Phase II Study of Post-Operative Stereotactic Radiosurgery for Solid Tumor Spine Metastases
Phase: PHASE2
Conditions: Solid Tumor Spine Metastases
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

 
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J12133: Phase II Study of Post-Operative Stereotactic Radiosurgery for Solid Tumor Spine 
Metastases  
NCT01752036 
 
Research Site:  
  
The Johns Hopkins University School of Medicine  
  
*Co-Principal Investigator: Kristin Redmond, M.D., M.P.H.  
 
Department of Radiation Oncology   
  
401 North Broadway, Suite 1440  
 
Baltimore, MD 21231  
 
Telephone: 410-614-1642  
 
Fax: 410-502-1419  
 
 
Email: kjanson3@jhmi.edu  
 
Michael Lim, M.D.  
 
Department of Neurosurgery  
 
 
Co-Investigators:  
Lawrence Kleinberg, M.D., Department of Radiation Oncology  
 
Ziya Gokaslan, M.D., Department of Neurosurgery  
 
Jean-Paul Wolinsky, M.D., Department of Neurosurgery  
 
Stephanie Terezakis, M.D., Department of Radiation Oncology  
 
Daniel Sciubba, M.D., Department of Neurosurgery  
 
Statistician:   
  
Xiaobu Ye, M.D., M.S.  
    
  
  
Telephone: 410-614-6261 
Email: xye3@jhmi.edu  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

 
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SCHEMA  
  
  
Surgical resection (gross total,   
subtotal, or biopsy) on 
spine metastasis  
  
  
 
  
Enrollment  
 
  
 
  
Stereotactic radiosurgery (SRS)  
  
600 cGy x 5 fractions  
  
  
 
  
  
Follow-up imaging and   
clinical evaluation every  
 
  
3 months   
  
  
 
  
1) Is the rate of 
radiographic local 
recurrence better than 
would expect for 
conventional radiation 
therapy?   
 
2)
ra
re
wo
co
th
3) Is the rate of 
radiation myelopathy 
acceptable?  
 

 
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Future Prop
  
Randomized 
prospective t
stereotactic  
radiosurgery 
bed boost ver
  
conventional 
radiation ther
 
  
1) 
Is radiogra
<20%?  
  
2) 
Is time to r
>9 months?  
  
3) 
Is radiation
<10%  
This concept 
should go no 
further  
  
  
  
Table of Contents  
SCHEMA ....................................................................................................................................... 
2  
1. 
OBJECTIVES .......................................................................................................................... 
5  
1.1 
Primary Objective ............................................................................................................ 
5  
1.2 
Secondary Objectives ....................................................................................................... 
5  
2. 
BACKGROUND ..................................................................................................................... 
5  
2.1 
Study Disease and Rationale ............................................................................................ 
5  
3. 
PATIENT SELECTION .......................................................................................................... 
6  
3.1 
Eligibility Criteria ............................................................................................................ 
6  
3.2 
Exclusion Criteria ............................................................................................................. 
7  
3.3 
Inclusion of Women and Minorities................................................................................ 8  
4. 
REGISTRATION PROCEDURES ......................................................................................... 
8  
5. 
TREATMENT PLAN.............................................................................................................. 8  
5.1 
Treatment Planning .......................................................................................................... 
8  
Yes  
No  

 
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5.2 
Follow Up ....................................................................................................................... 
11  
5.3 
Toxicity .......................................................................................................................... 
12  
5.4 
Duration of Therapy ....................................................................................................... 
12  
5.5 
Criteria for Removal from Study ................................................................................... 
12  
6..................................................................................................................................................... 12  
CORRELATIVE/SPECIAL STUDIES ..................... ERROR! BOOKMARK NOT 
DEFINED.  
7. 
STUDY CALENDAR 
........................................................................................................... 13  
8. 
MEASUREMENT OF SYMPTOMATIC PROGRESSION 
................................................ 14  
9. 
STATISTICAL CONSIDERATIONS 
.................................................................................. 14  
9.1 
Study 
Design/Endpoints.................................................................................................... 14  
9.2 
Sample Size/Accrual Rate .............................................................................................. 
15  
9.3 
Statistical Analysis plan ................................................................................................. 
16  
10. 
ADVERSE EVENTS AND RECORDING 
.......................................................................... 16  
10.1 
Definition of Adverse Event (AE) .............................................................................. 
16  
10.2 
Radiation Related Adverse Events ............................................................................... 
16  
11. 
SERIOUS ADVERSE EVENTS (SAE) AND REPORTING ........................................... 
17  
11.1 
Serious Adverse Event................................................................................................ 17  
11.2 
SAE Reporting Guidelines for Johns Hopkins Hospital .............................................. 
17  
12. 
DATA AND SAFETY REPORTING/ REGULATORY CONSIDERATIONS ........... 17  
12.1 
Data Quality Monitoring ............................................................................................ 
18  
12.2 
Data Safety Monitoring Plan ...................................................................................... 
18  

 
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12.3 
Data Reporting ............................................................................................................ 
18  
REFERENCES ............................................................................................................................. 20  
APPENDIX B: ............................................................................................................................. 
24  
APPENDIX C: ............................................................................................................................. 
25 APPENDIX D: 
............................................................................................................................. 27  
APPENDIX E: ............................................................................................................................. 
28 APPENDIX F: 
............................................................................................................................. 29  
  
  
  
 

 
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1.  
OBJECTIVES  
  
 
1.1  
Primary Objective  
  
To estimate the rate of radiographic local recurrence at 12 months in patients treated with 
a post-operative stereotactic radiosurgery boost for resected spine metastases.  
  
