Phase III Multicenter Randomized Study Comparing Local Tumor Control After Post-Operative Single-Fraction or Hypofractionated Stereotactic Radiosurgery in the Treatment of Spinal Metastases
Phase: PHASE3
Conditions: Spinal Metastases
Sponsor: Memorial Sloan Kettering Cancer Center

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Phase III Multicenter Randomized Study Comparing Local Tumor Control 
After Post-Operative Single-Fraction or Hypofractionated Stereotactic 
Radiosurgery in the Treatment of Spinal Metastases 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Ilya Laufer M.D. 
Neurosurgery 
Co-Principal 
Investigator(s)/Department: 
Yoshiya Yamada M.D. 
Mark Bilsky M.D. 
Eric Lis M.D. 
Radiation Oncology 
Neurosurgery 
Radiology 
Investigator(s)/Department: 
Patrick Boland M.D. 
Zhigang Zhang Ph.D 
George Krol M.D. 
Sasan Karimi M.D. 
Sean McBride M.D. 
Adam Schmitt M.D. 
Daniel Higginson M.D. 
Orthopedic Surgery 
Biostatistics 
Radiology 
Radiology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Consenting Professional(s)/Department: Yoshiya Yamada M.D. 
Ilya Laufer M.D. 
Mark Bilsky M.D. 
Patrick Boland M.D. 
Adam Schmitt M.D. 
Daniel Higginson M.D. 
Radiation Oncology 
Neurosurgery 
Neurosurgery 
Orthopedic Surgery 
Radiation Oncology 
Radiation Oncology 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Participating Institutions – If multicenter 
study coordinated by MSKCC: 
PI's Name 
Site's Role 
Massachusetts General Hospital 
John H. Shin M.D. 
Data Collection 
Johns Hopkins University 
Daniel M. Sciubba M.D. 
Data Collection 
Stanford University 
Scott Soltys M.D. 
Data Collection 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
 
 
 
 
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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 2 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 4 
 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 4 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION............................................................ 8 
 
4.1 
Design............................................................................................................................. 8 
 
4.2 
Intervention ..................................................................................................................... 9 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 9 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ........................................................................... 9 
 
6.1 
Subject Inclusion Criteria................................................................................................. 9 
 
6.2 
Subject Exclusion Criteria ............................................................................................. 10 
 
7.0 
RECRUITMENT PLAN ..................................................................................................... 10 
 
8.0 
PRETREATMENT EVALUATION .................................................................................... 10 
 
9.0 
TREATMENT/INTERVENTION PLAN.............................................................................. 11 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................. 11 
 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 13 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................... 15 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 15 
 
14.0 BIOSTATISTICS .............................................................................................................. 16 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES17 
 
15.1 Research Participant Registration ................................................................................. 17 
 
15.2 Randomization .............................................................................................................. 18 
 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 19 
 
16.1 Quality Assurance ......................................................................................................... 22 
 
16.2 Data and Safety Monitoring ........................................................................................... 23 
 
17.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 25 
 
17.1 Privacy .......................................................................................................................... 26 
 
17.2 Serious Adverse Event (SAE) Reporting ....................................................................... 26 
 
17.2.1 ................................................................................................................................... 27 
 
18.0 INFORMED CONSENT PROCEDURES .......................................................................... 28 
 
19.0 REFERENCES ................................................................................................................. 30 
 
20.0 APPENDICES .................................................................................................................. 33 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 

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Metastatic disease of the spine affects nearly 20% of patients with cancer and poses a 
growing problem as improved neo-adjuvant strategies allow longer life expectancy. 
 
This is a Phase III multicenter clinical trial designed to prospectively evaluate the 
comparative effectiveness of single-fraction and hypofractionated stereotactic radiosurgery 
(SRS) in patients who underwent decompressive surgery for spinal metastases with a 
primary endpoint of local tumor control. Secondary objectives will evaluate complications and 
quality of life measures. Collaborating institutions include Massachusetts General Hospital 
(MGH), Johns Hopkins University (JHU), and Stanford University. 
 
Eligible patients will have undergone spinal decompressive surgery for the treatment of high 
grade metastatic epidural spinal cord compression and demonstrate post-operative 
separation between tumor and the spinal cord on CT myelogram or MRI perfusion. This is a 
non-inferiority study in which patients will be randomized in a 1:1 ratio to undergo either 
single-fraction SRS (24 Gy) or high-dose hypofractionated SRS (27 Gy in 3 fractions) within 
8 weeks of surgery. The treatment duration will be 1 to 7 days. 
 
Study enrollment of 150 patients will be completed within two years.  After randomization, 
patients will be followed up at 3, 6, 9, 12, 18, and 24 months (± 8 weeks) when possible or 
until death. The study duration will be up to four years. The primary endpoint will be local 
tumor control after SRS as monitored through imaging at follow up. 
 
 

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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective: 
 
• 
The primary objective of this study is to evaluate the comparative effectiveness of 
single-fraction and high-dose hypofractionated SRS in achieving local tumor control 
for patients who underwent spinal decompressive surgery as treatment for metastatic 
epidural spinal cord compression tumors. 
 
Secondary Objectives: 
 
• 
To compare the risks and complication profiles of radiation-related toxicity between 
the two cohorts, 
• 
To compare quality of life (QOL), as measured by the MD Anderson Symptom 
Inventory – Spine Tumor Module (MDASI), between the two cohorts and 
• 
To compare pain control, as measured by the Brief Pain Inventory (BPI), between the 
two cohorts. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Metastatic spine tumors 
 
The incidence of metastatic spine tumors is nearly 20% and has been increasing due to 
improvements in neo-adjuvant strategies. These allow for longer patient survival and thus 
increased incidence of progression to metastatic disease1. The median survival for patients 
undergoing surgery for spinal metastatic tumors ranges from 7.0 – 16.5 months2-6.  More 
specifically, the median survival varies depending on the histological type of primary 
cancer2,4. However, with the development of superior systemic therapies which extend 
survival, these numbers are becoming outdated. 
 
Diagnosis of spinal metastasis is made reliably based on clinical, radiographic and histologic 
grounds. Metastases to the skeletal system are the third most often involved system after the 
lungs and liver. Of this, nearly half are metastases of the spine. The majority of spinal 
metastases involve disease of the vertebral body with or without epidural compression. It is 
estimated that 5-10% of patients with spinal metastases will develop symptomatic spinal cord 
compression requiring surgical intervention7. The NOMS paradigm provides a widely- 
accepted guide to relevant considerations (Neurologic, Oncologic, Mechanical and Systemic) 
when determining the optimal combination of systemic, radiation and surgical therapies for 
individual patients with spinal metastases8. Yet despite advances in surgical and radiologic 
treatments, local recurrence of spinal metastasis remains a challenging problem and can 
lead to progression of spinal column instability,  nerve/spinal cord compression and may 
require repeat surgery9,10. Further study on improving the local recurrence of spinal 
metastases is warranted and has great clinical implications for the evaluation and counseling 
of patients. 

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3.2 
Surgery for the treatment of high grade epidural spinal cord compression 
metastases 
 
Surgical treatment of spinal metastases largely serves a palliative function.  Clinical features 
of spinal metastases include any or all of the following: pain (local or radicular), sensory and 
motor deficits, and bowel/bladder dysfunction. The goals of surgical intervention include 
preservation or restoration of both neurologic function and spinal stability as well as 
improvement of pain control appropriate for the patient’s burden of disease.  Currently, 
surgical indications include spinal cord compression secondary to radioresistant and/or 
previously radiated spinal metastases or mechanical instability of the spinal column.  After 
surgery, local tumor control is of paramount importance in order to maintain neurologic 
function, prevent hardware fracture and instability, and to maintain pain control. 
 
