Phase II Protocol Evaluating Stereotactic Body Radiation Therapy for Oligometastatic Disease of the Bone
Phase: PHASE2
Conditions: Bone Cancer
Sponsor: Dana-Farber Cancer Institute

Page 1
DF/HCC Protocol #: 16-207
TITLE:  Phase II Protocol Evaluating Hypofractionated-Stereotactic Body Radiation Therapy 
for Oligometastatic Disease of the Bone.
Coordinating Center:
Dana-Farber/Brigham and Women’s Cancer Center
*Principal Investigator (PI):
Tracy Balboni, MD, MPH
Brigham and Women’s Hospital/ Dana-Farber Cancer Institute
TBalboni@partners.org
BIDMC Site PI:
Lauren Hertan, MD
Beth Israel Deaconess Medical Center
lhertan@bidmc.harvard.edu
Other Investigators:
Monica Krishnan, MD
Brigham and Women’s Hospital/ Dana-Farber Cancer Institute
MKrishnan@partners.org
Statistician:
Study Coordinator:
Yu-Hui Chen
Claudia Roldan
Dana Farber Cancer Institute
Brigham and Women’s Hospital
ychen@jimmy.harvard.edu
croldan@bwh.harvard.edu
Responsible Research Nurses:
Responsible Data Manager: 
Beverly Spicer, RN
Claudia Roldan
Brigham and Women’s Hospital
Brigham and Women’s Hospital
bspicer@lroc.harvard.edu
croldan@bwh.harvard.edu
Eileen Mann, RN
Brigham and Women’s Hospital
emann@bwh.harvard.edu
NCI-Supplied Agent(s): N/A
Other Agent(s): N/A
IND #: N/A
IND Sponsor: N/A
Protocol Type / Version # / Version Date: Revised Protocol, V8.0, October 10, 2018

DF/HCC Protocol #:16-207
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INDEX
SCHEMA.........................................................................................................................................5
1.
Introduction..........................................................................................................................6
1.1
Study Disease...........................................................................................................6
1.2
Rationale ..................................................................................................................7
2.
OBJECTIVES......................................................................................................................8
2.1
Study Design............................................................................................................8
2.2
Primary Objectives...................................................................................................8
2.3
Secondary Objectives...............................................................................................8
3.
PARTICIPANT SELECTION.............................................................................................8
3.1
Eligibility Criteria....................................................................................................8
3.2
Exclusion Criteria ....................................................................................................9
3.3
Inclusion of Women and Minorities ......................................................................10
4.
PRETREATMENT EVALUATIONS/MANAGEMENT.................................................10
4.1
Table of acceptable time intervals of pretreatment assessments ...........................10
4.2
Information regarding washout from prior therapies.............................................10
5.
REGISTRATION PROCEDURES ...................................................................................10
5.1
General Guidelines for DF/HCC Institutions ........................................................10
5.2
Registration Process for DF/HCC Institutions.......................................................11
5.3
General Guidelines for Other Investigative Sites ..................................................11
5.4
Registration Process for Other Investigative Sites.................................................11
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................11
5.6
Criteria for Taking a Participant Off Study ...........................................................12
6.
RADIATION THERAPY..................................................................................................12
6.1
Dose Specifications: SBRT....................................................................................12
6.2
Technical Factors...................................................................................................13
6.3
EBRT Localization, Simulation, and Immobilization ...........................................13
6.4
Treatment Planning/Target Volumes.....................................................................13
6.5
Critical Structures ..................................................................................................14
6.6
Treatment Verification...........................................................................................16
6.7
Quality Assurance..................................................................................................16
6.8
Radiation Quality Assurance Reviews...................................................................17
6.9
Radiation Adverse Events......................................................................................17
6.10
Radiation Adverse Event Reporting ......................................................................19
7.
DRUG THERAPY.............................................................................................................19
8.
SURGERY.........................................................................................................................19

DF/HCC Protocol #:16-207
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9.
OTHER THERAPIES........................................................................................................19
10.
TISSUE/SPECIMEN SUBMISSION................................................................................19
11.
PARTICIPANT ASSESSMENTS.....................................................................................20
11.1
Definitions..............................................................................................................20
11.2
Methods/Requirements for assessments ................................................................20
11.3
Response Criteria...................................................................................................22
12.
DATA COLLECTION ......................................................................................................22
12.1
Demographic, Disease and Treatment Information...............................................22
12.2
Additional Data Collection ....................................................................................23
*For pre-menopausal women for whom pregnancy is a possibility (i.e., have not 
undergone a hysterectomy)....................................................................................24
12.3
Data Storage...........................................................................................................24
13.
STATISTICAL CONSIDERATIONS...............................................................................24
13.1
Study Design/Primary Endpoint ............................................................................24
13.2
Sample Size, Accrual Rate and Study Duration ....................................................24
13.3
Stratification Factors..............................................................................................25
13.4
Interim Monitoring Plan ........................................................................................25
13.5
Analysis of Primary Endpoints..............................................................................25
13.6
Analysis of Secondary Endpoints..........................................................................25
14.
REGULATORY CONSIDERATIONS.............................................................................26
14.1
Data Safety Monitoring..........................................................................................26
14.2
Multicenter Guidelines...........................................................................................26
14.3
COLLABORATIVE AGREEMENTS LANGUAGE...........................................26
15.
PUBLICATION PLAN .....................................................................................................26
APPENDIX A
PERFORMANCE STATUS CRITERIA ..................................................29
APPENDIX B
STUDY PARAMETERS...........................................................................30
APPENDIX C
ADVERSE EVENT REPORTING REQUIREMENTS............................31
PROCEDURES FOR AE AND SAE RECORDING AND REPORTING.......................32
ADVERSE EVENT REPORTING REQUIREMENTS....................................................33
Reporting to the study sponsor: N/A .................................................................................33
Reporting to the Institutional Review Board (IRB)...........................................................33
Reporting to the Food and Drug Administration (FDA): N/A ..........................................34
Reporting to the NIH Office of Biotechnology Activities (OBA): N/A............................34
Reporting to the Institutional Biosafety Committee (IBC): N/A.......................................34
Reporting to Hospital Risk Management...........................................................................34
MONITORING OF ADVERSE EVENTS AND PERIOD OF OBSERVATION ...........34
APPENDIX D: SYMPTOM AND PAIN BASELINE ASSESSMENT.......................................35

