal tissue (excluding those tissues stipulated 
as OAR) should receive greater than 110% prescribed dose. This is only a suggestion and not a 
hard constraint. 
 
8.3.5.3 Fractionation  
 
24 Gy in 2 fractions, 12 Gy per fraction, delivered daily on Monday to Friday excluding weekend 
and statutory holidays. 
 
8.3.5.4 Corrections for Interruptions 
 
Protocol treatment should be completed within 10 days. If delays occur in delivery there are no 
corrections to be applied to the radiation dose delivered. 
 
8.3.6 
SBRT Treatment Planning 
 
8.3.6.1 Beam Energy 
 
6MV to 18 MV 
 
8.3.6.2 Beam Arrangement 
 
For IMRT, > 6 fields are acceptable and co-planar beam arrangement is preferable. For VMAT, 
co-planar is preferable but non-coplanar arcs may be accepted. All Cyberknife beam arrangements 
are acceptable. 

 
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8.3.6.3 Beam Modifiers 
 
MLC are permitted for linacs. For Cyberknife, its own collimation system is used. 
 
8.3.6.5 Planning Priorities 
 
The protocol priorities are: 1) OAR, 2) PTV coverage, 3) Unspecified tissues. 
 
8.3.6.6 Inhomogeneity Corrections 
 
Inhomogeneities corrections are required for the final dose calculation. 
 
8.3.6.7 Acceptable Dose Heterogeneity 
 
The aim is to maximize coverage of the PTV by at least 100% of the prescribed 24 Gy and to 
achieve this 80% of CTV should get 100% of the prescribed 24Gy. 
 
A dose heterogeneity of +50% is allowed in the PTV. 
 
8.3.6.8 Planning technique 
 
Inverse planning technique should be used and calculation dose grid size must be less than or equal 
to 0.25cm×0.25cm×0.25cm. 
 
8.3.6.9 Treatment Delivery Constraints 
 
For step and shoot IMRT plans, no minimum segment size will be specified, but each centre should 
follow department policy according to the already existing clinical SBRT protocol. The treatment 
planning system beam model must have been commissioned such that the monitor units delivered 
by the minimum segment size can be calculated with acceptable accuracy against measurements. 
The number of segments per field should be minimized for IMRT (total of 60-90 segments for 
IMRT plan is reasonable). 
 
8.3.7 
SBRT Verification 
 
8.3.7.1 Position Verification/Correction 
 
Position verification images must be acquired before all fractions. The method must be CBCT for 
non-Cyberknife systems. Bony anatomy must be matched and residual translations should be < 0.1 
cm and rotations < 1º at start of treatment. If the treatment length is longer than 30 minutes (or 
acceptable time according to centre protocol), or there is any suspect that the patient position may 
have been changed, intra-fractional scan to check patient position must be done. Fast CBCT 
(Turbo) protocol should be used if available. 
 
The Cyberknife uses its own stereoscopic imaging system and the spine SBRT protocol should be 
adhered to for verification. 
 
8.3.7.2 Dose Verification  
 
The plan must be verified using an independent dosimetry system such as 2D or 3D diode or 
ionization chamber array or films. Greater than 95% of measured points meeting the criterion of 
3% absolute dose difference and 3mm distance-to-agreement is acceptable. Cyberknife has its own 
method of dose verification and specifics should be adhered to. A combination of Monte Carlo 
calculation and a MLC position verification for each patient is allowed. 

 
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8.4 
Radiotherapy Quality Assurance 
 
The Radiotherapy Quality Assurance process will include four main steps: 
• 
Credentialing for delivery of SBRT and CRT to spinal metastases prior to local activation and 
at investigator level. 
• 
Prospective Centre Based Individual Pre-Treatment Case Review of treatment plans prior to 
start radiotherapy for every patient registered on the study. 
• 
Retrospective External Individual Post-Treatment Case Review for all patients after all 
radiotherapy. 
• 
Planning MRI and dosimetry data submission for quality assurance review. 
 
8.4.1 
Credentialing Requirements 
 
All centres participating in the study will require credentialing for the delivery of SBRT and CRT 
to spinal metastases prior to local activation. This credentialing will consist of a Facility 
Questionnaire and demonstration of the ability to comply with protocol specifications for treatment 
planning and delivery using anonymized archival data (dummy run). 
 
Credentialing will be mandated for each radiation oncologist investigator, and the site must receive 
approval from the central QA Reviewer before local activation. 
 
Please review the Radiotherapy Quality Assurance Manual for more details about documents to be 
submitted, the Facility Questionnaire, timing of the reviews and procedures for documentation 
uploading. All machines used for SC.24 treatments must be declared by each institution. 
 
8.4.2 
Prospective Centre Based Individual Pre-Treatment Case Review 
 
The treatment plans will be reviewed for every patient registered on the study. This review will be 
performed prior to the commencement of radiotherapy by another local radiation oncologist 
designated for this purpose and identified as study participant, i.e. “local QA reviewer”.  The 
following will be reviewed: contoured volumes, dose summary statistics, dose distributions, and 
DVHs. Specifications for the review are included in the Radiotherapy Quality Assurance Manual. 
 
8.4.3 
Retrospective External Individual Post-Treatment Case Review 
 
A final review will be completed for all patients after all radiotherapy has been completed and the 
required documents submitted (see Radiotherapy Quality Assurance Manual for details). 
 
8.5 
Submission of QA Documents for Review 
 
All QA documents will be “uploaded” electronically to a secure website. The SC.24 Central QA 
Reviewer will access the website to review all QA documents. See the RTQA Manual on the SC.24 
CCTG trial specific website for further details. 

 
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9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT 
 
All patients entered on study must be evaluated according to the schedule outlined in Appendix I 
with documentation submitted according to the schedule in Appendix IV. 
 
9.1 
Evaluation During and After Protocol Treatment 
 
Patients will be evaluated during radiotherapy as well as at 4 weeks, 3 and 6 months after the end 
of radiotherapy.  
 
Investigations 
After Treatment 
History and 
Physical Exam 
including: 
• 
Physical Exam 
• 
ECOG PS 
As per institutional standards, perform 
if clinically indicated 
Radiology 
• 
MRI entire spine 
At 3 and 6 months 
Pain / Analgesic 
Assessment 
• 
Patient Diary* 
At 4 weeks and at 3 and 6 months 
Adverse Events** 
Adverse events > grade 2 will be recorded 
and graded according to the NCI Common 
Terminology Criteria for Adverse Events 
(CTCAE) (Appendix V). 
During radiotherapy treatment♦ and 
post radiotherapy at 4 weeks and at 3 
and 6 months 
Health-Related 
Quality of Life*** 
• 
EORTC QLQ-C30 and QLQ-BM22 
questionnaires 
At 4 weeks and at 3 and 6 months 
Economic 
Analysis*** 
• 
EQ-5D-5L questionnaire 
At 4 weeks and at 3 and 6 months 
Other Assessments • 
SINS  score (use scoring sheet♦♦) 
At 3 and 6 months 
Correlative 
Studies♦♦♦ 
• 
Optional, for consenting patients only: 
Plasma and Serum  
Immediately after the second fraction 
of protocol therapy 
*  
See Appendix VII. Worst Pain to be recorded only for the site included in the radiotherapy target volume. The 
diary MUST capture all medications that affect pain directly (e.g. opioids, non-opioid analgesics) or indirectly 
(e.g. steroids, co-analgesics) as well as any pre-medications given for the protocol radiotherapy treatment. Other 
medications may also be listed. Site staff may assist the patient with listing medication names /routes on the diary. 
**  Report only Adverse Events > grade 2, using the CTCAE v 4.0. See Appendix V. 
*** The Quality of Life and Economic Analysis questionnaires will be completed by the patient electronically. See 
Appendix VI. 
♦  
Adverse events experienced by the patient during / shortly after radiotherapy treatment, including whether the patient 
experienced pain exacerbation (Pain Flare) at the treated site, must be evaluated. 
♦♦  
See Appendix III. 
♦♦♦  See Section 13 and the SC.24 Specimen Collection Manual that is posted on the trial webpage. 

 
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10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
10.1 
Evaluability 
 
Phase II: 
The primary outcome measure of the phase II study is feasibility as defined by the ability to accrue 
54 patients over an 18 month period (beginning after the first centre is locally activated) to a study 
that randomizes patients with spinal metastases, and suitable to receive radiation therapy, to 
Stereotactic Body Radiotherapy (SBRT) or Standard Conventional Radiotherapy (CRT) within a 
Canadian multicentre setting. 
 
Phase III: 
The primary outcome measure of the phase III study is complete pain response in the treatment 
area at 3 months post-radiation. 
 
Secondary outcome measures include complete pain response in the treatment area at 6 months, 
radiation site progression-free survival (RSS PFS) at 3 and 6 months, adverse event profile, Health 
Related Quality of Life and radiotherapy quality assurance (RTQA) compliance. 
 
10.1.1 Evaluable for Complete Pain Response to Radiotherapy 
 
All patients who have received at least one dose of radiotherapy and provide complete worst pain 
score information for the treated site of radiation treatment and opioid analgesic intake information 
at baseline and at least the 3 month follow up contact will be considered evaluable for response to 
radiotherapy. Patients will have response classified according to the definitions in Section 10.2.1. 
 
10.1.2 Evaluable for Radiation Site Progression Free Survival (RSS PFS) 
 
All patients who have received at least one dose of radiotherapy and have an MRI of entire spine 
at baseline and at least the 3 month follow up contact will be considered evaluable for RSS PFS. 
Patients will have RSS PFS assessed as described below in Section 10.2.3. 
 
10.1.3 Evaluable for the Spinal Instability Analysis 
 
All patients who have had their baseline SINS score and at least one follow-up SINS score (at either 
3 and/or 6 months) assessed will be considered evaluable for the spinal instability analysis. 
 
10.1.4 Evaluable for Adverse Events 
 
All patients will be evaluable for adverse event evaluation from the time of their first treatment 
with CRT or SBRT. 
 
