Adaptive Staged Stereotactic Body Radiation Therapy in Treating Patients With Spinal Metastases That Cannot Be Removed by Surgery
Phase: NA
Conditions: Melanoma, Metastatic Malignant Neoplasm in the Spine, Renal Cell Carcinoma, Soft Tissue Sarcoma, Spinal Cord Compression
Sponsor: Albert Einstein College of Medicine

Title:  Adaptive Staged Stereotactic Body Radiation Therapy in Treating Patients With 
Spinal Metastases That Cannot Be Removed by Surgery
NCT02527304
IRB Approval Date: 12/15/2016
IRB Study No.:  2015-4957
PI: Madhur Garg

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Adaptive High-Dose Radiotherapy for  Metastatic 
Epidural Disease in the Spine
CONFIDENTIAL
The information contained in this document is regarded as confidential and, 
except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless law or regulations require such disclosure.  
Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them.
Principal Investigator
Madhur Garg, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Fax: 718-882-6914
Email: mgarg@montefiore.org
Co-Investigators (Radiation Oncology)
Nitin Ohri, MD
Albert Einstein College of Medicine
Department of Radiation Oncology
1300 Morris Park Avenue, Mazer 105
Bronx, NY 10461
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Phone: 718-303-3143
Fax: 718-430-8618
William Bodner, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Fax: 718-882-6914
Maury Rosenstein, MD, PhD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Fax: 718-882-6914
Jana Fox, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Fax: 718-882-6914
IRB NUMBER: 2015-4957
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Keyur Mehta, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Fax: 718-882-6914
Kartik Mani, MD, PhD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Fax: 718-882-6914
Rafi Kabarriti, MD
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-4361
Fax: 718-882-6914
Co-Investigators (Neuroradiology)
Allan Brook, MD
Montefiore Medical Center 
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Department of Radiology (Neuroradiology)
111 East 210th Street 
Klau, Room 1 
Bronx, NY 10467
Tel: 718.920.7050
Co-Investiagtors (Neurology)
Mary Welch, MD
Montefiore Medical Center
Department of Neurology
111 East 210th Street
Bronx, NY 10467-2401
Phone: (718) 920-5505
Fax: (718) 515-0697
Co-Investigators (Neurosurgery)
Reza Yassari, MD
Montefiore Medical Center 
Department of Neurological Surgery
3316 Rochambeau Avenue 
Bronx, NY 10467
Tel: 718.920.7487 
Fax: 718.515.8235
Co-Investigators (Physical Medicine & Rehabilitation)
Dr. Gregory Syrkin, MD
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Montefiore Medical Center
150 East 210th Street
Bronx, NY 10467-2412
Phone: (718) 920-2751
Email: gsyrkin@montefiore.org
Co-Investigators (Medical Physics)
Wolfgang Tomé, PhD
Albert Einstein College of Medicine
Department of Radiation Oncology
1300 Morris Park Avenue, Mazer 106
Bronx, NY 10461
Phone: 718-430-3188
Fax: 718-430-8618
Email: wtome@montefiore.org
Co-Investigators (Statistics)
Shankar Viswanathan, DrPH, MSc
Albert Einstein College of Medicine
1300 Morris Park Avenue, Belfer 1312D
Bronx, New York 10461
Phone: 718-430-3762
Fax: 718-430-8780
Email: shankar.viswanathan@einstein.yu.edu
Research Coordinator
Juhi Purswani
               
 
Montefiore Medical Center
Department of Radiation Oncology
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111 East 210th Street
Bronx, NY 10467
Phone: 718-920-5636
Fax: 718-882-6914
Email: jpurswani@montefiore.org
                           