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APPENDIX E: SYMPTOM AND PAIN ASSESSMENT IN THE PAST 24 HOURS ...............39
APPENDIX F: PAIN AND SYMPTOM ASSESSMENT IN THE PAST 7 DAYS (FOLLOW-
UP).....................................................................................................................................44
APPENDIX G: SYMPTOM AND PAIN ASSESSMENT IN THE PAST 24 HOURS (LONG-
TERM FOLLOW-UP).......................................................................................................50

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SCHEMA
COHORT 1: 
COHORT 2: 
Patients with life expectancy of at least 3 
months with metastatic disease in the 
bone and/or spine requiring re-irradiation
Treatment: SBRT to site(s) of disease 
occurring in the bone or spine
Consultation: including baseline 
evaluation and informed consent
Simulation: CT simulation scan; 
dedicated diagnostic imaging (MRI) to 
be done within 21 days of initiation of 
treatment, as applicable
Follow-Up:
1 week post treatment
- Telephone, email, or in person follow-up
1 month post treatment: 
- Telephone, email, or in person follow-up
3 months post treatment: 
- Telephone, email, or in person follow-up
- Imaging scans (CT and/or MRI as per 
treating physician’s discretion)
6 months post treatment (and every 6 months 
through year 2 and then annually years 3 
through 5):
- Telephone, email, or in person follow-up
- Imaging scans (CT and/or MRI) at 
clinician’s discretion
Patients with life expectancy of at least 3 
months with oligometastatic disease with 
spine and/or bone metastases
Treatment: SBRT to up to 3 sites of 
disease occurring in the bone or spine
Consultation: including baseline 
evaluation and informed consent
Simulation: CT simulation scan; 
dedicated diagnostic imaging (MRI) to 
be done within 21 days of initiation of 
treatment, as applicable
Follow-Up:
1 week post treatment
- Telephone, email, or in person follow-up
1 month post treatment: 
- Telephone, email, or in person follow-up
3 months post treatment: 
- Telephone, email, or in person follow-up
- Imaging scans (CT and/or MRI as per 
treating physician’s discretion)
6 months post treatment (and every 6 months 
through year 2 and then annually years 3 
through 5): 
- Telephone, email, or in person follow-up
- Imaging scans (CT and/or MRI) at 
clinician’s discretion

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1. INTRODUCTION
1.1
Study Disease
1.1.1
Bone Metastases 
Bone is one of the most common sites of metastatic disease, affecting up to 70% of patients with 
advanced breast or prostate cancer and 15-30% of patients with carcinoma of other sites.1  Bone 
metastases can be a significant source of morbidity, with symptoms including pain, fracture, 
hypercalcemia, and spinal cord or nerve root compression.  Treatment for bone metastases is 
often a collaborative effort between multiple practitioners including surgeons, radiation 
oncologists, medical oncologists, pain medicine specialists and palliative medicine clinicians.  
External beam radiation (EBRT) is often used for management of bone metastases and has been 
shown in multiple trials to offer symptom relief and local control.2,3  However, with standard 
palliative fractionation, either single fraction or multiple fractions, for metastatic disease there 
are moderate rates of toxicity, particularly fatigue and nausea/vomiting.3–5
1.1.2
Oligometastatic disease with long anticipated life expectancy
An oligometastatic state is considered a transitional state between localized and widespread 
systemic disease,6 and though variably construed, is typically defined as patients with <4 
metastatic lesions.  Although some investigators hypothesize that these patients may still be 
curable, at the very least data support that these patients have life expectancies that are long, 
typically median survivals greater than 1-2 years.7,8  With standard EBRT dosing among patients 
with longer life expectancies, there is a very real risk of local recurrence that can cause 
significant morbidity.  In studies evaluating all patients with bone metastases, the median 
survival is approximately 9 months.3  In patients with oligometastatic disease whose life 
expectancy surpasses this, local recurrence can be a source of significant morbidity.  In a 
subgroup analysis of the Dutch Bone Metastasis Study specifically looking at patients who 
survived for longer than a year, around half of patients treated with EBRT for symptomatic bone 
metastases had progressive pain at a mean duration of 17-18 weeks from radiation.9  As these 
patients are living longer, local control of metastatic disease that could cause morbidity becomes 
even more important. 
In patients with long anticipated life expectancies as indicated by (1) oligometastatic disease 
and/or (2) a prognostic algorithm estimating a median life expectancy greater than 12 months, 
hypofractionated radiation therapy / stereotactic body radiation therapy (SBRT), a technique that 
conforms very closely to the target, thereby enabling high target doses and minimizing dose to 
normal surrounding tissue, can be a useful tool. Multiple publications looking at SBRT in 
oligometastatic disease have shown promising outcomes.  These studies have treated 
oligometastatic sites throughout the body including lung, liver, lymph node and bone metastases.  
Among these patients with long overall survival (median survival of approximately 24 months), 
good local control (approximately 75% at 2 years) and low rates of toxicity (<10% risk of grade 
3 toxicity) have been reported.7,8 