10.1.5 Evaluable for Quality of Life Assessment 
 
All patients who have completed a baseline quality of life questionnaire (EORTC QLQ-C30 and 
QLQ-BM22) and at least one follow-up questionnaire are evaluable for quality of life assessment. 
 
10.1.6 Evaluable for Economic Analysis 
 
All patients who have completed a baseline economics analysis questionnaire (EQ-5D-5L) and at 
least one follow-up questionnaire are evaluable for economic analysis. 
 
 

 
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10.1.7 Evaluable for Radiotherapy Quality Assurance (RTQA) Compliance 
 
Canadian and Australian centres will be evaluable for RTQA compliance from the time they are 
locally activated to participate on the study. 
 
10.2 
Definitions 
 
10.2.1 Response Outcomes 
 
Pain response to radiotherapy is based on the International Bone Metastases Consensus Endpoint 
definitions [Chow 2002]. 
 
Complete Pain Response:  
 
A Complete Pain Response is defined as a pain score of zero (0) at the treated site with no 
concomitant increase in analgesic intake (stable or reducing analgesics in daily oral morphine 
equivalent)  
 
Partial Pain Response: 
 
Partial response is defined as any of the following:  
i. 
Reduction in worst pain score of two or more at the bony metastatic site on a 0–10 scale without 
analgesic increase. 
ii. Analgesic reduction of 25% or more from baseline without an increase in worst pain score with 
reference to baseline. 
iii. For patients who were using opioid analgesics at the baseline assessment, a daily oral morphine 
equivalence of zero (0) without an increase in worst pain score relative to the baseline worst 
pain score. 
 
Pain Progression: 
 
Pain progression is defined as any of the following: 
i. 
An increase in worst pain score of two or more points above baseline at the treated site without 
reduction of analgesic use. 
ii. An increase of 25% or more in daily oral morphine equivalent compared with baseline, without 
reduction in worst pain score. 
iii. For patients who were not using opioid analgesics at the baseline assessment (daily oral 
morphine equivalence = 0), consumption of any opioid analgesic without a reduction in worst 
pain score relative to the baseline worst pain score. 
 
Stable Pain: 
 
Stable pain (SD) is assigned to the remaining evaluable patients, who do not meet any of the 
categories of Complete/Partial Response and Pain Progression. 
 
 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
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AMEND #3: 2018-OCT-31 
10.2.2 Radiation Site Progression Free Survival (RSS PFS) 
 
Radiation site progression free survival is defined as the time from randomization to local 
progression or death. 
 
The response  assessment will be an investigator interpretation of the following criteria: lesion 
status, size, epidural disease extent (Bilsky scale and 3 D measurements), degree of angular 
kyphosis and height of vertebral body [Sahgal 2015]. 
 
Local progression may be defined as: 
• 
Gross unequivocal increase in tumor volume or linear dimension. 
• 
Any new or progressive tumor within the epidural space. 
• 
Neurologic deterioration attributable to pre-existing epidural disease with equivocal increased 
epidural disease dimensions on MRI. 
 
Biopsy is recommended in those situations in which pseudoprogression due to radiation reaction 
cannot be ruled out. 
 
10.2.3 Overall Survival 
 
Overall survival is defined as the time interval between the date of randomization and the date of 
death from any cause. Patients who are still alive at the time of the final analysis or who have 
become lost to follow-up will be censored at their last date known to be alive. 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
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AMEND #1: 2017-FEB-02 
11.0 
SERIOUS ADVERSE EVENT REPORTING 
 
This protocol does not contain investigational agent(s), and adverse events occurring as a result of 
radiotherapy treatment should be reported to CCTG in the manner described below. In addition, 
your local Research Ethics Board (REB) should be notified. 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix V). All appropriate treatment areas should have access to a copy of the CTCAE. A copy 
of the CTCAE can be downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ is used 
in the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CCTG. 
 
11.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events which are unexpected and related to protocol treatment must be 
reported in an expedited manner (see Section 11.2 for reporting instructions). These include 
events occurring during the treatment period (until 30 days after last protocol treatment 
administration) and at any time afterwards. 
• 
Unexpected adverse events are those which are not consistent in either nature or severity with 
information provided in section 3. 
• 
Adverse events considered related to protocol treatment are those for which a relationship to 
the protocol treatment cannot reasonably be ruled out. 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. 
 
11.2 
Serious Adverse Event Reporting Instructions 
 
All reportable serious adverse events must be reported using a web-based Electronic Data Capture 
(EDC) system being used for this trial. For details about accessing the EDC system and completing 
the on-line SAE report form, please refer to the CCTG Generic Data Management Guidebook for 
EDC Studies posted on the SC.24 section of the CCTG website (www.ctg.queensu.ca). 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
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Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to CCTG 
via EDC system. 
 
Within 10 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 
 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website 
 
FAX paper SAE Report to: 
 
SC.24 Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533-2941 
 
Please use the same timelines for submission as for direct EDC reporting. 
 
Once internet connectivity is restored, the information that was FAXED to CCTG on the paper 
SAE Report must also be entered by the site into the EDC SAE web application.  
 
Local internet interruption: 
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE Report 
from the trial website, please phone the SC.24 trial team (613-533-6430) to obtain a copy of the 
SAE Report by FAX. Once completed, the report must be FAXED back to CCTG as indicated 
above. Once internet connectivity is restored, the information that was FAXED to CCTG on the 
paper SAE Report must also be entered by the site into the EDC SAE web application.  
 
In cases of prolonged internet interruptions, please contact the CCTG Safety Desk for further 
instructions (613-533-6430).  
 
11.3 
Other Protocol Reportable Events – Pregnancy Reporting 
 
11.3.1 Pregnancy Prevention 
 
Women of Child bearing Potential (WOCBP) and males who are enrolled in the trial must have 
agreed to use contraceptive method(s) as described in Eligibility Criterion 5.1.12. Investigators may 
wish to additionally advise the female partners of male participants about pregnancy prevention 
guidelines when appropriate and compliant with local policy. 
 
11.3.2 Pregnancy Reporting 
 
The investigator is required to report to CCTG any pregnancy occurring in female participants or 
female partners of male participants during treatment. Pregnancies occurring up to 6 months after 
the completion of radiotherapy must also be reported. 
 
The investigator should report the pregnancy in a timely manner, within 24 hours of learning of the 
pregnancy using the CCTG Pregnancy Reporting Form, available from the trial webpage. 

 
PROTOCOL DATE: 2015-JUL-24 
 
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Once informed consent has been obtained, the form should be updated to provide further pregnancy 
information and to reflect the outcome of the pregnancy. All follow-up reports must be submitted 
to CCTG in a timely manner. For pregnant partner of trial participant (and pregnant participants, if 
required by local policy), a copy of the signed signature page of the pregnancy follow-up consent 
must be submitted to CCTG.  
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812/ safety-desk@ctg.queensu.ca). 
 
If the pregnancy results in death (e.g. spontaneous abortion, stillbirth); is life-threatening; requires 
inpatient hospitalization or prolongation of existing hospitalization; results in persistent or 
significant disability/incapacity; is a congenital anomaly/birth defect, then an SAE report must be 
additionally submitted as described above. Please note, hospitalization for labour/delivery alone 
does not constitute an ‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health  
 
The CCTG will provide expedited reports of SAEs to Health Canada for those events which meet 
regulatory requirements for expedited reporting, i.e. events which are BOTH serious AND 
unexpected, AND which are thought to be related to protocol treatment (or for which a causal 
relationship with protocol treatment cannot be ruled out). 
 
11.5 
Reporting Serious Adverse Events to Investigators 
 
CCTG will notify Investigators of all serious adverse events from this trial that are reportable to 
regulatory authorities in Canada as reported to CCTG. This includes all serious events that are 
unexpected and related (i.e. possibly, probably, or definitely) to protocol treatment. The reports 
will be posted to the CCTG trial SC.24 web-based safety monitoring utility. 
 
Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes. 
The date of REB Submission for these SAEs will need to be entered into the CCTG trial SC.24 
web based safety monitoring utility and documentation of REB submission must be retained in the 
study binder on site. The REB submission template provided by CCTG can be used to assist with 
tracking, submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be filed 
in the trial files on site. 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
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12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
12.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity (see also Sections 3.1.1.1 or 3.1.2.1). 
• 
Investigator discretion 
• 
Request by the patient. 
• 
Completion of therapy as outlined in Section 8.0. Efforts should be made to maintain the 
investigations schedule and continue follow-up, even if patients discontinue protocol treatment 
prematurely and/or no longer attend the participating institution. 
 
12.2 
Therapy After Protocol Treatment is Stopped 
 
After protocol radiotherapy is completed, further treatment is at the discretion of the investigator. 
However, according to Section 5.2.5 patients are not expected to receive chemotherapy within one 
week of completing protocol radiotherapy. 
 
12.3 
Follow-up Off Protocol Treatment 
 
All patients will be followed until 6 months after the end of radiotherapy. 
 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
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AMEND #1: 2017-FEB-02; AMEND #2: 2018-APR-03 
13.0 
CENTRAL REVIEW PROCEDURES AND SPECIMEN COLLECTION 
 
13.1 
Radiotherapy Quality Assurance (RTQA) 
 
RTQA, consisting of (1) credentialing at the investigator level and prior to centre local activation, 
(2) prospective centre-based review of treatment plans prior to start of radiotherapy for every 
patient randomized on the study, (3) retrospective external review for all patients after completion 
of radiotherapy, and (4) planning MRI and dosimetry data submission for quality assurance review, 
will be required for all patients randomized to the study. See section 8.4 and the SC.24 RTQA 
Manual posted on the trial webpage for details. 
 
13.2 
Central Radiology Review 
 
Central radiology review for the purposes of the radiation site progression-free survival (RSS PFS) 
secondary endpoint will be required for all patients randomized to the study. The central reviewer 
will be blinded to study radiotherapy treatment allocation. Please see the SC.24 trial webpage 
(www.ctg.queensu.ca) for details of electronic upload of MRI files.  
 
13.3 
Central Pathology Review 
 
There will be no central pathology review for this study. 
 