Research Nurse
Hilda Haynes-Lewis, NP
Montefiore Medical Center
Department of Radiation Oncology
111 East 210th Street
Bronx, NY 10467
Phone: 718-920-7750
Fax: 718-231-5064
Email: hhaynes@montefiore.org 
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Adaptive Staged SBRT for Spinal Metastases
SCHEMA
Sample size: 15 patients
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Abbreviations
ACRIN
American College of Radiology Imaging Network
AE
Adverse Event
AJCC
American Joint Committee on Cancer
ANC
Absolute neutrophil count
AUC
Area under the curve
BID
Twice daily
BSA
Body surface area
chemoRT
Chemoradiotherapy
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTV
Clinical Target Volume
DFS
Disease-free survival
ECOG
Eastern Cooperative Oncology Group
EQD2
Equivalent dose in 2-Gy fractions
Fx
Fractions
FDG
Fludeoxyglucose
GFR
Glomerular filtration rate
GTV
Gross tumor volume
Gy
Gray
IMRT
Intensity modulated radiotherapy
IV
Intravenous
LA-NSCLC
Locally-advanced non-small cell lung cancer
LD
Longest diameter
LLN
Lower limit of normal
LRC
Locoregional control
MRI
Magnetic Resonance Imaging
MESCC
Metastatic Epidural Spinal Cord Compression
OS
Overall survival
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PET
Positron emission tomography
PHI
Protected health information
PI
Principal investigator
PO
By mouth
PTV
Planning target volume
RECIST
Response Evaluation Criteria in Solid Tumors
RT
Radiotherapy
RTOG
Radiotherapy Oncology Group
Rx
Prescription
SAE
Serious adverse event
SBRT
Stereotactic Body Radiation Therapy
SUV
Standardized uptake value
ULN
Upper limit of normal
VMAT
Volumetric modulated arc therapy
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Contents
1.0  OBJECTIVES ..........................................................................................................12
1.1 Primary Objective..................................................................................................12
1.2  Secondary Objectives ..........................................................................................12
2.0  BACKGROUND.......................................................................................................13
2.1  Spinal Cord Compression ....................................................................................13
2.2  Conventional Radiotherapy..................................................................................14
2.3  SBRT for Spinal Cord Compression ....................................................................15
3.0  PATIENT ELIGIBILITY ............................................................................................17
3.1  Inclusion Criteria ..................................................................................................17
3.2  Exclusion Criteria .................................................................................................18
4.0  STUDY DESIGN......................................................................................................19
4.1  General Design ....................................................................................................19
Treatment ...................................................................................................................................................19
Follow-up....................................................................................................................................................19
4.2  Study Calendar ....................................................................................................20
3.  Primary Endpoint...................................................................................................21
4.4  Secondary Endpoints ...........................................................................................21
5.0  RADIOTHERAPY ....................................................................................................22
5.1  Dosimetry .............................................................................................................22
5.2  CT simulation, Immobilization and Patient setup .................................................22
5.3  Target Volumes and Coverage ............................................................................22
5.4  Critical Structures.................................................................................................23
5.5  Radiotherapy Adverse Events..............................................................................24
6.0  RESPONSE ASSESSMENT...................................................................................25
6.1  Primary Endpoint – Radiographic Response .......................................................25
6.2  Secondary Endpoints – NRPS, FACT-G, Ambulation..........................................25
7.0 STATISTICAL CONSIDERATIONS .........................................................................26
7.1 Data Analysis ........................................................................................................26
8.0  REGULATORY CONSIDERATIONS ......................................................................27
8.1  Protection of Human Subjects..............................................................................27
8.2  Compliance with the Protocol and Protocol Revisions.........................................27
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9.0  DATA HANDLING AND RECORD KEEPING .........................................................28
9.1  Confidentiality.......................................................................................................28
9.2  Source Documents...............................................................................................28
9.3  Case Report Forms..............................................................................................28
10.0  DATA SAFETY AND MONITORING BOARDS.....................................................30
11.0  ADVERSE EVENTS..............................................................................................31
11.1  Adverse Event Definitions ..................................................................................31
11.2  Adverse Event Reporting ...................................................................................32
12.0  REFERENCES......................................................................................................34
13.0  APPENDICES .......................................................................................................35
13.1 Appendix A – Eligibility Checklist ........................................................................35
13.2 Appendix B – Common Toxicity Criteria .............................................................38
13.3 Appendix C – ECOG Performance Status ..........................................................39
13.4 Appendix D – Neurologic  and Functional Assessment ......................................40
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1.0  OBJECTIVES
1.1 Primary Objective

To assess the feasibility of single-fraction radiotherapy to provide a short-interval 
treatment response in patients with MESCC, such that radiographic 
decompression is achieved, or additional stereotactic radiotherapy to full 
therapeutic doses can be delivered while respecting spinal cord constraints, based 
on the following metrics:
o
Shortest distance between gross disease and the spinal cord before and 
after treatment
o
Epidural tumor volume before and after treatment
o
Extent of epidural compression before and after treatment
1.2  Secondary Objectives

To evaluate pain control using the Numerical Rating Pain Scale (NRPS) before 
and after treatment

To evaluate patient quality of life using the Functional Assessment of Cancer 
Therapy-General (FACT-G) before and after treatment