A prospective multicenter trial that randomized patients with spinal cord compression 
secondary to solid metastatic tumors showed that patients who underwent surgery followed 
by radiation had superior outcomes compared to patients who only underwent radiation 
therapy without surgery. The surgical arm showed higher rate of ambulation recovery, 
preservation of ambulation and bowel/bladder continence as compared to the radiation 
arm11.  While the trial has several shortcomings, it provides fairly convincing evidence that 
surgery plays a beneficial role in patients with spinal cord compression secondary to solid 
tumors as compared to radiation treatment alone. This is further supported by the outcomes 
of numerous large retrospective case series. 
 
Surgical intervention includes either posterior and/or anterior approach including 
laminectomy or corpectomy to various degrees and may involve instrumentation posteriorly 
(pedicle fixation, screw/rod system) and/or anteriorly (cage). 
 
3.3 
Post-operative SRS 
 
Spinal metastases exhibit a range of sensitivity to radiation therapy.  In patients with previous 
radiation to the surgical site, and/or with primary tumor histologies that respond poorly to 
conventionally fractionated radiation, spinal SRS provides safe and durable local control. 
The efficacy and safety of post-operative SRS in the treatment of spinal metastatic tumors 
was recently described12.  Single-fraction SRS and high-dose hypofractionated SRS both 
provide excellent tumor control (9% vs 4.1% estimated 1-year cumulative recurrence 
incidence) after spinal decompression surgery for high grade spinal cord compression. 
These data suggest that high-dose hypofractionated SRS may provide superior local tumor 
control compared to single-fraction SRS, however our retrospective study was not powered 
to detect this difference. The current trial is designed to evaluate whether single-fraction SRS 
provides comparable local control to high-dose hypofractionated SRS. 

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3. 4 
Radiobiology of Stereotactic Radiosurgery (SRS) 
 
Radiation therapy is a well-established treatment for localized spinal metastases13,14. The 
outcomes of treatment of spinal metastases using conventional external beam radiation 
therapy (cEBRT) delivered as a series of low-dose fractions have been fairly well 
documented15-18. Several prospective studies have shown that response to cEBRT may be 
predicted based on the primary tumor histology, leading to a dichotomization in 
characterizing tumor histologies as either radiosensitive or radioresistant14,15,19,20. 
Hematologic malignancies were fairly uniformly considered radiosensitive, showing excellent 
local control rates after cEBRT.  Breast and prostate were also reported to consistently 
respond to cEBRT.  On the other hand, the majority of solid tumor metastases were 
classified as radioresistant to cEBRT. 
 
The doses of cEBRT that can be delivered to the tumor are often limited by the risk of toxicity 
to surrounding organs since the beam is delivered to a broad field.  On the other hand, 
image-guided stereotactic radiosurgery (SRS) allows the delivery of several high-dose 
fractions or a single high-dose of radiation with very high spacial precision thereby largely 
sparing surrounding organs from risk of exposure to high doses of irradiation21. 
 
Radiation employs numerous pathways in order to kill tumor cells. The mechanisms of tumor 
response from single-fraction radiotherapy may differ from that of fractionated radiotherapy. 
Laboratory data show that single-fraction high-dose radiation employs tumor kill pathways 
that are not recruited at low-dose radiation fractions22.  Radiation doses above 8Gy induce 
vascular endothelial apoptosis through activation of sphingomyelin-ceramide pathway and 
the extent of apoptosis increases as the radiation dose increases from 11 to 25 Gy23. 
Furthermore, crypt stem cell clonogen apoptosis has been shown to require radiation doses 
that were on average 3.9 Gy higher than for endothelial apoptosis24. 
 
3.5 
Single-fraction SRS 
 
Single-fraction spine SRS provides durable and consistent local control in patients with spinal 
metastases13. The dose escalation study of single-fraction SRS treatment of spinal 
metastases that was carried out at MSKCC showed that 24 Gy dose resulted in 3-year 
recurrence risk of 2.4% which was significantly better than the 10% risk after lower doses21,25. 
Furthermore, tumor control was independent of tumor volume and histology.  MD Anderson 
reported similar tumor control along with improvement in the quality of life26. 
 
3.6 
Hypofractionated SRS 
 
Hypofractionated SRS was used to treat seventy-four spinal metastases, with actuarial one- 
year local control rate of 84%27. The radiation was administered in five 6 Gy fractions or in 
three 9 Gy fractions, without a statistically significant difference in tumor control.  Similar 
results were reported after five fractions to a total dose from 30 Gy to 35 Gy (1-year 80% and 
2-year 73% actuarial local control). The experience in the use of hypofractionated SRS in 
the treatment of brain and lung tumors is more extensive and similarly indicates that 
hypofractionation provides a safe and effective treatment option28. 

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3.7 
SRS Toxicity Profile 
 
Multiple studies reported low risk of toxicity after spinal SRS.  The majority of events involved 
Grade 1 or 2 skin and esophageal toxicity21. To date, hypofractionated treatment of the spine 
has not been reported to result in Grade 3 or 4 neurologic toxicity.  Single cases of Grade 3 
vomiting, diarrhea, costochondritis and dysphagia were reported after hypofractionated 
treatment29,30. To date, radiation literature describes nine cases of radiation myelopathy that 
have been attributed to single-fraction spinal radiation, confirming that this is an exceedingly 
rare consequence of spinal radiation31.  Furthermore, in this institution no cases of radiation- 
induced myelopathy have been observed using cord point-maximum dose of 14Gy in 
patients without prior radiation history.   A crude rate of Grade ≥3 esophageal toxicity of 6.8% 
was reported in our institution following single-fraction spine SRS32. Two Grade 4 acute 
esophageal toxicities, four Grade 4, and one Grade 5 late esophageal toxicities occurred.  All 
of these events occurred in patients with either iatrogenic esophageal manipulation or with a 
history of radiation recall chemotherapy. 
 
Some evidence suggests that administration of individual radiotherapy doses of 20 Gy or 
greater per fraction may lead to an increased risk of vertebral compression fracture33. These 
findings remain limited as there are few studies that have compared single-fraction and 
hypofractionated SRS dosing schemes particularly in the post-operative period, thereby 
underscoring the clinical value of this prospective trial. 
 
3.8 
Quality of Life Measures: MDASI and BPI 
 
As part of this study, we aim to assess a variety of symptoms experienced by cancer patients 
and to what degree these symptoms impede with daily living at baseline and at 3, 6, 9, 12, 
18, and 24 months (± 8 weeks) after treatment during follow up care. In order to measure 
this, we will utilize the MD Anderson Symptom Inventory – Spine Tumor Module (MDASI) as 
an optional measure to evaluate each cohort of the study. MDASI has been validated as an 
instrument for use in clinical trials29,34,35 with Cronbach alpha reliability ranges from 0.82 to 
0.9434. This instrument (see Appendix A) contains 24 questions that ask patients to self- 
report about symptoms experienced in the last 24 hours on a scale of 0 (not present) to 10 
(as bad as you can imagine). Thus, higher scores indicate more severe symptoms. Scoring 
of symptom severity and scoring of symptom interference will be performed as indicated in 
the Outcome Measure section of the MDASI User Guide (see Appendix B). 
 