13.4 
Specimen Collection 
 
The collection of blood is an important part of this trial. Blood will be carefully banked as part of 
the CCTG tissue bank at Queen’s University in Kingston, Ontario. 
 
The blood may be used by researchers now or in the future to develop predictive biomarkers for 
SBRT. Samples will be used for research purposes only and will not be sold. A scientific review 
process of any proposals to use the blood will take place and any proposals approved will have 
undergone ethics approval. Patients will not be identified by name. The only identification will be 
by a patient study number assigned at the time of randomization to the trial and patient initials. 
Material issued to researchers will be anonymized and only identified by a coded number. 
 
All patients on whom a blood sample is collected will be aware of this retrieval and will have given 
their consent. 
 
There will be no specimen collection kits provided for this study. Red topped tubes will be used to 
collect serum and EDTA-lavender topped tubes will be used to collect plasma.  
 
Specimens will be stored at participating centers at -80°C immediately after collection and then 
batch-shipped (i.e. multiple samples from one site in one shipment) to the CCTG Tissue Bank, 
frozen on dry ice, for subsequent storage and ultimate analysis. A Specimen Submission Form 
should accompany all shipments. Details of specimen, collection, processing, packaging and 
shipping (including the Specimen Submission Form) can be found in the SC.24 Specimen 
Collection Manual that is posted on the trial webpage. 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
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AMEND #1: 2017-FEB-02; AMEND #2: 2018-APR-03; AMEND #3: 2018-OCT-31 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Objectives and Design 
 
This study is a randomized multicentre phase II/III study. 
 
The primary endpoint of the phase II study is feasibility of accrual patients to the study, which is 
defined as the ability to accrue 54 patients over an 18-month period to a study that randomizes 
patients with spinal metastases to Stereotactic Body Radiotherapy (SBRT) or Standard 
Conventional Radiotherapy (CRT) within a Canadian multicentre setting. 
 
The primary endpoint of the phase III study is the complete pain response rate at 3 months 
post-radiation. 
 
Secondary Endpoints: 
• 
Complete pain response in the treatment area t 6 months post-radiation 
• 
Radiation site progression-free survival (RSS PFS) at 3 and 6 months 
• 
SINS score at 3 and 6 months 
• 
Overall survival 
• 
Adverse event profile 
• 
Health-related Quality of Life 
• 
Radiotherapy Quality Assurance (RTQA) compliance 
 
14.2 
Primary Endpoints and Analysis 
 
The primary endpoint of the phase II study is feasibility which is defined as the ability to accrue 54 
patients over an 18 month period to a study that randomizes patients with spinal metastases to 
Stereotactic Body Radiotherapy (SBRT) or Standard Conventional Radiotherapy (CRT) within a 
Canadian multicentre setting. 
 
The primary endpoint of the phase III study is the complete pain response at 3 months post-
radiation, which is defined as in section 10.2.1. The analysis of the primary outcome will be based 
on the intent-to-treat principle, which will include all randomized patients, regardless of whether 
radiation therapy is given, given as per protocol, or whether there has been fidelity to treatment 
allocation. Patients that are inevaluable for the primary endpoint due to missing data will be 
considered as non-responder for the intent-to-treat analysis of the primary endpoint. The primary 
test will be the Cochran-Mantel-Hanzeal test stratified by baseline stratification factors of 
Histology (radioresistant vs. radiosensitive) and “Mass” on imaging (present vs. absent), a Chi-
square analysis will also be applied to test the complete pain response rates between the two arms, 
and the 95% confidence limits of the rate difference between the two arms will be evaluated. 
Logistic regression will be used to estimate the treatment effect while adjusting for unbalanced 
important factors and to explore factors that are predictive of the complete pain response. 
 
 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
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14.3 
Sample Size and Duration of Study 
 
For the randomized phase II portion of the study, a convenience sample size of 54 patients is 
considered sufficient to evaluate whether accrual is feasible. This sample size would also provide 
an opportunity to estimate the CRT and SBRT 3 month complete pain relief response rates, which 
would provide the basis for the sample size calculation of the future randomized controlled 
trial. We chose a sample size that provides for standard error rates in both treatment arms to be 
less than 10%. Assuming that the CRT response rate is 10% to 30%, with 27 patients, the standard 
error for the estimated response rate will be 5.8% to 8.8%, respectively. Assuming that the SBRT 
response rate is about 30% to 50%, with 27 patients, the standard error for the estimated response 
rate would be 8.8% to 9.8%, respectively. 
 
The trial was activated in July 2015. By November 2016, 44 patients had been enrolled onto the 
study and the accrual rate indicated that the sample size would be reached in 18 months, thereby 
meeting the primary objective of the phase II feasibility study. Other metrics of trial conduct were 
examined including treatment related toxicity and tolerability as well compliance with radiotherapy 
including quality assurance measures. No safety signals were detected in either arm. Notably, spinal 
fracture within the treatment fields occurred in 2 patients - both on the conventional treatment arm 
(CRT). Compliance with protocol mandated radiotherapy and quality assurance measures was high. 
 
Based on the demonstration of feasibility of trial conduct and continued need to critically evaluate 
the efficacy of SBRT in the treatment of painful spinal metastases, approval was sought and granted 
in January 2017 for conversion of the study design from a randomized phase II feasibility study to 
a randomized phase II/III study comparing the two radiotherapy treatment strategies. 
 
Sample size estimate for the phase III controlled trial is with a two-sided 5% level test and 80% 
power. Based on the results of a randomized phase II trial [Sprave 2018] with similar enrollment and 
radiobiology criteria as the current study, we estimate the complete pain responses will be 20% for 
the CRT and 40% for the SBRT treatment arms, respectively. 
 
Assuming a 15% drop out/inevaluable rate, we expect the complete pain response rates for the 
intent-to-treat analysis to be 17% and 34% for the CRT and SBRT arms, respectively. The sample 
size for the phase III study is 228. Multiple sensitivity analyses will also be performed to further 
evaluate the results: (i) complete case analysis that excludes those with missing/inevaluable; (ii) 
multiple imputation analysis that assigns different portions of those missing/inevaluable to be either 
responders or non-responders. A secondary “as treated” sensitivity analysis will be performed to 
include only eligible patients who have received protocol-assigned radiation therapy. 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
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AMEND #1: 2017-FEB-02 
Table: Sample Size Parameters for a Subsequent Randomized Controlled Trial 
 
CRT response 
SBRT response 
Effect size 
Drop-out rate 
Total Sample Size 
10 
30 
20 
0.1 
160 
10 
30 
20 
0.05 
152 
15 
35 
20 
0.1 
186 
15 
35 
20 
0.05 
176 
20 
40 
20 
0.1 
206 
20 
40 
20 
0.05 
194 
25 
45 
20 
0.1 
220 
25 
45 
20 
0.05 
210 
30 
50 
20 
0.1 
230 
30 
50 
20 
0.05 
218 
10 
25 
15 
0.1 
252 
10 
25 
15 
0.05 
238 
15 
30 
15 
0.1 
298 
15 
30 
15 
0.05 
284 
20 
35 
15 
0.1 
338 
20 
35 
15 
0.05 
320 
25 
40 
15 
0.1 
370 
25 
40 
15 
0.05 
350 
30 
45 
15 
0.1 
392 
30 
45 
15 
0.05 
372 
This table shows potential sample sizes for the planned RCT study with two-sided alpha = 0.05 and power 
= 80%. The sample size is very sensitive to the CRT response rate. For example, for an effect size of 20%, if 
the response rate with CRT is 10%, the sample size will be 160 patients while if the response rate is 30%, the 
sample size will increases to 230. 
 
14.4 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office DSMC will review the 
safety profile of the study radiotherapy every 6 months and investigators will review the data 
annually at their meetings. 
 
14.5 
Interim Analysis 
 
There is no planned interim analysis for the phase III part of the study. A single final analysis will 
be performed when all patients have met their projected follow-up period of 6 months. 
 
14.6 
Secondary Endpoint and Analysis 
 
Complete pain response in the treatment area at 6 months post-radiation. All analyses for the 
primary endpoint will be performed for the complete pain response at 6 months post-radiation. 
 
 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
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AMEND #1: 2017-FEB-02; AMEND #2: 2018-APR-03; AMEND #3: 2018-OCT-31 
Radiation site progression-free survival (RSS PFS) is defined as the time from the date of 
randomization to the date of documented local progression, as defined in Section 10.2.2; or the date 
of death. Patients who have not progressed or died by the cutoff date of final analysis, RSS PFS 
will be censored on the date of the last disease assessment. A Kaplan-Meier curve for proportions 
of RSS PFS in each treatment arm will be displayed. The RSS PFS rates at 3 and 6 months and 
their 95% confidence intervals will be estimated. The 95% confidence intervals for the medial RSS 
PFS will be computed using the method of Brookmeyer and Crowley. The difference in 
distributions of RSS PFS in the two treatment arms will be compared using the log-rank test 
stratified by the stratification factors at randomization except study centre. Other potential 
important factors that predict RSS PFS will be assessed using Cox regression. Overall survival will 
be analysed similarly. 
 
The incidence of acute severe adverse incidences for each arm will be calculated with its 95% 
confidence interval, and the analyses will be performed in a tiered comparison, i.e., comparing the 
overall incidence rates between treatment arms first, then comparison of radiotherapy and disease 
related symptoms and compared by means of Chi-square analysis or Fisher exact test. 
 
SINS scores will be summarized for data at baseline, 3 and 6 months evaluations. The potential 
prognostic effects of baseline SINS score on the complete pain response at 3 months post-radiation 
and the overall survival will be explored using logistic and Cox regression models respectively. 
 
14.7 
Quality of Life Analysis 
 
The quality of life (QoL) of patients will be assessed using EORTC QLC-C30 and the Bone 
Metastases module (BM22) questionnaires. 
 
The EORTC QLQ-C30 is a self-administered cancer specific questionnaire with multi-dimensional 
scales. It consists of both multi-item scales and single item measures, including five functioning 
domains, a global quality of life domain, three symptom domains and six single items. For each 
domain or single item measure a linear transformation will be applied to standardize the raw score 
to range between 0 and 100. 
 