 
1.2  
Secondary Objectives  
  
1.2.1  To estimate the time to radiographic local recurrence in patients treated 
with a post-operative stereotactic radiosurgery boost for resected spine metastases  
  
1.2.2  To estimate the rate of re-treatment at 12 months in patients treated with a 
post-operative stereotactic radiosurgery boost for resected spine metastases  
  
1.2.3  To estimate the rate of symptomatic local recurrence at 12 months in 
patients treated with a post-operative stereotactic radiosurgery boost for resected 
spine metastases  
  
1.2.4  To estimate the rate of radiation myelopathy in patients treated with a 
post-operative stereotactic radiosurgery boost for resected spine metastases  
  
1.2.5  To estimate the rate of wound dehiscence in patients treated with a 
postoperative stereotactic radiosurgery boost for resected spine metastases  
  
1.2.6  To estimate the time to return to chemotherapy in patients treated with a 
post-operative stereotactic radiosurgery boost for resected spine metastases  
  
1.2.7  To evaluate whether symptomatic local recurrence rates vary with tumor 
histology in patients treated with a post-operative stereotactic radiosurgery boost 
for resected spine metastases  
  
  
 
2.  
BACKGROUND  
  
 
2.1  
Study Disease and Rationale  
  
Approximately 40% of cancer patients are diagnosed with spine metastases at some point 
during their disease course (1) and up to 90% of terminal cancer patients have evidence 
of metastatic spinal disease on post-mortem studies (2-6).  Management of spine 
metastases varies depending on the individual patient circumstances, but may include 
systemic therapy alone or radiation therapy.  In patients with spinal instability, spinal 
cord compression, or neurologic deficits as a result of their spine disease, the standard of 

 
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care is direct decompression and/or stabilization followed by radiation therapy based on a 
large randomized study which revealed significantly higher rates of ambulation in 
patients undergoing surgical resection followed by radiation therapy versus radiation 
therapy alone (7).    
  
  
Rates of local recurrence following surgical resection alone are high (Gilbert, Black, 
Greenberg, Rodriguez, Sorensen), likely at least in part as a result of difficulty attaining a 
widely negative surgical margin, especially in the epidural space.  As such, radiation 
therapy is typically offered following surgical resection of a metastatic spine lesion in 
order to decrease the risk of local recurrence and development of neurologic deficits or 
cord compression.  Historically most patients have been treated with conventional 
radiation therapy which generally involves 2-3 weeks of daily radiation treatment to both 
the involved vertebral levels as well as a vertebral level above and below.  However, 
recurrence rates following conventional radiation therapy to the spine are high and 
patients frequently require retreatment for progressive or recurrent symptomatic disease 
(Klekamp and Samii, Chow E, Sze WM, Wu JS).    
  
More recently, a 1-5 day course of stereotactic radiosurgery has been utilized as a method 
of delivering a higher biological equivalent dose and hopefully reducing local recurrence 
rates particularly in patients with oligometastatic disease, radioresistant primaries, 
recurrence after prior radiation therapy, high risk of epidural disease, or who have social 
or clinical need for shortened treatment duration.  The safety and efficacy of SRS in 
patients with intact vertebral disease has been well established and is currently being 
compared to conventional radiation therapy in the context of a randomized controlled 
trial (RTOG 0631).  Data suggests that in spite of the smaller field size with SRS, rates of 
marginal failure are low and local control rates are high (Ahmed IJROBP 2011; Gerszten, 
Jin, Ryu, Chang, Ryu).  Although frequently performed in standard clinical practice, only 
3 small retrospective studies have been published to date exploring the efficacy of SRS in 
post-operative patients with resected spine metastases (Rock, Moulding, Gerszten), and 
the role and benefit of SRS in this setting remains uncertain.  
  
As systemic therapies improve and survival times increase for many cancers, it is likely 
that the incidence and prevalence of spinal metastases will increase as well, and 
improving management of spine metastases will be critical in minimizing pain, 
improving neurologic function, and potentially improving survival. The purpose of the 
study is to prospectively examine the efficacy of post-operative SRS boost in patients 
who have undergone surgical resection of metastatic spine disease.  
  
 
3.  
PATIENT SELECTION  
  
 
  
3.1  
Eligibility Criteria   
  
3.1.1    Age ≥12 years  
  

 
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3.1.2 Histologically proven solid tumor malignancy with metastasis to the spine. 
Diagnosis may be acquired from needle biopsy, cytology, surgical biopsy or 
resection.  
  
3.1.3 Radiographic evidence of spinal metastasis is required and may be obtained from 
radionuclide bone scans, computed tomography imaging, and magnetic resonance 
imaging. Other studies may be used with principal investigator approval, but plain 
radiograph (X-ray) alone is not sufficient.  
  
3.1.4 The patient must have undergone surgical resection (gross total, subtotal, or biopsy) 
of the spinal lesion(s) no more than 16 weeks prior to SRS treatment.  
  
3.1.5 Treating physician must deem that SRS is appropriate treatment for the metastatic 
spinal lesion(s).  
  
3.1.6 Each SRS target must be the equivalent of ≤3 vertebral levels  
  
3.1.7 The patient must have a Karnofsky Performance Score of 40 or greater (Appendix 
F).  
  
3.1.8 If a woman is of child-bearing potential, a negative urine or serum pregnancy test                          
must be demonstrated prior to treatment. Women of childbearing potential and                           
men must agree to use adequate contraception (hormonal or barrier method of                           
birth control; abstinence) for the duration of study participation and for up to 12                          
weeks following the study. Should a woman become pregnant or suspect she is                          
pregnant while participating in this study she should inform her treating physician                          
immediately.  
  