To evaluate functional outcomes using ambulation score and standardized 
neurologic exams before and after treatment
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2.0  BACKGROUND
2.1  Spinal Cord Compression
Metastatic epidural spinal cord compression (MESCC) is a relatively rare but 
serious complication of cancer occurring in approximately 5% of diagnosed patients (and 
can be the presenting symptom in up to 20% of undiagnosed cases).  It is a medical 
emergency, which if not addressed, can lead to permanent neurologic deficits including 
paraplegia.  Although patients with this presentation often do poorly (median survival is 
estimated at between 3-6 months), there are prognostic indicators of improved outcomes 
including the preservation of ambulation ability, radiosensitive tumor histology, low 
systemic extent of disease, and single involved region of the spine [1].  
Prompt diagnosis and treatment using a multidisciplinary approach has now 
become the standard of care.  Diagnosis is aided by clinical suspicion based on 
presenting symptoms, with the most common including back pain, motor deficits, sensory 
deficits and autonomic dysfunction.  Approximately 60% of patients remain ambulatory at 
presentation [2].  Diagnosis is confirmed radiographically with MRI being the current 
method of choice (sensitivity and specificity of up to approximately 93% and 98% 
respectively) [3].  
First line therapy for MESCC begins with corticosteroids to reduce edema and 
provide cytoreductive effects on some sensitive histologies [4].  Until recently, the 
standard of care for patients was conventional fractionated radiotherapy delivered on an 
emergent basis.  However, a prospective randomized study in 2005 by Patchell et al 
demonstrated that immediate surgical decompression for a subset of patients followed by 
adjuvant radiation conferred a number of benefits when compared to radiation therapy 
alone [5].  Patients preserved the ability to ambulate (84% vs. 57%, p=0.001) and more 
regained this ability (10 patients vs. 3 patients).  Furthermore, those patients undergoing 
surgery had improved survival times (median 126 days vs. 100 days, p=0.003).  The key 
conclusion from this study was that when used judiciously on a carefully selected cohort 
of patients, surgical decompression can provide a viable alternative to definitive 
radiotherapy.  These criteria include a non-radiosensitive or unknown primary histology, 
single area of compression, symptoms present no longer than 48 hours, or relapsed or 
progression of disease while receiving radiotherapy [1].  It is estimated that 10-15% of 
patients are appropriate candidates for surgery [2].
For the majority of patients that do not meet the aforementioned criteria or who are 
poor surgical candidates due to medical comorbidities or other factors, the correct 
treatment approach is an open question.  Definitive radiotherapy remains the standard of 
care with or without corticosteroids, however there has been no clear demonstration of 
the effectiveness of conventional treatment for improving neurologic function in patients 
with MESCC, among several tested dosing regimens [2].  In this pilot study, we plan to 
evaluate the use of staged high-dose radiotherapy for patients with MESCC, to determine 
if a treatment response can be observed within a short enough interval to improve 
symptoms or provide additional radiotherapy safely.  We will utilize SBRT where possible 
as this technique has shown promise in providing disease and symptomatic control to 
date.
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2.2  Conventional Radiotherapy
Conventional radiotherapy has historically been the standard of care and remains 
the most common treatment of MESCC [2].  There have been several randomized trials 
regarding the optimal dosing regimen in these patients, however none has been found to 
be significantly effective in improving functional outcomes.  
An early example analyzed 276 patients with MESCC comparing two 
hypofractionated regimens; sequential single-fraction dosing (8 Gy x 2 on days 1 and 8) 
vs. a split-course regimen (5 Gy x 3, 4-day treatment break, followed by 3 Gy x 5). They 
found no difference in pain control or post-treatment motor function, with ambulation 
preserved in approximately 70% in both groups [6].  A larger retrospective comparison 
from the same year reviewed 1,304 patients comparing five distinct regimens (8 Gy x 1, 
4 Gy x 5, 3 Gy x 10, 2.5 Gy x 15, and 2 Gy x 20), and also found no difference in functional 
outcomes, however noted that local control was improved in the longer courses.  Notably, 
a multivariate analysis identified several factors aside from the treatment regimen that 
influenced functional outcomes, including age, performance status, tumor histology, 
number of spinal cord lesions, ambulatory status and interval to treatment [7].  
These results were further corroborated by a non-randomized prospective trial 
including 265 patients with MESCC, comparing a short-course regimen (8 Gy x 1 or 4 Gy 
x 5) to a long-course (3 Gy x 10, 2.5 Gy x 15, or 2 Gy x 20).  The authors found that the 
radiation schedule had no significant impact on functional outcomes based on univariate 
analysis (performance status, tumor type, number of vertebrae involved, ambulatory 
status prior to treatment, and time to symptoms were all significant), though long-courses 
were associated with improved local control [8].  A systematic review and clinical practice 
guideline recently recommended that for non-surgical patients, those with poor prognoses 
should receive 8 Gy x 1, whereas those with more favorable prognoses should be treated 
with 3 Gy x 10 [4].  It should be reiterated that improvement of motor function was 
observed in only 28% of patients after shortcourse radiotherapy and in 29% of patients 
after longercourse radiotherapy, indicating neither is effective for this purpose.  Further 
progression of motor deficits was prevented in 56% and 55% of patients, respectively.
Most recently, another prospective randomized trial comparing 10 Gy x 1 vs. 4 Gy 
x 5 for patients with MESCC again found both groups performed similarly without a noted 
improvement in neurologic outcomes [ASTRO 2014].  Improvement in mobility status was 
even less impressive, occurring in only 10.5% of patients on each arm while improvement 
in bladder control occurred in 2.6 to 10.5% of patients.  Although the 10 Gy arm was not 
inferior to the 20 Gy arm, this study again showed that conventional definitive 
radiotherapy had a poor vital and functional prognosis overall.
Currently 10 Gy x 1 using conventional techniques remains an option based on 
existing clinical data.  However, there is clearly a need for a more effective treatment for 
patients with MESCC who cannot undergo surgery. 
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2.3  SBRT for Spinal Cord Compression
Within the last 10 years, the use of stereotactic body radiation therapy (SBRT) has 
shown increasing promise in treating spine metastases.  A number of retrospective and 
prospective studies have demonstrated effective local and symptomatic control.
A small retrospective series from Yamada et al initially demonstrated that 
stereotactic treatment or retreatment of paraspinal lesions up to 70 Gy could be achieved 
safely using non-invasive body frames.  35 patients underwent treatment with 90% 
reporting palliation of pain or parasthesias with local control rates of 75-81% [9].  Notably 
there were no cases of radiation induced myelopathy indicating high-dose per fraction 
was possible while respecting spinal cord constraints.  A larger phase I-II study of spine 
SBRT then reported on treatment of 63 patients (74 metastatic lesions) with 27-30 Gy in 
3-6 fractions.  Similarly, they noted 1-year local control rates of 84% [10].  A much larger 
cohort of 500 patients were prospectively followed by Gertszten et al after receiving single 
fraction doses of 12.5 o 25 Gy.  Long-term pain control was consistent with previous 
findings of 86%, with local control reported at 90%.  Further, 84% of patients with a 
progressive deficit reported some clinical improvement [11].   
Although these findings and others support the use of SBRT for local and 
symptomatic control for spinal metastases, patients with MESCC present a unique 
problem of the tumor abutting the thecal sac and cord directly, potentially limiting its 
application while respecting constraints on the spinal cord dose.  In these cases, a 
therapeutic dose of16-24 Gy in 1-3 fractions often cannot safely be delivered.  
More recently, a prospective clinical trial reported on the effectiveness of SBRT for 
patients with MESCC, as measured by the reduction of epidural tumor volume and 
improvement in thecal sac patency.  They enrolled 62 patients with MESCC who were 
treated with 14-20 Gy in a single fraction.  The results demonstrated a 64% reduction of 
the epidural tumor volume at 2 months following treatment, with 80% of the patients also 
showing improvement in thecal sac patency.  Notably, however, 16% of these patients 
had neurologic progression (9/62 patients).  Of these 9 patients, 5 had decompressive 
surgery thereafter in which 2 showed necrosis, 2 died from intraoperative complications 
and 1 had tumor progression [12].  This trial indicated that a radiographic response can 
be observed rapidly, however there is clearly a risk of neurological toxicity from delivering 
single doses of 14 Gy or higher to tumors abutting the spinal cord.
Previous studies have estimated spinal cord constraints ranging from 10-14 Gy for 
single fraction SBRT treatments [10, 13, 14].  RTOG 0631, an ongoing prospective 
randomized trial which investigated the use of SBRT for palliation of spine metastases 
(16 Gy SBRT vs. 8 Gy x 1 conventional), applied these constraints using 10 Gy to 10% 
of the spinal cord (cross sectionally) to a maximum of 6mm above and below the target 
volume, and max dose of 14 Gy.  However, patients are excluded if there was frank 
epidural compression within 3 mm of the spinal cord.
Based on the above findings, we are proposing a trial for patients with inoperable 
MESCC utilizing adaptive planning and a staged application of radiotherapy.  Such an 
approach can potentially deliver therapeutic doses to the tumor while respecting the 
established spinal cord constraints.  We hypothesize that a single fraction of treatment 
may induce a short-interval radiographic response (within approximately 2-3 weeks), 
which can then be used to plan an additional treatment if needed.  The response may 
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also allow us to achieve therapeutic dose levels by reducing the volume of overlap with 
the spinal cord.  We will also observe the radiographic response from high-dose single 
fraction regimens if decompression can be achieved in this fashion.
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3.0  PATIENT ELIGIBILITY
Patients will be recruited via physician referral.  Each of the criteria in the checklist that 
follows must be met in order for a patient to be considered eligible for this study. The 
eligibility checklist must be completed on the case report form and maintained in each 
patient’s chart.
3.1  Inclusion Criteria