BM22 has 22 questions consisting of the 4 subscales (painful sites (PS) and pain characteristics 
(PC) on the symptom scale and functional interference (FI) and psychosocial aspects (PA) on the 
functional scale). The subscale will also be linear transformed to standardize the raw score to range 
between 0 and 100. 
 
The quality of life data will be analyzed to look for statistically and clinically significant differences 
between the study treatment groups. The standard CCTG QoL Response Analysis categorizing 
patients as either having improved, stable, or worsened QoL will be used as follows [Osaba 2005]. 
A change in score of 10 points from baseline is defined a priori as clinically relevant. For functional 
scales and global health status, patients will be considered to have QoL improvement if reporting 
a score of 10 points or better than baseline at any time of QoL assessment. Conversely, patients 
will be considered to have worsened QoL if reporting a score minus 10 points or worse than 
baseline at any time of QoL assessment without above defined improvement. Patients whose scores 
fall between 10-point changes from baseline at every QoL assessment will be considered as stable. 
In contrast to functional scales, for the determination of patient’s QoL response, classification of 
patients into improved and worsened categories will be reversed for symptom scales. 
 
 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
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AMEND #2: 2018-APR-03 
14.8 
Economic Analysis 
 
The costs and utility values of treating spinal bone metastases with SBRT and CRT will be 
conducted on the SC.24 data set of patients randomized between SBRT and CRT as treatment for 
painful spinal bone metastases.  
 
SC.24 compares pain responses as a primary outcome and captures quality of life data using the 
EORTC QLQC30 and BM22 tools. For the cost-utility analysis, we will collect health system 
resource utilization data as well as health preference data. Health system resources (e.g. RT 
planning and delivery details) utilized by patients by treatment modality will be derived from the 
source documents for SC.24. RT planning costs and health system costs will be derived from 
provincial sources and publications and will examine events related to treatment outcomes, 
including changes in pain medication utilization, and sequelae of vertebral body metastases (given 
the 6 month study follow-up post RT). 2017 Canadian dollars will be applied to resources utilized.  
 
Health preference values will to be collected using the EuroQol (EQ-5D-5L) questionnaire. The 
EQ-5D-5L will be collected prospectively during treatment and follow-up visits to a subgroup of 
patients enrolled in the trial. Health preference values have not previously been described in this 
population or by treatment modality.  
 
EQ-5D-5L is a self-administered questionnaire that consists of two pages comprised of : 1) the EQ-
5D-5L descriptive system with five dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) and each dimension comprises levels (no problems, slight 
problems, moderate problems, severe problems, and extreme problems); 2) the EQ VAS record of 
the respondent’s self-rated health status on a vertical graduated (0-100) visual analogue scale. 
Descriptive analyses will be performed to compare health utility values between treatment arms.  
 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
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AMEND #1: 2017-FEB-02 
15.0 
PUBLICATION POLICY 
 
15.1 
Authorship of Papers, Meeting Abstracts, Etc. 
 
15.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether to 
publish the trial under a group title, or with naming of individual authors. If the latter approach is 
taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group may be credited as 
authors depending upon their level of involvement in the study. 
• 
Additional authors, up to a maximum of 15, will be those who have made the most significant 
contribution to the overall success of the study. This contribution will be assessed, in part but 
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the 
study chair. 
• 
In the event of a separate paper dealing with the quality of life outcomes, the first author will 
generally be the Quality of Life Coordinator on the trial committee. 
 
15.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
"A study coordinated by the Canadian Cancer Trials Group. Participating 
investigators included: (a list of the individuals who have contributed 
patients and their institutions)." 
 
15.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write up the results of the study within a reasonable 
time of its completion. If after a period of six months following study closure the manuscript has 
not been submitted, the central office reserves the right to make other arrangements to ensure timely 
publication. 
 
Dissemination of Trial Results 
CCTG will inform participating investigators of the primary publication of this trial. The complete 
journal reference and, if where publicly available, the direct link to the article will be posted on the 
Clinical Trial Results public site of the CCTG web site (http://www.ctg.queensu.ca). 
 
15.3 
Submission of Material for Presentation or Publication 
 
Material may not be submitted for presentation or publication without prior review by the CCTG 
Senior Investigator, Senior Biostatistician, Study Coordinator, and approval of the Study Chair. 
Individual participating centres may not present outcome results from their own centres separately. 
Supporting groups and agencies will be acknowledged. 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
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AMEND #1: 2017-FEB-02 
16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
16.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
16.2 
Inclusivity in Research 
 
CCTG does not exclude individuals from participation in clinical trials on the basis of attributes 
such as culture, religion, race, national or ethnic origin, colour, mental or physical disability (except 
incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal record, 
unless there is a valid reason (i.e. safety) for the exclusion. 
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of CCTG that vulnerable persons or groups will not be automatically excluded from a 
clinical trial (except for incompetent persons) if participation in the trial may benefit the patient or 
a group to which the person belongs. 
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately. 
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a CCTG clinical trial under this policy but excluded by local policy, it 
is expected that they would not be enrolled in the trial. It is the centre’s responsibility to ensure 
compliance with all local SOPs. 
 
It is CCTG’s policy that persons who cannot give informed consent (i.e. mentally incompetent 
persons, or those physically incapacitated such as comatose persons) are not to be recruited into 
CCTG studies. It is the responsibility of the local investigator to determine the subject’s 
competency, in accordance with applicable local policies and in conjunction with the local REB (if 
applicable). 
 
Subjects who were competent at the time of enrolment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, investigators must follow applicable local policies when determining if it 
is acceptable for a substitute decision maker to be used. CCTG will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation. 
 
 

 
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16.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in an CCTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring 
that all local policies are followed. 
 
Additionally, in accordance with GCP 4.8.2, CCTG may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential participant’s 
willingness to participate in the study.  
 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating investigator (as defined on the participants list) is ultimately responsible, in terms of 
liability and compliance, for ensuring informed consent has been appropriately obtained. CCTG 
recognizes that in many centres other personnel (as designated on the participants list) also play an 
important role in this process. In accordance with GCP 4.8.5, it is acceptable for the Qualified 
Investigator to delegate the responsibility for conducting the consent discussion. 
 
CCTG requires that each participant sign a consent form prior to their enrollment in the study to 
document his/her willingness to take part. CCTG may also require, as indicated above, that 
participants/potential participants be informed of new information if it becomes available during 
the course of the study. In conjunction with GCP 4.8.2, the communication of this information 
should be documented. 
 
CCTG allows the use of translators in obtaining informed consent. Provision of translators is the 
responsibility of the local centre. Centres should follow applicable local policies when procuring 
or using a translator for the purpose of obtaining informed consent to participate in a clinical trial.  
 
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be 
obtained by having the consent form read and explained to the subject.  
 
16.3.1 Obtaining Consent for Pregnancy Reporting 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner) should not be collected about or from them unless or until they are a willing participant in 
the research. The rights and protections offered to participants in research apply and consent must 
be obtained prior to collecting any information about or from them. 
 
If the main consent form adequately addresses the collection of information regarding the outcome 
of a pregnancy of a trial participant, a “Pregnancy Follow-up” consent form will not be required by 
CCTG. 
 
Trial-specific consent forms for “Pregnancy Follow-up” can be found on the trial webpage. The 
appropriate consent form must be used to obtain consent from any non-trial participant (such as the 
pregnant partner or exposed individual). 
 
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy. Similarly, male participants will not be 
withdrawn from the main study should their partner refuse/withdraw permission. 
 
 

 
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Obtaining Consent for Research on Children 
 
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner), consent must be obtained from the parent/guardian. 
 
16.4 
Discontinuation of the Trial 
 
If this trial is discontinued for any reason by the CCTG all centres will be notified in writing of the 
discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any potential 
risks to the health of patients participating on the trial or other persons, the CCTG will provide this 
information to centres as well. 
 
If this trial is discontinued at anytime by the centre (prior to closure of the trial by the CCTG), it is 
the responsibility of the qualified investigator to notify the CCTG of the discontinuation and the 
reason(s) why.  
 
Whether the trial is discontinued by the CCTG or locally by the centre, it is the responsibility of 
the qualified investigator to notify the local Research Ethics Board and all clinical trials subjects of 
the discontinuance and any potential risks to the subjects or other persons. 
 
16.5 
Retention of Patient Records and Study Files 
 
All essential documents must be maintained in accordance with ICH-GCP. 
 
In accordance with GCP 4.9.5, essential documents must be retained for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. In most cases, this 
will be for 10 years following the completion of the trial (10 years post final analysis, last data 
collected, or closure notification to REB, whichever is later) at the centre, or until notified by CCTG 
that documents no longer need to be retained.  
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access.  
 
CCTG will inform the investigator/institution as to when the essential documents no longer need 
to be retained.  
 
16.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI).  
 
Forms are to be submitted according to the schedule in the protocol. There are minimum standards 
for performance. 
 
 
 

 
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16.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the study 
as part of the overall quality assurance program. The monitors/auditors will require access to patient 
medical records to verify the data, as well as essential documents, standard operating procedures 
(including electronic information), ethics and pharmacy documentation (if applicable). 
 
16.8 
Case Report Forms 
 
A list of forms to be submitted as well as expectation dates, are to be found in Appendix IV. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For 
details of accessing the EDC system and completing the on-line Case Report Forms please refer to 
the “Registration/Randomization and Data Management Guidebook” posted on the SC.24 area of 
the CCTG website (www.ctg.queensu.ca). 