A second optional tool we will employ is the Brief Pain Inventory (BPI) to assess both the 
severity of pain experienced by participants and to what degree pain invades their ability to 
carry out daily functions at baseline and at 3, 6, 9, 12, 18, and 24 months (± 8 weeks) after 
treatment during follow up care. The BPI has been validated as an instrument for use in 
clinical trials29,36 with Cronbach alpha reliability ranges from 0.77 to 0.9137. Patients are 
asked a total of 9 questions regarding their pain during in the last 24 hours (see Appendix C). 
Response formats include: Yes/No, scale of 0 (no pain) to 10 (pain as bad as you can 
imagine), illustrated region(s) of pain, pain relief as measured by 0% (no relief) - 100% 
(complete relief), pain interference of daily functions scale of 0 (does not interfere) to 10 
(completely interferes). Higher score responses indicate more severe pain. No scoring 
algorithm exists, however the arithmetic mean of the four most severe items can be used as 
a measure of pain severity as indicated in the BPI User Guide (see Appendix D). The 

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arithmetic mean of the seven interference items (of question 9) can be used as a measure of 
pain interference37. 
 
3.9 
Benefit 
 
Spinal radiosurgery has been shown to provide durable and effective tumor control with very 
low risk of significant toxicity.  Retrospective review of post-operative SRS suggests that 
there may be a difference in the tumor control provided by hypofractionated and single- 
fraction SRS12.  Hypofractionated SRS requires more patient visits and may be associated 
with higher cost.  However, higher dose per fraction treatment (ie. single-fraction vs 
hypofractionated) may be associated with a higher risk of vertebral body fractures and 
generally requires increased complexity of dose planning.  Clear delineation of the 
differences in tumor control and toxicity profile will facilitate the best treatment selection in 
the future. The current study is designed to prospectively study the safety and efficacy of 
post-operative SRS administered as either single-fraction or hypofractionated dose and to 
determine its impact on the quality of life. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is a therapeutic Phase III prospective randomized non-inferiority study investigating the 
efficacy and safety of post-operative single-fraction or high-dose hypofractionated SRS. 
Diagnostic and eligibility decisions for patients entering the study will involve the RSA and 
ultimately will be made by the consenting professionals. 
 
Eligible patients will have undergone surgery for spinal decompression and stabilization in 
order to treat spinal metastases and demonstrate adequate separation between tumor and 
the spinal cord on post-operative CT myelogram or MRI perfusion.  Contrast used for the CT 
myelogram will not affect renal function and will be performed regardless of the participant’s 
renal function. The CT myelogram or MRI perfusion will be performed at all participating 
sites. CT myelogram will be used for treatment planning, since spinal instrumentation 
generates artifact in MR imaging which may complicate spinal cord contouring. For instances 
in which the CT myelogram cannot be tolerated by the patient, MRI with perfusion will be an 
acceptable alternative for treatment planning.  However, post-operative MR imaging provides 
adequate resolution in order to reliably diagnose tumor recurrence and will be used to 
monitor patients for recurrence, unless patients are unable to undergo MR imaging. 
 
Patients who are candidates for either single-fraction or high-dose hypofractionated SRS will 
be recruited into the study and randomized in a 1:1 fashion to one of the two treatment arms. 
An Acute Toxicity Assessment (see Appendix E) will be performed via phone or clinic visit 
within 4 weeks (± 10 days) after the completion of SRS.  Patients will have the option to 
complete the MD Anderson Symptom Inventory – Spine Tumor Module (MDASI) and the 
Brief Pain Inventory (BPI) at the time of recruitment and at 3, 6, 9, 12, 18 and 24 months (± 8 
weeks) after their treatment during follow-up care. At these same time points, the study 
investigators will complete the Spine Clinic Assessment form (see Appendix F). Follow-up 
MRI imaging will also be obtained at the same time points, including axial and sagittal T1, T2, 
STIR and gadolinium-enhanced T1 sequences. For those patients that are not candidates for 

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MRI, CT imaging will be performed.  Patients will be monitored for development of radiation- 
and surgery-related toxicity or complications. Imaging will be reviewed for evidence of local 
tumor progression. 
 
4.2 
Intervention 
 
In this study, patients who fulfill the diagnostic criteria of high grade metastatic spinal cord 
compression and who have undergone decompression surgery and post-operatively 
demonstrate separation between tumor and the spinal cord as stated above will be eligible 
for study entry. Patients will require SRS based on the radioresistant nature of their primary 
histology and/or previous radiation history.  Eligible patients will be recruited and following 
informed consent will be randomized to undergo single-fraction (24Gy) or hypofractionated (3 
fractions of 9Gy, total dose of 27Gy) SRS within eight weeks of having undergone spinal 
decompression surgery. The contouring and dosimetry will be done using standard 
institutional practice and dose constraints. If more than one lesion will require treatment, the 
patient will be evaluated for inclusion in the protocol.  If the other lesions meet the inclusion 
criteria, they will be treated according to the randomization assignment for the index study 
lesion.  If they do not meet the inclusion criteria, they will be treated according to the 
discretion of the treatment team. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
All patients enrolled in the study will undergo post-operative SRS.  This is a high-dose 
conformal radiation treatment delivered with high spacial precision using image-guided 
intensity-modulated radiation therapy equipment available at MSKCC, MGH, JHU, and 
Stanford. There is a wealth of published institutional experience with this treatment. This 
device is FDA-approved for this indication. The only difference to be assessed in this study 
will be in the fractionation pattern, with both single-fraction doses and hypofractionated doses 
having been safely used in the past. Dose constraints have been enumerated for single- 
fraction SRS (see Appendix G) and hypofractioned SRS (see Appendix H). 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
1)  Histologically diagnosed metastatic cancer (Diagnosis made or confirmed at MSKCC for 
MSKCC participants. Institutional pathologic determination accepted from participating 
multicenter sites.) 
2)  Age ≥18 years 
3)  Life expectancy ≥3 months 
4)  ECOG ≤ 3 
5)  Spinal surgery carried out with the goal of spinal cord decompression and spinal 
stabilization within 8 weeks 
6)  Post-operative CT myelogram or MRI perfusion with evidence of separation of tumor and 
the spinal cord 
 
It should be noted that patients with multiple lesions will be eligible as long as there are no 
overlapping fields of radiation, including at various time frames. 

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6.2 
Subject Exclusion Criteria 
 
1)  Primary spine tumor 
2)  Age < 18 
3)  Pregnancy 
4)  Lack of adequate (≥ 2 mm) separation between the spinal cord and the tumor on post- 
operative CT myelogram or MRI perfusion 
5)  Radiosensitizing chemotherapy (taxol, taxotere, cisplatin, gemcitabine, 5-fluorouracil) 
given within one week of radiation treatment 
 
7.0 
RECRUITMENT PLAN 
 
Due note is taken of the NIH policy of inclusion of women and minorities in research 
protocols. Patients will not be excluded from the protocol based on gender, race or age. The 
study population will be representative of the range of patients undergoing post-operative 
SRS at the participating sites. 
 