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1.1.3
Re-irradiation
Many anatomic structures have maximum cumulative tolerable doses; higher doses can cause 
severe toxicity.  Re-irradiation, particularly in the spine, presents technical challenges due to 
safety concerns in re-irradiating normal tissues.  The spinal cord has a tolerance that, if exceeded, 
can lead to cord myelopathy and/or spinal nerve radiculopathy10 causing significant morbidity.  
SBRT allows high doses to be given in a highly conformal nature, minimizing dose to the spinal 
cord while still allowing the tumor to receive a high dose of radiation.  A publication from Beth 
Israel Hospital reported their use of SBRT for re-irradiation of epidural spinal metastases.  In 
patients with a local recurrence who were previously treated with EBRT (3 Gy x 10), SBRT was 
given (either 8 Gy x 3 if the tumor did not touch spinal cord or 5-6 Gy x 5 when tumor abutted 
the cord).  They reported very low toxicity (40% grade 1 fatigue and 20% grade 2 nausea), 
adequate pain relief (65%), and good local control (93% of the patients had stable or improved 
disease).11
1.2
Rationale
We hypothesize that SBRT as used in this trial will allow high doses in only a few fractions to 
very conformal fields with acceptable toxicity.  There are small, preliminary, published series of 
SBRT showing good local control and minimal toxicity using SBRT for metastasis in the spine 
and non-spine bone.  A series from MD Anderson Cancer Center which treated 63 patients with 
spinal metastasis with fractionated SBRT (either 6 Gy x 5 or 9 Gy x 3) showed no grade 3 or 
higher neurologic toxicity, low rates of overall toxicity (4 patients with grade 3 toxicity), and a 1-
year freedom from tumor progression of 84%.12  A series from Memorial Sloan-Kettering Cancer 
Center that treated 93 patients with spinal metastasis using single-fraction SBRT (18-24 Gy) 
showed a local failure rate of 7.5% at two years.13  The Mayo Clinic published their series of 
SBRT for non-spine oligometastatic disease showing excellent local control (92% at 1 year and 
86% at 2 years) and no grade 3 or higher toxicities.  Of the toxicity they observed, fatigue and 
pain flare were the most common.14  Given the good local control and low rates of toxicity, there 
are two clinical situations where SBRT can be a useful tool in patients with metastatic disease: 
(1) patients with excellent life expectancies heralded either an oligometastatic state or (2) those 
who need adequate re-irradiation dose delivery to a previously treated bony site.  These clinical 
applications are based on the goals of providing adequate dose to (a) control the lesion for the 
patient’s long life expectancy and (b) ensure normal tissue sparing to minimize treatment risks, 
particularly in the re-irradiation setting.
The rationale behind the current study is the premise that in patients with metastatic disease who 
have a good life expectancy, the use of SBRT may increase local control and decrease morbidity, 
both from side effects of treatment as well as from disease progression. 
Given the aforementioned data showing good local control and minimal toxicity using SBRT in 
oligometastatic disease as well as metastatic disease in the bone and spine, we propose a Phase II 
protocol to further evaluate the local control, patient quality of life outcomes, and toxicities of 
SBRT in the management of bony metastatic disease in its two major clinical applications: (a) 
patients with an oligometastatic state and a prognostic estimate of greater than 3 months and (b) 
re-irradiation of previously irradiated bony metastatic lesions. 

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2. OBJECTIVES
2.1
Study Design
This Phase II protocol will enroll patients on two cohorts. The first will comprise patients with 
oligometastatic disease and a life expectancy of at least 3 months. Oligometastatic state is 
defined by ≤3 active sites of disease, including the primary site. Life expectancy will be 
determined by agreement of both the Chow et al.15 and TEACHH16 models, indicating a median 
life expectancy of >3 months.  The second cohort will be comprised of patients with life 
expectancy >3 months (as indicated by the Chow et al.15 and TEACHH16 models) who require 
re-irradiation of spinal disease. All patients will be treated with SBRT and followed and assessed 
for local control, local progression-free survival, progression free survival, overall survival, 
treatment toxicity and quality of life. The two cohorts will be evaluated separately.
2.2
Primary Objectives
To determine the 6-month local control rates of patients in both cohorts, evaluated separately.
2.3
Secondary Objectives
1. To assess patient reported quality of life, symptom control, and satisfaction with treatment 
using a modified version of the MD Anderson Symptom Inventory (MDASI) 
2. To assess the rate of acute and chronic toxicity (e.g., fracture, myelopathy, radiculopathy)  
3. To determine the median time to local failure, 1-year local progression-free survival, 1 year 
progression-free survival and 1-year overall survival in both cohorts.
4. To determine the 6-month local control rates, median time to local failure, 1-year local 
progression-free survival, and 1-year overall survival of patients in both cohorts, evaluated 
together. 
3. PARTICIPANT SELECTION
3.1
Eligibility Criteria 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study:
Both cohorts: 
-
≥18 years of age
-
ECOG performance status ≤2
-
Pathologically proven metastatic solid tumor (non-hematologic malignancy) of the bone 
(spine or non-spine bone)
-
Bony metastatic lesions must be ≤8 cm in maximum dimension and evaluable on either a 
CT or MRI scan; metastatic lesions in the spine must involve ≤3 contiguous vertebral 

DF/HCC Protocol #:16-207
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bodies
-
No other active malignancy within the past 2 years, except for non-melanoma skin 
cancers or carcinoma in situ of the cervix
-
Ability to understand and the willingness to sign a written informed consent document
-
Surgery to the lesion in question is allowed if size criteria outlined above are met
-
Not currently pregnant or breast feeding
Cohort 1: Oligometastatic state
-
Oligometastatic state is defined by ≤ 3 active sites of disease, including the primary site
-
Agreement of both the Chow et al.15 and TEACHH16 models, indicating a median life 
expectancy of >3 months  
-
Among patients with multiple sites of metastatic disease, the other sites that will not be 
treated on this protocol have either been previously treated or are planned for local 
treatment 
Cohort 2: Re-irradiation
-
Previous radiation in the current area of disease requiring radiation
-
Life expectancy of >3 months as defined by agreement of both the Chow et al.15 and 
TEACHH16 models  
3.2
Exclusion Criteria
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study. 
-
SBRT target size >8 cm in maximum diameter (or >100 cc in volume)
-
Hematologic malignancies (including lymphoma, multiple myeloma)
-
Prior RT of greater dose intensity than 100 Gy2 based on a biological effective dose 
(BED) calculation [BED (Gy2) = nd x (1+d/α/ß; where n=number of fractions, d=dose per 
fraction, α/ß=2)]
-
Epidural tumor <2 mm from spinal cord
-
Requirement of active receipt of systemic therapies concurrent with SBRT (concurrent 
hormonal therapies are allowed)
-
Inability to lie flat and still for treatment delivery despite anti-anxiety and/or pain 
medications
-
Non-English speakers are excluded from this study due to use of questionnaires which 
have not been validated in other languages.
-
Patients lacking the capacity to describe their symptoms are excluded as that precludes 
them (or anyone on their behalf) from filling out the validated questionnaires about 
symptoms/toxicity. 
-
Pregnant women are excluded from this study because radiotherapy has the potential for 
teratogenic or abortifacient effects.
-
Individuals with a history of a different malignancy are ineligible except for the 
following circumstances: if they have been disease-free for at least 2 years and are 
deemed by the investigator to be at low risk for recurrence of that malignancy; or if 
diagnosed and treated within the past 2 years for cervical cancer in situ or basal cell or 