3.1.9 Ability to understand and the willingness to sign a written informed consent   
document.  
  
3.2 Exclusion Criteria  
  
3.2.1 Prior radiation or radiosurgery to the involved level of the spine  
  
3.2.2 Spine disease from leukemia, lymphoma or myeloma  
  
3.2.3 Patients with uncontrolled intercurrent illness including, but not limited to, ongoing 
or active infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit 
compliance with study requirements will be excluded.  
  
3.2.4 Pregnant women are excluded. We recommend that women of child-bearing 
potential use an acceptable method of birth control to avoid pregnancy for 6 

 
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months following stereotactic radiosurgery and that male subjects use effective 
contraception for the same period.  
  
  
  
 
3.3   
Inclusion of Women and Minorities  
  
Both men and women and members of all races and ethnic groups are eligible for this 
trial.    
  
  
 
4.  
REGISTRATION PROCEDURES  
  
Patients will be accrued from Johns Hopkins Medical Institutes in Baltimore, MD.  Contact 
information for the Principal Investigator is listed on the cover page.    
  
To register the patient, the following documents must be completed and faxed to 443-
2878354 or emailed the Study Coordinator.    
  
• 
Copy pathology report  
• 
Source documentation verifying eligibility  
• 
Eligibility checklist  
• 
Signed patient consent form  
• 
HIPAA authorization form  
  
If the patient is deemed eligible for the study, the Study Coordinator will register the patient 
and assign a study number.  
  
  
 
5.  
TREATMENT PLAN  
  
5.1 Treatment Planning  
  
5.1.1 Simulation  
  
  
All patients will be immobilized in a reproducible radiosurgery setup as 
deemed most appropriate by treating physician and clinical team.  Patients 
will undergo CT simulation preferably both with and without intravenous 
contrast.  If there is a contraindication to CT contrast it is ok to withhold it at 
the discretion of the treating physician.  In addition, unless there is a 
contraindication to MRI they will undergo MRI simulation including T1 with 
gadolinium, T2 and STIR axial and saggital sequences.  For precise 
delineation of the spinal cord, patients should undergo CT myelogram 
(optional) unless the spinal cord is adequately visualized on simulation MRI.  

 
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Scans should include at least 1 vertebral level above and below the involved 
levels.  
  
  
  
5.1.2 Image Fusion  
  
Following completion of simulation scans, the following datasets will be 
fused using the treatment planning software: 1) CT simulation; 2) CT 
myelogram (if performed); 3) pre-operative diagnostic scan; 4) MRI 
simulation.  The exact sequences of these scans to fuse will be at the 
discretion of the treating radiation oncologist and neurosurgeon.  If a patient 
is unable to undergo one of these scans he may remain on the protocol at the 
discretion of both the treating physician and principal investigator.    
  
5.1.3 Tumor and Object At Risk (OAR) Delineation  
  
Tumor and OARs will be delineated and approved by both the treating 
radiation oncologist and treating neurosurgeon.    
  
5.1.3.1    Gross Tumor Volume (GTV)  
  
GTV will defined as the residual disease as visualized on post-operative 
imaging.  
  
  
5.1.3.2    Clinical Target Volume (CTV)  
  
CTV will account for the GTV, tumor bed, and other sites of potential 
microscopic disease spread at the discretion of the treating physicians.  
The CTV should include areas of disease on pre-operative imaging as well 
as surgical findings as documented in operative notes and in personal 
communications with the surgeon.  Surgical incision does not need to be 
included in the treatment volume except in unique situations where it is 
believed to be a region at high risk of recurrence.  
  
5.1.3.3 Planning Target Volume (PTV)  
  
  
PTV will include the CTV plus approximately 1.5-2 mm geometric 
expansion.  PTV should be reduced as necessary so that the PTV does not 
extend into the cord contour.    
  
5.1.3.4   Object at risk (OAR)  
  
Adjacent OARs will be contoured on the simulation films.  The maximal 
dose constraints are as follows:  

 
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Spinal cord (as defined on CT myelogram plus 2 mm).  Should be 
delineated at least 1 vertebral body above and below PTV: 25 Gy to 0.1 cc   
  
Cauda equina (defined as thecal sac on CT myelogram without margin).   
Should be delineated at least 1 vertebral body above and below PTV: 25  
Gy to 0.1 cc  
  
Esophagus: 32.5 Gy  
  
Heart/pericardium: 35 Gy  
  
Great vessels: 55 Gy  
  
Trachea: 32.5 Gy  
  
Skin: 40 Gy  
  
Kidney: According to current Johns Hopkins Hospital standard SBRT 
practices  
  
5.1.4 Radiation Prescription and Dosimetry   
  
Patients will be treated to a total dose of 30 Gy with a once daily fractionation 
schedule of 6 Gy per fraction, administered Monday through Friday.  
Treatment may begin on any weekday with break for weekend, as long as the 
patient receives at least 2 fractions the first week.  Radiation treatment 
planning will be performed by a specialized dosimetrist or physicist.  Goal 
PTV coverage is >90% receiving >90% of prescription dose but coverage 
should be compromised as necessary to meet normal tissue constraints as 
outlined above and will not be considered a protocol deviation.  Final plan 
approval and spinal cord dose is at the discretion of the treating physician and 
final prescription dose may be reduced to meet spine cord constraints if 
deemed necessary by the treating physician (for example, in cases of epidural 
disease or disease abutting the spine cord).  
  
5.1.5 Equipment  
  
Patients will be treated using a megavoltage linear accelerator with nominal 
beam energy of 6 MV.  
  
 
5.1.6 Beam Verification  
  
  

 
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Either on-line cone beam CT guidance or orthogonal imaging will be used 
according to the standard Johns Hopkins radiosurgery protocol for precise 
patient setup.  Images will be reviewed and approved by a physician prior to 
initiation of treatment.    
  