Localized spine metastasis from the C1 to L5 levels with documented epidural 
extension or spinal cord compression by a diagnostic imaging study (MRI, 
diagnostic CT, or CT myelogram recommended).  Site(s) may have a maximal 
involvement of 3 contiguous vertebral bodies. Patients with other visceral 
metastasis, and radioresistant tumors (including soft tissue sarcomas, 
melanomas, and renal cell carcinomas) are eligible.

History/physical examination by the treating physician within 7 days prior to study 
therapy

Neurological and functional examination within 7 days prior to study therapy by the 
treating physician (see Appendix D).

Negative serum pregnancy test

Age > 18

Diagnostic Imaging (MRI with gadolinium is recommended, other modalities 
include CT myelogram or diagnostic CT with iodinated contrast) of the involved 
spine within 21 days prior to initial study therapy to determine the extent of the 
spine involvement

Numerical Rating Pain Scale within 7 days prior to study therapy; Documentation 
of the patient’s initial pain score is required. Patients taking medication for pain at 
the time of registration are eligible.

Women of childbearing potential must:
o
Have a negative serum or urine pregnancy test within 1 week prior to the 
start of study therapy
o
Agree to utilize an adequate method of contraception throughout treatment 
and for at least 4 weeks after study therapy is completed 
o
Be advised of the importance of avoiding pregnancy during trial participation 
and the potential risks of an unintentional pregnancy.

All patients must sign study specific informed consent prior to study entry or within 
1 week of first treatment, provided other criteria were met.
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Patients considered for enrollment are strongly recommended to have been 
discussed at multidisciplinary tumor board with input from surgery, medical 
oncology and radiation oncology prior to enrollment.
3.2  Exclusion Criteria

Histologies of myeloma or lymphoma

Candidates planned for surgical decompression

Spine instability as determined by SINS score >12 [15]

Compression fracture identified by > 50% loss of vertebral body height

Bony retropulsion at the index spine as predominant cause of epidural extension 
or cord compression

Prior radiation to the spinal cord at the index spine where the composite dose 
(including study treatment) would exceed documented constraints
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4.0  STUDY DESIGN
4.1  General Design
Treatment
This will be a pilot study assessing the feasibility of staged radiotherapy and 
adaptive planning on the management of inoperable epidural extension or spinal cord 
compression (documented by diagnostic imaging).  All patients should be started on 
dexamethasone unless medically contraindicated and dosed per institution guidelines.  
Initial treatment after evaluation and registration will consist of an initial fraction of 8-24 
Gy delivered using a SBRT or 3D conformal approach to the affected region(s).  The 
patients will be re-imaged within 14-21 days by the same modality as diagnosis to assess 
for radiographic response.  If feasible, a second fraction will be delivered at this point per 
discretion of the treating physician.
Follow-up
Patients will be evaluated with a history, physical examination, pain score, and 
neurologic assessment at each treatment visit by the treating physician, or more 
frequently as clinically indicated.  Interval diagnostic imaging will be completed 14-21 
days after initial treatment to assess response.  Thereafter, a third set of diagnostic 
images will be obtained at 8-10 weeks following initial treatment.  Patients will be followed 
thereafter by the treating physician for survival and recurrence as clinically indicated.
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4.2  Study Calendar
Screening
Treatment
Post-Treatment
Day -21 to -1
Day -7 to -1
Day 1
Day 14-21
Week 8-10
History
X
X
X
Physical Exam
X
X
X
SINS Score
X
Vital Signs & 
Weight
X
X
X
Neurologic 
Evaluation
XA
X
X
NRPS
X
X
X
ECOG PS
X
X
X
FACT-G
X
X
X
Pregnancy Test
X
Diagnostic 
Imaging
X
X
XC
Radiation 
Therapy
X
XB
A Appendix D: Neurologic and Functional Assessment. 
B If indicated, a second fraction will be delivered at this point at the discretion of the treating physician.
C should810Follow-up imaging thereafter should occur at the discretion of the treating physician. 
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3.  Primary Endpoint
The primary endpoint of this study is the radiographic response of the spinal tumor, as 
measured by:

Distance between the gross disease and spinal cord ≥ 3mm after treatment.