DF/HCC Protocol #:16-207
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squamous cell carcinoma of the skin.
3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
4. PRETREATMENT EVALUATIONS/MANAGEMENT
4.1
Table of acceptable time intervals of pretreatment assessments
Assessment
Acceptable time interval 
prior to initiation of SBRT 
(days)
History & physical exam
28
Performance status
28
Adverse event evaluation
28
Pregnancy test*
21
Radiologic evaluation
21
QOL questionnaire 
28
* For pre-menopausal women for whom pregnancy is a possibility (i.e., have not undergone a 
hysterectomy) 
4.2
Information regarding washout from prior therapies
For non-hormonal therapies, the study requires a wash out period of 3 half lives of the systemic 
agent. However it is also acceptable to begin sooner if there is agreement between the treating 
radiation oncologist and the medical oncologist based on discussion of data regarding particular 
biologic properties of the systemic agent, data regarding its safety when given with radiation 
therapy, and/or the needs of the patient. 
5. REGISTRATION PROCEDURES
5.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would cause 

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treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible. 
5.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  
5.3
General Guidelines for Other Investigative Sites
N/A
5.4
Registration Process for Other Investigative Sites
N/A
5.5
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue as 
detailed in section 6.1 or until one of the following criteria applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the treatment 
regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
The research team updates the relevant Off Treatment/Off Study information in OnCore. 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Tracy Balboni, MD at pager # 39896.

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5.6
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in REDCap. 
The research team updates the relevant Off Treatment/Off Study information in OnCore. 
6. RADIATION THERAPY
Protocol treatment must begin within 4 weeks after enrollment on the study.
6.1
Dose Specifications: SBRT 
6.1.1
Prescription Dose: To be determined by the treating physician from the following 
previously employed regimens according to the clinical circumstances of each case 
(e.g. meeting normal-tissue constraints)

Spine: 18 Gy x 1, 9 Gy x 3, or 6 Gy x 5

Non-Spine Bone: 18Gy x 1, 9 Gy x 3 or 6 Gy x 5
6.1.2
Dose will be normalized such that at least 95% of the Planning Target Volume (PTV) 
receives the prescription dose and will be scored as per protocol. The minimum 
allowable dose within the PTV is >80% of the prescribed dose to a volume that is at 
least 1 cc.
6.1.3
Participants will be treated entirely via SBRT and shall receive prescription doses to the 
PTV (with the above constraints). All attempts should be made to deliver the PTV dose 
with the above heterogeneity constraints with adherence to the critical structure 
parameters listed below in Table 1. 
 See Section 6.5 below for specifics regarding when to implement a dose reduction.

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6.1.4
In the retreatment of the spinal cord and/or cauda equina, BED calculations will be 
employed to ensure retreatment dose does not exceed BED=140 Gy2 (alpha/beta = 2). 
In retreatment to other normal tissues, the prior dose received to the organ(s) at risk will 
be taken into account together with dose constraints given in Table 1 to formulate final 
dose constraints tailored to each patient scenario.  
6.2
Technical Factors
6.2.1
RT will be delivered with megavoltage equipment at energies ≥6 MV.
6.2.2
All treatments will be delivered on a dedicated stereotactic linear accelerator that 
includes dedicated imaging and a robotic couch top. Imaging can include either live 
imaging with orthogonal kV beams as part of a CyberKnife Treatment Delivery System 
or onboard conebeam CT imaging and orthogonal 2D/3D matching.
6.3
EBRT Localization, Simulation, and Immobilization
Simulation will be CT-based in all cases. The use of intravenous or intrathecal contrast at 
the time of simulation is allowed at the discretion of the treating physician, but is 
generally not required. Participants will be positioned on a flat tabletop with a customized 
immobilization for stabilization and setup reproducibility. CT images should be acquired 
at a slice thickness of 1-1.25 mm. For rib lesions which may move with respiratory 
motion, a 4D CT or inspiration/expiration breath hold, will be utilized for target 
delineation. Target volumes (Section 6.4.1) and normal critical structures (Section 6. 5) 
will be defined in the slices in which they are visualized. The treating radiation 
oncologist will review the fusion of the diagnostic MRI scan to the CT simulation scan, if 
applicable. 
6.4
Treatment Planning/Target Volumes
6.4.1
The definition of volumes will be in accordance with the International Commission on 
Radiation Units and Measurements (ICRU) Report #50: Prescribing, Recording, and 
Reporting Photon Beam Therapy.
6.4.1.1
The gross tumor volume (GTV) is defined by the physician as all known disease as 
defined by the planning CT and any other diagnostic imaging obtained.
6.4.1.2
The clinical target volume (CTV) is the GTV plus areas considered to contain 
microscopic disease, delineated by the treating physician. This is optional at the 
treating radiation oncologist’s discretion. This is in accordance with the International 
Spine Radiosurgery Consortium Consensus Guidelines for Target Volume Definition 
in Spinal Stereotactic Radiosurgery.17

