Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis
Phase: PHASE2
Conditions: Metastatic Cancer, Pain
Sponsor: Radiation Therapy Oncology Group

 
RTOG 0631, version date 09/23/16 
NRG ONCOLOGY 
 
RTOG 0631 
 
PHASE II/III STUDY OF IMAGE-GUIDED RADIOSURGERY/SBRT 
 FOR LOCALIZED SPINE METASTASIS 
 
 
 
Study Chairs (4/14/15) 
 
 
 
Principal Investigator/Radiation Oncology 
Samuel Ryu, MD 
Department of Radiation Oncology 
Stony Brook University School of Medicine 
101 Nicolls Road 
Stony Brook, NY 11794-7028 
631-444-7770/FAX 631-444-6034 
samuel.ryu@stonybrookmedicine.edu 
 
Neurosurgery Co-Chair 
Peter Gerszten, MD, MPH 
University of Pittsburgh Medical Center 
200 Lothrop Street, Suite A-402 
Pittsburgh, PA 15213  
412-647-0958/FAX 412-647-0989 
gersztenpc@upmc.edu 
  
Medical Physics Co-Chair 
Fang-Fang Yin, PhD 
Duke University Medical Center 
Box 3295 
Durham, NC 27710 
919-660-2185/FAX 919-681-7183 
fangfang.yin@duke.edu 
 
Radiation Oncology/IGRT Co-Chair 
Robert D. Timmerman, MD 
University of Texas Southwestern 
5801 Forest Park Road, NF3.302B 
Dallas, TX  75390-9183 
214-645-7651/ FAX 214-645-7622 
Robert.Timmerman@UTSouthwestern.edu  
 
Translational Research Co-Chair 
Adam Dicker, MD, PhD 
Thomas Jefferson University 
111 S. 11th Street 
Philadelphia, PA 19107 
215-955-627/FAX 215-955-0412 
adamdicker18@gmail.com 
 
Quality of Life Co-Chair 
Benjamin Movsas, MD 
Henry Ford Health System 
2799 W. Grand Blvd. 
Detroit, MI 48202 
313-916-5188/FAX 313-916-3235 
bmovsas1@hfhs.org 
 
Senior Statistician 
Stephanie Pugh, PhD 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19013 
215-574-0850/FAX 215-928-0153 
pughs@nrgoncology.org  
 
 
 
 
 
 
 

 
RTOG 0631, version date 09/23/16 
PHASE II/III STUDY OF IMAGE-GUIDED RADIOSURGERY/SBRT 
 FOR LOCALIZED SPINE METASTASIS 
 
 
 
 
 
Document History 
 
 
Version/Update Date 
Broadcast Date 
Closure with Amendment 10 
September 23, 2016 
August 4, 2017 
Amendment 10 
September 23, 2016 
October 31, 2016 
Amendment 9 
August 14, 2015 
August 24, 2015 
Amendment 8 
April 14, 2015 
May 11, 2015 
Update 
June 27, 2014 
June 27, 2014 
Amendment 7 
April 21, 2014  
May 13, 2014 
Update 
11/22/2013 
11/22/2013 
Amendment 6 
May 6, 2013 
May 16, 2013 
Amendment 5 
May 1, 2012 
May 3, 2012 
Amendment 4 
August 30, 2011 
September 22, 2011 
Amendment 3 
March 18, 2011 
May 19, 2011 
Amendment 2 
March 11, 2010 
March 23, 2010 
Update 
December 1, 2009 
December 1, 2009 
Amendment 1 
November 6, 2009 
November 19, 2009 
Update 
August 11, 2009 
August 11, 2009 
Update 
August 7, 2009 
August 7, 2009 
Activation 
July 20, 2009 
August 7, 2009 
 
 
 
 
 
Participating Sites (5/6/13) 
 U.S. Only 
 Canada Only 
 U.S. and Canada 
 Approved International Member Sites 
 
 
 
 
 
 
 
 
 
 
 
NRG Oncology 
1-800-227-5463, ext. 4189 
  
This protocol was designed and developed by NRG Oncology.  It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry.  
No other use or reproduction is authorized by NRG Oncology nor does NRG 
Oncology assume any responsibility for unauthorized use of this protocol. 

 
RTOG 0631, version date 09/23/16 
INDEX (09/23/16) 
 
 
 
Schema  
 
Eligibility Checklist  
 1.0 
Introduction 
 2.0 
Objectives 
 3.0 
Patient Selection  
 4.0 
Pretreatment Evaluations/Management 
 5.0 
Registration Procedures 
 6.0 
Radiation Therapy  
 7.0 
Drug Therapy 
 8.0 
Surgery 
 9.0 
Other Therapy 
10.0 
Tissue/Specimen Submission 
11.0 
Patient Assessments 
12.0 
Data Collection 
13.0 
Statistical Considerations 
 
References 
 
 
 
 
Appendix I  
- Study Parameters 
 
Appendix II 
- Performance Status Scoring 
 
Appendix III 
- Neurological Examination 
 
Appendix IV 
- Blood Collection 
 
Appendix V 
- Urine Collection 
 
 
 
 
 
 
  

 
RTOG 0631, version date 09/23/16 
NRG ONCOLOGY 
 
 
RTOG 0631 
 
Phase II/III Study of Image-Guided Radiosurgery/SBRT 
 for Localized Spine Metastasis 
 
 
SCHEMA (09/23/16) 
 
 
PHASE II COMPONENT 
R 
 
E 
 
G 
Radiosurgery/SBRT: 
I 
Single fraction dose of 16 Gy 
S 
 
T 
 
E 
 
R 
 
 
 
PHASE III COMPONENT 
S 
 
R 
 
T 
Number of Spine Metastases 
A 
Arm 1: Radiosurgery/SBRT:  
R 
1) 1 with a ≥5 NRPS score  
N 
             Single fraction dose of 16 or 18 Gy** 
A 
2) 2-3 with ≥5 NRPS scores 
D 
 
T 
 
O 
Arm 2: External Beam Radiation Therapy: 
I 
Type of Tumor 
M 
             Single fraction dose of 8 Gy 
F 
1) Radioresistant tumor* 
I 
 
Y 
2) Other 
Z 
Randomization ratio (Arm 1: Arm 2) = 2:1 
 
 
E 
 
 
Intended Radiosurgery/SBRT 
Single Fraction Dose** 
 
 
 
1) 16 Gy 
 
 
 
2) 18 Gy 
 
 
 
*Radioresistant tumors include soft tissue sarcomas, melanomas, and renal cell carcinomas. 
 
**Patients randomized to Arm 1 (experimental arm) will be stratified according to the single fraction dose 
for image-guided radiosurgery/SBRT, using either 16 or 18 Gy as preferred by the treating physician. 
 
See Section 5.0 for pre-registration requirements; see Section 6.0 for details of radiosurgery; see Section 
11.2 and Appendix I for follow-up requirements. 
 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility)  
Patients with localized spine metastasis from the C1 to L5 levels (a solitary spine metastasis; 2 separate spine 
levels; or up to 3 separate sites); each of the separate sites must have a maximal involvement of 2 contiguous 
vertebral bodies. 
  
 
Required Sample Size:                 Phase II component: 43 patients; 8/30/11: Completed 
(6/27/14)  Phase III component: 352 patients 
  

 
RTOG 0631, version date 09/23/16 
NRG Oncology Institution #   
 
RTOG 0631 
 
 
 
 
ELIGIBILITY CHECKLIST (4/21/14) 
Case #  
 
 
 
      
 
(page 1 of 3) 
 
 
_____ (Y) 1.  
According to a screening imaging study, is there localized spine metastasis from the C1 to L5 (a 
solitary spine metastasis); two separate spine levels; or up to 3 separate sites with a ≥5 NRPS 
score(e.g. C5, T5-6, and T12)? 
_____ 
 
Specify screening imaging study (bone scan, PET, CT scan, or MRI) 
 
_____ (Y) 2. 
Is the patient’s Zubrod Performance Status 0-2? 
 
_____ (Y) 3. 
Is the patient > 18 years old? 
 
_____ (Y) 4. 
Has a history and physical been performed within 2 weeks prior to registration? 
 
 ____ (Y)  5. 
Has a MRI of the involved spine been performed within 4 weeks prior to registration? 
 
_____ (Y) 6. 
Has the Numerical Rating Pain Scale been performed within 1 week prior to registration with a 
 
 
score of > 5 for at least one of the planned sites for spine radiosurgery? 
 
_____ (Y) 7.  
Has the patient had a neurological exam within 1 week prior to registration to rule out rapid  
 
 
neurologic decline? 
 
_____ (Y) 8. 
If epidural compression is present, is there a > 3mm gap between spinal cord and the edge of the 
 
 
epidural lesion? 
 
_____(Y) 9. 
If the patient has a paraspinal mass (≤ 5 cm in greatest dimension), is it contiguous with the spine 
 
 
metastasis? 
 
      (Y/NA) 10. If a women of child bearing potential, has the patient had a negative serum pregnancy test within  
 
 
2 weeks prior to registration? 
 
            (Y) 11.  If a woman of child bearing potential or a sexually active male, is the patient willing to use effective 
 
 
contraception while on treatment? 
 
______(Y) 12. Has the patient signed the informed consent? 
 
______(N) 13. Does the patient have myeloma or lymphoma? other visceral metastasis and radioresistant 
tumors (including soft tissue sarcomas, melanomas, and renal cell carcinomas) are eligible). 
 
______(N) 14. Is the patient non-ambulatory? 
 
______(N) 15. Is there spinal instability due a compression fracture? 
 
______(N) 16. > 50% loss of vertebral body height? 
 
______(N) 17. Is frank spinal cord compression or displacement or epidural compression within  3 mm of the  
 
 
spinal cord? 
 
______(N) 18. Is bony retropulsion causing neurologic abnormality? 
 
 ______(N) 19. Has the patient received prior radiation to the index spine? 
 
______(N) 20.  Is an MRI of the spine medically contraindicated for the patient? 
 
 
 
 
 
 
 
 
 
(Continued on next page)

 
RTOG 0631, version date 09/23/16 
NRG Oncology Institution #   
 
RTOG 0631 
 
 
 
 
ELIGIBILITY CHECKLIST (4/14/15) 
Case #  
 
 
 
 
     (page 2 of 3)  
 
 
 
The following questions will be asked at Study Registration:  
CREDENTIALING FOR IMRT and IMAGE-GUIDED SPINE RADIOSURGERY IS REQUIRED BEFORE 
REGISTRATION. 
 
 
         
1. 
Institutional person randomizing this case? 
 
                  (Y) 2. 
Has the Eligibility Checklist been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, iIs the patient eligible ? 
 
 
         
4. 
Date informed consent signed 
 
 
         
5. 
Patient’s Initials  
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient’s ID 
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnicity 
 
 
         
11. 
Gender 
 
 
         
12. 
Country of Residence 
 
 
         
13. 
Patient’s Zip  
 
 
         
14. 
Method of Payment 
 
 
         
15. 
Any care at VA or military hospital? 
 
 
         
16. 
Calendar Base Date 
 
 
         
17. 
Randomization Date 
 
___________ 
18.        E-mail address of the RA following the patient 
 
 
 
 
 
  
 
(Continued on next page) 

 
RTOG 0631, version date 09/23/16 
 
NRG Oncology Institution #   
 
RTOG 0631 
 
 
 
 
ELIGIBILITY CHECKLIST (6/27/14) 
Case #  
 
 
 
 
     (page 3 of 3)  
 
 
              (Y/N) 18.      Blood kept for cancer research? Have you obtained the patient's consent for his or her 
blood to be kept for use in research to learn about, prevent, treat, or cure cancer? 
 
              (Y/N) 19.     Urine kept for cancer research? Have you obtained the patient's consent for his or her 
urine to be kept for use in research to learn about, prevent, treat, or cure cancer? 
 
              (Y/N) 20.      Blood kept for medical research? Have you obtained the patient's consent for his or her 
blood to be kept for use in research about other health problems (for example: causes of 
diabetes, Alzheimer's disease or heart disease)? 
 
              (Y/N) 21.       Urine kept for medical research? Have you obtained the patient's consent for his or her 
urine to be kept for use in research about other health problems (for example: causes of 
diabetes, Alzheimer's disease, and heart disease)? 
 
              (Y/N) 22. 
Allow contact for future research? Have you obtained the patient's consent for allow 
someone from this institution to contact him or her in the future to ask him or her to take 
part in more research?  
 
 
For Phase III Component Only: 
 
                (N/Y) 23. 
Did the patient agree to participate in the quality of life component? 
 
 
         
 
If no, provide the reason: 
 
 
 
 
1. Patient refused due to illness 
 
 
 
 
2. Patient refused for other reason: specify _____________ 
 
 
 
 
3. Not approved by institutional IRB 
 
 
 
 
4. Tool not available in patient’s language 
 
 
 
 
5. Other reason: specify_________________ 
 
 
 
         
24. 
Specify number of spine metastases  
 
 
 
 
1.  1  
 
 
 
 
2.  2-3   
 
 
 
____________25. 
Specify type of tumor  
1. Radioresistant  (include soft tissue sarcomas, melanomas and renal cell carcinomas) 
2. Other 
Specify Other Tumor Type ______________ 
 
____________26 
Specify RT dose 
1. 16Gy 
2. 18Gy 
 
 
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, and 
dated checklist used at study entry must be retained in the patient’s study file and will be evaluated during an 
institutional NCI/NRG Oncology audit. 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 

 
RTOG 0631, version date 09/23/16 
1
1.0 
INTRODUCTION 
1.1 
Spine Metastasis  
 
Spine metastases are a common complication of cancer. While similar to other bone metastases 
in terms of vertebral bone involvement, spine metastases have unique clinical considerations. 
One is spinal bone pain, which is the most common initial presenting symptom. The other is that 
these metastases can present with a soft tissue mass at the paraspinal area or as an epidural 
compression. Therefore, patients with spinal metastases invariably have severe back pain, often 
with associated neurological problems, which can further compromise their performance status. 
 
 
The main presenting symptom of spine metastases is back pain. Therefore, the primary goal of 
radiosurgery for spinal metastases is pain control (relief). The treatment of spine metastases has 
largely been with conventional fractionated radiotherapy. Although the most common regimen of 
radiotherapy has been 30 Gy in 10 fractions, the radiation dose-pain response has not been well 
settled. An early RTOG study for bone metastasis reported that low-dose short course 
radiotherapy was as effective as a high dose protracted regimen (Tong 1982). Recently, RTOG 
97-14, which randomized the treatment of bone metastasis between a single dose of 8 Gy and 10 
fractions of 3 Gy for a total dose of 30 Gy, also showed a similar result. However, the duration 
and rate of pain control of bone metastases was limited by the conventional method of 
radiotherapy in both arms (Hartsell 2005). In a subgroup of patients with spine metastases in this 
study, only 61% of patients experienced partial or complete pain relief at 1 month post-treatment. 
Recently, there has been an increasing trend of diagnosing more localized spine metastases (i.e., 
oligometastases), although the true incidence of solitary spine metastasis is not known. These 
patients may have a prolonged survival time. Therefore, there is pressing need to improve the 
pain control of patients with spine metastases, which may be connected to an improvement in 
quality of life. 
 
 
Despite the common occurrence of spine metastases, there have been few prospective studies 
for this large group of patients (Greenberg 1980; Young 1980; Maranzano 1995; Helweg-Larsen 
1996; Patchell 2005). It is evident, from these studies, that a single dose of 8-10 Gy is equivalent 
to a fractionated regimen of 30 Gy in 10 fractions. This suggests that a further increase in the 
single dose of radiation may improve the rate of pain control. The difficulty is that there is a dose-
limiting organ, the spinal cord, within close proximity to the vertebral body, and spine metastases 
often are present with epidural tumor masses. Therefore, accurate targeting and radiation 
intensity-modulation will be required to minimize the spinal cord dose. In this effort, radiosurgery 
has emerged as an innovative treatment option for spinal metastases. While the spine region 
does have the benefit of minimal breathing-related organ movement and easy imaging, safely 
delivering a more intensive dose of radiation requires not only precise targeting due to the 
proximity of the spinal cord, but also accurate treatment planning and delivery. 
 
1.2 
Radiosurgery/SBRT of Localized Spine Metastasis 
 
Preclinical physical and dosimetric studies have demonstrated the applicability of patient 
positioning, immobilization, and dosimetric characteristics of spinal radiosurgery for spine 
metastases (Yin 2002; Yin 2002b). The first approach to establish clinical feasibility was to 
determine the accuracy and precision of radiosurgery to treat the spine and epidural/paraspinal 
tumors that are adjacent to the spinal cord. This clinical study demonstrated targeting accuracy 
within 1.5 mm for actual patient treatment (Ryu 2003). The accuracy of radiosurgical targeting for 
spine has been reported with various technologies (Ho 2007; Yin 2008).  
 
 
Subsequent clinical experience with single dose radiosurgery for spinal metastasis showed the 
efficacy of radiosurgery for pain control and improvement of neurological function in patients with 
epidural compression. In these studies, there was rapid pain relief reported with a median time to 
pain relief of only 2 weeks, with pain control seen in some patients as early as within 24 hours 
(Ryu 2003; Gertzen 2005; Degen 2005;  Ryu 2004). Median duration of pain control in the treated 
spine region was 13.3 months (Ryu 2008). Other investigators also demonstrated similar results 
of pain control in patients with spine metastasis (Gertzen 2005; Degen 2005; Gertzen 2006; 
Gertzen 2005b). Quality of life also was improved secondary to pain control (Degen 2005). Local 
tumor control at the treated spine was achieved in 95% of the patients. Recurrence at the 
immediately adjacent vertebrae was less than 5% (Ryu 2004). Patients with oligometastasis had 
a longer survival with more effective local treatment of the spine metastasis (Ryu 2007). This 

 
RTOG 0631, version date 09/23/16 
2
suggests that a more intensive treatment may be appropriate for patients with localized spine 
metastases in order to improve their clinical outcome and quality of life. A single institution clinical 
trial of radiosurgery for epidural spinal cord compression  showed that thecal sac patency was 
achieved in 82% of patients by radiographic reduction of epidural or paraspinal tumors (Ryu 
2008c). 
 
 
Spinal cord as the dose-limiting critical organ at risk is a key concern. Because of the nature of 
radiosurgery with rapid dose fall-off, there is a radiation dose gradient within the diameter of the 
spinal cord. The result of accumulated dose volume histogram (DVH) analyses of the spinal cord 
in 230 procedures at Henry Ford Hospital showed a partial volume tolerance of the spinal cord of 
10 Gy to the 10% cross-sectional area of the cord, provided that the spinal cord is defined as 6 
mm above and below the radiosurgery target volume (Ryu 2007). Other investigators used 
slightly different criteria of defining the spinal cord dose: these were a maximum dose of 12-14 Gy 
at the surface of an MRI-defined or myelogram-defined spinal cord (Chang 2007) or a maximum 
dose of 10 Gy in a myelogram-defined spinal cord (Yamada 2008). Taken together, these dose 
criteria were in a similar range. Therefore, we chose to use the spinal dose constraint as 10 Gy to 
10 % of the spinal cord defined as a maximum of 6 mm above and below the radiosurgery target. 
 
1.3 
Selection of Radiosurgery Dose (8/30/11) 
 
A radiation dose-response relationship for pain control has not been established. However, there 
is a trend for a radiation dose-pain control relationship when all the studies are compiled. A recent 
meta-analysis of ten randomized trials containing single fraction radiotherapy for painful bone 
metastasis showed single-fraction radiation (median 8 Gy, range 8-10 Gy) achieved a complete 
pain response of 33.4%, and an overall response rate of 62.1% (Wu 2003). Large scale clinical 
trials using single fraction radiation doses of 8 Gy resulted in similar pain control of bone 
metastasis (Hartsell 2005; Bone Pain Trial Working Party 1999; Steenland 1999). Therefore, the 
phase III portion of this trial will use either 8 Gy as the prescribing radiation dose; 3-dimensional 
conformal beam arrangement is also allowed per the treating physician’s discretion. 
 