Potential subjects will be identified by a member of the patient’s treatment team, the research 
team and/or the protocol investigators at MSKCC, MGH, JHU, or Stanford. All subjects for 
this study will be recruited from a pool of patients of the investigators. Subjects who appear 
to be eligible will be presented with the opportunity to participate. The study will be posted on 
the clinicaltrials.gov website. Furthermore, the trial will be posted on the MSKCC website 
under clinical trials. 
 
Patients will be approached and consented anytime between the pre-operative discussion 
about surgery and the start of SRS treatment planning. Once the post-operative CT 
myelogram or MRI perfusion demonstrates separation of tumor and the spinal cord and all of 
the inclusion criteria are met, the patient will be randomized before the start of radiation 
treatment planning to receive either single-fraction or hypofractionated SRS within 8 weeks 
of surgery. The recruiting physicians will be familiar with the patient’s medical history and 
health status at the time of recruitment since they will be directly involved in the post- 
operative radiation planning and will not require a waiver of authorization.  Screening for the 
eligibility will not require collection of any additional patient information since all of the 
information required to determine patient eligibility will be required in order to appropriately 
plan the post-operative SRS. 
 
Patients will not be recruited outside of the post-operative treatment pathway and no 
advertisement or patient compensation will take place. 
 
8.0 
PRETREATMENT EVALUATION 
 
Pretreatment evaluations may be performed within 8 weeks of consent, and include the 
following: 
 
1)  Complete patient history 
2)  Complete neurologic and physical exam (specifically assessment of: skin including 
incision site, motor/sensory function, and ambulatory status) 
3)  Pathology review confirming metastatic cancer 
4)  MDASI (optionally) 

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5)  BPI (optionally) 
6)  ECOG ≤ 3 
7)  Current medications 
8)  Post-operative CT myelogram or MRI perfusion 
9)  Serum pregnancy test for women of child-bearing potential 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Patients will undergo SRS treatment simulation in supine position following a CT myelogram 
or MRI perfusion. They will be immobilized in the custom-fitted cradle which will be used for 
the duration of their treatment.  A thermoplastic mould mask will be used for lesions above 
T4. Target volume contouring will be done according to the guidelines proposed by the 
International Spine Radiosurgery Consortium38    The gross tumor volume (GTV) will be 
contoured according to standard institutional practice to include the entire tumor visible on 
any of the pre- or post-operative imaging studies, including MRI and CT. Every attempt will 
be made to include the entire preoperative tumor volume into the GTV even if a part or all of 
it were resected during surgery. The clinical tumor volume (CTV) will be expanded to include 
all of the adjoining marrow spaces in the vertebral body as defined by Cox et al38. The 
planned treatment volume (PTV) will be expanded 2-3 mm around the CTV, but will not 
include the spinal cord. The spinal cord as defined on the CT myelogram or MRI perfusion 
will be excluded from all treatment contours. Inverse treatment planning will be carried out 
with the goal of maximizing the percentage of PTV receiving the 100% of the planned dose 
with a requirement of PTV V100 ≥ 80%.  GTV Dmin >15 Gy will be required with a goal V100 
> 90%. The prescribed dose will be normalized to the 100% isodose line or its equivalent, 
depending upon institutional practices.  In order to account for variability of delivery systems, 
doses will be prescribed that are equivalent to the absolute dose stipulated in the protocol. 
Volumetric modulated arc therapy (VMAT) may potentially be utilized.  In order to ensure 
homogeneity of treatment plans among institutions, the first three treatment volumes from 
each institution will be reviewed by representatives from each institution and differences in 
contouring will be discussed in order to arrive at consensus. 
 
Treatment will be administered using 6- and/or 15-MV photons using 7-9 coplanar beams 
with dynamic multi-leaf collimation.  At the time of treatment, a three-dimensional kilovoltage 
cone-beam CT image obtained once the patient is positioned will be used to match the 
vertebral anatomy to the simulation scan and immediately before treatment patient alignment 
will be checked using two-dimensional kilovoltage verification.  In case of 2mm or larger 
deviation, patient will be repositioned. 
 
The organ at risk tolerances will be different for the two treatment arms and are presented in 
Appendix G (Single-Fraction) and Appendix H (Hypofractionated). The single-fraction 
treatment will be administered in one day while the hypofractionated treatment will be 
administered every other day.  Total treatment time per fraction including set up will be 60-75 
minutes per fraction. 
 
Nausea, dysphagia and diarrhea will be treated according to standard institutional practice. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 

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Pre-treatment evaluations may be performed within 8 weeks of consent. After SRS, patients 
will be closely monitored for any evidence of toxicity, systemic illness or tumor progression. 
Acute toxicity assessment (see Appendix E) will occur by phone or clinic visit within 4 weeks 
(±10 days) after the completion of radiotherapy. Follow-up clinic visits will take place 3 
months, 6 months, 9 months, 12 months, 18 months and 24 months (± 8 weeks) after the 
completion of radiotherapy. At each follow-up visit, the investigators will complete the Spine 
Clinic Assessment form (see Appendix F).  Spine MRI or CT will also be performed at the 
time of each follow-up, in accordance with routine standard of care. 
 
Table 1: Pre-therapy and Follow-up Evaluations 
 
Item 
Pre-therapy 
(w ithin 8 w eeks of 
consent) 
Follow-up 
(3, 6, 9, 12, 18, 24 
months ± 8 w eeks after 
the completion of SRS) 
Inclusion/exclusion 
criteria 
X 
CT myelogram or MRI 
perfusion 
X 
Pathology diagnosis 
confirming metastatic 
disease 
X 
Medical history 
X 
Pregnancy test1 
X 
Physical exam 
X 
X 
Concomitant medications 
review 
X 
X 
ECOG 
X 
X 
Quality of Life 
assessments (MDASI 
and BPI)2 
X 
X 
Spine Clinic Assessment 
Form 
X 
X 
MRI/CT scan3 
X 
X 
Adverse-event/toxicity 
assessment4 
X 
X 
Consent 
X 
 
 
1  For women of child-bearing potential, a urine or blood pregnancy test must be 
completed within 2 weeks prior to SRS. 

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wound 
infection/dehiscence 
2.9% 
hardware fracture 
2.8% 
pneumonia 
2.1% 
pulmonary embolism 
2.1% 
postop hematoma 
0.7% 
radiculopathy 
0.7% 
stroke 
0.7% 
gastrointestinal bleed 
0.7% 
 
2  Patients will be asked to complete quality of life (MDASI and BPI) assessments at 
all timepoints, however this will remain optional. In instances where these 
questionnaires are not available in the participant’s primary language, the 
participant will not be required to complete the questionnaire(s). 
 
3  All patients are required to have MRI/CT based imaging at baseline and 3, 6, 9, 12, 
18, and 24 months (± 8 weeks) after SRS. The imaging modality should remain 
constant for each patient throughout. 
 
4  Only treatment-related adverse events will be reported. Acute toxicity assessment 
(see Appendix E) will occur by phone or clinic visit within 4 weeks (±10 days) after 
the completion of radiotherapy. 
 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
11.1 
Toxicities/Complications 
 
Subjects will be monitored for surgical complications. Our retrospective study found that major 
surgical complications occurred in 14.3% patients within 30 days of surgery. Among those 
patients that suffered complications from surgery within 30 days, Table 2 below depicts the 
likelihood of complications6,39: 
 
Table 2: Postoperative Complications 
  
 
 
 
 
 
 
 
Cerebrospinal fluid leak is a rare complication, 
occurring after less than 5% of operations. 
Neurologic injury is an exceedingly rare post- 
operative complication, occurring after far less 
than 1% of operations. 
 