 
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17.0 
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APPENDIX I - PATIENT EVALUATION FLOW SHEET 
 
Required Investigations 
Prior to 
Random-
ization  
After 
randomization 
and prior to 1st 
fraction of RT 
Day 0* 
Immediately 
after 2nd 
fraction of 
RT 
During 
RT 
treatment 
4 wks 
post-RT 
3 months 
post-RT 
6 months 
post-RT 
History and Physical 
 
 
 
 
 
 
 
 
Physical Exam 
< 4 weeks 
 
 
 
 
As per institutional standards 
– perform if clinically 
indicated 
ECOG Performance Status 
< 4 weeks 
 
 
 
 
Radiology 
 
 
 
 
 
 
 
 
MRI entire Spine 
< 8 weeks 
 
 
 
 
 
X 
X 
Pain / Analgesic Assessment 
 
 
 
 
 
 
 
 
Patient Diary 
< 7 days 
 
X 
 
 
X 
X 
X 
Adverse Events 
 
 
 
 
 
 
 
 
Baseline Symptoms / Adverse 
Events** 
< 7 days 
 
 
 
X♦ 
X 
X 
X 
Health-Related Quality of Life and Economic Analysis 
 
 
 
 
 
 
EORTC QLQ-C30 and QLQ-
BM22 questionnaires 
< 7 days 
 
X 
 
 
X 
X 
X 
EQ-5D-5L questionnaire 
Other Assessments 
 
 
 
 
 
 
 
 
SINS score*** 
< 7 days 
 
 
 
 
 
X 
X 
Pregnancy Test 
< 7 days 
 
 
 
 
 
 
 
Correlative Studies 
 
 
 
 
 
 
 
 
Serum and Plasma 
Collection♦♦ 
 
X 
 
X 
 
 
 
 
* 
Day 0 is defined as the day of the first fraction of radiotherapy, but prior to the administration of radiotherapy 
**  Report only Adverse Events > grade 2, using the CTCAE v 4.0. See Appendix V. 
***  See SINS scoring sheet on Appendix III  
♦ 
Evaluation of adverse events experienced by the patient during / shortly after  radiotherapy treatment, including whether the patient 
experienced  pain exacerbation (Pain Flare) at the treated site    
♦♦ 
See section 13 and the SC.24 Specimen Collection Manual posted on the SC.24 trial webpage. 
 

 
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APPENDIX II - PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
100 
Fully active, normal. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g. light housework, 
office work. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly. 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
selfcare but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only limited 
selfcare; confined to bed or 
chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
* The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 

 
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APPENDIX III - SPINAL INSTABILITY NEOPLASTIC SCORE (SINS) SCORESHEET 
 
Location 
• 
3 points: Junctional (C0-C2, C7-T2, T11-L1, L5-S1) 
• 
2 points: Mobile Spine (C3-C6, L2-L4) 
• 
1 point: Semi-rigid (T3-T10) 
• 
0 points: Rigid (S2-S5) 
Score:______ 
Pain relief with recumbency and/or pain with movement/loading of the spine 
• 
3 points: Yes 
• 
1 point: No (occasional pain but not mechanical) 
• 
0 points: Pain free lesion 
Score:______ 
Bone lesion 
• 
2 points: Lytic 
• 
1 point: Mixed (lytic/blastic) 
• 
0 points: Blastic 
Score:______ 
Radiographic spinal alignment 
• 
4 points: Subluxation / translation present 
• 
2 points: De novo deformiye (kyphosis / scoliosis) 
• 
0 points: Normal alignment 
Score:______ 
Vertebral body collapse 
• 
3 points: > 50% collapse 
• 
2 points: < 50% collapse 
• 
1 point: No collapse with > 50% body involved 
• 
0 points: None of the above 
Score:______ 
Posterolateral involvement of the spinal elements (facet, pedicle or costovertebral 
joint fracture or replacement with tumour) 
• 
3 points: Bilateral 
• 
1 point: Unilateral 
• 
0 points: None of the above 
Score:______ 
 
Sum Score: ______ 
Adapted from Fisher 2010.  
Interpretation: 
• 
Sum Score 0 – 6: Stable 
• 
Sum Score 7 - 12: Indeterminate (possibly impending) instability 
• 
Sum Score 13 – 18: Instability  
 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
CONFIDENTIAL 
57 
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AMEND #1: 2017-FEB-02 
APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of randomization.  
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection except for the 
Quality of Life instrument and the Patient Diary for which details are as follows: 
• 
The Quality of Life questionnaire data will be entered by the patient on tablet computers, which 
will be distributed to sites by the CCTG Central Office. For detailed technical and logistical 
information regarding how to obtain, store and maintain the tablets, as well access and login into 
CCTG electronic System for Patient Reported Outcomes (SPROUT) system run by the tablets, 
please refer to the Electronic Patient Reported Outcome User Guide, posted on the SC.24 webpage 
area of the CCTG website (www.ctg.queenu.ca) 
• 
The Patient Diary will be completed by the patient on paper and will be subsequently scanned and 
uploaded into the EDC system as “Supporting Documentation” by the centre CRA 
 
For details of accessing the EDC system and completing the on-line Case Report Forms please refer to the 
“CCTG EDC Generic Data Management Guidebook” posted on the SC.24 area of the CCTG web-site 
(www.ctg.queensu.ca). 
 
The electronic CRFs to be used in this trial, through the EDC system, are as follows: 
 
Electronic Folder 
Required  
To be completed 
electronically 
Supporting Documentation 
Required+ 
Eligibility Checklist 
Prior to randomization 
At the time of 
randomization 
Consent form* 
Pathology report(s) 
MRI Entire Spine report 
Patient Diary 
Baseline Report 
At the time of 
randomization 
Within 2 weeks of 
randomization 
Correlative Studies Report 
(Blood) 
Continuous Running Log 
folder 
Within 2 weeks after the 
first sample collection 
AND within 2 weeks after 
the first sample collection 
Consent form* 
Radiotherapy Report 
At completion of 
radiotherapy 
Within 2 weeks of 
completion of treatment 
 
Follow-up Report 
At each follow-up visit 
Within 2 weeks of 
completion 
MRI Entire Spine report 
Patient Diary 
Relapse / Progression 
Report 
At the time of Radiation 
Site Progression♦ 
Within 2 weeks of 
completion 
 
Death Report 
At the time of patient 
death** 
Within 2 weeks of 
knowledge of patient’s 
death 
Not required  
unless requested 
SAE Report*** 
At the time of SAE*** 
Within 24 hours of the 
event*** 
Not required  
unless requested 
+ 
Scan and upload into the EDC Supporting Document Upload Tool. 
* 
It is acceptable to submit only the signature page(s) of the main consent and only the check box page(s)/signature page(s) 
of the optional consent provided that the version date of the consent form is indicated.  
**  Deaths are only to be recorded on the CRFs if they occur within the 6 month study treatment / follow-up period. 
Deaths occurring after that time are outside the scope of this study and do not need to be reported. 
*** See Section 11.0 Serious Adverse Event Reporting for details. 
♦ 
See Section 10.2.2. 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
CONFIDENTIAL 
58 
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AMEND #1: 2017-FEB-02; AMEND #2: 2018-APR-03; AMEND #3: 2018-OCT-31 
The collection of the following information will NOT be done through the EDC system. Instead submit as 
follows: 
 
Data  
Required at 
Collection /Submission 
Comments 
Quality of Life 
Questionnaire 
Prior to randomization, Day 0 
and at each follow-up visit (4 
weeks and 3 and 6 months) 
Patient to enter data directly 
into tablet computers*  
Also: site CRA to scan and 
upload the actual diary to the 
EDC Supporting Document 
Upload Tool - 
Economic 
Analysis 
Questionnaire 
Patient Diary 
Prior to randomization, Day 0, 
and at each follow-up visit (4 
weeks and 3 and 6 months) 
Patient to complete on paper; 
site CRA to enter relevant 
data (as required) in the EDC 
system within corresponding 
folders  
Also: site CRA to scan and 
upload the actual diary to the 
EDC Supporting Document 
Upload Tool  
* See Appendix VI. Please also refer to the Electronic Patient Reported Outcome User Guide, posted on the SC.24 webpage 
area of the CCTG website (www.ctg.queenu.ca). A paper version of the questionnaire is also available in the SC.24 trial 
website to be used as a BACK-UP in RARE cases, if questionnaire completion through the tablet is not possible. If the 
questionnaires are completed on paper then it should be scanned and uploaded to the EDC Supporting Document Upload 
Tool and the site CRA should enter the data directly in SPROUT. 
 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
CONFIDENTIAL 
59 
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APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be accessed 
at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
 
 
 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
CONFIDENTIAL 
60 
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AMEND #1: 2017-FEB-02; AMEND #2: 2018-APR-03 
APPENDIX VI - 
HEALTH-RELATED QUALITY OF LIFE ASSESSMENT AND ECONOMIC 
ANALYSIS 
 
Introduction 
 
Health-Related Quality of Life Assessment 
 
The assumption that control of symptoms will automatically improve quality of life is probably true but 
hasn't yet been tested, especially in determining how certain symptoms may or may not affect quality of 
life. Current literature reveals interesting things; two in particular are: 
• 
additional and useful information may be obtained from quality of life measurements 
• 
a growing consensus that the goal of medical care today for most patients is the preservation of function 
and well-being in everyday life. 
 
We have reached the stage where the collection of information about psychological distress, social 
disruption, emotional trauma and painful side-effects is not only necessary but a routine component in many 
protocols. 
 
Quality of life data can be used in a variety of ways: 
• 
to try to achieve the best possible outcome for patients 
• 
to evaluate the extent of change in the quality of life of an individual or group across time 
• 
to evaluate new treatments and technologies 
• 
to support approval of new drug applications 
• 
to try to provide the best value for health care dollars 
• 
to compare costs and benefits of various financial and organizational aspects of health care services 
 
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be 
based on a combination of quality of life, survival, response, and adverse event data. 
 
Economic Analysis 
The assessment of overall health benefits is complicated by the need for a measure that can combine various 
benefits, such as overall survival, disease free survival, and quality of life into a single measure of benefit. 
Patients may value particular benefits differently. There is no obvious way to add together independently 
collected benefits for an individual or for a trial to yield a measure of overall benefit. Health utilities 
are a measure of how people value particular health outcomes. They provide a common denominator that 
can be combined with survival to form a measure of overall health benefits. 
 
Such a measure of overall health benefit can then be used as part of a health economic analysis. Health 
economic analyses assess the benefits and costs of an intervention, for consideration whether the 
intervention may be worth its "costs" -- including financial, toxicity, and social costs. 
 