A reduction in the epidural tumor volume or thecal sac compression by ≥ 10% after 
treatment
4.4  Secondary Endpoints

Pain control:  Pain scores as measured by the Numerical Rating Pain Scale 
(NRPS) estimation

Quality of Life:  Scores from Functional Assessment of Cancer Therapy (FACT-G)

Ambulation:  Based on ambulation score and standardized neurologic exam 
(Appendix D)

Progression-free survival: the interval from study registration to date of disease 
progression or death, censored at the date of data collection

Overall survival: the interval from study registration to death, censored at the date 
of data collection

Grade ≥ 2 radiation-induced lung toxicity, scored using CTCAE, v. 4

Any grade ≥ 3 treatment-related toxicity, scored using CTCAE, v. 4
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5.0  RADIOTHERAPY
5.1  Dosimetry
All patients will receive a first fraction of 8 to 24 Gy using a 3D or SBRT technique.  
The second treatment will be at the discretion of the treating physician and will be based 
on the clinical parameters, diagnostic interval imaging (2-3 weeks), and achievement of 
spinal cord dose constraints as described below.
The spinal cord constraints for the first fraction will be a maximum of 9Gy to less than 
0.01 cc and 8Gy to less than 0.1 cc volume, respectively. Composite dose 
constraints(combining both treatments) for the spinal cord area maximum of 18 Gy to less 
than 0.01 cc and16 Gy to less than 0.1 cc and respectively. Every effort will be made to 
plan for 90% composite target coverage while keeping the spinal cord dose limits.”
 If considering a larger single fraction dose (14-16 Gy or above), the constraint should be 
12 Gy to less than 0.01cc
5.2  CT simulation, Immobilization and Patient setup
Computed tomography will be the primary image platform for targeting and 
treatment planning.  The planning CT scans should be performed without IV contrast, 
however may be preceded with a CT myelogram where possible to accurately delineate 
the spinal cord.  Oral contrast may be given.  Axial acquisitions with gantry 0 degrees will 
be required with spacing 1.25-2.5 mm between scans in the region of the tumor.  Images 
will be transferred to the treatment planning computers for treatment planning.
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.  The arms should be positioned based on treatment location.  
Positions uncomfortable for the patient should be avoided to prevent unnecessary 
movement. A prone position is not allowed. A vacuum bag should be used for 
immobilization or for cervical spine or cervicothoracic junctional areas, a rigid head and 
neck immobilization device should be used. 
Verification CT scans or portal films prior to each treatment should be taken.
5.3  Target Volumes and Coverage
Image fusion between MRI (gadolinium contrast T1-weighted and T2-weighted 
images) and simulation CT is recommended for delineation of both the soft tissue tumor 
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component and the spinal cord.  If possible, CT myelogram should be obtained prior to 
simulation for accurate delineation of the true cord.  Special attention (and consideration 
of deformable registration) should be taken with image fusion when simulation CT and 
MRI images are taken in different imaging positions.
The gross tumor volume (GTV) should include only the gross disease visible on 
pre-treatment imaging.  A 0-3mm margin expansion is allowed to clinical target volume 
(CTV), as well as a further 1-2 mm expansion to planning target volume (PTV).
For 3D treatment, the target volume should also be delineated.  The treatment field 
can include a margin of 1-2 cm beyond the vertebral body(s) 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.
5.4  Critical Structures
Lung, true cord, esophagus, larynx, brachial plexus, heart/pericardium, kidneys, 
bowel and liver should be included based on the location of the spinal lesion, and 
contoured on the published atlases available on the RTOG web site. All critical structures 
will 
be 
outline 
as 
detailed 
in 
the 
RTOG 
0631 
protocol. 
(http://www.rtog.org/CoreLab/ContouringAtlases.aspx).  
Dosimetric constraints for 
organs at risk are listed in Table 2.  These have been adopted from RTOG 0631.
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Table 2 – Dosimetric Constraints
5.5  Radiotherapy Adverse Events
Reversible or permanent alopecia, bone marrow toxicity, skin pigmentation, and 
esophagitis are expected side effects of radiation therapy.  Radiation induced myocarditis 
or transverse myelitis rarely when the pericardium and spinal cord receive doses lower 
than 50 Gy.  Radiographic evidence of radiation change and subsequent fibrosis of the 
lung will occur within lung volume receiving  ≥ 20 Gy, usually within the
first six months after initiation of treatment.  It is essential to spare as much normal lung 
as possible in order to avoid symptomatic lung injury.  
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6.0  RESPONSE ASSESSMENT
6.1  Primary Endpoint – Radiographic Response
The primary endpoint of this study is achieving radiographic response in the 
metastatic spinal lesion.  
Radiographic response will be achieving 3mm in shortest distance axially between 
the gross disease and spinal cord at the level where the most severe compression was 
present, between pre-treatment and interval imaging scans.
Radiographic response will also be achieving a 10% reduction in epidural tumor 
volume or thecal sac compression between pre-treatment and interval imaging scans.  
Epidural tumor volume will be estimated by using target volumes contoured before and 
after treatment by the same practitioner. Thecal sac compression will be estimated using 
a method adapted from [12].  The thecal sac area at the level of compression is compared 
to the average value of thecal sacs measured at 1 vertebral body above and below this 
level. One minus the ratio of the compressed to normal thecal sac area will provide an 
estimate of the thecal sac compression.  These measurements will be taken at the same 
spine levels to maintain consistency. 
Response assessments will be completed by an attending radiation oncologist not 
directly involved in the patient’s clinical care.  This approach will preserve objectivity and 
mirrors an existing peer review process in place for all standard and stereotactic radiation 
treatments.  Collaboration with neuroradiology will also be encouraged during these 
assessments.
6.2  Secondary Endpoints – NRPS, FACT-G, Ambulation
Secondary endpoints include pain, quality of life and functional outcomes.
For evaluation of pain relief, the Numerical Rating Pain Scale will be used, as done 
in RTOG 0631. The NRPS is a measure of pain on an 11-point scale (0-10) and has been 
validated previously on similar cohorts [16].
For quality of life, the Functional Assessment of Cancer Therapy (FACT-G), v. 4.0, 
also will be collected (also utilized in RTOG 0631). The FACT-G is a commonly used tool 
measuring quality of life from 4 different perspectives (physical, social, emotional and 
functional) [17].  It is completed quickly, is accessible to those with varying educational 
backgrounds, 
and 
is 
available 
in 
many 
languages 
(http://www.facit.org/translation/translation_landing.aspx).
Functional outcomes and ambulation will be assessed by standard neurologic 
assessment (Appendix D) by the treating physician.
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7.0 STATISTICAL CONSIDERATIONS
7.1 Data Analysis
This pilot study will yield preliminary data on the primary endpoint of distance 
between gross disease and spinal cord of at least 3mm.  Data from the study will be 
summarized using standard descriptive statistics; formal hypothesis testing will not be 
performed.  Estimates of the treatment effect and standard error on the number of 
subjects achieving >=3 mm distance will also be used to determine the sample size 
required for the larger scale study. Therefore, the size of the pilot study should be 
sufficient to produce reasonably precise estimates of these parameters, where precision 
is measured by the width of the 95% confidence interval.  
The treatment effect will be estimated by p, the observed proportion of patients 
achieving at least 3 mm distance from the gross disease and spinal cord. Confidence 
intervals for the true proportion will be computed using Clopper-Pearson exact confidence 
interval.  With 24 subjects and assuming an expected response rate p = 50% produces a 
two-sided 95% confidence interval with a width equal to 58% (i.e. 21%<=p<=79% ). The 
width shows that the response rate will not be lower than 20%. Since this is a feasibility, 
study no power calculation is done.
Data regarding secondary endpoints will be reported in a descriptive manner.
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8.0  REGULATORY CONSIDERATIONS
8.1  Protection of Human Subjects
The Investigator must ensure that patients or their legally acceptable 
representatives are clearly and fully informed about the purpose, potential risks and other 
critical issues regarding clinical trials in which they volunteer to participate.  Preparation 
of the consent form is the responsibility of the Investigator and must include all elements 
required by CFR 21 Part 50.25 and the local IRB.
8.2  Compliance with the Protocol and Protocol Revisions
The study must be conducted as described in this approved protocol.  All revisions 
to the protocol must be provided to the PI.  The PI should not implement any deviation or 
change to the protocol without prior review and documented approval/favorable opinion 
from the IRB/IEC of an Amendment, except where necessary to eliminate an immediate 
hazard(s) to study patients.
The investigator must ensure that patients or their legally acceptable 
representatives are clearly and fully informed about the purpose, potential risks and other 
critical issues regarding clinical trials in which they volunteer to participate.  Preparation 
of the consent form is the responsibility of the PI.
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9.0  DATA HANDLING AND RECORD KEEPING
9.1  Confidentiality
Information about study subjects will be kept confidential and managed according 
to the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:

What protected health information (PHI) will be collected from subjects in 
this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their 
PHI.

In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected prior 
to the revocation of subject authorization.  For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission 
to collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period.
9.2  Source Documents
Source data is all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents   Examples of these original documents, 
and data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories, and at medico-technical departments involved in the clinical trial.
9.3  Case Report Forms
The study case report form (CRF) is the primary data collection instrument for the 
study.  All data requested on the CRF must be recorded.  All missing data must be 
explained.  If a space on the CRF is left blank because the procedure was not done or 
the question was not asked, write “N/D”.  If the item is not applicable to the individual 
case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry error has 
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been made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it.  All such changes must be initialed and dated.  DO 
NOT ERASE OR WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, 
print the clarification above the item, then initial and date it.  
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10.0  DATA SAFETY AND MONITORING BOARDS
The Albert Einstein College of Medicine/Albert Einstein Cancer Center Data Safety 
Monitoring Committee (DSMC) has the responsibility for ensuring data and safety 
monitoring along with the PI who is ultimately responsible for the ongoing monitoring and 
safety of clinical protocols.  The primary functions of the AECC DSMC are as follows:
1.
 To review and ensure protocol compliance with dose escalation in phase I trials 
2.
To review/assure protocol compliance for all trials that have two-stage phase II 
designs, 
3.
Reviewing all internal and external serious adverse reports, investigator alerts, 
action letters, and other safety reports for trials being performed at AECC-affiliated 
institutions and; 
4.
To implement and to determine the adequacy of DSM plans of all approved 
protocols. 
 The DSMC is an independent committee and meets on a monthly basis.  During its 
monthly meeting, the DSMC will review serious (grade 3 or higher) adverse events from 
this study.  In the event that the DSMC decides that a revision is warranted, the committee 
will immediately notify the principal investigator of this study.  The DSMC has the authority 
to close trials to patient accrual should the risk to patients be excessive or outweigh the 
potential benefits of the study.  All study suspensions and closures will be forwarded to 
the IRB/CCI and study sponsor from the DSMC.  
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11.0  ADVERSE EVENTS
An adverse event (AE) is defined as any untoward medical occurrence in a patient 
or clinical investigation subject and does not necessarily have to have a causal 
relationship with study treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of treatment.  During clinical trials, AEs can be 
spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. 
AEs will be recorded in the case report form for the duration of the trial, regardless 
of whether or not the event(s) are considered related to trial intervention or medication. 
All AEs considered related to trial intervention or medication will be followed until 
resolution, even if this occurs post-trial.
11.1  Adverse Event Definitions
Adverse Event (AE):  any new, undesirable medical experience or change of an existing 
condition that occurs during or after treatment, whether or not considered product-related.
Serious Adverse Event (SAE):  An AE occurring at any dose that results in any of the 
following outcomes (CFR 312.32)