 
 
Radiosurgery experiences recently have been reported with a single fraction of higher radiation 
doses for spinal metastasis. The majority of the spine metastases consistently responded to the 
higher doses of radiosurgery. Although the results cannot be directly compared to each other, 
these results suggest a trend towards a higher overall pain control with higher radiation doses 
(Ryu 2003; Ryu 2004; Gertzen 2006; Gertzen 2005b). There is no threshold dose that can be 
firmly stated. Based on the Henry Ford Hospital experience of radiosurgery dose escalation from 
10 Gy to 20 Gy in 2 Gy increments, there was a strong trend for increasing pain relief with higher 
radiation doses, particularly when a dose ≥ 16 Gy was employed (Ryu 2008; Ryu 2007).While 
there was no statistically significant difference, the sample size may have been the main limiting 
issue to detect a statistical difference in the dose-response analysis.  When the radiosurgery 
dose was ≥ 16 Gy, the probability of pain relief was reached in over 80% of the patients. The 
experience of the University of Pittsburgh also showed consistent results of pain relief with a 
median dose ≥ 16 Gy (Gerzten 2005; Gertzen 2005b; Gertzen 2006). Therefore, the phase III 
component of this study will use 16 or 18 Gy in 1 fraction. The spinal cord constraint is 10 Gy to 
the 10% partial spinal cord volume (spinal cord defined as a maximum of 6 mm above and below 
the target volume) [Ryu 2007]. 
 
Additional experience of radiosurgery with higher doses for spine metastasis suggest that a 
higher (than 16 Gy) radiosurgery dose was required to achieve similar pain relief, particularly in 
radioresistant tumors including soft tissue sarcoma, melanoma, and renal cell carcinoma as well 
as other tumors. (Gerszten 2005c; Nguyen 2010, Yamada 2008). Therefore, the phase III 
component of this study will use a radiosurgical dose of 16 Gy or 18 Gy per treating physician’s 
discretion and institutional experience. Maximum tolerated dose (MTD) has not been defined in 
spine radiosurgery, as the MTD of the spinal cord is not known. In this clinical trial, the proposed 
prescription doses are readily achievable with the defined spinal cord tolerance constraint 
described in Sections 1.2 and 6.3.1.2. 
 
1.4 
Advantages of Image-Guided Radiosurgery (8/30/11) 
 
The potential advantages of using image-guided radiosurgery for spine metastasis are many. 
First, pain control is rapid and durable. Second, since only the involved spine will be treated, bone 

 
RTOG 0631, version date 09/23/16 
3
marrow will be preserved. The spine is a key blood-forming organ. By reducing the radiation 
target, organ preservation of the bone marrow can be achieved. This will help facilitate 
continuation of systemic therapy, which is often essential for this group of patients. Third, 
radiosurgery is only one treatment as opposed to 10-15 visits for conventional fractionated 
radiotherapy. It is more convenient for the patient. Equally important is that a single session of 
radiosurgery does not interfere with ongoing chemotherapy schedules. Fourth, radiosurgery has 
the potential to be used for decompression of epidural compression. Last, radiosurgery is a non- 
invasive treatment; it has the potential to reduce the necessity of invasive open surgery in these 
patients. The non-invasiveness and shortened treatment time provided by spine radiosurgery has 
great potential to improve the quality of life in this group of patients who can have debilitating 
conditions and/or neurological deficits. Thus, it is anticipated that in the future image-guided 
radiosurgery may become a standard of care to treat localized spine metastasis with or without 
spinal cord compression. Indeed, as this technology is becoming so widely available, this clinical 
trial is critical to avoid both under-utilization and over-utilization of this emerging technique.   
 
 
It is important to first study this emerging technique of spine radiosurgery in a phase II trial within 
a national cooperative group. This phase II study will assess the experience of spine radiosurgery 
in the NRG Oncology community, which is the optimum forum to test and develop a new 
radiotherapeutic technology. Once the single arm phase II component is completed and the 
efficacy of spine radiosurgery is demonstrated, the phase III component will proceed to determine 
whether spine radiosurgery improves the treatment outcome of spine metastasis as compared to 
conventional radiotherapy. The phase III component will randomize patients to directly compare a 
single dose of external beam radiation (8 Gy) versus SBRT given in one fraction (16 Gy or 18 
Gy). The result will indeed demonstrate whether or not there is radiation dose-response in pain 
control of bone metastasis. 
 
1.5 
Hypothesis (8/30/11) 
 
In the prior RTOG study for bone metastases, 97-14, the duration and rate of pain control of bone 
metastases was limited by conventional radiotherapy (single dose of 8 Gy or 10 fractions of 3 Gy 
for a total dose of 30 Gy) [Hartsell 2005]. Although previous results defined partial pain relief as 
an improvement of ≥ 2 points, the current trial will define partial pain relief as an improvement of 
 
≥ 3 points to ensure stringent pain control. Complete pain relief will remain defined as no pain, as 
indicated by a post-treatment score of 0. Both partial and complete pain relief require no increase 
in narcotic medication. In RTOG 97-14, 253 patients (29% of total) were treated to the spine. The 
pain response rate was 51% at 3 months in these patients.  
 
 
The goal of the phase II component of this study is to demonstrate the technical feasibility of 
treating spine metastases with image-guided radiosurgery/SBRT in the NRG Oncology setting. 
Treatment compliance will be evaluated according to the radiosurgery guidelines (see Section 
6.0). Based on the RTOG experience of treating lung cancer with SBRT, the target rate for 
successful treatment delivery is 85% of patients successfully treated with SBRT for spine 
metastasis. 
 
 
The hypothesis of the phase III component, in which patients will be randomized to image-guided 
radiosurgery/SBRT in a single fraction dose of 16 or 18 Gy (experimental arm) OR conventional 
external beam radiotherapy in a single dose of 8 Gy (control arm based on the RTOG 97-14 
results) is that image-guided radiosurgery/SBRT will result in a 40% improvement (from 51% to 
70%) in the proportion of patients experiencing pain relief at 3 months as compared to the 
external beam radiotherapy. Patients randomized to Arm 1 (experimental arm) will be stratified 
according to the single fraction dose for image-guided radiosurgery/SBRT, using either 16 or 18 
Gy as preferred by the treating physician. 
 
1.6 
Primary Endpoint: Numerical Rating Pain Scale (NRPS) (8/30/11) 
1.6.1 
The primary endpoint is pain control at the treated site(s) at 3 months post-treatment. Pain 
recurring or progressing prior to 3 months post-treatment is considered a failure.  For evaluation 
of pain relief, the Numerical Rating Pain Scale (Jensen 1999) will be used. The NRPS is a 
simple measure of pain on an 11-point scale (0-10). In the study comparing the reliability and 
validity of several measures of pain intensity, the composites of 0-10 ratings have been shown 
to be useful when maximal reliability was necessary in studies with relatively small sample 

 
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4
sizes or in clinical settings in which monitoring of changes in pain intensity in individuals is 
needed.  
1.6.2 
Scoring Pain  
1.6.2.1 
Solitary Spine Lesion 
 
The NRPS will document the status of pain at the treated single spine site.  
1.6.2.2 
Multiple Spine Lesions 
 
When multiple spine lesions are treated, the index spine lesion will be used to assess the 
pain response. The index spine lesion is defined as the spine lesion with the highest 
pretreatment pain score.  If a patient has > 1 lesion with the same maximal pain score, the 
index lesion will be the most cephalad of these lesions. For example, for a patient who has 3 
spine lesions to be treated:  1) C5 lesion with pain score of 4; 2) T2-3 lesion with pain score 
of 6; and 3) T12 lesion with pain score of 6.  The index lesion in this case would be T2-3 
lesion, as it is the most cephalad lesion among the lesions with the highest pain score.  
If, however, the same patient had a pretreatment score at T12 of 7 (and the rest of the 
scores remained the same), the T12 lesion would be the index lesion. 
1.6.2.3 
Type of Tumor  
The stratification between radioresistant tumors and other tumors is due to the similarity of 
their expected responses. Radioresistant tumors include soft tissue sarcoma, melanoma, 
and renal cell carcinoma. It has been shown that these types of tumors, specifically 
melanoma and renal cell carcinoma, appear to have similar responses compared to any 
other tumor (Gerszten 2005 (c); Nguyen 2010).  Thus, these types of tumors are eligible for 
the study treatment but will be stratified among the treatment groups to not bias the results. 
1.6.3 
Definition of Pain Response 
1.6.3.1 
Complete pain relief is defined as a pain score of 0 at the index site at 3 months post-
treatment. Complete pain relief is based on no increase in narcotic pain medication. 
1.6.3.2 
Partial pain relief is defined as a reduction in the numerical pain score of ≥ 3 (i.e., an 
improvement of at least 3 points from the baseline NRPS) at the index site, as long as none 
of the other treated lesions have increased in pain score and as long as the patient did not 
require an increase in the level of narcotic pain medication. Patients who require an increase 
in narcotic pain medication will not be scored as having partial pain relief, even if their pain 
score has improved by at least 3 points on the scoring system. (Note: If a patient can only 
give one pain score for all sites, this score will be used for all treated sites at that time point, 
and the most cephalad lesion will be defined as the index lesion). 
1.6.3.3 
Stable response is defined as a post-treatment pain score the same as or within 2 points of 
the baseline pain score at the index site with no increase in narcotic pain medication. 
1.6.3.4 
Progressive response is defined as a post-treatment increase of at least 3 points from the 
baseline pain score at the index site. 
1.6.4 
Evaluation of Pain Response 
 
Complete or partial pain relief or a stable response at the index site requires no increase in 
narcotic pain medication and excludes progressive response at the secondary treated site(s). 
Although complete pain relief is the best outcome, partial relief also is a satisfactory outcome. 
Therefore, patients with complete or partial pain relief will be considered responders. Patients 
with complete or partial pain relief at the index site but a progressive response at the secondary 
site(s) will be considered non-responders. 
 
1.7 
Quality of Life Measurements (09/23/16) 
 
It is hypothesized that quality of life (QOL) will improve after radiosurgery due to rapid and 
durable pain control after spine radiosurgery. Indeed, in one study, QOL improved secondary to 
pain control (Degen 2005). In the current study, we will measure the QOL after radiosurgery using 
the Functional Assessment of Cancer Therapy: (FACT-G), the Brief Pain Inventory (BPI), and the 
EuroQol (EQ-5D).  
1.7.1 
Brief Pain Inventory (BPI) 
 
The pain originating from the spine directly affects the patient’s QOL because the spine is the 
major weight-bearing area. The Brief Pain Inventory (BPI), developed by Daut, et al. (1983) is a 
17-item patient self-rating scale assessing demographic data, use of medications, as well as 
the sensory and reactive components of pain. The BPI includes items that will address 
components of sensory pain, including severity, location, chronicity, and degree of relief due to 
therapy. The BPI also has items that address reactive pain components, such as depression, 
suffering, and the perceived availability of relief.  The scale is from 0-10, and there are 

 
RTOG 0631, version date 09/23/16 
5
breakpoints between scores of 4 and 5 and between 6 and 7, indicating that mild pain 
correlates with scores of 1-4, moderate pain with 5-6, and severe pain with scores of 7-10. 
Respectable reliability has been demonstrated using test-retest item correlation (e.g., for worst 
pain, r = .93).  Issues of the validity and reliability of the BPI have been examined in detail 
(Jensen 1999; Daut 1983).  The BPI’s ease of translation and brief administration have made it 
a frequently used tool in clinical trials where reduction or prevention of pain are the outcome 
measures. The BPI was previously used successfully in RTOG 97-14 studying patients with 
bone metastases treated with radiation therapy. 
 
 
The BPI asks patients to rate their pain for the last week on 0-10 scales at its ‘worst’, ‘least’, 
‘average’, and ‘now.’  The scales are presented on a 10 cm line, with each number equidistant 
from the next.  Each scale is bounded by the words ‘no pain’ at the 0 end and ‘pain as bad as 
you can imagine’ at the other.  Using the same type of scales, patients also are asked to rate 
how their pain interferes with several quality of life domains including activity, walking, mood, 
sleep, work, and relations with others.  These scales are bounded by ‘does not interfere’ at the 
0 end and ‘interferes completely’ at the other.   Patients also are asked to estimate the pain 
relief they are receiving from their pain treatment (in percent), to locate areas of pain on a 
human figure, and to estimate the cause of their pain (cancer disease, cancer treatment, or 
non-cancer). The patient can complete the BPI in approximately 5 minutes, and the 
assessment is available in 12 languages. 
 
 
Issues of the validity and reliability of the BPI have been examined in detail (Daut 1983; 
Cleeland 1989). The BPI is considered as the FDA standard for a pain assessment tool.  The 
typical standard deviation for the item “worst pain” in most cancer populations is 2.4. Therefore, 
the finding of a one-point difference in the “worst pain” item at different times or between two 
comparative 
groups 
is 
considered 
significant. 
Translations 
can 
be 
accessed 
at 
http://www.mdanderson.org/departments/prg/; click on “symptom assessment tools”.   
1.7.2 
The Functional Assessment of Cancer Therapy (FACT-G) 
 
Assessment of pain and its relief also are affected by multiple factors, including the patient’s 
understanding regarding the nature of pain, and emotional and social background. Therefore, 
as in RTOG 97-14, the Functional Assessment of Cancer Therapy (FACT-G), v. 4.0, also will 
be collected. The FACT-G is a commonly used tool measuring the multidimensional 
components of health related quality of life (HRQOL) across 4 scales: physical well-being (7 
items), social/family well-being (7 items), emotional well-being (6 items) and functional well-
being (7 items) The FACT, developed by Cella, et al. (1993)., is a five point patient self rating 
scale (from “not at all” to “very much”).  Test-retest reliability is high for the subscales with 
correlation coefficients ranging from a high of .88 for physical well-being to .82 for social and 
emotional well-being. It is written at the 4th grade reading level, and patients can complete the 
FACT-G in 5-10 minutes.  The FACT has been translated into more than 25 languages, and 
translations 
are 
accessible 
at 
the 
FACIT 
web 
site, 
http://www.facit.org/FACITOrg/Questionnaires. 
1.7.3 
The EuroQol (EQ-5D)  
 
The EuroQol (EQ-5D) instrument is intended to complement other forms of QOL measures, and 
it has been developed to generate a generic cardinal index of health, thus giving it considerable 
potential for future use in economic evaluation.  The EQ-5D is a two-part, patient-completed 
questionnaire that takes approximately 5 minutes to complete(Rabin 2001; Schulz 2002). The 
first part consists of 5 items covering 5 dimensions including: mobility, self care, usual activities, 
pain/discomfort, and anxiety/depression.  Each dimension can be graded on 3 levels including: 
1=no problems; 2= moderate problems; and 3=extreme problems.  Health states are defined by 
the combination of the leveled responses to the 5 dimensions, generating 243 health states to 
which unconsciousness and death are added (Badia 1998). The EQ-5D has been translated 
into multiple languages; these translations are available from the EuroQol web site at 
http://www.euroqol.org/.  The inclusion of the EQ-5D is exploratory, as it allows one to analyze 
important issues related to quality adjusted survival and cost utility analyses and determine if 
the instrument should be included in a future phase III trial.   
 
 
 
 

 
RTOG 0631, version date 09/23/16 
6
2.0 
OBJECTIVES 
2.1 
Primary Objective (8/30/11) 
2.1.1 
Phase II Component 
 
Determine the feasibility of successfully delivering image-guided radiosurgery/SBRT for spine 
metastases in a cooperative group setting 
2.1.2 
Phase III Component 
 
Determine whether image-guided radiosurgery/SBRT (single dose of 16 or 18 Gy) improves 
pain control (as measured by the 11 point NRPS) as compared to conventional external beam 
radiotherapy (single dose of 8 Gy) 
 
 
The endpoint is complete or partial pain relief at the treated index site at 3 months, (as 
measured by the 11 point NRPS). Complete pain relief is defined as a score of 0 on the NRPS, 
with no increase in narcotic pain medication. Partial pain relief is defined as an improvement 
from the baseline NRPS of at least 3 points on the rating scale (and no progressive pain 
response at any other treated lesion[s], with no increase in narcotic pain medication).  
 
2.2 
Secondary Objectives (Phase III Component) (09/23/16) 
2.2.1 
Determine whether image-guided radiosurgery/SBRT improves the rapidity of pain response at 
the treated site(s) as compared to conventional external beam radiotherapy, as measured by 
the NRPS; 
2.2.2. 
Determine whether image-guided radiosurgery/SBRT increases the duration of pain response 
at the treated site(s), as compared to conventional external beam radiotherapy, as measured 
by the NRPS; 
2.2.3 
Compare adverse events between the two treatments according to the criteria in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0; 
2.2.4 
Evaluate the long-term effects (24 months) of image-guided radiosurgery/SBRT on the 
vertebral bone (such as compression fracture) and the spinal cord by MRI; 
2.2.5 
Evaluate the potential benefit of image-guided radiosurgery/SBRT on change in and overall 
quality of life, as measured by the Functional Assessment of Cancer Therapy-General (FACT-
G); in pain as measured by the Brief Pain Inventory (BPI); and in health utilities as measured by 
the EuroQol (EQ-5D); 
2.2.6 
To implement a well-controlled specimen handling/storage process to facilitate future laboratory 
correlative studies. 
 
 
3.0 
PATIENT SELECTION (11/22/13) 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED  
For questions concerning eligibility, please contact the study data manager. 
 
3.1 
Conditions for Patient Eligibility (09/23/16) 
3.1.1 
The patient must have localized spine metastasis from the C1 to L5 levels by a screening 
imaging study [bone scan, PET, CT, or MRI] (a solitary spine metastasis; two separate spine 
levels; or up to 3 separate sites [e.g., C5, T5-6, and T12] are permitted.) Each of the separate 
sites may have a maximal involvement of 2 contiguous vertebral bodies. Patients can have 
other visceral metastasis, and radioresistant tumors (including soft tissue sarcomas, 
melanomas, and renal cell carcinomas) are eligible. 
 
 
See Figure 1 below for a depiction of eligible metastatic lesions: 1) a solitary spine metastasis; 
2) two contiguous spine levels involved; or 3) a maximum of 3 separate sites. Each of the 
separate sites may have a maximal involvement of 2 contiguous vertebral bodies.  Epidural 
compression (arrow) is eligible when there is a ≥ 3 mm gap between the spinal cord and the 
edge of the epidural lesion (see Section 3.1.10). A paraspinal mass ≤ 5 cm is allowed (see 
Section 3.1.11). 
 
 
 
 
 
 

 
RTOG 0631, version date 09/23/16 
7
 
 
Figure 1:  Diagram of Eligible Metastatic Lesions 
 
3.1.1.1  
There can be multiple small metastatic lesions shown in other vertebral bodies as shown 
in diagram (4) above. The metastatic lesion of each spine should be less than 20% of the 
vertebral body as opposed to the diffuse vertebral involvement. These small lesions are 
often seen in the MRI even when bone scan or PET was negative. Most of these lesions 
are not clinically required to be treated and  are therefore not included in the target volume 
of this protocol. Only the painful spine (pain score≥ 5) is to be treated .     
3.1.2 
Zubrod Performance Status 0-2;  
3.1.3 
Age ≥ 18; 
3.1.4 
History/physical examination within 2 weeks prior to registration; 
3.1.5 
Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing 
potential; 
3.1.6 
Women of childbearing potential and male participants who are sexually active must agree to 
use a medically effective means of birth control; 
3.1.7 
MRI (contrast is not required but strongly recommended) of the involved spine within 4 weeks 
prior to registration to determine the extent of the spine involvement; an MRI is required as it is 
superior to a CT scan in delineating the spinal cord as well as identifying an epidural or 
paraspinal soft tissue component. Note: If an MRI was done as a screening imaging study for 
eligibility (see Section 3.1.1), the MRI can be used as the required MRI for treatment planning. 
3.1.8 
Numerical Rating Pain Scale within 1 week prior to registration; the patient must have a score 
on the Scale of ≥ 5 for at least one of the planned sites for spine radiosurgery. Documentation 
of the patient’s initial pain score is required. Patients taking medication for pain at the time of 
registration are eligible. 
3.1.9 
Neurological examination within 1 week prior to registration to rule out rapid neurologic decline; 
see Appendix III for the standardized neurological examination.  Patients with mild to 
moderate neurological signs are eligible. These neurological signs include radiculopathy, 
dermatomal sensory change, and muscle strength of involved extremity 4/5 (lower extremity for 
ambulation or upper extremity for raising arms and/or arm function). 
3.1.10 
Patients with epidural compression are eligible provided that there is a ≥ 3 mm gap between the 
spinal cord and the edge of the epidural lesion. 
3.1.11 
Patients with a paraspinal mass ≤ 5 cm in the greatest dimension and that is contiguous with 
spine metastasis are eligible. 
3.1.12 
Patients must provide study specific informed consent prior to study entry. 
 