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6.4.1.3
The planning target volume (PTV) will provide a 0-2 mm margin around the CTV to 
compensate for the variability of treatment setup and internal organ motion. This is in 
accordance with the International Spine Radiosurgery Consortium Consensus 
Guidelines for Target Volume Definition in Spinal Stereotactic Radiosurgery.17
6.4.1.4
For conventional linac based SBRT, the ICRU reference points are to be located in 
the central part of the PTV and, secondly, on or near the central axis of the beams. 
Typically these points should be located on the beam axes or at the intersection of the 
beam axes.
6.4.1.5
Normal critical structures are to be defined on the treatment planning CT by the 
physician and/or treatment planner and will be based on the site being treated. Max 
doses are based on a point volume of 0.035 cc.
For example, for a thoracic spine metastasis around the level of the carina, the organs 
at risk would include: 
o
Heart
o
Right lung, left lung, total lung
o
Esophagus
o
Bronchial structures
o
Great vessels
o
Spinal cord
o
Skin
6.4.1.6
Volumetric modulated arc therapy (VMAT) or CyberKnife will be used to deliver 
conformal therapy to the entire PTV while limiting dose to critical structures as 
defined above. 
6.5
Critical Structures 
Critical structure dose constraints shall remain consistent with Table 1 above. While 
every effort should be made to deliver prescription doses to the PTV as specified while 
adhering to these constraints, it is recognized that certain anatomical factors may prevent 
this.
Excluding spinal cord and cauda equina, for purposes of compliance, up to a 5% absolute 
increase in the volume of a critical structure receiving greater than the specified dose will 
be considered “variation acceptable,” without a protocol deviation. Any increase in 
critical structure volume greater than 5% receiving more than the specified dose will be 
considered a “deviation unacceptable”.  For spinal cord and cauda equina, any dose 
higher than stated in Table 1 will be considered “deviation unacceptable”. It is at this 
point that a dose reduction should be considered.

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Table 1. Critical Structure Dose Constraints (from Benedict et al.18)

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6.6
Treatment Verification
6.6.1
A radiation oncologist will be present for set-up verification and treatment delivery of 
every fraction.
6.6.2
Orthogonal isocenter verification films (or images) must be obtained prior to each 
treatment. For VMAT the intensity profiles of each beam must be independently 
verified and compared to the planned field intensity. These images are to be archived 
by the institution for later review if requested by the study chair.
Set-up on the treatment machine will be verified using kV-kV imaging and cone-beam 
CT with robotic couch to match anatomy in all translational and rotational 
discrepancies. Exactrac imaging, kV-kV 2D/3D matching, or repeat cone-beam CT will 
be used between each rotational arc of radiation treatment to ensure stability of set-up 
and make ongoing set-up adjustments.
The CyberKnife Treatment Delivery System uses kV orthogonal X-ray imaging for live 
motion tracking to ensure stability of set-up and for motion correction throughout 
treatment. 
6.6.3
Management of Radiation Dose to the Patient from Daily Localization
According to the literature, the estimates of patient dose per imaging study for various 
imaging systems vary considerably. The doses are in the range of 0.1 cGy for 
BrainLab’s ExacTrac planar kV-systems and can be considered negligible compared 
with doses from MV portal imaging and kV and MV CT. The doses from CyberKnife 
kV X-ray imaging is estimated to be in the range of 0.025-0.2 cGy. The doses from 
helical MV CT scans on a tomotherapy unit are estimated to be in the range of 1 to 3 
cGy, similar to doses reported for kV cone beam CT on the Elekta Synergy machine. 
The doses for MV cone beam CT vary from 1 cGy to 10 cGy depending on the field 
size. Thus, the doses for 3D imaging systems used one time each day are in the range of 
0.1 to 10 cGy and can contribute from 0.06 to 6% to a daily dose of 1.8 Gy. As a 
technique of controlling participant dose, it is recommended that a QA procedure be 
established at each participating institution to verify the accuracy of the image 
registration software on a daily basis. This QA check should be performed by the 
therapists operating a particular treatment device and is aimed at reducing the use of 
repeat imaging to check that the registration software has functioned properly when a 
shift of participant position is carried out. Additionally, it is not recommended that an 
institution use a daily imaging technique that delivers greater than 3cGy/day to the 
patient. This limit dictates that repeat imaging on a particular day is held to a minimum 
when systems that deliver up to 3 cGy per study are used.
6.7
Quality Assurance
6.7.1
Radiation Documentation Requirements

DF/HCC Protocol #:16-207
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The institution will archive treatment prescription and verification images for later 
review by the study chair if requested. At least one port film or pretreatment alignment 
film per field along with the digitally reconstructed radiographs (DRRs) from the 
treatment planning program or, alternatively, a simulation verification radiograph shall 
be acquired and kept for evaluation if requested except where geometrically 
impractical. For CyberKnife SBRT, a screenshot of the alignment of the day of 
treatment X-Ray (Camera Image) to the DRR (Synthetic Image) will be acquired and 
kept for evaluation if requested. 
6.7.2
Compliance Criteria
Cases which meet criteria as stated in Section 6.1.2 will be scored as per protocol. 
The minimum allowable dose within the PTV is >80% of the prescribed dose to a 
volume that is at least 1 cc. Cases in which this small volume of at least 1 cc receives a 
minimum dose that is <80% but >75% will be scored as a “deviation acceptable”. 
Cases in which 1 cc receives less than 75% of the prescribed dose will be scored as a 
“deviation unacceptable”. However, if this is what is required to keep the spinal cord or 
cauda equina within the maximum dose constraint, as specified above, this variation is 
considered “deviation acceptable”.
6.7.2.1
Acceptable dose heterogeneity will be as follows: The maximum dose volume of the 
PTV must not be shared by a normal critical structure. (Section 6.4.1.5). The 
maximum point dose to normal critical structures outside the PTV including the 
unspecified tissue should not exceed dose specified in Table 1. The treating physician 
must carefully consider the tolerance dose/volume to each critical normal structure 
and unspecified tissue.
6.8
Radiation Quality Assurance Reviews 
RT quality assurance reviews will be ongoing and performed by the co-investigators and 
will be reviewed by the PI.
6.9
Radiation Adverse Events
6.9.1
All participants will be seen weekly by their treating radiation oncologist while 
undergoing therapy. The specific symptoms/side effects to be assessed will depend on 
the area(s) of the body undergoing treatment. A comprehensive list is below (see 
section 6.9.2); however every patient will not be assessed for every symptom if it is not 
relevant to the site(s) being treated. 
Every patient will be assessed for: 