  
  
  
5.1.7 Therapy Interruption  
  
For radiation therapy interruptions of up to and including 5 days, irradiation 
should be completed to the full prescribed dose.  On the last day, the total 
number of fractions and the reasons for interrupting therapy must be 
documented  
  
If radiation therapy interruption goes beyond 5 days, the patient will be 
removed from the protocol treatment.  Resumption and completion of 
treatment will then be at the discretion of the radiation oncologist in 
consultation with the principal investigator.  All patients who initiate protocol 
treatment will be followed per the study calendar.  
  
  
5.1.8 Risks of Radiation  
  
Short term toxicities of radiation therapy include fatigue, nausea, vomiting, 
diarrhea, hair loss in treated area, erythema or irritation of the skin, dry skin, 
difficulties with wound healing, difficulty or pain with swallowing, worsening 
or new neurologic deficits, injury to nerves or spinal cord causing disability 
and pain, weakness of limbs, bowel and bladder dysfunction, decrease in blood 
cell counts, edema of cord requiring steroids, damage to the baby if patient is 
or becomes pregnant, decreased sperm count, death.    
  
  
Long term toxicities include damage to spinal cord resulting in paralysis or 
death, damage to other normal structures such as kidney, lung, heart, liver, 
bowel, skin, esophagus, weakening of bone with increased risk of fracture, 
growth abnormalities of bones, muscles or other organs, second tumor or 
cancer caused by radiation.  
  
 
5.2  
Follow Up   
  
Patients will be followed until the time of data analysis for the study. At two years 
following completion of post-operative stereotactic radiosurgery, follow-up imaging 
will be performed only at the discretion of the treating physician. It is preferred that 
follow-up imaging and evaluation be performed at Johns Hopkins, but they may also 
be performed at outside facilities as necessary for insurance, scheduling, or other 
reasons. If a patient is unable to be seen at Johns Hopkins for follow-up we will 
collect patient reported toxicity via telephone.  

 
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Follow-up imaging should include CT and/or MRI followed by CT myelogram  
(optional) if the results of initial imaging studies are inconclusive and the patient has 
symptomatic evidence of progression.  
  
Follow-up evaluations will include a complete neurological exam and evaluation of 
the surgical wound, neurologic evaluation by the ASIA Impairment Scale 
(Appendix A), and pain evaluation by the 10 point visual analog scale (Appendix B) 
and MDACC brief pain inventory short form (Appendix C).  
  
 
5.3  
Toxicity  
  
Toxicity will be recorded according to the NCI Common Toxicity Criteria for 
Adverse Events (CTCAE) Version 4.  Early stopping will be considered for grade 4 
or greater spinal cord toxicity according to this scale that is attributable to the study 
intervention.  The criteria are available online at the Cancer Therapy Evaluation 
Program website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40  
  
Toxicity will also be monitored according to the RTOG/EORTC acute (Appendix D) 
and late (Appendix E) common toxicity assessments for CNS and spinal cord.  
Consideration for early stopping will be considered for grade 4 or greater spinal cord 
toxicity according to this scale attributable to study intervention.   
  
 
5.4  
Duration of Therapy  
  
In the absence of treatment delays due to adverse events, radiosurgery will be 
administered for a total of 5 fractions or until one of the following criteria applies:  
  
- Disease progression,  
- Intercurrent illness that prevents further administration of treatment,  
- Unacceptable adverse event(s),  
- Patient decides to withdraw from the study, or  
- General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator.  
  
 
5.5  
Criteria for Removal from Study  
  
Patients will be removed from study when any of the criteria listed applies:  
  
- Unacceptable adverse event(s),  
- Patient decides to withdraw from the study, or  
- General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator.  

 
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 The reason for study removal and the date the patient was removed must be 
documented in the Case Report Form. If a participant withdraws from the study, they 
will be followed for survival data.   
  
6. CORRELATIVE/SPECIAL STUDIES  
  
 
Not applicable.  
  
  
  

 
 
7.  STUDY CALENDAR  
Every effort should be made to adhere to the protocol timeline as closely as possible, but if studies are delayed or missed as a result of 
unavoidable conflicts such as hospitalization at an outside facility, deteriorating of patient status, or other adversity precluding presentation for 
evaluation, it will not be considered a protocol deviation.  
  
Pre- 
Study  
RT  
Follow-up Post RT*  
Mo 3  
Mo 6  
Mo 9  
Mo 12  
Mo 15  
Mo 18  
Mo 21  
Mo 24  
Q 6 Months9  
Surgical resection of spine lesion1  
X  
  
  
  
  
  
  
  
  
  
  
CT Myelogram (optional)  
X  
  
  
  
  
  
  
  
  
  
  
Radiographic evidence of spine mets  
X10  
  
  
  
  
  
  
  
  
  
  
Simulation  
X3  
  
  
  
  
  
  
  
  
  
  
Radiosurgery  
  
X  
  
  
  
  
  
  
  
  
  
Demographics  
X  
  
  
  
  
  
  
  
  
  
  
Medical history4 & Physical Exam  
X  
  
X  
X  
X  
X  
X  
X  
X  
X  
  
Vital signs and Weight  
X  
  
X  
X  
X  
X  
X  
X  
X  
X  
  
B-HCG11  
X2  
  
  
  
  
  
  
  
  
  
  
CBC w/Diff  
X  
  
X  
X  
  
  
  
  
  
  
  
Performance Status  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
ASIA Impairment Scale  
X2  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
Brief Pain Inventory & 10 Point Visual Analog 
Scale  
X2  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
NCI Common Toxicity Criteria  
X2  
X  
X8  
X8  
X8  
X8  
X8  
X8  
X8  
X8  
  
RTOG Acute/Late Morbidity Criteria5  
X2  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
CT Scan6 or MRI7  
  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
1Surgical resection includes gross total resection, subtotal resection, or biopsy. Margin status (negative, microscopically positive, gross disease) should be recorded.  Margin status should be based on 
the pathology report if possible, but when not recorded on pathology report may be based on the operative note, post-operative imaging and/or personal communications between the treating physician 
and surgeon  
2Baseline evaluations are to be conducted within 4 weeks prior to start of protocol therapy.  
3CT simulation is required for radiation treatment planning. CT simulation must be conducted within 8 weeks prior to protocol therapy.  MRI simulation for treatment planning is at the discretion of the 
treating physician.  