3.2 
Conditions for Patient Ineligibility (5/6/13) 
3.2.1 
Histologies of myeloma or lymphoma; 
3.2.2 
Non-ambulatory patients; 
3.2.3 
Spine instability due to a compression fracture; 
3.2.4 
> 50% loss of vertebral body height; 
(1) 
(2) 
(3) 
(4)

 
RTOG 0631, version date 09/23/16 
8
3.2.5 
Frank spinal cord compression or displacement or epidural compression within  3 mm of the 
spinal cord; 
3.2.6 
Patients with rapid neurologic decline;  
3.2.7 
Bony retropulsion causing neurologic abnormality; 
3.2.8 
Prior radiation to the index spine; 
3.2.9 
Patients for whom an MRI of the spine is medically contraindicated; 
3.2.10 
Patients allergic to contrast dye used in MRIs or CT scans or who cannot be premedicated for 
the use of contrast dye. 
 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT 
Note: This section lists baseline evaluations needed before the initiation of protocol treatment that do not 
affect eligibility.   
  
4.1 
Required Evaluations/Management (Phase III Component Only) (8/30/11) 
4.1.1 
The patient will complete the baseline Numerical Rating Pain Scale (NRPS) on the day of 
treatment identifying how much pain they are having at the index spine lesion to be treated. 
The patient can be on pain medication. 
 
Note: The Numerical Rating Pain Scale (NRPS) used to determine eligibility (a required score 
of ≥ 5; see Section 3.1.8) will not be used to assess treatment response. Documentation of the 
patient’s initial pain score is required. Treatment response will be assessed by the baseline 
NRPS completed on the day of treatment. Patients whose day of treatment NRPS score is < 5 
remain eligible for the study, will receive treatment, and will be followed per protocol 
specifications. 
4.1.2 
If the patient consents to participate in the quality of life component of the study, sites are 
required to administer the following baseline quality of life questionnaires prior to the start of 
protocol treatment: The Functional Assessment of Cancer Therapy-General (FACT-G); the 
Brief Pain Inventory (BPI), and the EuroQol (EQ-5D). 
 
 
5.0 
REGISTRATION PROCEDURES (09/23/16) 
 
 
 
 
Access requirements for OPEN, Medidata Rave, and TRIAD: Site staff will need to be 
registered with CTEP and have a valid and active CTEP Identity and Access Management (IAM) 
account.  
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all physicians 
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in 
the conduct of NCI-sponsored clinical trials). Associates will use the CTEP-IAM application to 
register (both initial registration and annual re-registration) with CTEP and to obtain a user 
account.  
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP 
Investigator Registration Procedures below for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.)  
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials 
Support Unit) websites and applications, including the CTSU members’ website. 
 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, please contact 
the CTEP Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
5.1  
Investigator Registration Requirements (09/23/16) 
Prior to the recruitment of a patient for this study, investigators must be registered members of a 
Lead Protocol Organization.  Food and Drug Administration (FDA) regulations and National 
Cancer Institute (NCI) policy require all investigators participating in any NCI-sponsored clinical 
trial to register and to renew their registration annually. Registration requires the submission of: 

 
RTOG 0631, version date 09/23/16 
9
 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature; 
 
a current Curriculum Vitae (CV); 
 
a completed and signed Supplemental Investigator Data Form (IDF); 
 
a completed Financial Disclosure Form (FDF) with an original signature. 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For questions, 
please 
contact 
the 
CTEP 
Investigator 
Registration 
Help 
Desk 
by 
email 
at 
<pmbregpend@ctep.nci.nih.gov>. 
 
5.2  
Pre-Registration Requirements for Spine Radiosurgery/SBRT (09/23/16) 
5.2.1 
The institution must complete or update all relevant parts of the NRG Oncology Facility 
Questionnaire: All questions in Part I (General Information for 3D-CRT and IMRT), in Part II 
(Information Specific to IGRT), and in Part III (Information for Heterogeneity Corrections and 
Motion Management) must be completed [available on the IROC Houston (formerly the 
Radiology Physics Center/RPC) web site at http://irochouston.mdanderson.org/] and send it to 
NRG Oncology for review prior to entering any cases, A TRIAD account for digital data 
submission must also be set-up. NRG Oncology will notify the institution when all requirements 
have been met and the institution is RT credentialed to enter patients onto this study..  
5.2.2 
In addition to the steps described in Section 5.1.1, credentialing for spine radiosurgery includes 
the process of irradiating the spine phantom provided by IROC Houston. Instructions for 
requesting and irradiating the spine phantom are available on the IROC Houston web site at 
http://irochouston.mdanderson.org; select “Credentialing” and “RTOG”. Upon review and 
successful completion of the phantom irradiation, IROC Houston will notify both the registering 
institution and NRG Oncology that the institution has completed this requirement.  
 
5.3 
Additional Pre-Registration Requirements for Image-Guided Radiotherapy (IGRT) 
(09/23/16) 
5.3.1 
IGRT Credentialing Process  
5.3.1.1 
Prior to entering patients on this study, institutions must perform a verification study. In order 
to complete the verification study, the institution must do the following: 
    Submit a series of planning and localization images along with a spreadsheet of IGRT 
data via TRIAD from an anonymized patient treated similarly to 0631 but not accrued 
to the study. Post-treatment imaging is mandatory for credentialing. 
   The Medical Physics Co-Chair, Dr. Yin, will review the images and spreadsheet and 
upon his approval of this data, NRG Oncology will notify the institution that this part of 
the credentialing is complete and the institution can continue to enroll patients on 0631. 
See the NRG Oncology/RTOG web site, 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0631  to obtain the 
spreadsheet. Since this study involves a single fraction treatment of the spine, simulation 
images and the treatment plan, onboard localization images (including setup images of 
simulation position prior to correction, images after reposition prior to treatment, and images of 
post-treatment) are required. Acquisition of additional images acquired during treatment are 
encouraged but not required. Pretreatment, during treatment, and post-treatment images may 
include three-dimensional (3D) volumetric images (either fan- or cone-beam CT with 
Megavoltage [MV] or kilovoltage [KV] x-rays). Additionally, orthogonal (MV or KV) 2D electronic 
images can be used. IGRT data and the completed spreadsheet are submitted to TRIAD. 
Select Benchmark submission. 
5.3.1.2 
Tolerance Levels for IGRT 
 
Three-dimensional views of gross tumor and other adjacent normal tissue structures, 
especially the spinal cord, are recommended as reference at the discretion of the treating 
radiation oncologist. Shifts of patient treatment position can be made based on the 
pretreatment images. After the position adjustments, the final accuracy of positioning should 
be < 2 mm identified from the post-shift images, compared with the pre-treatment position.    
 
For those institutions that plan to use orthogonal images for target localization and position 
adjustment, placement of fiducial markers such as seeds (typically 3 or more) in or outside 
the gross tumor is recommended. Fiducial markers are often placed under the guidance of 

 
RTOG 0631, version date 09/23/16 
10
ultrasound or CT scan.  An orthogonal view of fiducial markers and/or bony anatomy 
adjacent to the target volume can be used as a standard method. After shifts are made 
based on the pretreatment images and after the position adjustments, the final accuracy of 
positioning should be < 2 mm identified from the post-shift images, compared with the pre-
treatment position.   
 
5.4 
Digital RT Data Submission to NRG Oncology Using TRIAD (09/23/16) 
TRIAD is the American College of Radiology’s (ACR) image exchange application.. 
TRIAD provides sites participating in NRG Oncology clinical trials a secure method to 
transmit DICOM RT and other objects. TRIAD anonymizes and validates the images as 
they are transferred. 
 
TRIAD Access Requirements: 
 
Site physics staff who will submit images through TRIAD will need to be registered with 
The Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP 
Identity and Access Management (IAM) account. Please refer to Section 5.0 of the 
protocol for instructions on how to request a CTEP-IAM account. 
 
To submit images, the site physics user must have been assigned the 'TRIAD site user' 
role on the relevant Group or CTSU roster. NRG Oncology users should contact your site 
Lead RA to be added to your site roster.  You must have your CTEP IAM username on 
your Roster update request. Users from other cooperative groups should follow their 
procedures for assignment of roster roles. 
 
RAs are able to submit standard of care imaging through the same method. 
 
 
 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with proper user role, he/she will 
need to have the TRIAD application installed on his/her workstation to be able to 
submit images. TRIAD installation documentation can be found on the NRG 
Oncology/RTOG website Core Lab tab.    
 
This process can be done in parallel to obtaining your CTEP-IAM account username and 
password. 
 
If you have any questions regarding this information, please send an e-mail to the TRIAD 
Support mailbox at TRIAD-Support@acr.org. 
. 
5.5 
Regulatory Pre-Registration Requirements (09/23/16) 
5.5.1 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to: an active Federal 
Wide Assurance (FWA) number, an active roster affiliation with the Lead Network or a 
participating organization, a valid IRB approval, and compliance with all protocol specific 
requirements. 
 
Requirements for RTOG 0631 Site Registration: 
 CTSU Transmittal Sheet (optional) 
 IRB approval letter  
 IRB/REB Approved Informed Consent (English and native language versions*)  
*Note: Institutions must provide certification/verification of IRB/REB consent translation 
to NRG Headquarters (described below). 
 IRB/REB registration number renewal information as appropriate. 
 CTSU RT Facilities Inventory Form  

 
RTOG 0631, version date 09/23/16 
11
 NOTE:  Per NCI policy all institutions that participate on protocols with a radiation therapy 
component must participate in the Imaging and Radiation Oncology Core (IROC) 
monitoring program.  If this form has been previously submitted to CTSU it does not 
need to be resubmitted unless updates have occurred at the RT facility 
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS.  
 
ONLINE: www.ctsu.org  (members’ section)  Regulatory Submission Portal 
EMAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
FAX: 215-569-0206 
MAIL: CTSU Regulatory Office 
      1818 Market Street, Suite 1100 
      Philadelphia, PA 19103 
 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU website.   
 Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 Click on the Regulatory tab at the top of your screen 
 Click on the Site Registration tab 
 Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not 
reflect compliance with protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks. 
 
5.5.2 
Pre-Registration Requirements FOR NON-CANADIAN INTERNATIONAL INSTITUTIONS 
5.5.2.1 
For institutions that do not have an approved LOI for this protocol: 
International sites must receive written approval of submitted LOI forms from NRG Oncology 
prior to submitting documents to their local ethics committee for approval. See 
http://www.rtog.org/Researchers/InternationalMembers/LetterofIntent.aspx 
5.5.2.2  
For institutions that have an approved LOI for this protocol: 
 
All requirements indicated in your LOI Approval Notification must be fulfilled prior to enrolling 
patients to this study. 
 
5.6 
Registration (09/23/16) 
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria have 
been met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients must have signed 
and dated all applicable consents and authorization forms.   
 
5.6.1 
Oncology Patient Enrollment Network (OPEN) 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). 
OPEN is a web-based registration system available on a 24/7 basis. . To access OPEN, the site 
user 
must 
have 
an 
active 
CTEP-IAM 
account 
(check 
at 
< 
https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster.All site staff will use OPEN to enroll patients to this study. OPEN can be 
accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ web site 
https://www.ctsu.org. 
 
Prior to accessing OPEN site staff should verify the following: 
 
All eligibility criteria have been met within the protocol stated timeframes. 
 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable).   
 

 
RTOG 0631, version date 09/23/16 
12
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.   Please print this confirmation for your records.  If it is necessary to reprint the 
randomization confirmation or the transmittal form, they can be reprinted through Coordinator Online 
via the View a Patient Entry Report under Patient Entry. 
 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of the 
CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG Oncology 
for assistance with web registration at websupport@acr.org or 215-574-3191, Monday through 
Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask the site to fax in the eligibility checklist and 
will need the registering individual’s e-mail address and/or return fax number. This information is 
required to assure that mechanisms usually triggered by the OPEN web registration system (e.g. drug 
shipment and confirmation of registration) will occur.  
 
6.0 
RADIATION THERAPY (8/30/11) 
 
The Principal Investigator, Samuel Ryu, MD, and Co-Chairs will perform a rapid review of the treatment 
plan for the first 2 radiosurgery/SBRT cases from each institution prior to the institution delivering any 
protocol treatment on the phase II component or Arm 1 of the phase III component. Institutions 
should  allow 3 business days for each case to be received, processed, and reviewed. If the plan must be 
resubmitted, it will be given a rapid review (within 3 business days). Treatment plans for subsequent 
patients enrolled at a site will not be reviewed prior to delivery of treatment, but a review will be performed 
at a later date to evaluate protocol compliance.  
 
Questions regarding spine radiosurgery/SBRT should be directed to Dr. Ryu (preferably by e-mail, 
sryu1@hfhs.org, or alternatively by phone, 313-916-1027). 
 
Patients may receive external beam irradiation to other sites, brachytherapy (HDR or LDR), or a 
 
combination of external beam irradiation and brachytherapy at the discretion of the treating physician.
 
Dose/duration also will be at the discretion of the treating physician. However, the spine 
 
radiosurgery/SBRT and other radiotherapy must not occur at the same time or overlap. 
 
Patient registration must be done within 4 weeks after MRI of the involved spine. Note: The patient 
will complete the baseline Numerical Rating Pain Scale on the day of treatment. 
 
NOTE: Sections 6.1-6.7 (below) provide information regarding treatment with radiosurgery/SBRT 
for the phase II and phase III (Arm 1) components of this study. See Section 6.6.2 for IGRT 
requirements for Arm 1 patients. If the patient is randomized to Arm 2 of the phase III component, 
see Section 6.8 for details of external beam radiotherapy.  
 
6.1 
RADIOSURGERY/SBRT, PHASE II AND PHASE III (ARM 1) COMPONENTS (8/30/11) 
 
IMRT 
OR 
OTHER 
DOSE 
PAINTING 
TECHNIQUES 
ARE 
REQUIRED 
FOR 
RADIOSURGERY/SBRT. 3D-CRT IS NOT PERMITTED.  
6.1.1 
Dose Specifications 
6.1.1.1 
Dose Fractionation  
 
Patients treated with radiosurgery/SBRT will receive a prescribed dose of 16 or 18 Gy in 1 
fraction to cover at least 90% of the defined target volume (see Section 6.3.1.1). The 
radiation dose will be chosen based on the treating physician’s discretion and achievement 
of spinal cord dose constraints as described below. Coverage of target volume < 90% but > 
80% is a minor violation, and any coverage < 80% is a major deviation (see Section 6.3.2).  
 
See cord dose/volume constraints in Section 6.3.1.2. 
 
When the patient has multiple spine levels treated, the spinal cord constraint is applied to 
each treated spine level. The spinal cord volumes are defined based on the image 
fusion of simulation CT and MRI with T2-weighted and T1-weighted images with 
contrast. In addition to the spinal cord DVH constraints, the treating physician should 

 
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review each cross-sectional image to check if there is any excessive radiation dose 
distribution to the spinal cord. 
 
 
Radiosurgery should not be used for any cases with a spinal cord dose exceeding the 
constraints described in this study. Any spinal cord dose that does not meet these criteria is 
a major deviation (see Section 6.4.1.1). 
6.1.1.2 
Physical Factors  
 
Photon (x-ray) beams produced by linear accelerators with energies 4-18 MV will be 
allowed, preferably using photon beams with energy of 6 MV or less. IMRT or other dose 
painting techniques are allowed. Proton beams, and other charged particle beams (including 
electrons, heavy ions) are not allowed. Gamma Knife® or Perfexion™ treatment is not 
allowed.  
6.1.1.3 
Premedications  
 
No premedications are necessary.  
 
 
Pain control to help position the patient for the purpose of treatment (not for long-term pain 
control) is permitted to decrease patient movement due to pain. Note: Narcotics can be used 
or increased for the purposes of patient positioning for radiosurgery, as clinically necessary; 
however, the patient should return to the prior level of pain medication after radiosurgery. 
 
 
 
If it is necessary to minimize patient’s anxiety about the treatment and disease condition or 
for immobilization purposes, medications such as alprazolam or lorazepam are allowed.  
 
 
No steroid premedication is indicated, and it is recommended that all patients receiving 
corticosteroids begin tapering them immediately after radiosurgery.   
 
6.2 
Immobilization, Simulation, and Localization (11/22/13) 
6.2.1 
Patient Positioning 
 
Patients must be positioned in a stable supine position capable for reproducibility of positioning 
and immobilization from simulation to treatment, allowing the patient to feel as comfortable as 
possible. Positions uncomfortable for the patient should be avoided to prevent unnecessary 
movement. A prone position is not allowed. A variety of immobilization systems may be utilized 
including vacuum bag, alpha cradle, or stereotactic frames that surround the patient on three 
sides and large rigid pillows (conforming to patients external contours) with reference to the 
treatment delivery coordinate system. In addition, for cervical spine or cervicothoracic junctional 
areas, a rigid head and neck immobilization device should be used. Patient immobilization must 
be reliable enough to achieve the accuracy requirement of image-guidance (see Section 
5.2.1.2). 
6.2.1.1 
Repositioning for Treatment 
 
It is important to reproduce the treatment position. Pain can cause unintended movement, 
which can prolong treatment time and require repositioning. Therefore, it is important to 
allow the patient to feel as comfortable as the patient felt during the simulation.  
 
Spine radiosurgery/SBRT is an image-guided procedure. Body frames based only on frame 
fiducials are not be considered adequate image guidance. Recent development of in-room 
(or onboard) imaging technology has improved the stereotactic target localization and 
visualization under image-guidance. These methods can be used where available. 
Coordinate systems between imaging system and delivery system should be aligned for 
spine radiosurgery/SBRT. Image data from the repetition of the image-guided maneuver 
near (prior to the last delivered beam) or at the end of the treatment should be sent to the 
ITC (see Section 6.2.3). 
 
 
The treating physician can decide the day of treatment. Treatment can be given on the same 
day as positioning and simulation when feasible; however, it is not required. It is strongly 
recommended that institutions  treat the patient no later than the day following simulation. 
For the purpose of rapid review of the first case, institutions should allow 3 business days for 
their initial case to be received, processed, and reviewed (as specified in Section 6.0). 
 
 
6.2.2 
Simulation 

 
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CT simulation will be performed with proper patient positioning and immobilization. It is 
important to ensure that the target volume is within the attainable range of the frame-based or 
frameless stereotactic device. CT will be the primary image platform for targeting and treatment 
planning. The planning CT scans must allow simultaneous view of the patient anatomy and 
fiducial system for stereotactic targeting. The use of intravenous contrast is strongly 
recommended as this will help delineate the tumor and normal tissues.  Contrast will help 
visualize the soft tissue and adjacent normal tissues. Axial acquisitions with gantry 0 degrees 
will be required with slice thickness of ≤ 2.5-3 mm, depending on the manufacturer’s selected 
slice thicknesses. Images will be transferred to the treatment planning computers via direct 
lines, disc, or tape. 
6.2.3 
Localization 
 
Acceptable image-guided techniques include the following. The accuracy of localization should 
be less than 2 mm from simulation/planning to the end of treatment. 
1. Cone-beam CT equipment attached to the linear accelerator,  using either the 
treatment beam or an auxiliary kV x-ray head to obtain multiple projection images for 
volume reconstruction; 
2. Spiral dose delivery equipment that uses the treatment beam to gather helical CT 
information for image guidance; 
3. Any equipment that can produce stereoscopic planar views of the patient in the 
treatment position, capable of  localizing anatomic points in space or viewing implanted 
fiducial markers. It can use the treatment beam with a standard electronic portal 
imaging device (EPID) or a kV x-ray source with opposed imaging panel.  
4. A standard diagnostic-quality CT scanners positioned in the treatment room and 
geometrically coupled (e.g., on rails) with the treatment equipment. 
 