The collection of information about health utilities is becoming more common in clinical protocols. In 
clinical trials, health utilities are most often collected using a patient self-reported questionnaire (similar 
to the collection of quality of life data). 
 
 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
CONFIDENTIAL 
61 
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AMEND #2: 2018-APR-03 
Health utility and quality of life assessments provide different but complementary information. 
• 
Health utility is a measure of preference for a given health state that acknowledges the risk and 
uncertainty of outcomes in choices patients face and in clinical decision-making. 
• 
They can be used as a weighting factor to adjust survival by quality of life. 
• 
Depending on whether a disease-specific or generic quality of life instrument is used, often only 
utility assessments may be able to compare patient groups with different diseases. 
• 
Only utilities provide a single meaningful measure that can be incorporated in health policy and 
health economic analyses. 
 
Health utilities data can be used in a variety of ways: 
• 
to try and achieve the best possible outcome for patients and populations; 
• 
to evaluate the extent of change in health benefits of an individual, group, or population across time; 
• 
to evaluate new treatments, technologies, and patient management strategies; 
• 
to support approval of new drug applications or patient management strategies; 
• 
to try to provide the best value for health care dollars within and across diseases and health; 
• 
to compare costs and benefits of various financial and organizational aspects of health care services. 
 
Approval of new therapies or patient management strategies need to consider a combination of health 
benefit and cost data. This may be formally done using health utilities as part of a health economic analysis. 
 
Instructions for Administration of a Quality of Life and Economic Analysis Questionnaire.  
 
This study will use the CCTG electronic System for Patient Reported Outcomes (SPROUT) to collect 
Quality of Life and Economic data. SPROUT is a web-based, password protected, PIN-restricted system, 
which facilitates completion of the questionnaires by the patients, through the use of tablet computers, 
distributed to sites by the CCTG Central Office. The tablets will be equipped with a mandatory lock four-
number code which will not be able to be turned off by tablet users. The accounts of the tablets will also be 
locked and hospital users will be unable to add or remove software or change the settings of the device. 
Sessions will expire automatically after one hour, if a user remains logged in and the tablet is left untouched. 
Hospital staff (CRAs) and patients are given access to different screens within SPROUT, and the CRA is 
automatically logged out of their (set-up) screens before the patient can access their (questionnaire 
completion) ones. The data entered on the tablet by the patient is not stored within the device, but rather 
gets imported in real-time directly into the CCTG database, using SSL encryption. Stored data is protected 
by the CCTG network firewall.  
 
The instructions below are intended as a general guide for the administration of the electronic Quality of 
Life and Economic analysis questionnaires. The detailed technical and logistical information regarding how 
to obtain, store and maintain the tablets, as well access and login into the SPROUT system, is provided in 
a separate Electronic Patient Reported Outcome User Guide document, posted on the trial webpage. The 
User Guide also provides screen-shots for screens viewed by the patient and the site CRA within the 
SPROUT system.  

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
CONFIDENTIAL 
62 
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AMEND #2: 2018-APR-03 
1. Preamble 
 
Quality of life and economic data are collected for research purposes, and will usually not be used for 
the patient’s individual medical care. The assessment is in the form of a self reported questionnaire. 
Therefore, it must be completed by the patient only, without translation, coaching or suggestions as to 
the "correct" answer by relatives or health care personnel. 
 
The usual scheduled times to obtain the questionnaires are as follows: 
• 
pre-randomization or pre-registration (baseline) 
• 
during treatment 
• 
during follow-up 
 
The information provided by the patient in the completed questionnaire is confidential and should not 
be discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 
 
Patients may decline answering some or all the questions if they wish to do so. If the whole 
questionnaire has not been completed, please ask the patient to explain why and document the reason(s) 
on the appropriate case report forms. 
 
2. Pretreatment Assessment 
 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of 
treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, side-
effects, et cetera. 
 
The CRA should collect the questionnaire (tablet) as soon as it has been completed.  
 
3. Assessments During Treatment 
 
The quality of life and economic analysis questionnaires should be given to the patient before being 
seen by the doctor, and prior to treatment on the day of treatment, as required by the schedule in the 
protocol. If the patient does not have a doctor visit scheduled, or if it was not possible for the patient to 
complete the questionnaire before being seen by the doctor, s/he should still complete the questionnaire 
prior to treatment. 
 
4. Assessments During Follow-up 
 
The quality of life and economic analysis questionnaires should be given to the patient before being 
seen by the doctor, on follow-up visits as required by the schedule. 
 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel 
unwell. In that case, you may express sympathy that things are below par, but state that this 
is exactly the information we require if we are to understand more about how quality of 
life is affected. You may also remind them that it takes only a few minutes to complete. 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
CONFIDENTIAL 
63 
CONFIDENTIAL 
 
AMEND #2: 2018-APR-03 
It defeats the whole purpose of the assessment if it is delayed until the patient feels better! 
 
5. What If . . . 
 
Because the tablet(s) used to obtain the Quality of Life and Economic data are study-specific and must 
be shared by all patients in a given centre completion of the electronic questionnaire should occur at 
the clinic. However, there may be circumstances when the patient does not complete the questionnaire 
as required in the clinic. Three situations are described below. In these cases, it is beneficial if quality 
of life data can still be collected. 
 
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to 
give the questionnaire to the patient. 
 
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask 
the patient if s/he is willing to complete one. 
 
(1) If yes, and the patient is able / willing to come back to the clinic, schedule an appointment as 
soon as possible after the ‘missed’ visit when s/he can complete the questionnaire in the tablet 
kept at the clinic. 
 
(2) If yes but coming back into the clinic is not feasible, then ask the patient if s/he has 
internet access at home. 
 
a. If yes, proceed to provide the patient with the link to the SPROUT system and the 
specific PIN number associated with the questionnaire they need to complete. Please 
also explain that the PIN has an expiration date (provide this date to the patient) and 
that the questionnaire should be completed before that date.  
b. If not, and using the mail is possible, mail a blank paper questionnaire to the patient, 
and make arrangements for return of the questionnaire in a timely fashion. Record the 
date it was mailed and the date received on the questionnaire. 
c. If not, and using the mail is not feasible, then ask the patient if s/he is willing to 
complete a questionnaire over the phone. If the patient agrees, read out the questions 
and range of possibilities, and record the answers in the tablet kept in the hospital. 
Make a note that the questionnaire was completed over the phone. 
 
(3) If no, note the reason why the questionnaire was not completed on the appropriate case report 
form. 
 
B. The patient goes on an extended vacation and won't attend the clinic for regular visit(s). 
 
Inquire if the patient has internet access during their vacation. If yes, please provide the patient 
with the website link to the SPROUT system, the PIN number(s) associated with the 
questionnaire(s) that need to be completed and written instructions with respect to the date the 
patient should complete the questionnaire(s). If the patient will not have internet access during their 
vacation a supply of paper questionnaires, with instructions about when to complete them, and how 
to return them should be given to the patient to take with them. Written instructions may help ensure 
that the patient stays on schedule as much as possible. 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
CONFIDENTIAL 
64 
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AMEND #2: 2018-APR-03 
C. The patient does not want to complete the questionnaire in clinic. 
 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, 
and failing to comply with the patient's wishes is likely to result in the questionnaire not being 
completed at all, then the patient may be permitted to complete the questionnaire from home with 
instructions that it is to be completed the same day. Ask the patient if s/he has internet access at 
home. 
 
a. If yes, proceed to provide the patient with the link to the SPROUT system and the specific PIN 
number associated with the questionnaire they need to complete. Please explain that the 
questionnaire should be completed on the same day. 
b. If not, give the patient a blank paper questionnaire, and make arrangements for return of the 
questionnaire in a timely fashion. When the questionnaire is returned, a comment should be 
made as to why the patient took it away from the clinic before completion. 
 
6. Waiving the Quality of Life/Economic Analysis Component 
 
The only time that we will not require a patient to complete the quality of life or economic analysis 
questionnaires is if s/he is not literate in either English or French (or other languages that the 
questionnaire may be available in). In other words, if the assistance of a translator is required to 
comprehend the questions and reply, the questionnaires should not be completed. Translation of the 
questions is not acceptable. Please indicate on questionnaire. 
 
7. Unwillingness to Complete Quality of Life/Economic Analysis Questionnaire 
 
If a patient speaks and reads English or French (or other languages that the questionnaires may be 
available in), but does not wish to complete the questionnaires then s/he is NOT eligible and should 
NOT be put on study. 
 
8. Inability to Complete Quality of Life or Economic Analysis Questionnaires (for reason other than 
illiteracy in English or French) 
 
An eligible patient may be willing but physically unable to complete the questionnaires, because of 
blindness, paralysis, etc. If the patient is completing the QOL/economic assessment in the clinic, the 
questionnaire should be read to them and the answers recorded by a health care professional (e.g. 
preferably the clinical research associate assigned to the trial, but another clinic nurse, a doctor or social 
worker who is familiar with the instructions for administering the questionnaires would be acceptable). 
If the patient is completing the questionnaire at home, and a telephone interview by the clinical research 
associate is not possible, then a spouse or friend may read the questions to the patient and record the 
answers. However, this method should be a last resort, and the spouse or friend should be instructed to 
not coach or suggest answers to the patient. Whichever method is used, it should be noted. 
 
If these special arrangements are not possible or feasible, then the patient would not be required to 
complete the questionnaires, and this should be reported on the appropriate case report form. 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
CONFIDENTIAL 
65 
CONFIDENTIAL 
 
AMEND #2: 2018-APR-03 
9. Electronic and Paper Versions of the Quality of Life and Economic Analysis Questionnaires 
 
The patient should complete the Quality of Life and Economic Analysis questionnaires within the 
SPROUT system. See the Electronic Patient Reported Outcome User Guide, posted on the trial 
webpage, which provides both the URL for accessing SPROUT, as well as step-by-step instructions for 
the completion of the electronic questionnaire. However, as it is possible that the SPROUT system may 
be down, or that access through an electronic device may not be possible, under rare circumstances the 
patient may complete the questionnaire on paper. If needed, please obtain the properly formatted paper 
copy of the Quality of Life and Economic Analysis Questionnaires for this study from the trial webpage 
and, after the patient completes it, please upload onto the Supporting Documents area of the EDC 
system (see also Appendix IV of this protocol).  
 