 
4Medical history should be a complete history at pre-study evaluation, but later histories will be interval histories only.    
5Use RTOG Acute Toxicity Criteria during RT and for first 6 months following completion of RT.  Use RTOG Late Toxicity Criteria at baseline and at scheduled intervals 6 months following completion 
of RT.  
6CT scan may be performed with or without contrast  
7Imaging which is delayed or missed as a result of the deterioration of the patient’s clinical condition or other adversity will not be considered a protocol violation.  
8If a patient is unable to be seen for a follow-up consult, we will assess the patient’s condition via telephone.  
9Patients will be followed until the time of data analysis for the study. At two years post radiosurgery, follow-up imaging will be performed only at the discretion of the treating physicians.  
10Section 3.1.3  
11Pregnancy test is required for women who are of child-bearing potential  
*Follow-up visits may be performed within + or – 1 month from the scheduled visit date.  
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8.  
MEASUREMENT OF SYMPTOMATIC PROGRESSION  
  
A patient will be considered to have symptomatic progression if: 1) there is radiographic 
evidence of progression on CT, MRI and/or CT myelogram based on direct comparisons by at 
least 2 members of the team of the most recently obtained radiographic images compared to 
the immediate pretreatment images AND 2) progressive symptoms defined as worsening 
neurologic function attributable to tumor growth at the level treated according to the ASIA 
Impairment Scale OR worsening pain attributable to tumor growth at the treated level 
according to the MDACC brief pain inventory (short form) defined as a new score ≥5 at the 
treated level of spine  
  
9.  
STATISTICAL CONSIDERATIONS  
  
9.1   Study Design/Endpoints  
  
  
  
  
  
  
  
  
9.1.1  Study Design  
  
This is a phase II trial evaluating the rate radiographic local recurrence following 
post-operative stereotactic radiosurgery boost in patients with metastatic solid 
malignancies with spine metastases status post resection.  
  
  
9.1.2 Endpoints  
  
9.1.2.1 Primary Endpoint  
  
Radiographic local recurrence at 12 months in each patient.  
Radiographic local recurrence (LR) will be defined as evidence of 
progressive disease on CT and/or MRI in the treatment volume or at the 
margin of the treatment field when compared to imaging studies prior to 
the post-operative radiosurgical boost.  The determination of local 
progression will be made by at least 1 radiation oncologist and 1 
neurosurgeon and confirmed by a neuro-radiologist and the Principal 
Investigator.  If equivocal, the lesion may be followed with serial short 
interval scans for further clarification.  If the equivocal lesion develops 
into local recurrence on serial scans, the timing of local recurrence will be 
backdated to the date of the first suspicious CT or MRI.  
  
9.1.2.2 Secondary Endpoints  
  
9.1.2.2.1 Time to radiographic local recurrence in each patient  
  
9.1.2.2.2 Re-treatment at 12 months in each patient   
Retreatment is defined as either radiosurgery, conventional 
radiation therapy or surgical intervention to the area that was 

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treated because of tumor progression in that region as defined by 
imaging studies according to the primary objective  
  
9.1.2.2.3 Symptomatic local recurrence at 12 months in each patient   
Symptomatic local recurrence requires 2 of the following:  
1) EITHER:  
NEW pain in treated region of ≥5 on the MD Anderson 
Cancer Center brief pain inventory OR:  
Worse performance on ASIA Impairment Scale  
  
AND:  
2) Evidence of local recurrence on imaging as defined in the 
primary objective  
  
9.1.2.2.4 NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4 and RTOG/EORTC acute and late common toxicity 
assessments for CNS and spinal cord for each patients.  
Radiation myelopathy is defined as grade 4 or greater spinal 
cord toxicity according to this scale.  
  
9.1.2.2.5 Examination of wound at each follow-up visit for each patient.  
Wound dehiscence is defined as a re-opening of the surgical 
wound which is independent from wound infection.  
  
9.1.2.2.6 Time to return to chemotherapy in each patient measured from 
first day of radiosurgery treatment  
  
9.1.2.2.7 Tumor histology in each patient  
  
9.2 Sample Size/Accrual Rate  
  
 
9.2.1 Sample Size  
  
A total of 35 patients will be enrolled in the protocol.  Assuming a 60% 
radiographic local control rate at 12 months with conventional radiation 
therapy (Rades 2009), our trial will need a total of 35 patients to yield 80% 
power detecting 20% absolute improvement (LC=80%) at an alpha level of 
0.05 (one-sided) to be statistically significant.   
  
  
             9.2.2  Accrual  
    We anticipate enrollment of approximately 1-2 patients per month to the         
protocol with accrual completed in approximately 24 months.  
  
9.2.2.4   Stratification Factors  
  
  
  
  
  
    There will be no stratification factors upon initial enrollment in the protocol.    

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9.3   
Statistical Analysis plan  
  
 
9.3.1  Primary:   
The proportion of patients who were absence of local recurrence (local control) at 12 
months after initial SRS will be estimated along with 90% confidence interval. The 
local recurrence is defined in section 9.1.2.1.   
  