Patients will also be monitored for radiation 
toxicity including: acute (≤90 days from the start 
of treatment) and late (>90 days) toxicity.  All patients are going to be monitored for skin, 
subcutaneous tissue, spinal cord and fracture toxicity.  In addition, patients undergoing 
cervical radiation will be monitored for mucous membrane, pharynx and esophagus, larynx 
and upper GI toxicity.  Patients undergoing thoracic radiation will be monitored for upper and 
lower GI, lung and heart toxicity.  Patients undergoing lumbar radiation will be monitored for 
genitourinary and lower GI toxicity.  The severity of the toxicity will be graded according to 
Appendix I (Acute Radiation Toxicity) and Appendix J (Late Radiation Toxicity) based on the 
Radiation Therapy Oncology Group classification schema. 
 
Low-grade radiation-related toxicity may include fatigue, skin erythema, subcutaneous 
fibrosis and bone pain. More significant toxicity is rare (<1%) and may include esophagitis, 

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pericarditis, diarrhea, nausea, vomiting, myelosuppression, myelitis, acute radiation 
pneumonitis, late pulmonary fibrosis, esophageal stricture, small bowel obstruction and 
radiation enteritis. 
 
Participants should not be or become pregnant during the course of treatment because the 
radiation used in this study may be teratogenic. Participating sites should notify the MSK PI if 
an external participant becomes pregnant. 
 
11. 2 Adverse Events (AE) 
Defined 
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after treatment. For this 
study, we consider reportable adverse events to include radiation Grade 3 (and above) 
toxicity as enumerated in Section 11.1. Adverse events should be reported to both the site PI 
and the MSK PI, please see Section 16.0.3. 
 
Reporting Requirements 
 
For non-serious adverse events, we will only be capturing toxicities that are possibly related 
to study participation. Adverse event monitoring will be continued for 24 months following the 
completion of SRS treatment or until the time of death if death occurs prior to the 24 month 
follow-up. Adverse events should be described using a diagnosis whenever possible, rather 
than individual underlying signs and symptoms. When a clear diagnosis cannot be identified, 
each sign or symptom should be reported as a separate Adverse Event. Adverse events will 
be reported within 14 days. 
 
Adverse events will be assessed by the investigators according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
(http://ctep.info.nih.gov).  If CTCAE grading does not exist for an adverse event, the severity 
of mild, moderate, severe, and life-threatening, corresponding to Grades 1-4, will be used. 
 
As far as possible, each adverse event should be evaluated to determine: 
 
1.  The severity grade (CTCAE Grade 1-4) 
2.  Its duration (start and end dates or Ongoing at End of Study) 
3.  Its relationship to the study treatment (reasonable possibility that AE is related to 
study: No, Yes) 
4.  Action taken with respect to study (none, dose adjusted, temporarily interrupted, 
permanently discontinued, unknown, not applicable) 
5.  Whether medication or therapy was given (no concomitant medication/non-drug 
therapy, concomitant medication/non-drug therapy) 
6.  Whether it is serious, where a SAE is defined as in Section 17.2 (SAE) 
 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event form in CRDB. Once 
an adverse event is detected, it should be followed until its resolution or until it is judged to 
be permanent. 

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12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
The primary study endpoint, which is local tumor control, will be radiographically determined 
according to routine standard of care post-surgical and post-treatment imaging (MRI or CT) 
of the spine.  Local tumor control will be defined as the lack of local tumor progression at the 
irradiated site on follow-up imaging.  All imaging studies from collaborating institutions will be 
submitted for central review at MSK. T1, T1 gadolinium enhanced, T2 and STIR MR 
sequences will be used for follow-up imaging in order to monitor treatment response. 3-5mm 
slice thickness on MR imaging will be used. We will avoid strict imaging parameter 
restrictions since several medical centers will take part in the study and it will be challenging 
to strictly confine imaging criteria. Standard MRI sequences will be sufficient in order to 
monitor for recurrence. Volumetric measurements will not be used in this protocol. CT will be 
used in patients who cannot undergo MR imaging. 
 
Each month, the imaging studies from participating sites will be batched and submitted 
through MSK’s FTP Imaging Secure File Transfer system to the MSK PI. These scans 
should be de-identified prior to submission to MSK.  The study RSA will transfer images to 
MSK’s electronic Research PACS system. Central review will be carried out at two week 
intervals by MSK neuroradiologists (Dr. Eric Lis and Dr. Sasan Karimi) with expertise in 
interpretation of spinal oncology imaging. In cases of disagreement of the initial radiology 
read and central review interpretation, the results will be discussed with the treating surgeon 
or radiation oncologist in order to reach agreement. Site investigators will be notified of the 
review results within 24 hours.  The turn-around time for central imaging review will be 14 
days. Progression will be defined quantitatively as a 15% increase in maximal horizontal and 
vertical diameter, when not accounted for by fracture or evolving treatment change. The 
duration of response will be measured as lack of progression on imaging or until the last 
follow-up visit. 
 
Secondary endpoints will include clinical determination of MRC muscle strength assessment, 
ECOG, ASIA, and treatment-related toxicity at each follow-up visit. 
 
Secondary endpoint comparison of quality of life between the two cohorts will be determined 
through optional patient-reported responses for the MDASI - Spine Tumor Module at each 
follow up visit. The MDASI Spine Tumor Specific Items (questions #14-18) will be scored 
separately as a Spine Tumor Symptom Severity scale. 
 
Secondary endpoint comparison of pain control will be determined through optional patient- 
reported responses of the BPI. Pain severity at its worst (question #5) and the average of the 
pain interference (average of question #9) will serve as the pain endpoints. 
 
12.1 
CRITERIA FOR RADIOGRAPHIC TUMOR PROGRESSION 
 
 
Local disease progression will be defined as evident in the following ways: 
• 
New or progressive paraspinal or epidural 5% increase in enhancing soft tissue mass 
not accounted for by evolving post therapy change, 
• 
New bone destruction not accounted for by collapse. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 

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Patients may withdraw from the study at any time. They may also be discontinued from the 
study treatment and assessments at any time, at the discretion of the investigators. Specific 
reasons for discontinuing a subject from the study include: 
 
• 
Patient inability or loss to follow-up 
• 
Adverse events deemed significant by the investigators 
• 
Protocol non-compliance 
• 
Elective termination: A subject may withdraw consent at any point in the study 
• 
Patient death 
 
14.0 
BIOSTATISTICS 
 
The primary endpoint of this multicenter Phase III noninferiority study is the local tumor 
control after post-operative spinal stereotactic radiosurgery (SRS). A noninferiority study 
design is justified on the basis that both treatment options have their advantages and 
disadvantages with currently mixed data about the relative tumor control offered by 
hypofractionated and single-fraction SRS.  Some data suggest that single-fraction SRS may 
offer superior local control and since only one treatment visit is required it is cheaper and 
more convenient for patients. On the other hand, data suggest that single-fraction treatment 
may be associated with a higher risk of vertebral body fractures, which is considered a 
treatment-related toxicity.  Determining whether single-fraction SRS and hypofractionated 
SRS offer comparable local tumor control will allow physicians to make treatment decisions 
based on factors such as cost and toxicity risk. 
 