 
Although film procedures could fall under the description given in item 3 above, there are 
certain limitations that make it difficult to extend the definition to include this technology.  A 
major limitation for film is that it must be scanned with a densitometer to convert this information 
to digital data.  Additionally, in order to use this digital data in the fusion process, the film must 
be held perpendicular to the direction of the beam.  Although possible, this geometry is not 
available on most linear accelerators. Thus, radiographic film is not allowed as an image-guided 
technique for this study. However, film is allowed as a double check to verify the positioning 
obtained with any of the accepted IGRT techniques. 
 
 
Institutions are required to save and forward all the images used for patient setup adjustments.  
These images must be sent in DICOM or JPEG format to TRIAD.  This must include both the 
IGRT images and the treatment planning images. 
 
6.3 
Treatment Planning/Target Volumes (8/30/11) 
6.3.1 
Target Definition 
 
Image fusion between MRI (gadolinium contrast T1-weighted and T2-weighted images) and 
simulation CT is required for delineation of both the soft tissue tumor component and the spinal 
cord. Special attention should be taken with image fusion when simulation CT and MRI images 
are taken in different imaging positions. Spine curvature of MRI and CT simulation usually is not 
aligned well. In this situation special attention should be given to fuse the target spine to be 
treated. It is recommended but not required that MRIs are obtained with the simulation position. 
MR simulation should be used where available. 
6.3.1.1 
Radiosurgery Target Volume 
 
The radiosurgery target volume includes only the involved vertebral body and both left and 
right pedicles as shown in Figure 2 below and the grossly visible tumor, if a paraspinal or 
epidural lesion is present. An epidural lesion is included in the target volume provided 
that there is a ≥ 3 mm gap between the spinal cord and the edge of the epidural 
lesion. A paraspinal mass ≤ 5 cm in the greatest dimension contiguous with spine 
metastasis is included in the target volume. In this study, the terms, GTV or CTV, are not 
used.  
 
The target as defined above will not be enlarged (i.e., no “margin” for presumed 
microscopic extension). This target volume ultimately becomes the radiosurgery planning 
target volume.  The radiosurgery does not assume set-up errors. However, depending on 

 
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the radiosurgery system, a beam aperture margin of 2-3 mm beyond the target volume is 
allowed to meet the adequate dose coverage of the target. This margin can be reduced to 0-
1 mm at the area of spinal cord to meet the spinal cord dose constraints. The treatment plan 
is acceptable as long as ≥ 90% of the target volume receives the prescribed radiosurgery 
dose. 
 
 
Examples of radiosurgery target volumes are illustrated in Figure 2. Solid black represents 
the tumor that can be seen on the imaging studies.  
 
Most of the spine metastases involve the vertebral body and the gross tumor seen on MRI or 
CT scan, as shown in Figure 2a below. This is the most common type of spine metastasis. 
The radiosurgery target volume includes the involved vertebral body and both pedicles (solid 
red line).  
 
 
Metastatic lesions can be more extensive, involving the pedicles [Figure 2b]. The target 
volume can be more generous [dotted line of Figure 2b], or the target volume can include 
anterior and posterior elements of the spine [solid red line of Figure 2b]. The target volume 
may be chosen at the discretion of the treating Radiation Oncologist based on the extent of 
tumor involvement.  
 
 
When the metastasis involves only the posterior element, the target volume includes the 
spinous process and laminae [solid red line of Figure 2c].  
 
 
In any circumstance, when there is an epidural or paraspinal soft tissue tumor component, 
the visible epidural or paraspinal tumors are included in the target volume.  
 
Figure 2: Diagram of Spine Metastasis and Target Volume  
 
6.3.1.2 
Spinal Cord Volume  
 
Two spinal cord contour sets are required for this protocol:  the conventional and the partial 
spinal cord volumes. 
 
 
The conventional spinal cord volume is contoured on the simulation CT based on the image 
fusion with T2-weighted and T1-weighted MRI with contrast. It is recommended that a 
simulation CT be done with contrast, but this is not required. The conventional spinal cord 
should be contoured starting at least 10 cm above the superior extent of the target volume 
and continuing on every CT slice to at least 10 cm below the inferior extent of the target 
volume. This spinal cord volume is required to be consistent with image-guided radiotherapy 
volume definition of NRG Oncology protocols.  
  
 
The partial spinal cord volume is specific to this study.  The definition of partial spinal cord 
volume is shown in Figure 3below. The spinal cord is contoured based on the image fusion 

 
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with T2-weighted and T1-weighted MRI with contrast. It is recommended that a simulation 
CT image be done with contrast, but this is not required. The partial spinal cord should be 
contoured starting from 5-6 mm above the superior extent of the target volume to 5-6 mm 
below the inferior extent of the target volume.  The spinal cord should be drawn on every 
slice of simulation CT. The variation of 5-6 mm is due to the pre-determined slice 
thicknesses of 2.5-3 mm by different CT manufacturers.  
 
 
Three cord dose constraints are used in this study: 1) the dose constraints for the 
partial spinal cord is 10 Gy to no more than 10% of the partial spinal cord volume;  or 
2) the dose constraint for the conventional spinal cord is 10 Gy to the spinal cord 
volume less than 0.35cc; or 3) the maximum cord dose is 14 Gy for less than 0.03cc. 
These constraints are applied to the treated spine level. Any spinal cord dose exceeding 
these constraints is not acceptable and is a major deviation. 
 
Figure 3: Diagram of Defining Partial Spinal Cord Volume 
 
 
 
Radiosurgery is not recommended for any cases that do not meet the spinal cord 
constraints. Each CT slice within the radiosurgery plan should be checked to screen any 
unacceptably high radiation dose to the spinal cord at any particular slice. In this situation, 
the treating physician can make the decision of proceeding or stopping the radiosurgery or 
to perform re-planning. Critical organs including spinal cord, liver, kidneys, and lung should 
be analyzed for radiation dose distribution if any of them are transected by any radiation 
field. The dose-volume guidelines are described in Sections 6.3.2 and 6.4. 
6.3.2 
Dosimetry   
 
Intensity-modulated radiation therapy (IMRT) or other dose painting techniques will be used to 
deliver highly conformal dose distributions. Non-coplanar beams can be employed. Non-
opposing beams are preferable. Multiple beam directions or arcs of radiation will be used for 
geometrically complicated lesions. The beam arrangement should be placed mostly from the 
posterior direction to avoid the radiation beam entering through the lungs. Intensity-modulated 
arc therapy with either multiple static cones or dynamic conformal multileaf collimators (MLC) 
can be used. For arc rotational techniques, every effort should be used to limit the radiation 
through the lung.   
 
 
A common point should be defined, which is close to the center of the target volume for dose 
normalization. Preferably, this point is placed at the treatment isocenter if a linac based delivery 
system is used. The plan should be normalized to the common point or isocenter or its vicinity 
suitable for dose normalization. Typically, this point will be the isocenter of the beam rotation; 
however, it is not a protocol requirement for this point to be the isocenter. Inhomogeneity 
correction must be included for dose calculation. The prescription dose of 16 or 18 Gy will be 
delivered to the margin of the target volume and fulfill the requirements below. The treatment 
plan is acceptable as long as > 90% of the target volume receives the prescribed radiosurgery 
dose.  
 
Target 
spine  
 
Partial spinal 
cord 
5 - 6 mm  
5 - 6 mm  

 
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17
 
Successful treatment planning will require accomplishment of all of the following criteria: 
 
  
1)   Prescription Isodose Surface Coverage  
 
Patients will receive 16 or 18 Gy in 1 fraction of radiosurgery. This study requires 90% 
coverage of the target volume by the prescribed dose.  Typically, the 80-90% isodose line 
is used as prescription line. Depending on the delivery system, this prescription isodose 
line may be different. Coverage of < 90% of the target volume is a Variation Acceptable, 
and any coverage of < 80% of the target volume is a Deviation Unacceptable. 
 
2)   Target Dose Heterogeneity  
 
The treatment plan is per protocol  as long as ≥ 90% of the target volume receives the 
prescribed radiosurgery dose. Dose inhomogeneity can exist within the target volume.  
  
3)   High Dose Spillage  
Because of the irregular shape of target volume and the position of the spinal cord, there 
can be hot spots in the immediate vicinity outside of the target volume. The area of hot spot 
often can be seen in the immediate paraspinal areas or within the paraspinal muscle (e.g., 
psoas) or rib cage including intercostals muscle. Dose spillage is considered to be Per 
Protocol if the following dose limits are met.  Plans that do not meet these limits are scored 
as either Variation Acceptable or Deviation Unacceptable (see Section 6.6.1.1).   
The Per Protocol plan: 
 
limits dose outside of the target volume to greater than or equal to 105% of the 
prescription dose to a volume of less than or equal to 3.0 cc ; 
 
limits dose of greater than or equal to 105% of the prescription dose to a region 
within 1.0 cm from the edge of the target volume ; 
 
excludes all doses of greater than or equal to 110% of the prescription dose outside 
of the target volume.  
It is important to point out that these dose limits do not override the dose restrictions for the 
spinal cord stated below in Section 4 (Spinal Cord Dose) and in Section 6.4.1.1.  The high 
dose spillage conditions can be determined by expanding the target defined in Section 
6.3.1.1 by 1 cm.  Examination of the DVH for this rind around the target will determine the 
size of any high dose regions outside the target.  If the region of dose higher than 105% of 
the prescribed dose is seen to go outside of this margin region, the case will be scored 
according to the rules in Section 6.6.1.1. 
4) Spinal Cord Dose  
The most important requirement is the spinal cord dose constraint 10 Gy to the 10% of the 
partial spinal cord volume defined as 5-6 mm above and below the target. For multiple 
lesions, the partial cord volume and the 10% volume will increase.  In no case should the 
dose of 10 Gy be exceeded for a spinal cord volume of 0.35 cc.  The absolute maximum 
dose to any part of the spinal cord will be 14 Gy for a volume of 0.03 cc. Radiosurgery 
should not be used for any cases with spinal cord dose exceeding the described 
constraints in this study. Any spinal cord dose that does not meet these criteria is a major 
deviation. 
 
5)   Low Dose Spillage  
The falloff gradient beyond the target volume extending into normal tissue structures 
must be rapid in all directions and meet the following criteria: Using radiation beams 
directed from posterior to minimize passage of radiation through the lungs is strongly 
recommended.   
 

 
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6.4 
Critical Structures (4/21/14) 
Note: All required structures must be labeled as listed in the table below for digital RT data 
submission.  Resubmission of data may be required if labeling of structures does not 
conform to the standard dicom name listed. 
 
Standard Name 
Description 
PTV_1600 
PTV is defined as only the gross 
tumor 
Required for Rx Dose 16 Gy 
NonPTV1600 
External – PTV_1600 
Required for Rx Dose 16 Gy 
NonPTV1600_10 
External – (PTV_1600+10mm) 
Required for Rx Dose 16 Gy 
NonPTV1600_15 
External – (PTV_1600+15mm) 
Required for Rx Dose 16 Gy 
PTV_1800 
PTV is defined as only the gross 
tumor 
Required for Rx Dose 18 Gy 
NonPTV1800 
External – PTV_1800 
Required for Rx Dose 18 Gy 
NonPTV1800_10 
External – (PTV_1800+10mm) 
Required for Rx Dose 18 Gy 
NonPTV1800_15 
External – (PTV_1800+15mm) 
Required for Rx Dose 18 Gy 
PTV_800 
PTV is defined as only the gross 
tumor 
Required for Rx Dose 8 Gy 
PTV_100mm 
Expand PTVs by 10 cm 
Required 
Lung_L 
Left Lung 
Required when applicable 
Lung_R 
Right Lung 
Required when applicable 
Lungs 
Total Lung 
Required when applicable 
Esophagus 
10cm above/below the extent of PTV 
Required when applicable 
SpinalCord_Prt 
Partial Spinal Cord volume within 5-
6mm above/below the PTV 
Required when applicable 
SpinalCord 
Normal spinal cord contour 
Required when applicable 
BrachialPlexus 
Ipsilateral Brachial Plexus 
Required when applicable 
External 
 
Required 
Kidney_L 
 
Required when applicable 
Kidney_R 
 
Required when applicable 
Trachea 
 
Required when applicable 
Larynx 
 
Required when applicable 
Heart 
 
Required when applicable 
SkinOAR 
 
Required 
GreatVessels 
 
Required when applicable 
Stomach 
 
Required when applicable 
Duodenum 
 
Required when applicable 
Jejunum_Ileum 
 
Required when applicable 
Colon 
 
Required when applicable 
Rectum 
 
Required when applicable 
RenalHilum 
Renal hilum/vascular trunk 
Required when applicable 
RenalCortex 
 
Required when applicable 
SacralPlexus 
 
Required when applicable 
CaudaEquina 
 
Required when applicable 
 
6.4.1 
Critical Organ Dose-Volume Limits 
 
The following table lists maximum dose limits to a point or volume within several critical organs 
recommended for stereotactic body radiation therapy (SBRT). The recommended dose 
constraints are shown in volume and the maximum dose to the given volume for each organ 

 
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(Timmerman 2008). Note: The dose to the spinal cord has been modified from the original 
publication. 
 
Table 1: One Fraction Dose Constraints for Arms 1 and 2  
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Endpoint (≥ Grade 3) 
 
 
 
 
Spinal Cord 
Less than or equal to 
0.35cc 
10 Gy 
myelitis 
AND 
Spinal Cord 
Less than or equal to 
10% of the partial 
spinal cord  
10 Gy 
myelitis 
AND 
Spinal Cord  
Less than or equal to 
0.03cc 
14 Gy 
myelitis 
Cauda Equina 
<0.03 cc 
<5 cc 
16 Gy 
14 Gy 
neuritis 
Sacral Plexus 
<0.03 cc 
<5 cc 
18 Gy 
14.4 Gy 
neuropathy 
Esophagus* 
<0.03 cc 
<5 cc 
16 Gy 
11.9 Gy 
stenosis/fistula 
Ipsilateral Brachial Plexus 
<0.03 cc 
<3 cc 
17.5 Gy 
14 Gy 
neuropathy 
Heart/Pericardium 
<0.03 cc 
<15 cc 
22 Gy 
16 Gy 
pericarditis 
Great vessels* 
<0.03 cc 
<10 cc 
37 Gy 
31 Gy 
aneurysm 
Trachea* and Larynx 
<0.03 cc 
<4 cc 
20.2 Gy 
10.5 Gy 
stenosis/fistula 
Skin 
<0.03 cc 
<10 cc 
26 Gy 
23 Gy 
ulceration 
Stomach 
<0.03 cc 
<10 cc 
16 Gy 
11.2 Gy 
ulceration/fistula 
Duodenum* 
<0.03 cc 
<5 cc 
16 Gy 
11.2 Gy 
ulceration 
Jejunum/Ileum* 
<0.03 cc 
<5 cc 
15.4 Gy 
11.9 Gy 
enteritis/obstruction 
Colon* 
<0.03 cc 
<20 cc 
18.4 Gy 
14.3 Gy 
colitis/fistula 
Rectum* 
<0.03 cc 
<20 cc 
18.4 Gy 
14.3 Gy 
proctitis/fistula 
Renal hilum/vascular trunk 
<2/3 volume 
10.6 Gy 
malignant hypertension 
Parallel Tissue 
Critical Volume (cc) 
Critical Volume 
Dose Max (Gy) 
Endpoint (≥ Grade 3) 
Lung (Right & Left) 
1000 cc 
7.4 Gy 
Pneumonitis 
Renal cortex (Right & Left) 
200 cc 
8.4 Gy 
Basic renal function 
*Avoid circumferential irradiation 
 
 
These limits were formulated based on the widely accepted norms with radiosurgery in current 
practice. Participating centers are encouraged to observe prudent treatment planning principles 
in avoiding unnecessary radiation exposure to critical normal structures irrespective of these 
limits. 
 
 
In order to verify each of these limits, the organs must be contoured such that appropriate dose 
volume histograms can be generated. See Section 6.4.2 for instructions for the contouring of 
these organs. 

 
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20
6.4.1.1 
The spinal cord dose constraints are partially based on the previous published data (Ryu 
2008, Timmerman 2008). See Sections 6.3.1.2 and 6.3.2 for further details of the spinal cord 
dose. 
6.4.1.2 
The lung dose constraint is based on a critical volume model and requires no more than 
1,000 cc of lung tissue to be treated to a dose ≥ 7.4 Gy. Since the prescribed dose is only 16 
or 18 Gy, V20 as a single dose does not exist in this trial.   
6.4.2 
Contouring of Normal Tissue Structures 
Normal tissue contouring is required starting at 10 cm above the target volume to 10 cm 
below the target.  
6.4.2.1 
Spinal Cord 
 
Two spinal cord contour sets are required for this protocol: the conventional and 
partial spinal cord volumes. See Section 6.3.1.2 for details. 
6.4.2.2 
Esophagus 
 
The esophagus will be contoured using mediastinal windowing on CT to correspond to the 
mucosal, submucosa, and muscular layers. The esophagus should be defined starting at 
least 10 cm above the superior extent of the target volume and continuing on every CT slice 
to at least 10 cm below the inferior extent of the target volume. 
6.4.2.3 
Larynx and Pharynx 
 
The larynx and pharynx will be contoured to the mucosal, submucosa, and cartilages and 
airway channels associated with these structures. 
6.4.2.4 
Trachea and Airway 
 
The trachea and airway adjacent to the spines will be contoured including the mucosal, 
submucosa and cartilage rings and airway channels. 
6.4.2.5 
Lung 
 
Both the right and left lungs should be contoured using pulmonary windows. All inflated and 
collapsed lung should be contoured; however, paraspinal gross tumor, if any, should not be 
included in this structure. 
6.4.2.6 
Kidney 
 
Both the right and left kidneys should be contoured. Paraspinal gross tumor as defined 
above should not be included in this structure. 
6.4.2.7 
Skin 
 
The skin will be defined as the outer 0.5 cm of the body surface.  As such, it is a rind of 
uniform thickness (0.5 cm) which envelopes the entire body in the axial planes.  The cranial 
and caudal surface of the superior and inferior limits of the planning CT should not be 
contoured as skin unless skin is actually present in these locations (e.g., the scalp on the top 
of the head). 
 
6.5 
Documentation Requirements (8/30/11) 
6.5.1 
In general, treatment interruptions (e.g. due to intractable pain during the treatment) should be 
avoided by preventative medical measures and nutritional, psychological, and emotional 
counseling. Treatment breaks, including indications, must be clearly documented on the 
treatment record.  For Arm 1 patients, IGRT data must be submitted; see Section 6.6.2 for 
details. 
 
6.6 
Compliance Criteria for Arm 1 Spine Radiosurgery (8/30/11) 
6.6.1 
Dosimetry Compliance 
 
Section 6.0 describes appropriate conduct for treatment planning dosimetry. The optimal target 
coverage level is ≥ 90% volume to be covered by the prescription dose. Coverage of < 90% is a 
Variation Acceptable, and coverage of < 80% is a Deviation Unacceptable. Any spinal cord 
dose exceeding the dose constraint in Section 6.3.1.2 is not acceptable and is a major 
deviation. The table in Section 6.4 lists dose volume limits for specific organs and structures. 
Exceeding these limits by more than 2.5% constitutes a minor violation. Exceeding these limits 
by more than 5% constitutes a major deviation. 
6.6.1.1 
High Dose Spillage  
 
Per Protocol plan  
 
limits dose outside of the  target volume to greater than or equal to 105% of the 
prescription dose to a volume of less than or equal to 2.0 cc; 
 
limits dose of greater than or equal to 105% of the prescription dose to a region within 

 
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1.0 cm from the edge of the target volume;  
 
  
Variation Acceptable is defined by any one of the following  
 
allows doses outside of the target volume that are greater than or equal to 105% of 
the prescription dose to occupy a volume that is greater than 2.0 cc but does not 
exceed 3.0 cc;  
 
allows doses outside of the target volume that are greater than or equal to 105% of 
the prescription dose to extend beyond 1.0 cm but less than 1.5 cm from the edge of 
the target volume;  
 
allows doses outside of the target volume to go above 110% but not above 115% of 
the prescription dose.  
 