Death

Life-threatening adverse experience

Inpatient hospitalization or prolongation of existing hospitalization excluding  those 
for study therapy administration, transfusional support, disease staging/re-staging 
procedures, thoracentesis / paracentesis, or placement of an indwelling catheter, 
unless associated with other serious events

Persistent or significant disability or incapacity

Congenital anomaly / birth defect. 
The definition of SAE also includes important medical event.  Medical and scientific 
judgment should be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above.  
These should also usually be considered serious.  Examples of such events are intensive 
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treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias 
or convulsions that do not result in hospitalization; or development of drug dependency 
or drug abuse.  A new diagnosis of cancer during the course of treatment should be 
considered an important medical event.
The definition of “related” is that there is a reasonable possibility that the drug or the study 
intervention caused the adverse experience.
Unexpected Adverse Event:  An AE that is not mentioned in the Investigator's Brochure 
or package insert or the specificity or severity of which is not consistent with the 
investigator's brochure or package insert.
Life-threatening:  Any adverse experience that places the patient or subject, in the view 
of the investigator, at immediate risk of death from the reaction as it occurred.  It does not 
include a reaction that, had it occurred in a more severe form, might have caused death.
AEs will use the descriptions and grading scales found in the revised Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Appendix B). A list of AEs 
that have occurred or might occur can be found in sections above.  
11.2  Adverse Event Reporting
Study site personnel must notify the PI and the sponsor immediately of any SAE 
experienced by a patient.  In general, SAEs assessed as clearly being due to disease 
progression, and not due to study drug(s), should be excluded from AE reporting.  Study-
specific clinical outcomes of death because of disease progression are exempt from SAE 
reporting, unless the investigator deems them related to use of the study drug.  
Hospitalization for study drug administration is not an SAE.
The following steps will be taken to report promptly and document accurately any SAE, 
even if it may not appear to be related to the study treatment:

Report the SAE to the PI and the treating physician by email, telephone or fax 
within 24 hours of becoming aware that a patient has experienced an SAE.

Record the SAE accurately on the AE page of the patient’s CRF.