Lack of local radiographic progression will be defined as local tumor control.  Patients will be 
randomized in a 1:1 fashion and the local control in the two treatment arms (single-fraction 
SRS vs. hypofractionated SRS) will be assessed. The patients will be stratified according to 
participating center (MSK, MGH, JHH, Stanford), presence or absence of prior radiation 
history at the study level, and radioresistance of the primary tumor histology, with breast and 
prostate classified as radiosensitive and the remaining solid tumor metastases (i.e. 
melanoma, sarcoma, thyroid, renal, colorectal) classified as radioresistant. 
 
An intent-to-treat, stratified log rank test will be used to test whether or not the single-fraction 
SRS arm is inferior to the hypofractionated (3 fractions in total) SRS arm in terms of the local 
control rate. To set up a formal test we will use the 1-year local control rate as the surrogate 
of the efficacy (assuming that the two survival curves follow exponential distributions) and 
allow a 10% inferior margin. From a clinical standpoint, the investigators agreed that a 
difference of less than 10% is not regarded as significant. On this basis, we permit a 10% 
inferior margin. I.e., we will test H0: P1≤(P2-10%) vs H1: P1>(P2-10%), where P1 and P2 denote 
the 1-year local control rate for the single-fraction arm and the 3-fraction arm, respectively. 
To approximately assess the power of the test, we estimate that the 3-fraction arm will yield a 
1-year local control rate around 85% based on interim preliminary data from a multicenter 
Phase III trial (Protocol 10-154), and set the type I error (that is, declare single-fraction arm 
noninferior while it is not) rate at 0.10. When the two arms have equal efficacy, i.e., P1 = P2 = 
85%, the power (that is, declare the single-fraction arm noninferior while it is) of this 
noninferiority test40 is 80% when there are 75 patients in each arm. Besides, since deaths 
without local failure are likely, competing risk analysis will also be used to estimate the local 

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patient has multiple eligible lesions, all of them will be treated within the randomized arm and 
each eligible lesion (non-contiguous lesions treated with a separate radiation contour) will be 
treated as a separate study unit. After the enrollment of the final patient, a 2-year follow up is 
planned. Three interim analyses are planned and will be conducted at the time of the DSMB 
annual review of the study. The O’Brien-Flemming boundary will be applied for assessing 
statistical significance. Specifically, the rejection regions in terms of the corresponding Z- 
scores are Z>3.09, Z>2.06, Z>1.63 and Z>1.39 for the three interim looks and the final look, 
respectively. We expect that very few patients will have multiple lesions and thus we do not 
plan to examine the correlation among multiple lesions from the same patients. Instead, the 
analysis of the primary endpoint will be conducted at lesion level as mentioned above. Data 
will be collected from all four centers and analyzed at MSKCC. 
 
In consideration of the fact that a large cohort will be recruited, this study will be continuously 
monitored to protect patients from excess toxicity. For each arm, we anticipate that the true 
rate of any grade 4 toxicity within 24 months post SRS is less than 10%. All grade 4 toxicities 
or greater observed will be reviewed by the study chair. Moreover, using a stopping rule 
based on sequential probability ratio test (SPRT), each arm of the study is monitored for any 
grade 4 or above toxicities that are judged to be associated with the radiation treatment. This 
stopping rule specifies that for each arm, the study will be halted if any of the following 
conditions occur: >4/first 15; >6/first 35; >9/first 55; or if more than 12 unacceptable toxicities 
are observed within 24 months post SRS when the last (75th) patient has completed the trial. 
When the true toxicity rate is 10%, this stopping rule has a probability of 0.1 to stop the trial. 
When the true toxicity rate is 20%, this stopping rule has a probability of 0.8 to stop the trial. 
For this stopping rule we will use each patient as a study unit. 
 
Toxicity outcomes and patterns of complications are summarized and tabulated in Section 
11.0. Comparisons will be made using Wilcoxon rank sum tests and proportion tests. QOL 
results measured by MDASI scores and pain control results measured by BPI scores will 
also be summarized and compared between the two arms by Wilcoxon rank sum tests.  As 
multiple measurements will be taken and thus multiple tests will be conducted, test p-values 
will be adjusted by the false discovery rate method. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 

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verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
 
15.1.1 For Participating Sites: 
 
Central registration for this study will take place at Memorial Sloan Kettering Cancer Center 
(MSKCC). 
 
 
To complete registration and enroll a participant from another institution, the study staff at 
that site must contact the designated research staff at MSKCC to notify him/her of the 
participant registration. The site staff then needs to email registration/eligibility documents 
per the contact information provided by the the MSK study coordinator. These documents 
must be sent via a secure, encrypted email. 
The following documents must be sent for each enrollment within 24 hours of the informed 
consent form being signed: 
• The completed or partially completed MSKCC eligibility checklist 
• The signed informed consent and HIPAA Authorization form 
• Supporting source documentation (containing a minimum of two patient identifiers such 
as date of birth and initials) for eligibility questions (pathology report, radiology reports, 
MD notes, physical exam sheets, medical history, prior treatment records). 
 
 
Upon receipt, the research staff at Memorial Sloan Kettering Cancer Center will conduct an 
interim review of all documents.  If the eligibility checklist is not complete, the patient will be 
registered PENDING and the site is responsible for sending a completed form within 30 days 
of the consent. 
 
 
If the eligibility checklist is complete, participant meets all criteria, all source documentation is 
received, the participating site IRB has granted approval for the protocol, and the site is in 
good standing with MSKCC, the MSKCC research staff will send the completed registration 
documents to the MSKCC Protocol Participant Registration (PPR) Office to be enrolled as 
stated in section 15.1. The participant will be registered. 
 
Once eligibility has been established and the participant is registered, the participant will be 
assigned an MSKCC Clinical Research Database (CRDB) number (protocol participant 
number). This number is unique to the participant and must be written on all data and 
correspondence for the participant. This protocol participant number will be relayed back to 
study staff at the registering site via e-mail and will serve as the enrollment confirmation. 
15.2 
Randomization 
 
Randomization will be centralized at MSKCC. Patients will be randomized to the single dose 
arm (24 Gy) or the multi-dose arm (27 Gy in 3 fractions). Ineligible lesions and other lesions 
not being treated on protocol will be treated according to standard of care at the physician’s 
discretion. Immediately after consent is obtained at MSKCC and at participating sites, the 
RSA will register participants in the Protocol Participant Registration (PPR) system. Once the 
participant’s eligibility is established, the registration will be finalized and the participants will 

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be randomized using the Clinical Research Database (CRDB). Randomization will be 
accomplished by the method of random permuted block, and will be stratified by institution, 
prior radiation history, and radioresponsiveness of the primary disease site (radioresponsive 
tumors include prostate, lung, breast, etc and non-responsive tumors include melanoma, 
renal cell, colon and sarcoma). After the treatment arm is determined by randomization, the 
RSA will notify the research staff and/or investigators at MSKCC and participating sites of the 
treatment arm and participant ID via email within 24 hours of randomization. 
 
Data will be collected at other centers and sent to the RSA(s) at MSKCC according to Table 
6. Compiled data will be submitted to the biostatisticians at MSKCC for analysis. 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A designated Research Study Assistant will be responsible for accurate and confidential 
documentation, data recording, compliance, regulatory monitoring and coordination of 
activities of the study team. The data collected during this study will be handled in the same 
manner as all of patient health information in compliance with HIPAA regulations. All data 
collected during pre-enrollment assessment and during the course of the study will be 
entered into the Clinical Research Database (CRDB) Minimal Dataset. Data will be reported 
to the IRB every 6 months. 
 