Deviation Unacceptable is defined as any dose distribution where the limits stated for 
Variation Acceptable are not met.    
6.6.2 
IGRT: Treatment Delivery Compliance  
Pre-treatment imaging, pre-treatment/post-shift imaging (if applicable), and Post-
treatment imaging, including a completed IGRT spreadsheet of the shifts, are REQUIRED 
to be obtained and submitted. 
 
 
Setup images (obtained from the IGRT system) will be compared to corresponding reference 
images to identify any potential deviation. The institution’s IGRT systems must demonstrate < 2 
mm agreement between simulation/planning and treatment, as well as at the end of treatment.  
 
6.7 
R.T. Quality Assurance Reviews (11/22/13) 
 
The Principal Investigator, Samuel Ryu, MD, and his Co-Chairs will perform a rapid review of the 
treatment plan for the first 2 cases from each institution prior to the institution delivering any 
protocol treatment using radiosurgery/SBRT. Institutions should allow 3 business days for this 
initial case to be received, processed, and reviewed. If the plan must be resubmitted, it will be 
given a rapid review as described in Section 6.0. Treatment plans for subsequent patients 
enrolled at a site will not be reviewed prior to delivery of treatment, but a review will be performed 
at a later date to evaluate protocol compliance.  
 
 
Treatment planning images and dosimetry planning information in accepted format will be 
submitted to TRIAD for quality assurance (QA) purposes in all cases. See Section 12.2 for data 
submission. 
 
 
It is recommended that each institution have a policy of quality assurance according to the 
guideline of SBRT by ASTRO and ACR (Potters 2004; Bissonnette 2007; Yoo 2006). The 
standard practice of checking radiation output should be carried out each day of treatment. Tests 
aimed at guaranteeing agreement of the image guidance system and the treatment system, 
including repositioning accuracy, must be carried out each day an SBRT treatment is scheduled. 
Dose delivery must be carried out for these treatments.  
 
 
The Study Chair, Samuel Ryu, MD, and the Medical Physics Co-Chair, Dr. Yin, will perform an 
RT Quality Assurance Review on an ongoing basis. The final cases will be reviewed within 3 
months after this study has reached the target accrual or as soon as complete data for all cases 
enrolled has been received at  IROC Phila RT, whichever occurs first. 
 
 
 
Participating institutions must have a QA for spine radiosurgery based on the site’s radiosurgery 
method and equipment. The following can be used as a guideline. Detailed QA information can 
be found in the AAPM TG 142 report. 
 
 
Daily Stereotactic System QA 
1. Linac morning warm up and radiation output check; 
2. Localization system (mainly immobilization and imaging systems) QA, including the 
geometric alignment of the imaging system and delivery system;  
3. Linac isocenter accuracy QA, mainly checking the stability during gantry rotation and table 
rotation and the consistency of the room laser system with the Linac isocenter. 
 

 
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22
Individual Patient QA  
1. Dose calculation check;  
2. Fluence/map field check for IMRT; 
3. Collision check for each treatment field; 
4. Patient position setup and check. 
 
6.8 
EXTERNAL BEAM RADIATION THERAPY, PHASE III COMPONENT, ARM 2 (8/30/11) 
 
INTENSITY MODULATED RADIOTHERAPY (IMRT) IS NOT ALLOWED FOR ARM 2 IN THE 
PHASE III COMPONENT OF THE STUDY. 
6.8.1 
Dose Specifications  
6.8.1.1 
Dose Fractionation and Treatment Volume for 2D or 3D Treatment 
 
For Arm 2, external beam radiotherapy, the prescribed dose is 8 Gy in 1 fraction. Treatment 
volume will include the entire vertebral body(s) of the involved index spine, plus one 
vertebral body superior and one vertebral body inferior to the index spine. A treatment field 
margin of 1-2 cm laterally beyond the vertebral body(s) can be used, based on the treating 
physician’s discretion, and either 2D or 3D conformal therapy is allowed at the treating 
physician’s discretion. 
6.8.1.2 
Physical Factors 
 
External beam radiotherapy must be given using megavoltage equipment with 4-18 MV 
photons. Electrons, protons, Gamma Knife® or Perfexion™ treatment are not permitted. 
6.8.1.3 
Premedications 
 
No premedications are necessary. 
 
Pain control to help position the patient for the purpose of treatment (not for long-term pain 
control) is permitted to decrease patient movement due to pain. Note: Narcotics can be used 
or increased for the purposes of patient positioning for radiosurgery, as clinically necessary; 
however, the patient should return to the prior level of pain medication after radiosurgery. 
 
 
 
If it is necessary to minimize patient’s anxiety about the treatment and disease condition or 
for immobilization purposes, medications such as alprazolam or lorazepam are allowed. 
 
No steroid premedication is indicated, and it is recommended that all patients receiving 
corticosteroids begin tapering them immediately after external beam treatment.  
6.8.2 
Patient Positioning and Simulation 
6.8.2.1 
Patient Positioning  
Patients must be positioned in a stable supine position at the treating physician’s discretion. 
Any immobilization techniques can be used for conventional radiotherapy or 3D conformal 
therapy at the treating physician’s discretion. For cervical spine or cervicothoracic junctional 
areas, a head and neck immobilization device can be used. 
6.8.2.3 
Simulation 
Simulation of treatment fields is required prior to the treatment. There must be an acceptable 
DRR or simulation image and portal image documenting that the treatment site is adequately 
covered and verified by the treating Radiation Oncologist. Both digital and analog format 
images are acceptable, preferably digital images. 
6.8.3 
Treatment Planning  
6.8.3.1 
2D Treatment 
Treatment target volume will include the involved index spine, plus one spine level superior 
and one spine level inferior to the index spine. A treatment field margin of 1-2 cm laterally 
beyond the vertebral body(s) can be used, based on the treating physician’s discretion. 
 
Field arrangements to treat the target lesion may be chosen at the discretion of the treating 
Radiation Oncologist. In general, posterior only, anterior-posterior, opposed lateral (for c-
spine tumors), or posterior oblique field arrangements will be used. Either a SAD or SSD 
technique is acceptable. The treatment depth is set at the center of the spinal canal, as 
determined on the simulation CT or MRI or lateral film of conventional simulation.  
 
 
Anterior and posterior parallel opposed fields can be used for thoracic or lumbar spine. 
Equal or unequal weighting may be used (e.g., a ratio of doses of 1:2 AP:PA). The dose is 
prescribed to the center of the spinal canal of the involved index spine. 

 
RTOG 0631, version date 09/23/16 
23
 
 
Parallel opposed lateral fields can be used for cervical spine. When lateral fields are used, 
the isocenter should be at mid-thickness, with the dose prescribed to the center of the spinal 
canal. 
 
 
The prescription point is set at the center of the spinal canal of the involved index spine, as 
determined on the simulation CT or MRI or anterior/lateral films of conventional simulation. 
Dose is prescribed to a point, not the treatment volume. While dose is prescribed to a point, 
it is recommended (but not required) that the goal of appropriate treatment planning aim to 
achieve coverage of the target lesion volume by at least 90% of the prescribed dose. Three-
dimensional conformal therapy is allowed, but IMRT is not allowed for Arm 2. 
6.8.3.2 
3D Treatment 
CT simulation is required. Treatment volume will include the entire vertebral body(s) of the 
involved index spine, plus one vertebral body superior and one vertebral body inferior to the 
index spine. Non-coplanar beams can be employed. Multiple beam directions can be used.  
 
 
Target volume should be delineated. A treatment field margin of 1-2 cm beyond the vertebral 
body(s) can be used in any direction, based on the treating physician’s discretion, as long as 
more than or equal to 90% of the target spine volume is covered by the prescription dose. 
 
A common point should be defined, which is close to the center of the target volume for dose 
normalization. Preferably, this point is placed at the treatment isocenter if a linac-based 
delivery system is used. The plan should be normalized to the common point or isocenter or 
its vicinity suitable for dose normalization. Typically, this point will be the isocenter of the 
beam rotation; however, it is not a protocol requirement for this point to be the isocenter. 
Inhomogeneity correction must be included for dose calculation. The prescription dose will 
be delivered to the margin of the target volume. The treatment plan is acceptable as long as 
more than or equal to 90% of the target volume receives the prescribed dose, with the same 
normal tissue constraints described in Table 1. Dose inhomogeneity can exist within the 
target volume. 
6.8.4 
Critical Structures 
See Section 6.4.1, Table 1, “One Fraction Dose Constraints for Arms 1 and 2”. 
 
For 2D treatment, contouring of normal tissue structure is not required. However, spinal cord 
dose should be recorded at the point of dose prescription, i.e., at the center of the spinal canal. 
Normal tissue structures can be delineated and the dose can be recorded at the treating 
physician’s discretion. Any adverse events should be reported as described in Section 6.10. 
 
For 3D treatment, the same normal tissue constraints described in Table 1 apply. The normal 
tissues as well as the target volume should be delineated as described in Section 6.3.1.2. If the 
normal tissue constraints are not met at the 10 Gy level, the total dose can be lowered to 8 Gy 
at the treating physician’s discretion. Any adverse events should be reported as described in 
Section 6.10. 
6.8.5 
Documentation Requirements  
6.8.5.1 
For 2D treatment, portal images of each field must be obtained on or before the day of 
therapy but sites are not required to submit these. 
6.8.5.2 
Planning images and dosimetry information for 2D treatment are not required to be 
submitted. 
6.8.5.3 
Isodose plans and documentation of isocenter positions for 3D radiotherapy are required to 
be submitted per Section 12.2. 
6.8.5.4 
In general, treatment interruptions (e.g., due to intractable pain during the treatment) should 
be avoided by preventative medical measures. Treatment breaks, including indications, must 
be clearly documented on the treatment record.   
6.8.6 
Compliance Criteria for 3D Treatment  
Dosimetric compliance for the protocol is that coverage of < 90% but ≥ 80% of the target 
volume is a Variation Acceptable, and any coverage of < 80% of the target volume is a 
Deviation Unacceptable.  
 

 
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24
EBRT will follow the normal tissue dose constraints as shown in Section 6.4, Table 1. 
Exceeding these limits by more than 2.5% constitutes a minor violation. Exceeding these limits 
by more than 5% constitutes a major deviation. 
6.8.7 
Compliance Criteria for 2D Treatment  
The treatment chart, including the prescription page, must be submitted. Treatment planning 
information and portal images of each field must be obtained on or before the day of therapy, 
will be archived at the site and will only be submitted if requested. 
 
6.9 
Radiation Therapy Adverse Events  
6.9.1 
Radiation Myelitis 
 
Given the proximity and position of spinal cord in relation to the radiosurgery target, every effort 
should be made to minimize the radiation dose to the spinal cord. Radiation myelitis is a 
subacute or chronic clinical syndrome after radiation. The symptoms may include paresthesia, 
sensory changes, and motor weakness including paralysis. There is no active treatment for 
radiation myelitis; therefore, it is important to prevent any injury to the spinal cord. 
Corticosteroids are used when clinical symptoms develop.  
 
 
In the Henry Ford Hospital experience, one case of radiation myelitis was reported.(Ryu 2007).  
The patient had a diagnosis of invasive breast cancer. The initial treatment was mastectomy 
followed by chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). After 9 years, 
she developed recurrence at the chest wall and was treated with radiotherapy and then 
continued hormonal therapy. After another 6 years, she presented to our institution with voice 
change due to vocal cord paralysis and difficulty in swallowing. MRI showed contrast enhancing 
mass involving the clivus, occipital condyles, and C1 vertebra with epidural compression. This 
was consistent with metastatic involvement. She was treated with single dose radiosurgery 16 
Gy, prescribed to the 90% isodose line encompassing the gross tumor volume.  The same 
spinal cord dose constraints described above were used. The doses to the spinal cord volume 
of 30%, 20%, 10%, 5%, and 1% were 6.2 Gy, 7.6 Gy, 9.6 Gy, 11.1 Gy, and 13.0 Gy, 
respectively. The maximum point dose to the spinal cord in this patient was 14.6 Gy, which was 
even lower than the average maximum of other patients. The spinal cord volume within the 
80% isodose line was 0.06 cc, and 0.32 % cord volume. The patient had a complete neurologic 
recovery and pain relief, and a complete tumor response radiographically. She then received 
chemotherapy with carboplatin and docetaxel for 6 months and continued trastuzumab as well 
as zoledronic acid and fulvestrant (at another institution). However, 13 months after 
radiosurgery, she developed right lower extremity weakness with 4/5 muscle strength. There 
was no sensory deficit. MRI revealed T2 signal abnormality in the cervicomedullary junction at 
the level of radiosurgery target, and contrast enhancement in the ventral aspect of medulla and 
right cerebellum. These changes appeared to be consistent with radiation effect. She was 
treated with dexamethasone and had symptom improvement. This patient did not have any 
other comorbidities or other metastatic progression. 
6.9.2 
Radiation Esophagitis 
 
Patients with thoracic spine treatment will likely develop esophageal mucositis within the first 2 
weeks. These symptoms subside with time; however, adequate symptomatic treatment 
including hydration is advised. There are no long-term adverse events reported with spine 
radiosurgery. However, it is prudent to minimize the radiation spillage in the normal esophagus. 
The consequences of esophageal toxicity, e.g., swallowing difficulty, dysphagia, cough, 
dehydration, and fistula, should be documented. 
 
 
In the Henry Ford Hospital experience, one case of tracheoesophageal fistula was reported in 
patient with multiple myeloma (Ryu 2008b). This patient was severely immunocompromised 
from previous bone marrow transplantation and systemic chemotherapy with multiple medical 
comorbidities including a mycobacterial granulomatous infection involving the esophagus. The 
patient was treated for spinal cord compression at T4 and paraspinal mass with a dose of 16 
Gy. The patient had excellent tumor response but later developed a tracheoesophageal fistula 
at the treated site. Biopsy also revealed granulomatous infection. It was believed that radiation 
contributed, at least in part, to the development of the fistula.   
6.9.3 
Radiation Laryngitis or Pharyngitis 
 
Patients with cervical spine treatment will likely develop laryngopharyngeal mucositis within the 
first 2 weeks. These symptoms subside with time; however, adequate symptomatic treatment 

 
RTOG 0631, version date 09/23/16 
25
including hydration is advised. No long-term laryngopharyngeal toxicity has been reported with 
spine radiosurgery. However, it is prudent to minimize the radiation spillage in the normal larynx 
and pharynx. The consequences of toxicity, e.g., swallowing difficulty, dysphagia, cough, 
dysphonia dehydration, and fistula, should be documented. 
6.9.4 
Tracheal Injury 
 
Although no cases of tracheal injury have been reported with spine radiosurgery, it is prudent to 
minimize the radiation spillage in the normal trachea. The consequences of tracheobronchial 
toxicity, e.g., cough, dyspnea, hypoxia, impairment of pulmonary function test parameters, 
pleural effusion or pleuritic pain (associated with collapse), should be documented. 
6.9.5 
Radiation Pneumonitis 
 
There have been no reported cases of symptomatic radiation pneumonitis with spine 
radiosurgery. However, it is prudent to minimize the radiation spillage in the lung tissue. It is 
strongly recommended to use radiation beams directed from posterior to avoid passage of 
radiation through the lungs.  
 
 
 
Patients with symptoms of pneumonitis will be promptly evaluated and treated. Mild radiation 
pneumonitis may be treated with non-steroidal anti-inflammatory agents or steroid inhalers. 
More significant pneumonitis will be treated with systemic steroids, bronchodilators, and 
pulmonary toilet. Supra- and concurrent infections should be treated with antibiotics. 
Consideration of prophylaxis of opportunistic infections should be considered in immuno-
compromised patients. 
6.9.6 
Compression Fracture of Treated Vertebra 
 
There has been no formally reported incidence of vertebral compression fracture as the result 
of spine radiosurgery; the incidence is estimated to be 5-30% (Jin 2006; Yamada 2008). 
Patients with multiple myeloma appear to be more prone to develop compression fracture than 
patients with other histology. There is no known radiation dose relationship. This study is 
designed to follow up the potential bony change of the treated spine by imaging studies. The 
most common symptom from compression fracture is pain. Kyphoplasty or vertebroplasty can 
be used to address the compression fracture; however, retropulsed compression causing 
neurological signs may need surgery.  
6.9.7 
Other Adverse Events 
 
Short-term or long-term injury to the kidney or upper airway has not been reported. If other 
severe adverse events occur, details should be documented.  
 
6.10 
Adverse Events (AEs) and Serious Adverse Events (SAEs) Reporting Requirements 
(09/23/16) 
 
Adverse events (AEs) as defined in the tables below and all serious adverse events (SAEs) 
will be reported to the Cancer Therapy Evaluation Program (CTEP) via the CTEP Adverse 
Event  Reporting System (CTEP-AERS) application as directed in this section. 
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
3.0 for routine adverse event (AE) reporting on the case report form.  
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be 
reported via the CTEP-AERS. CTEP-AERS utilizes the NCI CTCAE version 4.0 and the 
application can be accessed via the CTEP web site  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1389817585865 
 
All appropriate treatment areas should have access to both the CTCAE versions 3.0 and 4.0. . 
The 
CTCAE 
versions 
3.0 
and 
4.0 
are 
located 
on 
the 
CTEP 
website 
at                    
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm   
 
 
Definition of an AE: Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not considered related 
to the medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or 
definite). (International Conference on Harmonisation [ICH], E2A, E6).  

 
RTOG 0631, version date 09/23/16 
26
 
Routine adverse event reporting guidelines are available at 
(http://www.rtog.org/ResearchAssociates/AdverseEventReporting.aspx).  
 
 
 
Definition of an SAE: Any adverse experience occurring during any part of protocol treatment 
and 30 days after that results in any of the following outcomes: 
 
Death; 
 
A life-threatening adverse experience; 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
 
A persistent or significant disability/incapacity; 
 
A congenital anomaly/birth defect. 
 
 
Important medical events that do not result in death, are not life threatening, or do not require 
hospitalization may be considered an SAE, when, based upon medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition. Due to the risk of intrauterine exposure of a fetus to potentially 
teratogenic agents, the pregnancy of a study participant must be reported via CTEP-AERS in an 
expedited manner.  
Serious adverse events (SAEs) that meet expedited reporting criteria defined in the table below 
will be reported via CTEP-AERS.  SAEs that require 24 hour CTEP-AERS notification are defined 
in the expedited reporting table below.  Contact the CTEP-AERS Help Desk if assistance is 
required. 
 
 
 
AdEERS REPORTING REQUIREMENTS 
 
All serious adverse events that meet expedited reporting criteria defined in the reporting table 
below will be reported via CTEP-AERS, the CTEP Adverse Event Reporting System, accessed 
via the CTEP web site, https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1389817585865 
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG 
Oncology requirements for expedited adverse event reporting. 
 
CTEP-AERS provides a radiation therapy (RT)-only pathway for events experienced that involve 
radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only 
pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
NRG Oncology at 1-215-574-3191. An electronic report must be submitted immediately upon re-
establishment of the Internet connection 
 AdEERS-24 Hour Notification requires that an CTEP-AERS 24-hour notification is 
electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 
24-hour notification must be followed by a CTEP-AERS  Calendar Day Report. Serious 
adverse events that require 24 hour CTEP-AERS notification are defined in the expedited 
reporting table below. 
 Supporting source document is not mandatory.  However, if the CTEP-AERS report indicates 
in the Additional Information section that source documentation will be provided, then it is 
expected.  Supporting source documentation should include the protocol number, patient ID 
number, and CTEP-AERS ticket number on each page. For instructions to submit supporting 
documentation, , contact NRG Oncology at 1-215-574-3191. 
 A serious adverse event that meets expedited reporting criteria outlined in the following table 
but is assessed by the CTEP-AERS as “expedited reporting NOT required” must still be 
reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the “NOT 
Required” assessment; the CTEP-AERS allows submission of all reports regardless of the 
results of the assessment. 
 