Pain – at the site(s) being treated

Pain – at other locations

Tiredness

Skin reddening or irritation

DF/HCC Protocol #:16-207
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
Skin peeling 

Nausea/Vomiting

Hair loss
6.9.2
Comprehensive list of possible toxicities. The anticipated toxicity for each individual 
patient is very dependent on the location and the anticipated toxicities will be discussed 
in detail with the patient.  These are listed in both the standard consent form the patient 
will sign for radiation treatment and the protocol-specific consent form as well as 
below. 
Short Term Reactions (Appearing during radiation therapy or within 1 month 
thereafter; temporary, generally resolving within 2-3 months):
Common (> 20%):

Tiredness 

Skin reddening & irritation that is reversible

Loss of hair in the area of treatment

Loss of taste

Mild sore throat and difficulty swallowing 

Decreased blood counts that are reversible

Weight loss that is reversible

Pain flare
Rare (≤ 5%): 

Nausea 

Diarrhea 

Bladder irritation 

Fever and chills (within the first few hours of radiation) 

Severe esophagitis 
Long Term Reactions (Appearing months after radiation; permanent, does not 
resolve)
Uncommon (10-20%):

Mild scarring of skin or muscle without changes in function

Mild scarring of the lung not requiring treatment

Bone fractures
Rare (≤ 5%):

Loss of hair in the treatment area

Damage to spinal cord or nerves resulting in pain or other sensory 
changes

Damage to spinal cord or nerves resulting in loss of motor function

DF/HCC Protocol #:16-207
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
Damage to the esophagus limiting function
Extremely Rare (≤ 1%):

Tumors caused by radiation

Damage to bone or muscle limiting function

Sterility

Damage to the heart
6.10
Radiation Adverse Event Reporting
All adverse event reporting requirements are found in Appendix C.
6.11     Toxicity Assessment and Management
 
Any observations with respect to symptoms or side effects that are possibly, probably, or 
definitely related to SBRT treatment will be followed for AE reporting.
7. DRUG THERAPY
N/A – No medications will be given as part of this study.  Medications for pain relief or other 
reasons may be given at the discretion of the treating physician and are covered in Section 9 
below.
8. SURGERY 
Surgery to the metastatic site(s) is allowed, but is not required, prior to enrollment on this study. 
The study does not include any surgical procedures.  
9. OTHER THERAPIES
The following may be given at the discretion of the treating radiation oncologist:

Dexamethasone – to be taken pre-treatment to prevent pain flare 

Benzodiazepines – as needed for anxiety during the SBRT planning and/or treatment

Pain medications – as needed to control pain and allow the patient to be comfortable 
while undergoing treatment
10. TISSUE/SPECIMEN SUBMISSION
N/A: No tissue or specimens will be collected as part of this study nor will any previously 
collected tissue or specimens be used in any way as part of this study. 

DF/HCC Protocol #:16-207
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11. PARTICIPANT ASSESSMENTS
11.1
Definitions
11.1.1 Target Lesion(s) – Spine or non-spine bone metastatic site(s) being treated with SBRT. 
Up to a total of 3 lesions, as per the inclusion criteria. These will be recorded and 
measured at baseline. A sum of the longest diameter (LD) for all target lesions will 
be calculated and reported as the baseline sum LD. The baseline sum LD will be 
used as the reference by which to characterize the objective tumor response.
11.1.2 Non-Target Lesion(s) – Any other lesions, either sites of stable disease or sites that 
have been or will be treated with other modalities than SBRT. Presence or absence of 
these lesions will be determined at the discretion of the treating radiation oncologist in 
collaboration with other treating physicians. 
11.2
Methods/Requirements for assessments
11.2.1 Target Lesion(s): Will be evaluated via CT and/or MRI at the discretion of the treating 
physician. The same diagnostic modality(ies) will be used for assessment at each of the 
specified time points. A diagnostic radiologist reading the scan will be asked to 
measure the lesion(s) in the largest dimensions. 
11.2.2 Non-Target Lesion(s): Will be evaluated via CT, PET/CT, and/or MRI at the discretion 
of the treating physician. 
11.2.3 Toxicity Assessment
Toxicity assessments will be done using the CTEP Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) which is identified and located on the 
CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
11.2.4 QOL Assessment
QOL Assessment will be done using a modified MD Anderson Symptom Inventory (see 
Appendices D, E, F, and G), which is a validated questionnaire. The modified version to be 
used includes MDASI core questions, a spinal symptom inventory, and additional items 
pertinent to radiation therapy for palliation of bone metastases and pain.  
11.2.5 Timing of Assessments
Baseline assessments will be done for the target lesion, non-target lesion(s), pre-existing 
toxicity and QOL.  Participants’ first assessment post-treatment will occur at 1 week (± 3 
days) to assess for QOL. Participants will then undergo another evaluation at 1 month (± 1 