In the pages that follow, the quality of life and economic analysis questionnaires that will be used in 
this study (combined QLQ-C30, QLQ-BM22 and EQ-5D-5L) have been provided in paper version. 
The question content of the electronic and paper versions is identical. 
 

 
 
 
AMEND #1: 2017-FEB-02 
Quality of Life Questionnaire – ENGLISH PAPER VERSION 
 
CCTG Trial: SC.24 
 
PLEASE NOTE: In this study, Quality of Life data is meant to be provided by the patient electronically, 
by direct keying of information into a tablet computer. Therefore, this paper questionnaire is NOT meant 
to be used to collect data, and it is only provided as a BACK-UP for when, in very rare circumstances, it is 
not possible for the patient to complete the information directly into the tablet. See Appendix VI of the 
protocol for more details. 
 
If the paper questionnaire is used, the Clinical Research Associate (CRA) should complete the first (this) 
page before giving to the patient. After the patient provides the data and the paper questionnaire is 
returned, the CRA should scan and upload it in the patient-specific Supporting Documents area of the 
SC.24 Electronic Data Capture (EDC) system.  
 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to randomization 
 Day 0 (day of first fraction of radiotherapy, prior to treatment being given) 
After Treatment: 
 4 weeks      3 months      6 months 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home      clinic      another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ - __ __ __ - __ __ __ __ 
 
    dd        mmm          yyyy  
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial SC.24 
Page 1 of 5 
Please go on to the next page 
 
EORTC QLQ-C30 (Core 30 Questionnaire Version 3.0 © copyright 1995 EORTC Quality of Life Study Group. All rights reserved.) 
European Organization for Research and Treatment of Cancer (EORTC) 
 
 
Quality of Life Questionnaire (SC.24) 
 
We are interested in some things about you and your health. Please answer all the questions yourself by circling 
the number that best applies to you. There are no 'right' or 'wrong' answers. Choose the best single response that 
applies to you. The information that you provide is for research purposes and will remain strictly confidential. 
The individuals (e.g. doctors, nurses, etc.) directly involved in your care will not usually see your responses to 
these questions -- if you wish them to know this information, please bring it to their attention. 
 
 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
1. 
Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
 
 
 
 
 
2. 
Do you have any trouble taking a long walk? 
1 
2 
3 
4 
 
 
 
 
 
3. 
Do you have any trouble taking a short walk outside of 
the house? 
1 
2 
3 
4 
 
 
 
 
 
4. 
Do you need to stay in a bed or a chair during the day? 
1 
2 
3 
4 
 
 
 
 
 
5. 
Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
6. 
Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
 
 
 
 
 
7. 
Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
 
 
 
 
 
8. 
Were you short of breath? 
1 
2 
3 
4 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial SC.24. EORTC QLQ-C30 
Page 2 of 5 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
9. 
Have you had pain? 
1 
2 
3 
4 
 
 
 
 
 
10. Did you need to rest? 
1 
2 
3 
4 
 
 
 
 
 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
 
 
 
 
 
12. Have you felt weak? 
1 
2 
3 
4 
 
 
 
 
 
13. Have you lacked appetite? 
1 
2 
3 
4 
 
 
 
 
 
14. Have you felt nauseated? 
1 
2 
3 
4 
 
 
 
 
 
15. Have you vomited? 
1 
2 
3 
4 
 
 
 
 
 
16. Have you been constipated? 
1 
2 
3 
4 
 
 
 
 
 
17. Have you had diarrhea? 
1 
2 
3 
4 
 
 
 
 
 
18. Were you tired? 
1 
2 
3 
4 
 
 
 
 
 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
 
 
 
 
 
20. Have you had difficulty in concentrating on things, like 
reading a newspaper or watching television? 
1 
2 
3 
4 
 
 
 
 
 
21. Did you feel tense? 
1 
2 
3 
4 
 
 
 
 
 
22. Did you worry? 
1 
2 
3 
4 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial SC.24. EORTC QLQ-C30 
Page 3 of 5 
Please go on to the next page 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
23. Did you feel irritable? 
1 
2 
3 
4 
 
 
 
 
 
24. Did you feel depressed? 
1 
2 
3 
4 
 
 
 
 
 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
 
 
 
 
 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
 
 
 
 
 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
 
 
 
 
 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
For the following questions please circle the number between 1 and 7 that best applies to you. 
29. How would you rate your overall health during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
30. How would you rate your overall quality of life during the past week? 
1 
Very Poor 
2 
3 
4 
5 
6 
7 
Excellent 
 
 
 
 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial SC.24 – EORTC QLQ-BM22  
Page 4 of 5 
Please go on to the next page 
© Copyright 2008 EORTC Quality of Life Study Group. All rights reserved 
Patients sometimes report that they have the following symptoms or problems. Please indicate the 
extent to which you have experienced these symptoms or problems during the past week.  
Please answer by circling the number that best applies to you. 
During the past week have you had pain in any of the 
following parts of your body? 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
31. in your back? 
1 
2 
3 
4 
 
 
 
 
 
32. in your leg(s) or hip(s)? 
1 
2 
3 
4 
 
 
 
 
 
33. in your arm(s) or shoulder(s)? 
1 
2 
3 
4 
 
 
 
 
 
34. in your chest or rib(s)? 
1 
2 
3 
4 
 
 
 
 
 
35. in your buttock(s)? 
1 
2 
3 
4 
During the past week : 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
36. Have you had constant pain? 
1 
2 
3 
4 
 
 
 
 
 
37. Have you had intermittent pain? 
1 
2 
3 
4 
 
 
 
 
 
38. Have you had pain not relieved by pain medications? 
1 
2 
3 
4 
 
 
 
 
 
39. Have you had pain while lying down? 
1 
2 
3 
4 
 
 
 
 
 
40. Have you had pain while sitting? 
1 
2 
3 
4 
 
 
 
 
 
41. Have you had pain when trying to stand up? 
1 
2 
3 
4 
 
 
 
 
 
42. Have you had pain while walking? 
1 
2 
3 
4 
 
 
 
 
 
43. Have you had pain with activities such as bending or 
climbing stairs? 
1 
2 
3 
4 
 
 
 
 
 
44. Have you had pain with strenuous activity (e.g. 
exercise, lifting)? 
1 
2 
3 
4 
 

This box to be completed by the clinical research associate:     Pt. Serial #: _____________      Pt. Initials: ____ ____ ____ 
 
CCTG Trial SC.24 – EORTC QLQ-BM22  
Page 5 
© Copyright 2008 EORTC Quality of Life Study Group. All rights reserved 
During the past week: 
Not 
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
45. Has pain interfered with your sleeping at night? 
1 
2 
3 
4 
 
 
 
 
 
46. Have you had to modify your daily activities because of 
your illness? 
1 
2 
3 
4 
 
 
 
 
 
47. Have you felt isolated form those close to you (e.g. 
family, friends)? 
1 
2 
3 
4 
 
 
 
 
 
48. Have you worried about loss of mobility because of 
your illness? 
1 
2 
3 
4 
 
 
 
 
 
49. Have you worried about becoming dependent on others 
because of your illness? 
1 
2 
3 
4 
 
 
 
 
 
50. Have you worried about your health in the future? 
1 
2 
3 
4 
 
 
 
 
 
51. Have you felt hopeful your pain will get better? 
1 
2 
3 
4 
 
 
 
 
 
52. Have you felt positive about your health? 
1 
2 
3 
4 
 
 
 
 
 
 
Please check to make sure you have answered all the questions. 
 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
 
Today's date (Year, Month, Day): ________________________________ 
 
 
Thank you. 
 
 

 
 
 
AMEND #2: 2018-APR-03 
Health Utilities Questionnaire – ENGLISH PAPER VERSION 
 
CCTG Trial: SC.24 
 
PLEASE NOTE: In this study, Heath Economics data is meant to be provided by the patient 
electronically, by direct keying of information into a tablet computer. Therefore, this paper questionnaire 
is NOT meant to be used to collect data, and it is only provided as a BACK-UP for when, in very rare 
circumstances, it is not possible for the patient to complete the information directly into the tablet. See 
Appendix VI of the protocol for more details. 
 
If the paper questionnaire is used, the Clinical Research Associate (CRA) should complete the first (this) 
page before giving to the patient. After the patient provides the data and the paper questionnaire is 
returned, the CRA should scan and upload it in the patient-specific Supporting Documents area of the 
SC.24 Electronic Data Capture (EDC) system. 
 
 
This page to be completed by the Clinical Research Associate 
 
Patient Information 
CCTG Patient Serial No: ___________ 
 
Patient Initials: 
____ ____ ____ 
 
(first-middle-last)  
Institution: ___________________________________________ 
Investigator: ______________________________ 
 
Scheduled time to obtain quality of life assessment: please check () 
 Prior to randomization 
 Day 0 (day of first fraction of radiotherapy, prior to treatment being given) 
After Treatment: 
 4 weeks      3 months      6 months 
 
Were ALL questions answered? ___ Yes ___ No If no, reason: ________________________________________ 
 
Was assistance required? ___ Yes ___ No If yes, reason: ________________________________________ 
Where was questionnaire completed:  home      clinic      another centre 
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
 
Date Completed:  __ __ - __ __ __ - __ __ __ __ 
 
    dd        mmm          yyyy  
 
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING 
TO THE PATIENT FOR QUESTIONNAIRE COMPLETION. 
 