9.3.2 Secondary:  
  
Time to radiographic local recurrence will be calculated from the date of initial SRS to 
the date of LR was documented. Probability of time to LR and median time to LR will 
be estimated using Kaplan-Meier method.   
  
A proportion of patient being retreated during first 12 months since initial SRS will be 
estimated along with 95% confidence interval.  
  
The symptomatic local recurrence rate at 12 months will be estimated along with 95% 
confidence interval using binomial distribution.  
  
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and 
RTOG/EORTC acute and late common toxicity assessments for CNS and spinal cord 
will be used for scoring toxicity and adverse events. The proportion of patients who 
experience grade 3 or above toxicities will be estimated, along with 95% confidence 
intervals by each type of toxicity. Observed sever adverse event associated with SRS 
including radiation myelopathy will be summarized using descriptive statistics.   
  
Time to return to chemotherapy will be calculated from the date of initial SRS to the 
starting date of chemotherapy. The chemotherapy date is censored if patient has not had 
chemotherapy at time the study database is closed for final analysis. Probability of time 
to return to chemotherapy will be estimated using Kaplan-Meier method.       
  
Patient’s tumor histology and wound healing will be summarized using descriptive 
statistics.   
     
10.   ADVERSE EVENTS AND RECORDING   
  
 
10.1  
Definition of Adverse Event (AE)  
  
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition during or following an exposure to a 
treatment, whether or not considered causally related to the treatment.  An undesirable 
medical condition may be symptoms (headache, nausea), signs (tachycardia, enlarged 
liver), or abnormal results of an investigation (MRI, laboratory finding).  In clinical trials, 

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from the time of signing an informed consent, an AE may include an undesirable medical 
condition, occurring at any time, even if no trial treatment has been administered.  
  
10.2      Radiation Related Adverse Events   
  
All radiation related adverse events will be recorded on the local toxicity case report 
forms.  
  
11.  
SERIOUS ADVERSE EVENTS (SAE) AND REPORTING  
  
 
11.1  
Serious Adverse Event  
  
11.1.1 Definition of Serious Adverse Event  
  
A serious adverse event is an AE occurring at any point during a clinical trial that 
fulfills one or more of the following criteria:  
  
● Results in death.  
  
● Is immediately life threatening.  
  
● Requires in-patient hospitalization or prolongation of existing hospitalization.  
  
● Is a congenital abnormality or birth defect.  
  
● Unexpected event that cause harm or place person at a greater risk of harm 
than was previously known or recognized, and which was possibly related to 
the research.  Unexpected means that the event was not described in the 
consent form or the event exceeded the expected severity.  
  
● Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above.  
  
11.2      SAE Reporting Guidelines for Johns Hopkins Hospital  
  
All SAE, with the exception of death, must be reported to the Johns Hopkins Hospital 
Institutional Review Board (JH-IRB) within 10 working days of the principal 
investigator learning of the event.  Reporting for the death of a patient which was 
unexpected (i.e.: not related to a risk of participation that was listed in the protocol or 
the consent document, and was more likely than not to be caused by the research 
procedure/intervention, must be reported to the JH-IRB within 3 working days of 
when the principal investigator receives the report of the death.  Reporting for death of 
a participant that was expected due to the nature of the patient’s underlying disease or 
condition, or identified as caused by a possible risk of the study 
procedure/intervention as described in this protocol or consent form, must be reported 

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to the JH-IRB within 10 working days from the time the principal investigator learns 
of the event.  If death occurs 30 days after the participant has stopped or completed 
their study treatment, the principal investigator does not have to report the death until 
the time of continuing review.    
12.  
   DATA AND SAFETY REPORTING/ REGULATORY CONSIDERATIONS  
  
 
12.1   
Data Quality Monitoring  
  
In addition to the ongoing quality assurance evaluations for each individual at the time 
of treatment, there will be regular internal monitoring meetings between the principal 
investigator, a medical oncologist, and the study coordinator to assess the data quality.  
These meetings will occur annually and a monitoring report of the findings will be 
submitted to the Data Safety Monitoring Committee on an annual basis.  Any protocol 
deviations or violations will be documented in the monitoring reports.  The review 
will include: consent forms, eligibility criteria, protocol compliance, treatment 
administration, toxicity reports, response, regulatory compliance, case report forms 
(completeness as well as verifying that information coded on the case report forms are 
supported by source documents), and all other materials related to the trial.  This is a 
Level I study under the SKCCC Data Monitoring Plan (date).  The Clinical Research 
Office QA group will assume external auditing responsibilities by performing an audit 
at the end of the first year and then periodically thereafter depending on the rate of 
accrual and prior audit results.  The Safety Monitoring Committee will review this 
trial for safety and data quality annually.  
  
 
12.2    
Data Safety Monitoring Plan  
  
This is a DSMP Level I study under the SKCCC Data Safety Monitoring Plan 
(12/6/2012).  The Clinical Research Office QA Group will perform an audit after  
the first subject has been treated and then periodically depending on the rate of  
accrual and prior audit results.  All trial monitoring and reporting will be reviewed  
annually by the SKCCC Safety Monitoring Committee.  
  
The PI is responsible for monitoring the study.  Data must be reviewed to assure the 
validity of data, as well as, the safety of the subjects.  The PI will also monitor the 
progress of the trial, review safety reports, and clinical trial efficacy endpoints and to 
confirm that the safety outcomes favor continuation of the study. The PI will also be 
responsible for maintaining the clinical protocol, reporting adverse events, assuring 
that consent is obtained and documented, reporting of unexpected outcomes, and 
reporting the status of the trial in the continuing renewal report submitted to the IRB 
and to the trial monitoring review group.  
  