The data will also be collected in the Caisis database, with source information stored in the 
patient records. 
 
List of variables and population characteristics: 
 
• 
Patient demographic data (gender, date of birth, height, weight) 
• 
Medical and surgical history 
• 
Concomitant medication 
• 
Toxicity 
• 
AE’s* 
• 
Number and location of metastatic sites, as well as whether the sites are positive or 
negative on imaging 
• 
Epidural Spinal Cord Compression (ESCC) score (0-3)41 
 
*If an adverse event meets the criteria for an SAE, then an SAE report must be completed as 
per the instructions for SAE reporting in section 17.2. 
 
 
 
16.0.1 
Data and Source Documentation for Participating Sites 
 
Data 
The participating sites will enter data remotely into MSKCC’s internet-based Clinical 
Research Database, termed CRDBi-Multicenter. In case of problems with the system, the 
MSKCC research team should be contacted directly. The site staff will receive CRDB training 
prior to enrolling its first participant. The participating Site PI is responsible for ensuring 
these forms are completed accurately and in a timely manner. 
 
Source Documentation 

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Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation should include a 
minimum of two identifiers to allow for data verification. MSK will maintain the confidentiality 
of any subject‐identifiable information it may encounter. Source documentation should be 
consistent with data entered into CRDBi-Multicenter. Relevant source documentation to be 
submitted throughout the study includes: 
o Baseline measures to assess pre–protocol disease status 
o Acute Toxicity Assessment Forms 
o Spine Clinic Assessment Forms 
o Treatment records 
o Toxicities/adverse events not previously submitted with SAE Reports 
o Response designation 
o Radiology imaging via MSK’s Secure File Transfer system 
o Radiology reports 
 
 
16.0.2 
Data and Source Documentation Submission for Participating Sites 
 
Participating sites should enter data directly into CRDBi‐ Multicenter. Source documentation 
should be sent to MSK at the contact information provided by the MSK study coordinator. 
Submissions should include a cover page listing relevant records enclosed per participant. 
  
 
16.0.3 Data and Source Documentation Submission Timelines for Participating Sites 
Data and source documentation to support data should be transmitted to MSKCC according 
to Table 6 below. 

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Table 6: Timelines/Requirements for Data and Source Documentation Submission 
 
 
 
 
 
 
 
 
Baseline 
At completion 
of SRS 
Follow-up* 
SAE 
Off 
Study 
SUBMISSION SCHEDULE 
Source 
Documentation 
CRDBi-MCT 
Within 24 
hours of 
registration 
Within 14 days 
of completion of 
SRS 
Within 14 days of 
visit 
Within 3 days of 
knowledge of the 
event (see section 
17.2.1); updates to 
be submitted as 
available 
Within 14 
days of 
partici- 
pant 
removal 
Within 7 
days (see 
15.1.1) 
REQUIRED FORMS (in CRDBi-MCT) 
Administrative 
X 
Disease 
X 
Pathology 
X 
Medical History 
X 
Physical Exam 
X 
X 
Concomitant Drug 
X 
X 
X 
Prior Therapy 
X 
Surgery 
X 
External Beam 
Radiation 
X 
Outcome 
X 
X 
Toxicity**** 
X 
X 
X 
X 
Spine Details 
X 
X 
X 
Diagnostic Test 
To be submitted with other data forms whenever applicable 
Hospitalization 
To be submitted whenever a hospitalization occurs, unless included in the SAE form 
Patient Status 
To be submitted within Minimal Dataset whenever patient status changes 
Radiology Imaging 
Studies 
X 
X 
X 
Radiology Reports 
X 
X 
X 
QOL Assessments 
(MDASI/ BPI)** 
X 
X 
Acute Toxicity 
Assessment 
Form*** 
X 
X 
Spine Clinic 
Assessment Form 
X 
X 
X 

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*Follow-up visits: 3, 6, 9, 12, 18, 24 months (± 8 weeks) after the completion of SRS. 
**QOL assessments will be requested at all timepoints, however this will remain optional. 
***Acute Toxicity Assessment must occur within 4 weeks (± 10 days) after completion of 
SRS. 
****Toxicities/adverse events that meet reporting requirements as outlined in section 11. 
 
16.0.4 Data Review and Queries for Participating Site Data 
 
Research staff at MSKCC will review data and source documentation as it is submitted. Data 
will be monitored against source documentation and discrepancies will be sent as queries to 
the participating sites. Queries will be sent by MSKCC Research staff twice a month. 
 
 
Participating sites should respond to data queries within 14 days of receipt. 
 
 
 
16.1 
Quality Assurance 
 
Principal investigators will maintain complete and accurate medical and treatment histories in 
the patients’ medical records. The data will be prospectively entered by the designated RSA 
into the Caisis database at the time of enrollment and during the designated follow-up 
events.  The RSA will assist the PI in data quality assurance. The RSA will confirm up-front 
registration of all subjects, verify eligibility by review of each case with the principal 
investigators at the time of enrollment, review records to confirm that informed consent is 
properly obtained and procedures are performed according to study protocol, and monitor 
protocol accrual. A weekly meeting with participation of the investigators and the RSA will be 
held in order to review the data collected each week and to address omissions and 
inconsistencies in the data to maintain compliance to the protocol. 
 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team. 
 
 
16.1.1 
Quality Assurance for Participating Sites 
 
Each site accruing participants to this protocol will be audited by the staff of the MSKCC 
study team for protocol and regulatory compliance, data verification and source 
documentation. 
 
Audits will be conducted annually during the study (or more frequently if indicated), and at 
the end or closeout of the trial. The number of participants audited will be determined by 
auditor availability and the complexity of the protocol. Each audit will be summarized and a 
final report will be sent to the PI at the audited participating site within 30 days of the audit. 

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16.1.2 
Response Review 
 
 
Since therapeutic efficacy is a stated primary objective, all sites participant’s responses are 
subject to review by MSKCC’s Therapeutic Response Review Committee (TRRC). 
Radiology will need to be obtained from the participating sites for MSKCC TRRC review and 
confirmation of response assessment. These materials must be sent to MSKCC promptly 
upon request. 
 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitoring% 
20Plans.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality.  There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
16.3 
Regulatory Documentation 
 
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSKCC Institutional Review Board/Privacy Board (IRB/PB). Prior to implementing this 
protocol at the participating sites, approval for the MSKCC IRB/PB approved protocol must 
be obtained from the participating site’s IRB. 
 
The following documents must be provided to MSKCC before the participating site can be 
initiated and begin enrolling participants: 
 
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 

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• 
Participating Site IRB approved consent form 
• 
Participating Site IRB membership list 
• 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number 
• 
Curriculum vitae and medical license for each investigator and consenting 
professional 
• 
Documentation of Human Subject Research Certification training for investigators and 
key staff members at the Participating Site 
• 
Documentation of Good Clinical Practice (GCP) training for the PI and co-PI at the 
participating site 
 
 
Upon receipt of the required documents, MSKCC will formally contact the site and grant 
permission to proceed with enrollment. 
  
 
16.3.1 
Amendments 
 
Each change to the protocol document must be organized and documented by MSKCC and 
first approved by the MSKCC IRB/PB. Upon receipt of MSKCC IRB/PB approval, MSKCC 
will immediately distribute all non expedited amendments to the participating sites, for 
submission to their local IRBs. 
 