 
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27
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur within 30 Days of the Last Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via A CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite require 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half-lives, rounded UP to the nearest whole day, after the agent/intervention was last 
administered.  Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 
 

 
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28
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials: 
The following are protocol-specific exceptions to expedited reporting via CTEP-AERS:  grade 1 and grade 
2 adverse events.  Routine adverse event reporting on the case report form fulfills safety reporting 
requirements for these events during protocol treatment. 
 
6.10.1 
Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment in 
patients on NCI/CTEP-sponsored clinical trials must be reported via  CTEP-AERS  within 30 days 
of AML/MDS diagnosis.  
 
Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event: 
 
 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
 
Myelodysplastic syndrome (MDS) 
 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified. 
 
7.0 
DRUG THERAPY 
 
Not applicable to this study. 
 
8.0 
SURGERY 
8.1 
Spine Instability and/or Compression Fractures 
 
Patients with overt spinal instability or direct spinal cord or cauda equina compression, 
particularly with bony retropulsion, should be evaluated by a qualified spine surgeon for possible 
open surgical intervention. These patients are not eligible for this study. The decision for open 
surgical intervention will be determined by the institution’s treating neurosurgeon and radiation 
oncologist. 
 
9.0 
OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
each site’s source documents as concomitant medication.  
9.1.1 
Steroids 
 
Prophylactic use of steroids is not necessary. No steroid premedication is indicated for 
radiosurgery treatment. If the patient has already started steroid medication, it  can be tapered 
immediately after radiosurgery is completed (see Section 6.1.3). 
9.1.2 
Analgesics 
 
Pain control to help position the patient for the purpose of treatment (not for long-term pain 
control) is permitted to decrease voluntary patient movement. Note: Narcotics can be 
increased for the purposes of patient positioning for treatment, as clinically necessary 
for pain control (see Section 6.1.3). 
 
 

 
RTOG 0631, version date 09/23/16 
29
 
9.1.3 
Anti-Anxiety Medications 
 
If it is necessary to minimize patient’s anxiety about the treatment and disease condition or for 
immobilization purposes, medications such as alprazolam or lorazepam are allowed for the 
radiosurgery procedure. 
9.1.4 
Supportive Therapy for Acute Radiation Reactions 
 
Supportive therapy is allowed for medical care of acute radiation symptoms, such as treatment 
of mucositis. 
9.2 
Non-permitted Therapy 
 
Chemotherapy is not permitted within 24 hours prior to or concurrently with radiosurgery. In 
addition, the patient can receive chemotherapy no earlier than 24 hours after radiosurgery.  
 
10.0 
SPECIMEN SUBMISSION — Phase III Component Of The Study (09/23/16) 
For patients who have consented to participate in the specimen submission component of the study (See 
the Sample Informed Consent).  
 
NOTE: Patients must be offered the opportunity to participate in the correlative components of the 
study, such as specimen submission. If the patient consents to participate in the specimen component 
of the study, the site is required to submit the patient’s specimens as specified below. Sites are not 
permitted to delete the specimen component from the protocol or from the sample consent. 
 
10.1 
Specimen Submission (09/23/16) 
 
The NRG Oncology Biopspecimen Bank-San Francisco at the University of California San 
Francisco acquires and maintains high quality specimens from NRG Oncology trials. NRG 
Oncology encourages participants in protocol studies to consent to the banking of their 
specimens. The NRG Oncology Biopspecimen Bank provides specimens to investigators for 
translational research studies. Translational research studies integrate the newest research 
findings into current protocols to investigate important biologic questions. Note: The NRG 
Oncology Biopspecimen Bank will provide collection kits and instructions at no charge for the 
submission of specimens in this protocol; see Appendices IV and V. 
 
In this study, it is strongly encouraged that blood (serum/plasma/whole blood) and urine be 
submitted to the NRG Oncology Biopspecimen Bank for the purpose of banking and for 
translational research. If the patient consents, serum, plasma, whole blood, and urine will be 
collected at baseline and serum, plasma, and urine at 3 months from randomization. 
 
We will explore promising biomarkers to date with regard to side effects from treatment. Although 
substantial evidence has been obtained from a series of studies suggestive of a genetic basis for 
clinical radiosensitivity of normal tissue, much work still remains to be accomplished in this area.   
 
The whole blood collected will be utilized for single nucleotide polymorphisms (SNPs).  Single 
nucleotide polymorphisms (SNPs) are the most common variation responsible for genetic 
diversity between individuals, accounting for more than 85% of the variability.  Recent advances 
in SNP identification and analysis have made SNP genotyping an invaluable tool to examine the 
variations responsible for disease susceptibility and radiation responsiveness. SNP genotyping 
applications have recently extended into personalized health care.  
 
The pretreatment plasma, serum and urine and 3 month post-treatment collection of these fluids 
will be tested for a number of cytokines and proteins that are thought to be predictive of long-term 
radiation toxicity.  This may lead to identification of promising similar or new biomarkers with the 
goals of 
1. Identifying factors predictive of outcome such that patients may be better stratified in 
future trials;  
2. Developing novel treatment strategies which target the molecular abnormalities identified. 
 
10.2 
Specimen Collection for Translational Research and Tissue Banking (09/23/16) 
 
For patients who have consented to participate in the tissue/blood component of the study. See 
Appendix IV for urine and blood collection kits and detailed collection instructions. Collection kits 
with one pre-paid shipping label per case can be requested from NRGBB@ucsf.edu. Batch 

 
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30
shipping all samples from each case in one shipment is requested for this trial. As the effects of 
many specimen processing parameters on the measurements of biomarkers is unknown, please 
follow the instructions in the appendix carefully and record processing information as requested.  
Any deviations from the instructions should be recorded but may make a specimen unbankable. 
10.2.1 
Blood Sample Preparation 
 
20-30 ml peripheral blood (Two 10 ml EDTA tubes and one 10ml Red-top tube) will be taken 
from each individual before treatment and 20 mls (one 10 ml EDTA tube and one 10ml red-top 
tube) at 3 months from randomization. Use sterile techniques to avoid contamination. 
 
See Appendix IV for detailed instructions on kit requests, collection, processing, storage and 
shipping. (Note: if the site misses the pre-treatment collection time point then the site may 
collect whole blood at any time point or follow-up visit but this must be noted on the Specimen 
Transmittal Form) 
10.2.2 
The following materials must be provided to the NRG Oncology Biopspecimen Bank: A 
Specimen Transmittal (ST) Form documenting the date of collection of the biospecimen; the 
NRG Oncology protocol number; the patient’s case number; the collection time point, and 
method of storage, for example, stored at -80° C, must be included. 
 
10.3 
Storage Conditions (8/30/11) 
Store at -80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not available:  
 Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only). 
OR: 
 Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out 
Monday-Wednesday only). 
OR: 
 Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored. 
 
10.4 
Specimen Collection Summary (09/23/16) 
 
Specimens taken from 
patient: 
Collected When: 
Submitted as: 
 
Shipped: 
Plasma: 5-10 mL of whole 
blood in EDTA tube #1 
(purple/lavender top) and 
centrifuge per Appendix IV 
1) Pre-Treatment 
2) 3 months from 
randomization 
Frozen plasma samples 
containing a minimum of 
0.5 mL per aliquot in 1 mL 
cryovials (5 vials) 
Plasma sent frozen on dry 
ice via overnight carrier 
(ship Mon-Wed only) 
Batch ship whole case in 
one shipment or with other 
cases. 
Serum: 5-10 mL of whole 
blood in Red-top tube and 
centrifuge per Appendix IV 
1) Pre-Treatment 
2) 3 months from 
randomization 
Frozen serum samples 
containing a minimum of 
0.5 mL per aliquot in 1 mL 
cryovials (5 vials) 
Serum sent frozen on dry 
ice via overnight carrier 
(ship Mon-Wed only) 
Batch ship whole case in 
one shipment or with other 
cases. 
Whole blood for DNA: 5-10 
mL of anticoagulated whole 
blood in EDTA tube #2 
(purple/lavender top) and 
mix per Appendix IV 
Pre-treatment. (Note if 
site misses this 
collection time point site 
may collect whole blood 
at any time point or 
follow-up visit but must 
note this on the 
Specimen Transmittal 
Form). 
Frozen whole blood 
samples containing 1 ml 
per aliquot in 1 ml 
cryovials (3 to 5 vials) 
Whole blood sent frozen 
on dry ice via overnight 
carrier (ship Mon-Wed 
only) 
10-15 mL clean-catch urine 
 
1) Pre-Treatment 
2) 3 months at 
randomization 
5-10 ml unpreserved urine 
aliquotted into one- two 
sterile 15 ml polypropylene 
tubes.  
Urine sent frozen on dry ice 
via overnight carrier (ship 
Mon-Wed only) 

 
RTOG 0631, version date 09/23/16 
31
Batch ship whole case in 
one shipment or with other 
cases. 
 
 
 
 
 
10.5 
Submit materials for Banking and Translational Research as follows: (09/23/16) 
 
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank-San Francisco 
University of California San Francisco 
UCSF Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143 
 
Courier Address (FedEx, UPS, etc.): For Trackable FFPE and ALL Frozen Specimens 
NRG Oncology Biospecimen Bank-San Francisco 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
Questions: 415-476-7864/FAX 415-476-5271; NRGBB@ucsf.edu 
 
10.6 
Reimbursement (4/14/15) 
NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per 
the requirements/methods specified by the new National Clinical Trials Network (NCTN) Program. 
This information will be made available with the other registration materials in the Oncology 
Patient Enrollment Network (OPEN) portal system.  
10.7 
Confidentiality/Storage (12/1/09) 
 
(See 
the 
Patient 
Tissue 
Consent 
Frequently 
Asked 
Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx 
for 
further details.) 
10.7.1 
Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the 
patient’s case number only. The NRG Oncology Biopspecimen Bank database only includes 
the following information: the number of specimens received, the date the specimens were 
received, documentation of material sent to a qualified investigator, type of material sent, and 
the date the specimens were sent to the investigator. No clinical information is kept in the 
database. 
10.7.2 
Specimens for banking will be stored for an indefinite period of time. Specimens for the 
translational research component of this protocol will be retained until the study is terminated, 
unless the patient has consented to storage for future studies. If at any time the patient 
withdraws consent to store and use specimens, the material will be returned to the institution 
that submitted it. 
 
11.0 
PATIENT ASSESSMENTS (09/23/16) 
 
11.1 
Study Parameters: See Appendix I for a summary of patient assessments and timeframes. 
 
 
11.2 
Evaluations: Phase III Component (09/23/16) 
11.2.1 
The patient will complete the Numerical Rating Pain Scale (NRPS) documenting the worst pain 
of treated spine lesion(s) at the baseline clinic visit (on the day of treatment) and at home at 1, 
2, and 3 weeks after randomization and will record their pain medications and any side effects 
they are experiencing. Documentation of the patient’s initial pain score is required. 
 
Sites will make 3 copies of the NRPS (available on either the I1 or F1 forms) for the patient to 
complete at home at these time points, and patient will bring in the NRPS and record of pain 
medications and side effects at the clinic visit 1 month after randomization. At this clinic visit, 
patients will complete the 1 month NRPS on the same day of the week as the patient’s 

 
RTOG 0631, version date 09/23/16 
32
treatment occurred, and sites will summarize the patient’s pain level, pain medications, and 
document any adverse events on the F1 form (see Section 12.1). Patients also will complete 
the NRPS at the 3 (required), 6, 12, and 24 month clinic visits. The physician may ask this 
question of the patient during the visit and record the pain score in the patient’s chart rather 
than having the patient complete the NRPS on paper. 
 
The NRPS score should be collected for each spinal metastasis site treated. The highest 
numerical pain score of the index lesion will be followed for the primary endpoint of pain 
response (i.e., improvement at this treated site of ≥ 3 points on the NRPS, as long as other 
sites remain stable or decrease). If there is more than one site with identical highest pain score, 
then the most cephalad lesion will be defined as the index lesion. 
 
The NRPS is an 11-point scale (0-10). Patients are instructed that 0 indicates no pain and that 
10 indicates the worst pain imaginable. In general, scores of 1-4 indicate mild pain, scores of 5-
6 indicate moderate pain, and scores of 7-10 indicate severe pain. Patients will be instructed to 
report the pain score of each treated site. Patients can complete the NRPS in approximately 1 
minute. 
11.2.2 
An MRI of the treated spine will be obtained at baseline and at 3, 6, 12, and 24 months after 
randomization to assess the paravertebral or epidural tumor response as well as the subacute 
or long-term change of vertebral bone after radiosurgery. 
11.2.3 
Quality of Life Assessments  
 
Patients participating in the phase III component and who agree to participate in the quality of 
life component of the study will complete the quality of life assessments at baseline and at 3, 6, 
12, and 24 months after randomization. 
 
 
 
 
NOTE: Patients must be offered the opportunity to participate in the quality of life component of 
the study.  Sites are not permitted to delete the quality of life component from the protocol or 
from the sample consent. 
11.2.3.1 
The Functional Assessment of Cancer Therapy-General (FACT-G) 
 
The FACT-G is a commonly used tool measuring general quality of life across 4 scales: 
physical well being (7 items), social/family well-being (7 items), emotional well-being (6 
items), and functional well being (7 items). It has been written at the 4th grade reading level, 
and patients can complete the FACT-G in 5-10 minutes. The FACT has been translated into 
26 
languages, 
and 
translations 
are 
accessible 
at 
the 
FACIT 
web 
site, 
http://www.facit.org/FACITOrg/Questionnaires 
11.2.3.2 
The Brief Pain Inventory (BPI) 
 
The BPI asks patients to rate their pain for the last week on 0-10 scales. Patients also are 
asked to rate how their pain interferes with their quality of life (QOL). In addition, patients are 
asked to estimate the pain relief they receive from their pain treatment. The patient can 
complete the BPI in approximately 5 minutes. The BPI has been validated in 12 languages. 
Translations can be accessed at https://www.mdanderson.org/research/departments-labs-
institutes/departments-divisions/symptom-research/symptom-assessment-tools/brief-pain-
inventory.html; click on “symptom assessment tools”. If a translation is used, the site must 
transcribe the data to the appropriate NRG Oncology data form and attach the patient’s 
original. 
11.2.3.3 
The EuroQol (EQ-5D) 
 
The EuroQol (EQ-5D) is a two-part questionnaire that the patient can complete in 
approximately 5 minutes. Note: The EQ-5D has been translated into multiple languages; 
these translations are available from the EuroQol web site at http://www.euroqol.org/. The 
site research nurse or CRA should encourage the patient not to skip questions on the EQ-
5D or take breaks during the completion of this questionnaire, as this will invalidate the 
assessment. If this occurs, sites will document it on the Health Utility Measurement (HP) 
form. 
 
11.3 
Pain Response Definitions (also see Section 13.4.1) 
 
Pain response will be defined as follows:  
11.3.1 
Complete response: Post-treatment pain score of 0 at the index site;  
11.3.2 
Partial response: Post-treatment improvement of at least 3 points at the index site;  

 
RTOG 0631, version date 09/23/16 
33
11.3.3 
Stable response: Post-treatment pain score within 2 points of the initial pain score at the index 
site; 
11.3.4 
Progressive response: A post-treatment increase of at least 3 points at the index site.  
11.3.5 
A complete, partial, or stable response at the index site requires no increase in narcotic pain 
medication and no increase in pain score at the secondary treated site(s). Although complete 
response is the best possible outcome, partial response is also a satisfactory outcome. 
Therefore, patients with complete or partial response will be considered responders. Any 
patient with a complete or partial response at the index site but a progressive response at the 
secondary sites will be considered a non-responder.   
 
11.4 
Criteria for Discontinuation of Protocol Treatment (5/1/12) 
11.4.1 
Protocol treatment is discontinued when there is systemic or local progression of disease 
resulting in hospice enrollment. If the patient is unable to have follow-up imaging studies, 
clinical examinations, neurologic exams, the institution should contact Data Management for 
instructions.  
 
12.0 
DATA COLLECTION 
Data should be submitted to: 
NRG Oncology* 
 1818 Market Street, Suite 1600 
 Philadelphia, PA  19103 
 
*If a data form is available for web entry, it must be submitted electronically. 
 
Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be 
used (first-last). Last names with apostrophes will be identified by the first letter of the last name. 
 
12.1 
Summary of Data Submission (8/14/15) 
 
 
 
Item 
Due 
Demographic Form (A5) 
Initial Evaluation Form (I1) with NRPS 
Within 2 weeks of study entry (Phase II and 
Phase III components) 
 
 
The Functional Assessment of Cancer Therapy-
General (FACT-G) [FA] † 
Within 2 weeks of study entry  
The Brief Pain Inventory (BPI) (QL) † 
The EuroQol (EQ-5D) [HP] † 
 
 
Adverse Event Form (AE) 
At 1 and 3 months post-study entry (Phase II 
component) Note: If no AEs to report, submit a 
Communication Memo (CM) for suppression. 
 
 
Follow-up Form (F1) with NRPS† 
At 1, 3 (NRPS-required at 3 months), 6, 12, and 
24 months post-study entry  
 
 
The Functional Assessment of Cancer Therapy-
General (FACT-G) [FA] † 
At 3, 6, 12, and 24 months post-study entry  
The Brief Pain Inventory (BPI) (QL) † 
The EuroQol (EQ-5D) [HP] † 
 
† For Phase III component only 
 
12.2 
Summary of Dosimetry Digital Data Submission (Submit to TRIAD; see Section 5.3) (8/14/15) 
 
Item 
Due 
Preliminary Dosimetry Information (DD) 
 
†Digital Data Submission – Treatment Plan submitted to TRIAD exported from 
treatment planning system 
Within 1 week post-
radiosurgery & 3D-

 
RTOG 0631, version date 09/23/16 
34
Digital data submission includes the following: 
CRT external beam 
(see Section 6.0 for 
details 
on 
rapid 
review of cases on 
Arm 1) 
 
DICOM CT, DICOM Structures 
 
DICOM Plan 
 
DICOM Dose 
 
All required structures MUST be labeled per the table in Section 6.4. 
 
The “RTOG 0631 Datasheet” is available in the Forms section of the of 
the NRG Oncology/RTOG web site, 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0631. 
Submit the Data Sheet via TRIAD with the digital data listed above. 
Upon submission of the digital data via TRIAD, complete an online digital 
data transmission form (DT) located in the Forms section on the NRG 
Oncology/RTOG web site at    
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0631 
 
 
 
Note: All simulation and portal films and/or digital film images will be kept by the 
institution and only submitted if requested. 
 
 
 
Modified digital patient data as required submitted to TRIAD 
 
 
 
IGRT Submission (Arm 1 Only) 
 
IGRT images obtained on the day of treatment (IG) See Section 6.6.2 for time 
points Submit to TRIAD. Must be DICOM or JPEG format 
Within 1 week post-
radiosurgery 
† IGRT Data Collection Spreadsheet on Set-up Variances [SG] submitted via 
TRIAD along with the images. 
NOTE: ALL SIMULATION AND PORTAL FILMS AND/OR DIGITAL FILM 
IMAGES WILL BE KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF 
REQUESTED. 
 
 
Modified digital patient data as required submitted to TRIAD select “append” in 
TRIAD 
 
 
 
Final RT DATA 
 
Radiotherapy Form (T1) Via the web 
Within 1 week of RT 
end 
Treatment Record (T5) submitted to HQ  address at the top 
 
NOTE: For 2D cases, DRRs and portal images will be archived at the site and will only be submitted if 
requested. 
 