Using the standard IRB-SAE report form, submit all known patient information 
within 24 hours of SAE occurrence to the clinical trial office to submit to IRB and 
DSMB.  Date and sign each report before submission.  Include the following 
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information (or as much as possible to obtain and still report the event within 24 
hours): 
o
Study protocol number and indication
o
Study site and investigator’s identification
o
Patient’s ID (patient number and initials), age or date of birth, and sex
o
Date of enrollment
o
Description of SAE, including date of onset and duration, severity, and outcome
o
Date of first and most recent (last) dose administered
o
Action taken regarding study treatment
o
Relationship of SAE to study treatment
o
Concomitant medications, including regimen and indication
o
Intervention, including concomitant medications used to treat SAE
o
Pertinent laboratory data/diagnostic tests conducted and date
o
Pertinent medical history of patient
o
Date of hospital admission/discharge
o
Date of death (if applicable)
Within 10 days of initial IRB notification, the PI is required to submit a completed Adverse 
Event Report to the IRB.  The treating physicians should perform appropriate diagnostic 
tests and therapeutic measures and submit all follow-up substantiating data, such as 
diagnostic test reports and autopsy report to the PI, IRB, and DSMB.
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12.0  REFERENCES
1.
Cole, J.S. and R.A. Patchell, Metastatic epidural spinal cord compression. Lancet Neurol, 
2008. 7(5): p. 459-66.
2.
Rades, D. and J.L. Abrahm, The role of radiotherapy for metastatic epidural spinal cord 
compression. Nat Rev Clin Oncol, 2010. 7(10): p. 590-8.
3.
Loblaw, D.A., et al., Systematic review of the diagnosis and management of malignant 
extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines 
Initiative's Neuro-Oncology Disease Site Group. J Clin Oncol, 2005. 23(9): p. 2028-37.
4.
Loblaw, D.A., et al., A 2011 updated systematic review and clinical practice guideline for 
the management of malignant extradural spinal cord compression. Int J Radiat Oncol Biol 
Phys, 2012. 84(2): p. 312-7.
5.
Patchell, R.A., et al., Direct decompressive surgical resection in the treatment of spinal 
cord compression caused by metastatic cancer: a randomised trial. Lancet, 2005. 
366(9486): p. 643-8.
6.
Maranzano, E., et al., Short-course versus split-course radiotherapy in metastatic spinal 
cord compression: results of a phase III, randomized, multicenter trial. J Clin Oncol, 2005. 
23(15): p. 3358-65.
7.
Rades, D., et al., Evaluation of five radiation schedules and prognostic factors for 
metastatic spinal cord compression. J Clin Oncol, 2005. 23(15): p. 3366-75.
8.
Rades, D., et al., Final results of a prospective study comparing the local control of short-
course and long-course radiotherapy for metastatic spinal cord compression. Int J Radiat 
Oncol Biol Phys, 2011. 79(2): p. 524-30.
9.
Yamada, Y., et al., Multifractionated image-guided and stereotactic intensity-modulated 
radiotherapy of paraspinal tumors: a preliminary report. Int J Radiat Oncol Biol Phys, 2005. 
62(1): p. 53-61.
10.
Chang, E.L., et al., Phase I/II study of stereotactic body radiotherapy for spinal metastasis 
and its pattern of failure. J Neurosurg Spine, 2007. 7(2): p. 151-60.
11.
Gerszten, P.C., et al., Radiosurgery for spinal metastases: clinical experience in 500 
cases from a single institution. Spine (Phila Pa 1976), 2007. 32(2): p. 193-9.
12.
Ryu, S., et al., Radiosurgical decompression of metastatic epidural compression. Cancer, 
2010. 116(9): p. 2250-7.
13.
Ryu, S., et al., Partial volume tolerance of the spinal cord and complications of single-dose 
radiosurgery. Cancer, 2007. 109(3): p. 628-36.
14.
Yamada, Y., et al., High-dose, single-fraction image-guided intensity-modulated 
radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys, 2008. 71(2): p. 
484-90.
15.
Fourney, D.R., et al., Spinal instability neoplastic score: an analysis of reliability and 
validity from the spine oncology study group. J Clin Oncol, 2011. 29(22): p. 3072-7.
16.
Jensen, M.P., et al., Comparative reliability and validity of chronic pain intensity measures. 
Pain, 1999. 83(2): p. 157-62.
17.
Cella, D.F., et al., The Functional Assessment of Cancer Therapy scale: development and 
validation of the general measure. J Clin Oncol, 1993. 11(3): p. 570-9.
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13.0  APPENDICES
13.1 Appendix A – Eligibility Checklist
Inclusion Criteria
Must be answered YES for eligibility
1. Does the patient have pathologically proven malignancy?
Yes / No
2. Does the patient have demonstrated metastatic epidural cord compression on 
diagnostic imaging?
Yes / No
3. Has the patient been evaluated by neurosurgery or orthopedic surgery and is not 
proceeding?
Yes / No
4. Has the patient had an appropriate pre-treatment work-up, including complete 
history, physical examination and neurologic evaluation?
Yes / No
5. Does the patient have ECOG Performance Status 0-2?
Yes / No
6. Is the patient at least 18 years old?
Yes / No
7. Is either of the following true?:
 - The patient is not a woman of childbearing potential.
 - The patient has undergone negative serum or urine pregnancy test within 72 
hours prior to the start of study therapy, agrees to utilize an adequate method of 
contraception throughout treatment and for at least 4 weeks after study therapy is 
completed, and has been advised of the importance of avoiding pregnancy 
during trial participation and the potential risks of an unintentional pregnancy.
Yes / No
8. Has the patient signed study-specific informed consent?
Yes / No
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Exclusion Criteria
Must be answered NO for eligibility
1. Has the patient had prior radiotherapy to the area in question which would 
exceed published constraints if enrolled?
Yes / No
2. Does the patient have spinal instability as indicated by imaging or physical 
exam?
Yes / No
3. Does the patient have a radiosensitive histology including myeloma or 
lymphoma?
Yes / No
4. Is the patient pregnant or breastfeeding?
Yes / No
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13.2 Appendix B – Common Toxicity Criteria
NCI CTCAE Version 4.0
Toxicity will be scored using NCI  CTC Version 4.0 for toxicity and adverse event 
reporting.  A copy of the NCI CTC Version 4.0 can be downloaded from the CTEP 
homepage: (http://ctep.info.nih.gov).  All appropriate treatment areas have access to a 
copy of the CTC Version 4.0
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13.3 Appendix C – ECOG Performance Status
Performance Status
Definition
0
No symptoms; normal activity level
1
Symptomatic, but able to carry out normal daily activities
2
Symptomatic; in bed less than half of the day; needs some 
assistance with daily activities
3
Symptomatic; in bed more than half of the day
4
Bedridden
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13.4 Appendix D – Neurologic  and Functional Assessment
Neurologic Assessment (adapted from RTOG 0631, Appendix IV)
Symptoms:
Level
Tenderness
Radiculopathy
Cervical Spine
Thoracic Spine
Lumbar Spine
Sacrum
Strength (MRC grade):
Arm
Level
L
R
Leg
Level
L
R
Deltoid
C5/6
Iliopsoas
Bicep
C5/6
Quadriceps
Tricep
C6/7/8
Hamstrings
Digits
C7/8/T1
Ant Tibilalis
Interossei
C8/T1
Gastroc
Sensation:
Arm
Trunk
Leg
L
R
L
R
L
R
Normal
Decreased
Urinary Incontinence:
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Present:  ____________   Absent:  _______________
Sphincter Tone:
Normal:  ____________   Decreased:  _______________   Absent:  _______________
Functional Assessment ((adapted from ICORG phase III trial, ASTRO 2014)
Mobility Score 
I
Ambulatory without aid
II
Ambulatory with aid
III
Not Ambulatory
IV
Paraplegia
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