Participating sites must obtain approval for all non expedited amendments from their IRB 
within 90 calendar days of MSKCC IRB/PB approval. If the amendment is the result of a 
safety issue or makes eligibility criteria more restrictive, sites will not be permitted to 
continuing enrolling new participants until the participating site IRB approval has been 
granted. 
 
The following documents must be provided to MSKCC for each amendment within the stated 
timelines: 
 
• 
Participating Site IRB approval 
• 
Participating Site IRB approved informed consent form and HIPAA  authorization 
 
 
16.3.2 
Additional IRB Correspondence 
 
 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most current 
approved version of the informed consent form should be submitted to MSKCC within 7 days 
of expiration. Failure to submit the re-approval in the stated timeline will result in suspension 
of study activities. 
 
 
Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant who 
does not meet all the eligibility criteria, pretreatment evaluation, or who requires alteration in 
their study plan. If a deviation from this protocol is proposed for a potential or existing 

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participant at MSKCC or a participating site, approval from the MSKCC IRB/PB is required 
prior to the action. Participating sites should contact the MSKCC PI who will in turn seek 
approval from the MSKCC IRB/PB. 
 
A protocol violation is anything that occurs with a participant, which deviated from the protocol 
without prior approval from the MSKCC IRB/PB. For protocol violations that are identified 
after they occur, the participating site should report to MSKCC as soon as possible. The 
MSKCC PI will in turn report the violation to the MSKCC IRB/PB. 
 
Participating sites should report deviations and violations to their institution’s IRBs as soon as 
possible per that site’s institutional guidelines. Approvals/acknowledgments from the 
participating site IRB for protocol deviations and violations should be submitted to MSKCC as 
received. 
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB according to 
local guidelines, and submit copies of that correspondence to MSKCC. 
 
 
 
 
 
 
16.3.3 
Document maintenance 
 
The MSKCC PI and the Participating Site PI will maintain adequate and accurate records to 
enable the implementation of the protocol to be fully documented and the data to be 
subsequently verified. 
 
 
The participating sites will ensure that all participating site IRB correspondence (IRB 
approval letters referencing protocol version date and amendment number, IRB approved 
protocol, appendices, informed consent forms, deviations, violations, and approval of 
continuing reviews) is maintained in the regulatory binder on site and sent to MSKCC. 
 
A regulatory binder for each site will also be maintained at MSKCC; this binder may be paper 
or electronic. 
 
 
After study closure, the participating site will maintain all source documents, study related 
documents and CRDBi-MCT data for 3 years. 
 
 
16.4 
Noncompliance 
 
If a participating site is noncompliant with the protocol document, accrual privileges may be 
suspended until the outstanding issues have been resolved. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
There are no unforeseen additional risks to the patients from this study. Every effort will be 

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and benefits, potential toxicities and side effects will be thoroughly discussed with the patient 
at the time of enrollment. This discussion will largely be identical to the discussion that takes 
place at the time of treatment consent outside of the study, since the risks of participating in 
this study will be identical to the risks of post-operative radiation which would be 
administered outside of the study. Informed consent is a prerequisite to enrollment on the 
study. Enrollment in the study is entirely voluntary. It will be made clear that the patients have 
a right to refuse participation and that their care will not be adversely affected in case of 
refusal.  Furthermore, the patients will have the right to withdraw from the study at any time, 
without any adverse consequences to their treatment. The patients will not incur any 
additional costs or burdens related to participation in the study. 
 
In accordance with institutional policy, privacy and confidentiality of medical records will be 
strictly observed. All data pertaining to the study will also be likewise protected. 
 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
This study defines Serious Adverse Event may include the following: 
 
• 
any Grade 4-5 toxicity that is a direct result of protocol treatment, with the exception 
of vertebral body fracture which is a common occurrence after spinal radiosurgery 
and infrequently represents a significant adverse event 
• 
any hospitalization within 30 days of treatment 
• 
any hospitalization after 30 days of treatment if it is directly related to the protocol 
intervention. 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 
calendar days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be 
submitted electronically to the SAE Office at  sae@mskcc.org. The report should contain the 
following information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 

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• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
 
The PI’s signature and the date it was signed are required on the completed report. Only one 
event will be captured as the cause of death. All SAEs and deaths that occur within the trial 
period or within 30 days after administration of the last dose of radiation therapy my be 
reported primarily for the purposes of serious adverse event (SAE) reporting, this includes 
deaths that are due to progression of disease. 
 
All trial treatment-related toxicities and SAEs must be followed up until resolution. 
 
17.2.1 
 
17.3 
Serious Adverse Event (SAE) Reporting for Participating Sites 
 
Responsibilities of Participating Sites 
 
• 
Participating sites are responsible for reporting all SAEs to their local IRB per local 
guidelines. Local IRB SAE approval/acknowledgements must be sent to MSK upon 
receipt. 
• 
Participating sites are responsible for submitting the SAE Report form found in MSK’s 
internet based Clinical Research Database to MSK within 3  calendar days of learning 
of the event. 
• 
When a death is unforeseen and indicates participants or others are at increased risk 
of harm, participating sites should notify the MSK PI as soon as possible but within 24 
hours of the time the site becomes aware of the event. SAE contact information: 
Email: kahns@mskcc.org to the attention of 14-233 Research Staff 
 
AND 
 
Email: lauferi@mskcc.org 
 
 
Responsibility of MSK 
 
• 
MSK Research Staff are responsible for submitting all SAEs to the MSK IRB/PB as 
specified in 17.2. 
• 
The MSK PI is responsible for informing all participating sites about all unexpected 
SAEs that are either possibly, probably or definitely related to the study intervention 
within 30 days of receiving the stamped SAE from the MSK IRB/PB. 
• 
The MSK PI is responsible for informing all participating sites within 24 hours or on 
the next business day about a death that is unforeseen and indicates participants or 
other are at increased risk of harm. 

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17.4 
Safety Reports 
 
MSK must submit external safety reports to the MKS iRB/PB according to institutional 
guidelines. All external safety reports will be made available to the participating sites. For 
those safety reports that require an amendment, the participating sites will receive a special 
alert. 
 
Participating sites are responsible for submitting safety reports to their local IRB per their 
local IRB guidelines. All local IRB approvals/acknowledgements of safety reports must be 
sent to MSK upon receipt. 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
 
The consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
18.1 
For Participating Sites 
 
The investigators listed on the Consenting Professionals Lists at each participating site may 
obtain informed consent and care for the participants according to good clinical practice and 
protocol guidelines. 

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A note will be placed in the medical record documenting that informed consent was obtained 
for this study, and that the participant acknowledges the risk of participation. 

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19.0 
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20.0 
APPENDICES 
 
 
 
 
Appendix A: 
MD Anderson Symptom Inventory (MDASI) – Spine Tumor 
Appendix B: 
MD Anderson Symptom Inventory (MDASI) User Guide 
Appendix C: 
Brief Pain Inventory (BPI) 
Appendix D: 
Brief Pain Inventory (BPI) User Guide 
Appendix E: 
Acute Toxicity Assessment Form 
Appendix F: 
Spine Clinic Assessment Form 
Appendix G: 
MSKCC Single-fraction SRS Plan Evaluation Criteria 
Appendix H: 
MSKCC Hypofractionated SRS Plan Evaluation Criteria 
Appendix I: 
Acute Radiation Toxicity 
Appendix J: 
Late Radiation Toxicity