 
13.0     STATISTICAL CONSIDERATIONS       
13.1 
   Study Endpoints (09/23/16)    
13.1.1      Primary Endpoint 
13.1.1.1    
Phase II Component 
Successful delivery of image-guided radiosurgery/SBRT in the NRG Oncology setting 
13.1.1.2        Phase III Component 
 
     Complete or partial pain response at 3 months after study entry, as measured by the NRPS 
13.1.2      Secondary Endpoints (Phase III Component) 
13.1.2.1     Rapidity of pain response, defined as time from study entry to complete or partial pain relief; 
13.1.2.2 
Duration of pain response, defined as time from complete or partial pain relief to pain 
worsening ( ≥ 3 points);  
13.1.2.3    
Adverse events based on the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0;  
13.1.2.4 
Long-term effects (24 months) of on vertebral bone (compression fracture) and spinal cord; 
13.1.2.5 
Overall quality of life, as measured by Functional Assessment of Cancer Therapy (FACT-G); 
pain, as measured by the Brief Pain Inventory (BPI); and health utilities, as measured by the 
EuroQol (EQ-5D); 
13.1.2.6 
Collection of serum, plasma, buffy coat cells, and urine for future translational research.  
 
13.2 
Sample Size (6/27/14)  

 
RTOG 0631, version date 09/23/16 
35
13.2.1 
Phase II Component Sample Size Derivation 
 
The sample size calculations for the phase II component will address the specific primary 
hypothesis that multiple NRG/RTOG institutions can successfully treat spine metastases with 
image-guided radiosurgery/SBRT. Thus, accrual from the Principal Investigator’s institution, 
Henry Ford Hospital, will be limited to 5 patients. Treatment compliance will be deemed as 
acceptable, marginally acceptable with minor deviation, or unacceptable with major deviation 
as detailed in Section 6.0. Successful treatment will include acceptable or marginally 
acceptable treatment reviews. Based on the results of NRG Oncology RTOG 0236, in which 
85% of patients were successfully treated with SBRT for lung cancer, we expect a similar 
success rate for SBRT in the spine metastases population. A success rate below 70% is 
unacceptable for continuation to the phase III component. Based on the one-sided exact 
binomial test with alpha 0.10, 41 patients would be required to detect an 18% relative reduction 
in the success rate (from 85% to 70%) with a statistical power of 0.85. Adjusting by 
approximately 5% to allow for patients that are found retrospectively ineligible, the total 
sample size required for the phase II component is 43 patients.  
13.2.2 
Phase III Component Sample Size Derivation 
 
The phase III component will be pursued after establishing treatment feasibility in the phase II 
component. The sample size calculations for the phase III component will address the specific 
primary hypothesis that the use of image guided radiosurgery/SBRT (Arm 1) will result in a 
statistically significant improvement in pain relief at 3 months as compared to the use of 
external beam radiation (Arm 2), based on the Numerical Rating Pain Scale (NRPS). 
 
 
The proportion of patients experiencing pain relief at 3 months after randomization will be of 
interest. We expect that patients treated with external beam radiation (Arm 2) will have 
response rates similar to those evidenced in NRG Oncology RTOG 97-14 (Section 13.2.2.1). In 
the subgroup of patients treated for spine metastases in NRG Oncology RTOG 97-14, 51% of 
patients experienced partial or complete pain relief at 3 months post-treatment. We hypothesize 
that image-guided radiosurgery/SBRT (Arm 1) will result in a statistically significant 
improvement in the proportion of patients experiencing pain relief 3 months after randomization: 
 
 
H0:  p1 = p2 vs.   HA:  p1 > p2    
 
where pi is the proportion of patients experiencing pain relief in arm i.   
 
 
Based on the one-sided exact binomial test with alpha 0.025 and a 2:1 randomization scheme, 
228 patients would be required to detect a 40% improvement in the response rate (from 51% to 
70%) due to image-guided radiosurgery/SBRT (Arm 1) with a statistical power of 0.80. 
Assuming a 5% ineligibility rate, a death rate of 15%, and a patient non-compliance rate of 
15%, the total sample size required for the phase III component would be 352 patients. 
13.2.2.1 
Stratification and Randomization 
 
Patients will be stratified in the phase III component according to the number of spine 
metastases treated (1 vs. 2) and the tumor type (radioresistant [soft tissue sarcoma, 
melanoma, and renal cell carcinoma] versus other types). The treatment allocation scheme 
described by Zelen (1974) will be used because it balances patient factors other than 
institution. Within each stratum, patients will be randomized in a 2:1 ratio to either image-
guided radiosurgery/SBRT or external beam radiation. The 2:1 randomization allocation will 
be used to accommodate increased demand for image-guided radiosurgery/SBRT.        
 
13.3 
Patient Accrual  
 
Most of the more than 570,000 people in the U.S. who die of cancer each year have tumor 
metastases (Jemal 1979). Bone is the third most common site of metastasis. The spine is 
certainly a common site. (Black 1979) There is an increasing trend of more frequently diagnosing 
patients with localized spine metastases because of longer survival by effective combined 
modality treatment, although the incidence of solitary spine metastasis is not known. There is an 
emerging role for image-guided radiosurgery in the treatment of localized spinal metastasis. 
There are no competing cooperative trials at this time. 
 
 
RTOG 97-14 accrued an average of 17.1 bone metastases patients per month. Limited to 
patients with spine metastases, average accrual was 5.6 patients per month. Accrual to RTOG 
0631 is expected to be comparable to accrual for RTOG 9714 spine metastases patients. We 

 
RTOG 0631, version date 09/23/16 
36
project that the accrual of RTOG 0631 during the first 6 months will be negligible, in part due to 
the process of IRB approval and the credentialing process which will be performed in cooperation 
with IROC Houston. Since the credentialing process will include actual irradiation of a spine 
phantom, this may delay the time to accrue the first patient. After this initial 6 month period, it is 
projected that this study will accrue 5 patients per month and that it will take 15 months to accrue 
the sample size of 43 patients for the phase II component. If the average monthly accrual for the 
last 6 months of the phase II component is less than 3, the phase III component will not be 
undertaken.  
 
 
If the phase III component is pursued, patient accrual would be expected to increase to at least 6 
patients per month. It will take approximately 5.5 years (65 months) to accrue the projected 
sample size of 352 patients. The NRG Oncology Data Monitoring Committee (DMC) will begin 
evaluating patient accrual semi-annually during the phase III component. If the average monthly 
accrual rate for the trial in the fifth and sixth quarters after study activation (i.e., in months 13-18) 
is less than 20% of the rate projected in the paragraph above (i.e., less than 1 patient per month), 
the study will close to further accrual. If the average monthly accrual rate is greater than 20% but 
less than 50% of projected (i.e., between 1-3 patients per month), the trial will be placed on 
probation for 6 months. If the average monthly accrual rate at the end of the probationary period 
is less than 50% of projected (3 patients per month), the study will close to future accrual.   
 
13.4 
Analysis Plan (09/23/16) 
13.4.1 
Phase II Analysis of Treatment Delivery 
Ineligible patients and patients without treatment data will not be evaluated. Successful 
treatment delivery is defined as acceptable or minor variation as detailed in section 6.0. Toxicity 
burden will be evaluated to identify patients not completing treatment due to excessive toxicity.  
 
Image-guided radiosurgery/SBRT will be deemed feasible in a cooperative group setting if 32 
out of the 41 evaluable patients successfully complete treatment (Section 13.2.2). Given that 
feasibility has been established, the results will be provided to NCI for approval to proceed with 
the phase III component. 
13.4.2 
Phase III Evaluation of Treatment Response 
 
Patients will be treated at an index spine lesion and up to 2 additional spine lesions. The index 
site is the lesion with the highest baseline (day of radiosurgery) pain score. If multiple sites 
have the same baseline pain score, the index site is the most cephalad lesion. 
 
 
Scoring system for pain is a numerical 11-point scale (0-10). Patients are instructed that 0 
indicates no pain and that 10 indicates the worst pain imaginable. In general, scores of 1-4 
indicate mild pain, scores of 5-6 indicate moderate pain, and scores of 7-10 indicate severe 
pain. However, the clinical interpretation of the intermediate values will differ amongst the 
patients. Since patients have different perceptions and tolerances of pain, change in pain is 
most often the outcome of interest.  
 
 
Pain response will be categorized as following: 1) complete response, post-treatment pain 
score of 0 at the index site; 2) partial response, post-treatment improvement of at least 3 points 
at the index site; 3) stable response, post-treatment pain score within 3 points of the initial pain 
score at the index site, or 4) progressive response, a post-treatment increase of at least 3 
points at the index site. A complete, partial, or stable response at the index site requires no 
increase in narcotic pain medication and no increase in pain score at the secondary treated 
site(s). Although complete response is the best possible outcome, partial response is also a 
satisfactory outcome. Therefore, patients with complete or partial response will be considered 
responders. Any patient with a complete or partial response at the index site but a progressive 
response at the secondary sites will be considered a non-responder.   
13.4.3 
Phase III Analysis of Treatment Response 
 
The primary endpoint is complete or partial pain response at 3 months after randomization. As 
noted above, partial pain relief is defined as an improvement of at least 3 points on the rating 
scale (and no increase in the pain score at any other treated lesion[s], with no increase in 
narcotic pain medication). Complete pain relief is defined as a score of 0 on the rating scale, 
with no increase in narcotic pain medication.   
 

 
RTOG 0631, version date 09/23/16 
37
 
All eligible, randomized patients will be included in the analysis regardless of treatment 
compliance (intent-to-treat analysis). Although missing assessments should be minimized due 
to current improved data collection methods, up to 10% of patients are still expected not to be 
assessed. These patients will be included in the analysis and will be initially assumed to have 
the similar response rate as the assessed patients with the same baseline pain scores.  
 
 
We hypothesize that the use of radiosurgery will increase the percentage of patients 
experiencing a complete or partial response at 3 months from the 51% response rate achieved 
from conventional radiotherapy to 70% with image-guided radiosurgery/SBRT, a relative 
increase of 40%.  
 
 
H0:  p1 = p2  vs.   HA:  p1 > p2    
    
 
where pi is the proportion of complete or partial responders in arm i.  
 
The one-sided exact binomial test with a significance level of 0.025 will be used to test for 
differences in the response rate. Sensitivity analyses of this result using other ways of imputing 
pain responses for the non-assessed patients (such as all classified as nonresponders or 
responders) will be performed. Subset analyses based on the number of treated sites also will 
be performed. Descriptive statistics of the actual change scores will also be provided. The 
mean change score and standard deviations will be reported.  
13.4.3.1 
Secondary Endpoints   
13.4.3.1.1 
Rapidity of Pain Response   
Patients will be assessed weekly during the first month after randomization and also at 3, 
6, 12, and 24 months. The median time to pain response, as defined above, will be 
estimated using the Kaplan-Meier approach. (Kaplan 1958). The null and alternative 
hypotheses are: 
 
 
 
 
H0:  S1(t)  =S2 (t)      vs.         HA:  S1 (t) > S2 (t)  
where Si (t) is the distribution of response times for patients in arm i 
 
The stratified log-rank test will be used to test for a statistically significant difference in 
rapidity distributions with alpha=0.025 (Mantel 1966). In addition, the Cox proportional 
hazards regression model will be used to determine hazard ratios and 95% confidence 
intervals for the treatment difference (1972). Unadjusted ratios and ratios adjusted for 
stratification variables and other covariates of interest will be computed. 
13.4.3.1.2 
Duration of Pain Response   
Patients will be assessed weekly during the first month after randomization and also at 3, 
6, 12, and 24 months. Pain response begins when a patient improves at least 3 points, 
and pain response ends when the pain score increases by 3 points or when narcotic pain 
medication increases. Patients dying without a reported pain relapse will be censored at 
the day of death. The median duration pain response will be estimated using the Kaplan-
Meier approach (Kaplan 1958). The null and alternative hypotheses are: 
 
 
 
 
H0:  S1(t)  = S2 (t)      vs.         HA:  S1 (t) > S2 (t)  
where Si (t) is the distribution of response duration times for patients in arm i 
 
The stratified log-rank test will be used to test for a statistically significant difference in 
duration distributions with alpha=0.025 (Mantel 1966). In addition, the Cox proportional 
hazards regression model will be used to determine hazard ratios and 95% confidence 
intervals for the treatment difference (1972). Unadjusted ratios and ratios adjusted for 
stratification variables and other covariates of interest will be computed. 
13.4.3.1.3 
Incidence of Adverse Events 
 
Adverse events are reported according to the CTCAE Version 3.0. Differences in 
incidence rates at 3 months from the completion of treatment between the two treatment 
arms will be tested using the two-sided chi-square test at the 0.05 significance level. 
Univariate logistic regression will be used to model the distribution of acute adverse 
events.  Multivariate logistic regression will be used to model the distribution of acute 
adverse events, adjusting for covariates, including, but not limited to treatment arm, prior 
use of pilocarpine, time since completion of chemotherapy and/or radiation, and age. Both 

 
RTOG 0631, version date 09/23/16 
38
unadjusted and adjusted odds ratios and their respective 95% confidence interval will be 
computed (Hosmer 2000).  
13.4.3.1.4 
Treatment Differences in Quality of Life, Global Pain, and Health Utilities 
 
Participation in the quality of life component is not mandatory in this study. However, if 
patients agree to participate in this component, adherence to the component assessment 
schedule will be encouraged through reminders from participating institutions. Completion 
of all scheduled assessment is part of the routine delinquency assessment for participating 
institutions. In spite of these efforts, missing data is to a certain extent expected. 
 
 
Patients missing assessments due to death will be analyzed separately. If these patients 
are not equally distributed between the two treatment arms, we will conduct a sensitivity 
analysis to determine the impact of the exclusion. Imputation methods will be used to 
determine values for all alive patients missing assessments. Multiple imputation 
procedures provide a valid strategy for dealing with missing data sets, properly reflecting 
the uncertainty due to missing values.  The possible strategies for imputation and analyses 
will depend on the severity of the missing data problem and missing pattern (MNAR, MAR, 
MCAR) [Little 2002]. 
 
Patient scores on the FACT subscale range from 0 to 108 with higher scores indicating 
improved quality of life. The change scores from pretreatment to 3 months will be 
compared between the treatment arms. A mean difference of 7 points represents a 
clinically meaningful change (CMC). A difference of less than 7 points between the 
treatment arms will not be considered meaningful, even if it has statistical significance. If 
the baseline scores are not distributed similarly between the treatment arms, the percent 
change scores will be used to adjust for these varying baseline values. A 7 point CMC 
corresponds to varying percentage changes, depending on the baseline values. The null 
and alternative hypotheses are: 
H0:  ∆μ1 = ∆μ2       vs.         HA:  ∆μ1 > ∆μ2   
 
 
where ∆μi is the mean FACT change score from  baseline to 3 months for patients in arm i. 
 
Assuming that the data are normally distributed, the two sample t-test assuming equal 
variances will be used to test the hypothesis at the 0.025 significance level. If normality 
assumptions are not met, the Wilcoxon rank sum test will be used to test the hypothesis. 
 
In addition to change in QOL at 3 months after treatment, the overall trends in pain [Brief 
Pain Inventory (BPI)], QOL (FACT-G), and health utilities [EuroQol (EQ-5D)] will be 
described with longitudinal data analysis. All indicators will be assessed pretreatment and 
at 3, 12, and 24 months post-treatment. Specifically, the general linear mixed-effect model 
will be used to describe the change trend of these scores over time, allowing for 
adjustments using covariates of interest (Verbeke 2000). 
13.4.3.1.5 
Treatment Response and Quality of Life 
In addition to evaluating treatment differences in QOL, of particular interest is the 
relationship between treatment response and QOL. In RTOG 9714, sixty-six percent 
(167/253) of spine metastases patients completed both the baseline and the three-month 
FACT-G while 34% did not. The distributions of pretreatment variables for the patients with 
and without both FACT-G assessments were similar. Patients with pain relief showed 
significantly more improvement in the FACT-G total score, most of which was due to 
improvements seen in both the functional well-being (FWB) and the physical well-being 
(PWB) subscales. The difference in mean change scores between responders and 
nonresponders was 9.8 [95% CI (2.3, 17.3), p=0.01] for the FACT-G total score. 
Therefore, the change scores from pretreatment to 3 months post-treatment between 
patients who respond to treatment and patients who do not respond to treatment will be 
compared in RTOG 0631. The null and alternative hypotheses are: 
H0:  ∆μ1 = ∆μ2       vs.         HA:  ∆μ1 > ∆μ2   
 
 
where ∆μi is the mean FACT change score from  baseline to 3 months for patients in response group i. 
 
Assuming that the data are normally distributed, the two sample t-test assuming equal 
variances will be used to test the hypothesis at the 0.025 significance level. If normality 
assumptions are not met, the Wilcoxon rank sum test will be used to test the hypothesis. 

 
RTOG 0631, version date 09/23/16 
39
 
13.5 
Interim Reports to Monitor the Study Progress  
 
Interim reports with descriptive statistics will be prepared twice a year until the initial paper 
reporting the treatment results has been accepted for publication. In general, the interim reports 
will contain information about the patient accrual rate with a projected completion date for the 
accrual phase; data quality; compliance rate of treatment delivery with the distributions of 
important prognostic baseline variables; and the frequencies and severity of adverse events. The 
interim reports will not contain treatment efficacy results with respect to the primary or the 
secondary endpoints.  
 
The NRG Oncology Data Safety and Monitoring Board (DSMB) will monitor the phase II 
component of the study for safety and feasibility. The NRG Oncology Data Monitoring Committee 
(DMC) will monitor the phase III component of the study for safety and efficacy.  
 
 
This study also will be monitored by the Clinical Data Update System (CDUS), v. 3.0. Quarterly 
CDUS reports are submitted electronically.  
 
13.6 
Reporting the Initial Treatment Results   
 
The primary hypothesis of this study is to determine the efficacy of image-guided 
radiosurgery/SBRT in treating painful spine metastases.  This initial efficacy analysis will occur 
after each patient has been potentially followed for at least 3 months following completion of 
treatment. The long-term efficacy analysis will occur after each patient has been potentially 
followed for at least 24 months. The analyses will include tabulation of all cases entered and 
those excluded from the analyses with the reasons for such given; the distribution of the 
important prognostic baseline variables; and observed results with respect to the primary and the 
secondary endpoints. The primary hypothesis of radiosurgery benefit will be tested using the 
exact binomial test as specified in the analysis plan (Section 13.4.2). Also, where feasible, 
comparisons with respect to all endpoints will be made by each gender, racial, and ethnic 
category. 
 
13.7 
Gender and Minorities (4/21/14) 
In conformance with the national Institutes of Health (NIH) Revitalization Act of 1993 with regard 
to inclusion of women and minorities in clinical research, participation rates of women and 
minorities will be examined during the interim reports. Based on accrual statistics from RTOG 
9714, the projected accrual by gender, race, and ethnicity for both phases is shown below: 
 
 
Projected Distribution of Gender and Minorities 
 
 
Gender 
Males Females 
Total 
Ethnic Category 
 
 
 
Hispanic or Latino 
5 
7 
12 
Not Hispanic or Latino 
173 
210 
383 
Ethnic Category: Total of all subjects 
178 
217 
395 
Racial Category 
 
Native American or Alaskan Native 
3 
3 
6 
Asian 
3 
3 
6 
Black or African American 
29 
35 
64 
Native Hawaiian or other Pacific Islander 
4 
6 
10 
White 
139 
179 
318 
Racial Category: Total of all subjects 
178 
217 
395 
 

 
RTOG 0631, version date 09/23/16 
40
REFERENCES 
 
Badia, X., Herdman, M., Kind, P.  The influence of ill-health experience on the valuation of health.  
Pharmacoeconomics. 13: 687-696, 1998. 
 
Bissonnette J. Quality assurance of image-guidance technologies." Sem Radiat Oncol. 17: 278-286, 2007. 
 
Black P: Spinal metastases: Current status and recommended guidelines for management. Neurosurg. 5: 
726-746, 1979.  
 
Bone Pain Trial Working Party. 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: 
randomized comparison with a multifraction schedule over 12 months of patient follow-up. On behalf of the 
Bone Pain Trial Working Party. Radiother Oncol. 1999;52:111-121; 1999. 
 
Cella DF, Tulsky DS, Gray G, Sarafian B, et al.  The Functional Assessment of Cancer Therapy scale:  
Development and validation of the general measure. J Clin Oncol. 11: 570-579, 1993. 
 
Chang EL, Shiu AS, Mendel E, et al. Phase I/II study of stereotactic body radiotherapy for spinal metastasis 
and its pattern of failure J Neurosurg Spine. 7:151-160, 2007. 
 