This box to be completed by the clinical research associate:   Pt. Serial #: _____________   Pt. Initials: ____ ____ ____ 
 
CCTG Trial SC.24 
Page 1 of 2  
Please go on to the next page 
 
Canada (English) v.2 © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 
 
Under each heading, please tick the ONE box that best describes your health TODAY  
 
MOBILITY 
I have no problems in walking about  
 
I have slight problems in walking about  
 
I have moderate problems in walking about  
 
I have severe problems in walking about  
 
I am unable to walk about  
 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
I have slight problems washing or dressing myself  
 
I have moderate problems washing or dressing myself  
 
I have severe problems washing or dressing myself  
 
I am unable to wash or dress myself  
 
 
USUAL ACTIVITIES (e.g. work, study, housework,  
family or leisure activities) 
I have no problems doing my usual activities  
 
I have slight problems doing my usual activities  
 
I have moderate problems doing my usual activities  
 
I have severe problems doing my usual activities  
 
I am unable to do my usual activities  
 
 
PAIN / DISCOMFORT 
I have no pain or discomfort  
 
I have slight pain or discomfort  
 
I have moderate pain or discomfort  
 
I have severe pain or discomfort  
 
I have extreme pain or discomfort  
 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
I am slightly anxious or depressed  
 
I am moderately anxious or depressed  
 
I am severely anxious or depressed  
 
I am extremely anxious or depressed  
 
 
 
 

 
CCTG Trial SC.24 
Page 2 of 2 
 
Canada (English) v.2 © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 
 
The worst health 
you can imagine 
 
• We would like to know how good or bad your health is TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is TODAY. 
• Now, please write the number you marked on the scale in the box below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please check to make sure you have answered all questions. 
 
Please fill in your initials to indicate that you have completed this questionnaire: ______________ 
Today's date (Year, Month, Day): ________________________________ 
 
Thank you.  
YOUR HEALTH TODAY = 
10
0
20
30
40
50
60
80
70
90
100 
5
15
25
35
45
55
75
65
85
95
The best health you 
can imagine 

 
CCTG SC.24- Patient Diary 
Page 1 of 6 
 
AMEND #1: 2017-FEB-02 
APPENDIX VII - PATIENT DIARY 
 
 
 
CCTG Trial SC.24 
 
A RANDOMIZED PHASE II/III  STUDY COMPARING STEREOTACTIC BODY RADIOTHERAPY (SBRT) VERSUS 
CONVENTIONAL PALLIATIVE RADIOTHERAPY (CRT) FOR PATIENTS WITH SPINAL METASTASES 
 
 
 
 
Patient Initials: 
_____ - _____ - _____ 
 
 
   First      Middle      Last 
 
 
 
Patient Study ID #: 
CA__ __ __ __ __ __ 
 
 
Institution: 
_______________________________________ 
 
 
Investigator: 
_______________________________________ 
 
 
 
PATIENT DIARY  
 
To Whom It May Concern: 
 
The above patient is in a clinical study. In the event of a medical emergency, please telephone one of the 
individuals listed below: 
 
 
1. 
_______________________________________________ 
____________________ 
 
(Name) 
(Number) 
 
2. 
_______________________________________________ 
____________________ 
 
(Name) 
(Number) 
 
 
 
To the Patient: 
 
If you have any questions about your diary, please telephone the study nurse or CRA listed below. 
 
 
_______________________________________________ 
____________________ 
 
(Name) 
(Number) 
 
Hours of Availability: _________________________________________________________________ 
 

 
CCTG SC.24- Patient Diary 
Page 2 of 6 
 
INFORMATION FOR THE PATIENT 
 
Thank you for participating in this research study. 
 
This document is a diary that you will use to record information needed for this research 
study. The next two pages contain instructions to help you fill in the diary. The 
remainder of this document is the diary itself. 
 
You are being asked to complete this diary: 
• before you are entered into the study 
• on the first day you receive radiotherapy treatment, prior to getting the 
treatment 
• 4 weeks after you complete your study radiation treatment 
• 3 months after you complete your study radiation treatment 
• 6 months after you complete your study radiation treatment 
 
For each time you fill in the diary, you will be asked to give us two types of information 
for the prior 24 hours: 
• your pain in the area of your spine that was treated with study 
radiotherapy, 
• how much medication you have taken  
 
If you have any questions, please ask the Clinical Research Associate (CRA) or study 
nurse at your clinic to help you. 
 
 
 
Please go to the next page. 
 
 
 

 
CCTG SC.24- Patient Diary 
Page 3 of 6 
 
Your Pain 
 
We will ask you about your pain in the area of your spine that was treated with study radiotherapy. 
 
To tell us about your pain, you will be provided with a list of numbers and asked to rate your pain by choosing 
one number from 0 (no pain) to 10 (pain as bad as you can imagine) that best describes your 
pain in the last 24 hours. 
 
This is what that question looks like: 
 
Please rate your pain by circling the one number that best describes your pain at its WORST 
in your spine (area treated with study radiotherapy) in the last 24 hours: 
 
 
   0          1          2          3          4          5          6          7          8          9          10 
 
No pain 
Pain as bad as 
 
 
 
 
 
 
 
 
 
 
   you can imagine 
 
Some correct and incorrect sample answers are shown below: 
 
Correct: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Incorrect: 0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Incorrect: 0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
Please go to the next page 
 
 

 
CCTG SC.24- Patient Diary 
Page 4 of 6 
Your Medication 
 
To tell us how much medication you take in the last 24 hours, you will be asked to fill in a table. In most cases, 
the CRA or study nurse will have already filled in some information about the medications you usually take. 
For example, if you use 10 mg tablets of Medication A and 2 mg tablets of Medication B, the table will look 
like this: 
 
Name of medication 
Strength of each unit 
of medication* 
How is medication 
taken? ** 
Number of units taken  
Medication A 
10 mg 
By mouth 
 
Medication B 
2 mg 
By mouth 
 
 
 
 
 
 
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units. 
* 
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch. 
** 
For example, medications can be taken by mouth, rectally, or in patch form. 
 
 
Some correct and incorrect ways to fill in the table are shown below: 
 
 
Name of medication 
Strength of each unit 
of medication* 
How is medication 
taken? ** 
Number of units taken  
 
Medication A 
10 mg 
By mouth 
2 
 
Medication B 
25 mcg / h 
Patch 
1 every 3 days 
 
Medication C 
2 mg 
By mouth 
as needed 
 
Medication D 
2 mg / mL 
By mouth 
2 + 1 + 3 = 6 
 
Medication E 
5 mg 
By mouth 
2 or 3 
 
 
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units. 
* 
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch. 
** 
For example, medications can be taken by mouth, rectally, or in patch form. 
 
 
Now you are ready to fill out your diary. 
 
If you have any questions or need help, please contact the CRA or study nurse 
(contact information provided on the cover page). 
 
 
Thank you for valuable contribution to this research study. 
 

 
CCTG SC.24- Patient Diary 
Page 5 of 6 
 
AMEND #2: 2018-APR-03 
 
PAIN SCORE AND MEDICATION INTAKE 
 
 
CRA / Study Nurse to complete below, in advance: 
Please check the timing of this diary: 
□ Baseline 
□ Day 0 (day of first fraction of radiotherapy, prior to treatment being given) 
□ 4 weeks after end of radiotherapy 
□ 3 months after end of radiotherapy 
□ 6 months after end of radiotherapy 
 
 
 
Date:  _______ - _______ - _______ 
                Day            Month             Year 
 
 
 
 
Pain score assessed at:  
____________ 
 
area of spine treated with 
study radiotherapy 
 
 
 
 
 
Please rate your pain by circling the one number that best describes your pain at its WORST 
in your spine (area treated with study radiotherapy) in the last 24 hours: 
 
 
      0         1         2         3         4         5         6         7         8         9        10 
 
No pain 
Pain as bad as 
 
you can imagine 
 
 
 
 
Please go to the next page. 
 
 

 
CCTG SC.24- Patient Diary 
Page 6 of 6 
PAIN SCORE AND MEDICATION INTAKE (continued) 
 
In the following table, please record information for all the medications you took during the last 24 hours.  
 
 
Name of medication 
Strength of each unit 
of medication* 
How is medication 
taken? ** 
Number of units taken  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
e.g. If you take 2 tablets in the morning and 2 tablets at night of a particular medication, you took 4 units. 
* 
A unit of medication is a tablet or capsule, a millilitre (mL) of liquid, a suppository, or a patch. 
** 
For example, medications can be taken by mouth, rectally, or in patch form. 
 
 
If you wish, you can write down any other medications you have taken today here: 
 
 
__________________________________________________________________________ 
 
 
_________________________________________________________________________ 
 
If you wish, you can write down any symptoms you are having here: 
 
 
__________________________________________________________________________ 
 
 
__________________________________________________________________________ 
 
 
 
You have now completed the Patient Diary for THIS time point. 
 
Bring the diary to your next clinic visit 
 
Thank you for your valuable contribution to this research study. 
 
 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
CONFIDENTIAL 
81 
CONFIDENTIAL 
APPENDIX VIII – CTV DELINEATION 
 
Target volume outlining  
Several publications may inform contouring for spine lesions with the International Spine Radiosurgery 
consortium guidelines ([8] shown below) the most widely used.  
Clinical Treatment Volume (CTV) should be defined as per diagram below. 
 
 
 
 
 
 
 

 
PROTOCOL DATE: 2015-JUL-24 
 
CCTG TRIAL: SC.24 
 
 
CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
 
AMEND #1: 2017-FEB-02 
LIST OF CONTACTS 
 
 
Contact 
Tel. # 
Fax # 
STUDY SUPPLIES 
Forms, Protocols 
Available on CCTG Website: 
http://www.ctg.queensu.ca 
under: Clinical Trials 
 
 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
 Maaike Hum 
Study Coordinator 
CCTG 
Email: 
mhum@ctg.queensu.ca 
 
or: 
Dr. Wendy Parulekar 
Senior Investigator 
CCTG 
Email: 
wparulekar@ctg.queensu.ca 
613-533-6430 
613-533-2941 
STUDY CHAIR 
Dr. Arjun Sahgal 
Study Chair 
Email: 
Arjun.Sahgal@sunnybrook.ca 
416-480-4834 
416-903-0456 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 11.0 for 
details of reportable events. 
Dr. Wendy Parulekar 
Senior Investigator 
CCTG 
or: 
Maaike Hum 
Study Coordinator 
CCTG 
613-533-6430 
613-533-2941