DF/HCC Protocol #:16-207
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week) to assess for QOL. Participants will then be evaluated at 3 months (± 4 weeks) with 
imaging (CT or MRI as per treating physician) done at the time of follow-up (± 2 weeks). 
Participants will then be evaluated at 6 months (± 2 months) and every 6 months thereafter 
through year 2 (± 3 months) and annually years 3-5 (± 6 months), with imaging (CT or MRI 
as per treating physician) done at the time of follow-up (± 2 weeks). We will attempt to 
coordinate all visits and scans with the patient’s other medical providers to avoid duplicate 
visits or scans and minimize inconvenience to the patient and protocol violations. Please see 
Appendix B for additional study parameters. 
Pre-
Study Treatment
Week 
1b
Month 
1c
Month 
3d
Month 6e
Every 6 months 
after month 6 
through year 2f
Annually 
Years 
3-5g
Target Lesion(s) X
X
X
X
X
Toxicity 
Assessment
X
Xh
X
X
X
X
QOL 
Assessment
X
Xa
X
X
X
X
X
X
a: On mid-point and last day of radiation
b: ± 3 days
c: ± 1 week
d: ± 4 weeks
e: ± 2 months
f: ± 3 months
g: ± 6 months
h: During on treatment visit
Note: The baseline “pre-study” questionnaire can be given anytime between the initial consult 
appointment and the first radiation therapy treatment, as long as the patient has not yet received 
radiation
Note: Imaging will be done at clinicians’ discretion. 
Participants will be given the option on each survey to decline. 
Administration of questionnaires will be determined, as follows, by the time of follow-up. 
Questionnaire Version
Timeline
Appendix Reference
Symptom and Pain Baseline Assessment
Prior to initial RT
Appendix D
Symptom and Pain Assessment in the 
Past 24 Hours
Mid-point and on last day of 
treatment
Appendix E
Symptom and Pain Assessment in the 
Past 7 Days
1 week and 4 week follow-up
Appendix F
Symptom and Pain Assessment, Long-
Term Follow-Up
3 months, every 6 months for 
2 years, and annually from 
years 3 to 5
Appendix G

DF/HCC Protocol #:16-207
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11.3
Response Criteria
11.3.1 Evaluation of Target Lesion(s): Each target lesion will be evaluated independently 
given that this is a local treatment only.  Please note that the following criteria are 
adopted from the RECIST criteria for solid tumors for use in bony tumors, with tumor-
related bony changes plus any soft tissue component (where applicable) evaluated to 
assess the size of the lesion and to determine response as noted below. 

Complete Response (CR): Disappearance of the target lesion.

Partial Response (PR): At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesion, taking as reference the baseline sum LD.

Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter 
(LD) of target lesion, taking as reference the smallest sum LD recorded since 
the treatment started or the appearance of one or more new lesions. 

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD since the 
treatment started.

Unknown (UN): Assessment of target lesion cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given.
11.3.2 Local failure is defined as the presence of biopsy-proven recurrent cancer at the treated 
site or radiologic scans that demonstrate progression at that site. Local control is 
defined as the absence of local failure. Participants will be followed for 5 years after the 
completion of treatment or until death.
11.3.3 Local Progression-free survival (LPFS) is defined as the duration of time from registration 
to time of local failure or death. Participants will be followed for 5 years after the 
completion of treatment or until death.
11.3.4 Progression-free survival (PFS) is defined as the duration of time from registration to 
time of any progression or death. Participants will be followed for 5 years after the 
completion of treatment or until death.
11.3.5 Overall Survival is defined as the time between registration and death. Participants will 
be followed for 5 years after the completion of treatment or until death.
12. DATA COLLECTION
12.1
Demographic, Disease and Treatment Information
The following information will be recorded for each patient: 

Age

Race/Ethnicity

Marital Status

Diagnosis (pathology)

Site of original disease

Date of original diagnosis

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
Date of diagnosis of metastatic disease (if different from above)

Stage at diagnosis

Sites and number of metastases

Status of disease at each site (complete response, stable, progressing)

Previous chemotherapy treatment(s)

Previous radiation treatment(s)

Previous surgeries

Recent hospitalizations

Specialties of physicians involved in their cancer care (i.e. palliative medicine, pain 
medicine, etc).

Date of initial consultation with palliative care (if applicable)

Charleson Co-morbidity Score
12.2
Additional Data Collection
Maximum Time to Data Collection
Prior to 
1st 
treatment
Within 1 
Week after 
completion 
of 
treatment
2 weeks 
after 
completion 
of 
treatment
5 Weeks 
after 
completion 
of 
Treatment
4 Months 
after 
completion 
of 
treatment
10 months after 
completion of 
treatment, every 
6-9 months 
through year 2, 
then annually 
through year 5
Informed Consent
X
History
X
Medication Review
X
X
X
X
Physical exam (Ht, Wt, VS)
X
Performance Status
X
X
X
X
Pre-existing condition or 
Adverse event evaluation
X
X
X
X
Tumor measurements
X
X
X
Radiologic evaluation
X
X
X
B-HCG*
X
QoL questionnaire
X
X
X
X
X
X
Other malignancy related 
treatments undergone since 
last visit
X
X
SBRT GTV, CTV, PTV (as 
applicable) Dose Volume 
Information
X
Critical Normal Tissue Dose 
Volume Data
X

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Treatment Delivery 
Information
X
*For pre-menopausal women for whom pregnancy is a possibility (i.e., have not 
undergone a hysterectomy)
12.3
Data Storage
Data will be identified only by medical record number when it is entered into a REDCap 
(Research Electronic Data Capture) Database which will be only accessible to investigators and 
study staff on this protocol. REDCap is a secure, HIPAA compliant web-based application 
hosted by the Partners HealthCare Research Computing, Enterprise Research Infrastructure & 
Services (ERIS) group. The database design will be customized to suit the needs of this study. 
The system offers easy data manipulation with audit trails, reports for monitoring and querying 
participant records, and an automated export mechanism to common statistical packages. 
Additionally, REDCap will enable us to provide each study member with only the minimum 
necessary access to the database and PHI with ultimate control of this access at the PI’s 
discretion. Data may also be entered into an Excel or Access database file that will be stored on a 
password-protected secure Partners folder that is only accessible to investigators and study staff 
on this protocol.
13. STATISTICAL CONSIDERATIONS
13.1
Study Design/Primary Endpoint
The primary objective of this study is to evaluate the 6-month local control rate of SBRT. The 6-
month local control rate is the proportion of patients free of local failure at 6 months. Local 
failure is defined as the presence of biopsy-proven recurrence or radiologic scans that 
demonstrate progression at the treated sites. 
Two cohorts of patients will be enrolled. Cohort 1 is comprised of patients with oligometastatic 
disease defined as ≤3 active sites of disease, including the primary site. Cohort 2 comprises 
patients who require re-irradiation of spinal disease. The primary analysis includes eligible and 
treated patients from both cohorts evaluated separately.
13.2
Sample Size, Accrual Rate and Study Duration
We planned to enroll a total of 100 patients, 50 per cohort, into this study in the original design. 
As the accrual was rapid and about half of the patients were prostate cancer patients in cohort 1, 
the sample size for cohort 1 was increased from 50 to 100 to allow patients with other histologies 
to participate in this trial. 
The primary endpoint is local control rate at 6 months. Assuming a cumulative incidence of local 
failure at 6 months is 10%, the 6-month local control rate is 90% with 90% exact binomial 
confidence intervals of [83.6%, 94.5%] and [80.1%, 96.0%] for cohorts 1 and 2, respectively. 
The confidence intervals are narrow enough to provide a precise estimate local control rate. With 
the sample size increase in cohort 1, we can also estimate the local control rates with better 
precision for the subsets of patients with either prostate cancer or other histologies  To be 
conservative, unevaluable patients (patients without valid assessments demonstrating free of 
local failure at 6 months) will be considered as failures in the analysis although we do not 