Cleeland CS.  Measurement of pain by subjective report.  In:  Chapman CR; Loeser JD, editors.  Issues in 
pain measurement.  New York:  Raven Press; 1989: 391-403. 
 
Daut RL, Cleeland SS, Flannery RC.  Development of the Wisconsin Brief Pain Questionnaire to assess pain 
in cancer and other diseases.  Pain. 14: 197-210, 1983. 
 
Degen JW,  Gagnon GJ, Voyadzis JM, et al. CyberKnife stereotactic radiosurgical treatment of spinal tumors 
for pain control and quality of life. J Neurosurg Spine. 2: 540-5499, 2005. 
 
Gerszten PC, Burton SA, Welch WC, Brufsky AM, Lembersky BC, Ozhasoglu C, Vogel WJ. Single-fraction 
radiosurgery for the treatment of spinal breast metastases. Cancer. 104: 2244–2254, 2005. 
 
(b) Gerszten PC, Burton SA, Ozhasoglu C, Vogel WJ, Welch WC, Baar J, Friedland DM.  Stereotactic 
radiosurgery for spine metastases from renal cell carcinoma. J Neurosurg Spine. 3(4): 288-295, 2005. 
 
(c) Gerszten PC, Burton SA, Quinn AE, Agarwala SS, Kirkwood JM. Radiosurgery for the treatment of spinal 
melanoma metastases. Stereotact Funct Neurosurg. 83: 213-221, 2005. 
 
Gerszten PC, Burton SA, Belani CP, et al. Radiosurgery for the treatment of spinal lung metastases. 
Cancer.107:2653–2661, 2006. 
 
Greenberg HS, Kim JH, Posner JB. Epidural spinal cord compression from metastatic tumor: Results with a 
new treatment protocol. Ann Neurol. 8: 361-366, 1980. 
 
Hartsell WF, Scott CB, Bruner DW, et al. Randomized trial of short- versus long-course radiotherapy for 
palliation of painful bone metastasis. JNCI. 97: 798-804, 2005. 
 
Helweg-Larsen S. Clinical outcome in metastatic spinal cord compression: A prospective study of 153 
patients. Acta Neurol Scand. 94:269-275, 1996. 
 
Ho AK, Fu D, Cotrutz C, et al. A study of the accuracy of cyberknife spinal radiosurgery using skeletal 
structure tracking. Neurosurg. 60(Suppl 1):147-156, 2007. 
 
Hosmer DW, Lemeshow S. Applied Logistic Regression. New York: John Wiley & Sons; 2000. 
 
Jemal A, Murray T, Ward E, et al. Cancer statistics, AC Cancer J Clin. 55: 10-30, 2005. 
 
Jensen MP, Turner JA, Romano JM, Fisher LD. Comparative reliability and validity of chronic pain intensity 
measures. Pain. 83: 157-62, 1999. 

 
RTOG 0631, version date 09/23/16 
41
 
Jin R, Rock J, Jin JY, el al. Image-guided spinal radiosurgery for epidural compression of multiple myeloma. 
Intl J Rad Oncol Biol Phys. 66:S244, 2006. 
 
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Statist Assoc. 53: 457-
481, 1958. 
 
 
Little RJ, Rubin DB. Statistical Analysis with Missing Data. 2nd ed. New York: John Wiley; 2002. 
 
Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer 
Chemother. Rep 50: 163-170, 1966. 
 
Maranzano E, Latini P. Effectiveness of radiation therapy without surgery in metastatic spinal cord 
compression: Final results from a prospective trial. Int J Radiat Biol Phys. 15: 959, 1995. 
 
Nguyen QN, Shiu AS, Rhines LD, Wang H, Allen PK, Wang XS, Chang EL. Management of spinal 
metastases from renal cell carcinoma using stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys. 
15:1185-92, 2010. 
 
Patchell R, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, Young B. Direct decompressive surgical 
resection in the treatment of spinal cord compression caused by metastatic cancer: A randomized trial. 
Lancet. 366: 643-648, 2005. 
 
Potters L, Steinberg M, Rose C, et al. American Society for Therapeutic Radiology and Oncology and 
American College of Radiology practice guideline for the performance of stereotactic body radiation therapy. 
Intl J Rad Oncol Biol Phys. 60:1026-1032, 2004. 
 
Rabin, R., de Charro, F.  EQ-5D: A measure of health status from the EuroQol Group.  Ann Med. 33: 337-
343, 2001. 
 
Ryu S, Yin FF, Rock J, et al. Image-guided and intensity-modulated radiosurgery for spinal metastasis. 
Cancer.  97: 2013-2018, 2003. 
 
Ryu S, Rock J, Rosenblum M, Kim JH. Pattern of failure after single dose radiosurgery for single spinal 
metastasis. J Neurosurg. 101: 402-405, 2004. 
 
Ryu S, Jin JJ, Jin RY, Rock J, Ajlouni M, Movsas B, Kim JH. Partial Volume Tolerance of Spinal Cord and 
Complication of Single Dose Radiosurgery. Cancer. 109:628-636, 2007.  
 
Ryu S, Jin R, Jin JJ, Qing C, Rock J, Anderson J, Movsas B. Pain Control by Image-guided Radiosurgery for 
Solitary Spinal Metastasis. J Pain Sympt Manage. 35: 292-298, 2008. 
 
(b) Ryu S, Gerszten PC. Treatment failure and complications. In Gerstzen PC, Ryu S. eds. Spine 
Radiosurgery.  New York, NY: Thieme; 2008: 104-111.  
 
(c) Ryu S, Rock J, Jain R, et al. Radiosurgical Decompression of Epidural Spine Metastasis. 2008. (In 
review). 
 
Schulz, M., Chen, J., Woo, H., et al.  A comparison of techniques for eliciting patient preferences in patients 
with benign prostatic hyperplasia.  J Urol. 168: 155-159, 2002. 
 
Steenland ES, Leer J, van Houwelingen H, et al. The effect of a single fraction to multiple fractions on painful 
bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiother Oncol. 52:101-109, 1999. 
 
Timmerman R. Overview of hypofractionation. Sem Rad Oncol. 2008. (In print) 
 
Tong D, Gillick L, Hendrickson FR. The palliation of symptomatic osseous metastasis: Final results of the 
study by Radiation Therapy Oncology Group. Cancer. 50:893-899, 1982. 

 
RTOG 0631, version date 09/23/16 
42
 
Verbeke G, Molenberghs G. Linear Mixed Models for Longitudinal Data. New York: Springer-Verlag, Inc; 
2000. 
 
Wu JS, Wong JR, Johnson M, Bezjak A, Whelan T. Cancer Care Ontario Practice Guidelines Initiative 
Supportive Care Group. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful 
bone metastases. Int J Radiat Oncol Biol Phys. 55: 594-605, 2003. 
 
Yamada Y, Bilsky MH, Lovelock M, et al. High-dose, single-fraction image-guided intensity-modulated 
radiotherapy for metastatic spine al lesions.  Int J Radiat Oncol Biol Phys. 71:484-490, 2008. 
 
Yin FF, Ryu S, Ajlouni M, et al. A technique of intensity–modulated radiosurgery (IMRS) for spinal tumors. 
Med Phys. 12: 2815-2822, 2002. 
 
(b) Yin FF, Zhu JG, Yan H, Guan H, Hammond R, Ryu S, Kim JH. Dosimetric characteristics of Novalis 
shaped beam surgery unit. Med Phys. 29: 1729-1738, 2002. 
 
Yin FF,  Wang Z, Yoo S, et al. Integration of cone-beam CT in stereotactic body radiation therapy. Tech in 
Cancer Res & Treatment (TCRT). 7(2):133-140, 2008. 
 
Yoo S Kim GY, et al. A quality assurance program for the on-board imagers. Med Phys. 33(11): 4431-47, 
2006. 
 
Young RF, Post EM, King GA. Treatment of spinal epidural metastasis: Randomized prospective comparison 
of laminectomy and radiotherapy. J Neurosurg. 53: 741, 1980. 
 
Zelen M. The randomization and stratification of patients to clinical trials. J Chron Dis. 27: 365-375, 1974. 
 

 
RTOG 0631, version date 09/23/16 
43
 
APPENDIX I (09/23/16) 
 
STUDY PARAMETER TABLE:  
 
PHASE II COMPONENT (8/30/11) 
Assessments 
Pre-Treatment 
Day of Treatment 
Follow-up: At 1 and 3 months 
from registration 
History/physical 
Within 2 wks prior to 
registration 
 
X 
Performance status 
Baseline 
 
X 
Neurological exam 
Within 1 wk prior to 
registration 
 
X 
MRI of the spine 
Within 4 wks prior to 
registration 
 
 At 3 months from registration 
only 
Numerical Pain Scale and 
documentation of patient’s 
pain medication  
Within 1 wk prior to 
registration  
 
 
Adverse event evaluation 
 
 
X 
 
 
See Phase III Component on next page 
 
 

 
RTOG 0631, version date 09/23/16 
44
APPENDIX I (Continued) (09/23/16) 
 
STUDY PARAMETER TABLE: Also see Section 11.2 for details  
 
PHASE III COMPONENT 
Assessments  
Pre-Treatment 
1 month from 
randomization 
Follow-up: At 3, 6, 12, 24 months from 
randomization 
History/physical 
Within 2 wks 
prior to 
registration 
 
X 
Performance status 
Baseline 
 
X 
Neurological exam 
Within 1 wk 
prior to 
registration 
 
X 
MRI of the spine 
Within 4 wks 
prior to 
registration 
 
X 
Numerical Pain Scale and 
documentation of patient’s pain 
medication* 
Within 1 wk 
prior to 
registration  
(On the day of 
treatment) 
 
(At home: At 1, 2, 
and 3 weeks; bring 
to clinic at 1 month) 
 
 In clinic at 1 
month 
X 
 
FACT-G (FA), BPI (QL), EQ-5D (HP) 
Baseline 
 
At 3, 6, 12 and 24 months from 
randomization 
Adverse event evaluation 
 
X 
X 
Blood & urine for banking and 
translational research  
Recommended 
 
Recommended at 3 months from 
randomization 
*NRPS at 3 months is required for analysis of the primary endpoint

 
RTOG 0631, version date 09/23/16 
45
APPENDIX II (09/23/16) 
 
 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction  
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
work of a light or sedentary nature.  For example, light housework, office 
work  
 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours  
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more of 
waking hours  
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed or  
 
5 
Death  
 
 
 
 

 
RTOG 0631, version date 09/23/16 
46
APPENDIX III (09/23/16) 
 
RTOG 0631 Neurological Examination 
 
1. Tenderness over the spine (Mark the spine level of tenderness on percussion) 
 
      C1    C2    C3    C4    C5     C6     C7           T1     T2     T3     T4     T5     T6    T7     T8     T9    T10   T11  T12  
 
       L1    L2     L3     L4     L5 
      sacrum       
 
2. Radiculopathy  (If present, mark all levels)  
 
      C1    C2    C3    C4    C5     C6     C7    C8         T1     T2     T3     T4     T5     T6    T7     T8     T9    T10   T11  T12  
 
       L1    L2     L3     L4     L5 
         S1 
 
3. Muscle strength of the extremities: (Mark 0-5 strength for each) 
 
Arm Muscles 
 
Strength 
Leg muscles 
 
Strength 
Right 
Left 
Right 
Left 
Deltoid  
C5/6 
 
 
Iliopsoas 
L2/3/4 
 
 
Biceps  
C5/6 
 
 
Quadriceps 
L2/3/4 
 
 
Triceps 
C6/7/8 
 
 
Hamstrings 
L4/5/S
1 
 
 
Digit Flex (hand 
grip) 
C7/8/T
1 
 
 
Ant Tibialis 
L4/5 
 
 
Interossei 
C8/T1 
 
 
Gastrocnemius 
Soleus 
L5/S1/
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continued on next page 
Modified MRC grade of muscle strength 
5  Normal strength 
5- Equivocal, barely detectable weakness 
4+ Definite, but slight weakness 
4 Able to move against gravity with resistance 
3 Able to move against gravity without resistance 
2 Active movement without gravity 
1 Flicker or trace of movement. 
0 No palpable muscle contraction 

 
RTOG 0631, version date 09/23/16 
47
APPENDIX III (Continued) (09/23/19) 
 
RTOG 0631 Neurological Examination 
 
 
4. Sensory change; Pinprick (Mark normal or decreased) 
 
 
Arm 
Trunk 
Leg 
 
Right 
Left 
Right 
Left 
Right 
Left 
Normal 
 
 
 
 
 
 
Decreased 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. Urinary incontinence (in patients who had initial abnormality or developed new symptom) 
 
Yes_______ 
or  
No_______      
 
 
6. Anal sphincter tone (in patients who had initial abnormality or developed new symptom) 
 
Normal_______ Decreased_______ or None_______ 
 
 

 
RTOG 0631, version date 09/23/16 
48
APPENDIX IV (09/23/16) 
 
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS 
This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood (as 
specified by the protocol): 
 
Kit contents: Note: Sites are expected to supply their own blood draw tubes. 
 
Twenty-five (25) 1 ml cryovials for all timepoints 
 
Biohazard bags (5) and Absorbent shipping material (5) 
 
One (1) Styrofoam container (inner) and Cardboard shipping (outer) box per case 
 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
 
Specimen Transmittal Form (STF) and Kit Instructions 
 
PREPARATION AND PROCESSING OF SERUM, PLASMA AND WHOLE BLOOD: 
(A) Serum (if requested): Red Top Tube (one 10 ml or two 5 ml) 
 
Label five (5) 1ml cryovials as necessary for the serum collected. Label them with the NRG study and 
case number, collection date, time, and time point, and clearly mark cryovials “serum”. 
Process: 
1. Allow one red top tube to clot for 30 minutes at room temperature. 
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4C (preferred). If sites are 
unable to process samples at 4C then spinning at room temperature is acceptable if done within 2 
hours of draw but must be noted on the Specimen Transmittal (ST) Form. 
3. Aliquot a minimum of 0.5 ml serum into five (5) for the serum collected with NRG Oncology study and 
case numbers, collection date/time, protocol time-point collected (e.g. pretreatment, post-treatment), 
and clearly mark specimen as “serum”. 
4. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -90 C, and store 
frozen until ready to ship. See below for storage conditions. 
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the 
Specimen Transmittal (ST) Form. 
 
(B) Plasma (If requested): Purple Top EDTA tube #1 (one 10 ml or two 5 ml) 
 
Label five (5) 1ml cryovials as necessary for the plasma collected. Label them with the NRG 
Oncology study and case number, collection date, time, and time point, and clearly mark cryovials 
“plasma”. 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 RPM 
for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room 
temperature is acceptable if done within 2 hours of draw but must be noted on the Specimen 
Transmittal (ST) Form.  
3. If the interval between specimen collection and processing is anticipated to be more than one hour, 
keep specimen on ice until centrifuging is performed. 
4. Carefully pipette and aliquot a minimum of 0.5 ml plasma into five (5) cryovials for the plasma collected 
labeled with NRG Oncology study and case numbers, collection date/time, time point collected and 
clearly mark specimen as “plasma”.  Avoid pipetting up the buffy coat layer. 
5. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -90C. 
6. Store frozen plasma until ready to ship on dry ice.  
7. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the 
Specimen Transmittal (ST) Form. 
 
(continued on next page) 

 
RTOG 0631, version date 09/23/16 
49
APPENDIX IV (Continued) (09/23/16) 
 
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
(C) Whole Blood for DNA (if requested): Purple Top EDTA tube #2 (one 5 ml or one 10 ml)  
 
Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with the 
NRG Oncology study and case number, collection date/time, and time point, and clearly mark cryovials 
“blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be 
mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the blood 
collected (3 to 5) labeled with NRG Oncology study and case numbers, collection date/time, time 
point collected and clearly mark specimen as “blood”. 
3. Place cryovials into biohazard bag and freeze tubes upright immediately at -70 to -80 Celsius. 
4. Store blood samples frozen until ready to ship on dry ice.  
5. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on STF. 
 
Freezing and Storage: 
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
 
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,  
 
Samples can be stored short term in a -20C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 
 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (please 
ship out on Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; 
Canada: Monday-Tuesday only). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to prevent 
thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of Styrofoam 
box. 
 
Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods 
together) in absorbent shipping material and place each specimen type in a separate biohazard bag.  
Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).  
Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 
stickers to outer cardboard box. 
 (continued on next page) 

 
RTOG 0631, version date 09/23/16 
50
 
APPENDIX IV (Continued) (09/23/16) 
 
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that 
there is enough room for plenty of dry ice. Add padding to avoid the dry ice from breaking the tubes. 
 
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-mail 
NRGBB@ucsf.edu or call (415)476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank-San Francisco 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-7864 or e-mail: NRGBB@ucsf.edu  

 
RTOG 0631, version date 09/23/16 
51
APPENDIX V (09/23/16) 
NRG ONCOLOGY URINE COLLECTION KIT INSTRUCTIONS 
This Kit is for collection, processing, storage, and shipping of urine specimens. 
 
Kit Contents: For two timepoints 
 
Two (2) Sterile Urine collection cup 
 Four (4) 15 ml polypropylene centrifuge tubes 
 
Two (2) 7 ml disposable pipettes 
 Biohazard bags 
 
Absorbent paper towel 
 Parafilm for sealing outside of tubes 
 
Preparation and Processing of Urine Specimens: 
Process: 
 
A clean catch urine specimen will be collected. To collect the specimen, use the following instructions: 
o 
Males should wipe clean the head of the penis and females need to wipe between the labia with soapy 
water/cleansing wipes to remove any contaminants.  
o 
After urinating a small amount into the toilet bowl to clear the urethra of contaminants, collect a sample of 
urine in the collection cup. 
o 
After 10-25 mL urine has been collected, remove the container from the urine stream without stopping the 
flow of urine. 
o 
Finish voiding the bladder into the toilet bowl. 
 
Aliquot 5-10 mls of Urine into each of two 15 ml polypropylene centrifuge tubes (disposable pipets are provided 
in the kit). Do not fill with more than 10 mls to avoid cracking of tubes due to expansion during freezing. Replace 
the cap and tighten on the tubes. Make sure the cap is not cross-threaded or placed on incorrectly or leaking will 
occur.  
 
Use parafilm to seal the cap around the outside rim of the urine tube to prevent leakage.  
 
Discard remaining Urine and collection cup. 
 
Label the specimen with the NRG Oncology study and case number, collection date and time, time point of 
collection, and clearly mark specimens as “urine”. 
 
Wrap Urine Tubes with absorbent material (paper towels) and place into biohazard bag and seal the bag. Freeze 
and store Urine samples in a -20C or -80C freezer until ready to ship. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED with NRG Oncology study and case 
numbers, collection date/time, and time point collected (e.g. pretreatment, post-treatment). 
 
Storage and Shipping: 
Freezing and Storage: 
 
Urine specimens may be sent in batches or with other frozen biospecimens, if within 30-60 days of collection. Store at 
-20C or -80C (-70C to -90C) until ready to ship. If a -80C Freezer is not available:  
 
Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to one week (please 
ship out Monday-Wednesday only; Canada: Monday-Tuesday only). 
 
OR: 
 
Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please ship out Monday-
Wednesday only; Canada: Monday-Tuesday only). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to prevent thawing 
due to delivery delays.  Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam box. 
 
Place sealed specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum). Add 
padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 stickers to 
outer cardboard box. 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that there is 
enough room for plenty of dry ice. Add padding to avoid the dry ice from breaking the tubes. 
 
Samples received thawed will be discarded, and a notification will be sent immediately to the Principal Investigator 
and Clinical Research Assistant of the submitting institution. The institution should send a subsequent sample, 
collected as close as possible to the original planned collection date. 
 
For questions regarding ordering, collection, or shipping of a Urine Collection Kit, please e-mail 
NRGBB@ucsf.edu or call (415)476-7864 or fax (415) 476-5271. 
Shipping Address: FedEx/UPS/Courier address (For all frozen samples) 
NRG Oncology Biospecimen Bank-San Francisco at University of California San Francisco 
2340 Sutter Street, Room S341, San Francisco, CA  94115 
Contact Phone: (415) 476-7864