 
12.3  
Data Reporting  
  
12.3.1 Method  
  
  
  
  
  

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Data will be collected on Case Report Forms (CRFs). These CRFs will be completed by 
the study coordinator. The CRFs for each subject will be kept in a separate research 
binder. Along with each completed CRF there will be corresponding source 
documentation filed for verification. The Principal Investigator, Research Study Nurse, 
and Study Coordinator will informally meet on a regular basis to make sure that the trial is 
progressing as mandated by the protocol. The CRO will audit this trial per their standards 
to ensure and verify that the protocol is be carried out according to specs as well as to 
verify that data included on subject CRFs are accurate. Exit reports generated as a result 
of these CRO audits will be forwarded to both the Safety Monitoring Committee as well  
as to the adjudicating IRB of record for review.  
  
  
  
  
 

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REFERENCES  
  
1. Klimo P Jr, Schmidt MH.  Surgical management of spinal metastases.  Oncologist 
2004;9(2):188-96.  
2. Cobb CA, 3rd, Leavens ME, Eckles N: Indications for nonoperative treatment of spinal 
cord compression due to breast cancer. J Neurosurg 1977;47:653-658.  
3. Jaffe W: Tumors and tumorous conditions of the bones and joints. Philadelphia, Lea & 
Febiger, 1958.  
4. Lenz M, Freid J: Metastases to the skeleton, brain and spinal cord from cancer of the 
breast and effect of radiotherapy. Ann Surg 1931;93:278-293.  
5. Sundaresan N, Krol G, DiGiacinto G: Metastatic tumors of the spine.; in Sundaresan N, 
Schmidek H, Schiller A (eds): Tumors of the spine: Diagnosis and clinical management. 
Philadelphia, WB Saunders, 1990  
6. Wong DA, Fornasier VL, MacNab I: Spinal metastases: The obvious, the occult, and the 
impostors. Spine 1990;15:1-4.  
7. Patchell RA, Tibbs PA, Regine WF, et al.  Direct decompressive surgical resection in the 
treatment of spinal cord compression caused by metastatic cancer: a randomized trial.  
Lancet 2005;366:643-8.  
8. Gilbert RW, Kim JH, Posner JB.  Epidural spinal cord compression for metastatic tumors: 
diagnosis and treatment.  Annal Neurol 1978;3:40-51.  
9. Black P.  Spinal metastases: current status and recommended guidelines for management.  
Neurosurg 1979;5:726-46.  
10. Greenberg HS, Kim JH, Posner JB.  Epidural spinal cord compression from metastatic 
tumor: diagnosis and treatment.  Annal Neurol 1980;8:361-6.  
11. Rodriguez M, Dinapoli RP.  Spinal cord compression with special reference to metastatic 
epidural tumors.  Mayo Clin Proc 1980;55:442-8.  
12. Sorensen PS, Boregesen SE, Rohde K, et al.  Metastatic epidural spinal cord compression:  
results of treatment and survival.  Cancer 1990;65:1502-8.  
13. Klekamp J and Samii H.  Surgical results for spinal metastases.  Acta Neurochir 
1998;140:957-967.  
14. Chow E, Harris K, Fan G, et al.  Palliative radiotherapy trials for bone metastases: a 
systematic review.  J Clin Oncol 2007;25(11):1423-1436.  
15. Sze WM, Shelley M, Held I, et al.  Palliative metastatic bone pain: single versus 
multifraction radiotherapy—a systematic review of randomized trials.  Cochrane Database 
Syst Rev 2004;2,CD004721.  
16. Wu JS, Wong R, Johnston M, et al.  Cancer Care Ontario Practice Guidelines Initiative 
Supportive Care Group.  Meta-analysis of dose-fractionation radiotherapy trials for the 
palliation of painful bone metastases.  Int J Radiat Oncol Biol Phys 2003;55(3):594-605.  
17. Ahmed KA, Stauder MC, Miller RC, et al.  Stereotactic body radiation therapy in spinal 
metastases.  Int J Radiat Oncol Biol Phys 2011;82(5):e803-e809.  
18. Gerszten PC, Burton SA, Ozhasoglu C, Welch WC: Radiosurgery for spinal metastases: 
Clinical experience in 500 cases from a single institution. Spine 2007;32:193-199.  
19. Jin JY, Chen Q, Jin R, Rock J, Anderson J, Li S, Movsas B, Ryu S: Technical and clinical 
experience with spine radiosurgery: A new technology for management of localized spine 
metastases. Technol Cancer Res Treat 2007;6:127-133.  

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20. Ryu S, Jin JY, Jin R, Rock J, Ajlouni M, Movsas B, Rosenblum M, Kim JH: Partial 
volume tolerance of the spinal cord and complications of single-dose radiosurgery. Cancer 
2007;109:628-636.  
21. Chang EL, Shiu AS, Mendel E, Mathews LA, Mahajan A, Allen PK, Weinberg JS, Brown 
BW, Wang XS, Woo SY, Cleeland C, Maor MH, Rhines LD: Phase I/II study of 
stereotactic body radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg 
Spine 2007;7:151-160.  
22. Rock JP, Ryu S, Shukairy MS, Yin FF, Sharif A, Schreiber F, Abdulhak M, Kim JH, 
Rosenblum ML: Postoperative radiosurgery for malignant spinal tumors. Neurosurgery 
2006;58:891-898.  
23. Moulding HD,  Elder JB, Lis E, et al.  Local disease control after decompressive surgery 
and adjuvant high dose single fraction radiosurgery for spine metastases.   J Neurosurg 
Spine 2010;13:87-93.    
24. Gerszten PC, Germanwala A, Burton SA, et al.  Combination kyphoplasty and spinal 
radiosurgery: a new treatment paradigm for pathologic fractures.  J Neurosurg Spine 
2005;3:296-301 

 
 

 
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APPENDIX B:  
10 point Visual Analog Scale  
  
  
  
  
  
  
  
  
 

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APPENDIX C:  
  

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MDACC Brief Pain Inventory (Short Form)  
  

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APPENDIX D:  
  
RTOG Acute Morbidity Scoring Criteria  
  
Organ  
Grade 0  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Skin  
No change over 
baseline  
Faint erythema, 
epilation, dry 
desquamation, or 
decreased sweating  
Tender or bright 
erythema, patchy 
moist desquamation, 
moderate erythema  
Confluent, moist 
desquamation other  
than skin folds, pitting 
edema  
Ulceration, hemorrhage, 
necrosis  
Eye  
No change over 
baseline  
Mild conjunctivitis 
with or without 
scleral injection, 
increased tearing  
Moderate  
conjunctivitis with or 
without keratitis 
requiring steroids 
and/or antibiotics, dry 
eye requiring  
artificial tears, iritis 
with photophobia  
Severe keratitis with 
corneal ulceration, 
objective decrease in 
visual acuity or in  
visual fields, acute 
glaucoma, 
panopthalmitis  
Loss of vision  
(unilateral or bilateral)  
Ear  
No change over 
baseline  
Mild external otitis 
with erythema, 
pruritis, secondary to 
dry desquamation not 
requiring medication.  
Audiogram 
unchanged over 
baseline.  
Moderate external 
otitis requiring topical 
medication, serous 
otitis media, 
hypoacusis on testing 
only  
Severe external otitis 
with discharge or moist  
desquamation, 
symptomatic 
hypoacusis, tinnitus, not 
drug related  
Deafness  
CNS  
No change over 
baseline  
Fully functional status 
with minor neurologic 
findings, no 
medications needed  
Neurologic findings 
present sufficient to 
require home care.  
Nursing care may be 
required.   
Medications including 
steroids and/or anti-
seizure agents  
Neurologic findings 
requiring hospitalization 
for initial management  
Serious neurologic 
impairment which 
included paralysis, 
coma, or seizures, 
despite medications.  
Hospitalization required  
Hematologic WBC 
(x1000)  
≥ 4.0  
3.0 - <4.0  
2.0 - <3.0  
1.0 - <2.0  
<1.0  
Platelets (x 
1000)  
≥ 100  
75 - <100  
50 - <75  
25 - <50  
<25 or spontaneous 
bleeding  
Neutrophils  
≥ 1.9  
1.5 - <1.9  
1.0 - <1.5  
0.5 - <1.0  
<0.5 or sepsis  
Hematocrit (%)  
≥ 32  
28 - <32  
<28  
Packed cell transfusion 
required  
N/A  
  
  
  
  
  
  
  
  
  
  
  
  

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APPENDIX E:  
RTOG Late Radiation Morbidity Scoring Criteria  
  
  
Organ  
Grade 
0  
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  
Skin  
None  Slight 
atrophy, 
pigmentation 
change, some 
hair loss  
Patchy 
atrophy, 
moderate 
telangiectasia, 
total hair loss  
Marked  
atrophy, gross 
telangioectasia  
Ulceration  
Death 
directly 
related 
to late 
radiation 
effect  
Subcutaneous 
Tissue  
None  Slight 
induration and 
loss of  
subcutaneous  
fat  
Moderate  
fibrosis but 
asymptomatic.  
Slight field 
contracture.  
<10% linear 
reduction  
Severe 
induration and 
loss of  
subcutaneous 
tissue.  Field 
contracture 
>10% linear 
measurement  
Necrosis  
Spinal Cord  
None  Mild  
L’Hermitte’s 
syndrome  
Severe  
L’Hermitte’s 
syndrome  
Objective 
neurologic 
findings at or 
below cord 
level treated  
Mono-, para-, 
quadra-plegia  
Brain  
None  Mild 
headache, 
slight lethargy  
Moderate 
headache, 
great lethargy  
Severe 
headaches, 
severe CNS 
dysfunction  
(partial loss of 
power or 
dyskinesia)  
Seizures, 
paralysis, coma  

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Eye  
None  Asymptomatic  
cataract, 
minor corneal 
ulceration of 
keratitis  
Symptomatic  
cataract, 
moderate 
corneal 
ulceration, 
minor 
retinopathy or 
glaucoma  
Severe  
keratitis, 
severe, 
retinopathy or 
detachment, 
severe 
glaucoma  
Panopthalmitis, 
blindness  
  
  
  
  
  

 
  
36  
APPENDIX F:  
  
Performance Status Criteria  
  
  
ECOG Performance Status Scale  
  
  
Karnofsky Performance Scale  
Grade  
Descriptions  
Percent  
Description  
0  
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.  
100  
Normal, no complaints, no evidence 
of disease.  
90  
Able to carry on normal activity; 
minor signs or symptoms of disease.  
1  
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).  
80  
Normal activity with effort; some 
signs or symptoms of disease.  
70  
Cares for self, unable to carry on 
normal activity or to do active work.  
2  
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about 
more than 50% of waking hours.  
60  
Requires occasional assistance, but 
is able to care for most of his/her 
needs.  
50  
Requires considerable assistance and 
frequent medical care.  
3  
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.  
40  
Disabled, requires special care and 
assistance.  
30  
Severely disabled, hospitalization 
indicated.  Death not imminent.  
4  
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.  
20  
Very sick, hospitalization indicated. 
Death not imminent.  
10  
Moribund, 
fatal 
processes 
progressing rapidly.  
5  
Dead.  
0  
Dead.  
  
  

 
  
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