DF/HCC Protocol #:16-207
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anticipate many unevaluable patients on this study.
Approximately 250 patients per year are treated with conventional external beam radiation 
therapy for bone metastases in our department, with approximately one third being spine 
metastases. We estimate that approximately 10% of those 250 would be eligible for this study, 
yielding about 2 patients per month. Additionally, we are currently treating an average of 4 
patients per month with SBRT for spinal metastases (75% eligible for cohort 1 and 25% eligible 
for cohort 2). It is expected that 70% of these patients will participate. Hence, we anticipate to 
accrue 3 and 1-2 patients per month for cohorts 1 and 2, respectively, and the accrual will be 
completed, in total for both cohorts, over about 3 years.
13.3
Stratification Factors
N/A
13.4
Interim Monitoring Plan
N/A
13.5
Analysis of Primary Endpoints
Proportion of patients with local control at 6 months in each cohort will be calculated along with 
the 90% exact binomial confidence intervals. This point estimate will serve to inform future 
study design.
13.6
Analysis of Secondary Endpoints
Secondary endpoints include, in each cohort, local progression-free survival (LPFS), 
progression-free survival (PFS), overall survival (OS) and patient reported quality of life (QOL) 
using the modified MD Anderson Symptom Inventory (MDASI).
LPFS is defined as the time from registration to local disease progression or death, whichever 
occurs first. PFS is defined as the time from registration to disease progression or death, 
whichever occurs first. Patients alive without documented progression will be censored at the 
date of last disease assessment. OS is defined as the time from registration to death or the date 
last known alive. Kaplan-Meier estimates will be used to describe event-time distributions.
Patient reported QOL, symptoms and satisfaction will be assessed using the modified MDASI 
general questionnaire and spine inventory at baseline, during treatment and all follow-up visits. 
The distributions of mean core symptom severity and mean interference score over time will be 
reported. The mean symptom severity of spine tumor will also be reported for patients with a 
spine site being treated on this study. The primary analysis for the QOL study is to evaluate the 
change in QOL from baseline to 3 months in this patient population using Wilcoxon signed rank 
test. Assuming 80% of patients complete the baseline and 3-month QOL assessments and a two-
sided test with alpha=0.05, the study will have about 89% power to detect a difference of 0.3 
standard deviation among all patients. All patients who receive at least one fraction of SBRT will 

DF/HCC Protocol #:16-207
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be monitored for toxicity, and the percent of patients with various toxicities will be tabulated for 
each cohort. The acute and chronic toxicity rates will also be reported. The probability of 
observing one or more toxicities with a true rate of 5% is 99.4% and 92.3% for cohort 1 and 
cohort 2, respectively.
14. REGULATORY CONSIDERATIONS
14.1
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team.
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; dose-limiting toxicity information; all grade 2 
or higher unexpected adverse events that have been reported; summary of all deaths occurring 
with 30 days of intervention for Phase I or II protocols; any response information; audit results, 
and a summary provided by the study team. Other information (e.g., scans, laboratory values) 
will be provided upon request. 
14.2
Multicenter Guidelines
N/A
14.3
COLLABORATIVE AGREEMENTS LANGUAGE
N/A 
15. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 

DF/HCC Protocol #:16-207
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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; some 
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).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
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.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to 
bed or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

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APPENDIX B
STUDY PARAMETERS
Assessments
Pre-Study
Simulation
 Radiation 
Treatment
Follow-Up (1)
Informed Consent and Registration
X
History/physical/vital signs
X
X
Performance Status
X
X
Pregnancy Test (B-HCG)
X
Diagnostic CT or MRI (at 
discretion of treating physician)
X(2)
Imaging study (CT or MRI to be 
determined by treating physician) 
X(3)
Toxicity Assessment
X
X(6)
X
QOL questionnaire
X
X(4)
X(5)
(1) Follow up schedule: initial evaluation at 1 week after completion of radiation 
therapy (via telephone, in person or email), then at 1 month after completion (via 
telephone, in person or email), 3 months, 6 months and every 6 months thereafter 
through year 2 (in person, telephone or email), then annually through year 5. Visits 
can be scheduled within a pre-specified time window around the anticipated date.
(2) Baseline imaging is to be done within 21 days of start of first fraction of radiation
(3) Follow up imaging is to be done within 2 weeks before or after scheduled follow 
up visit. 
(4) On mid-point and last day of radiation
(5) QOL questionnaire to be completed within 2 weeks of follow up visit. 
(6) During on treatment visit

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APPENDIX C
ADVERSE EVENT REPORTING REQUIREMENTS
DEFINITIONS:
Adverse Event (AE)
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or any procedure 
specified in the protocol, even if the event is not considered to be related to the study. 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests. 
Serious adverse event (SAE)
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that: 

Results in death

Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form.

Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry, are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier than planned).

Results in persistent or significant disability/incapacity. Disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions.

Is a congenital anomaly or birth defect; or

Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
Events not considered to be serious adverse events are hospitalizations for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures

elective or pre-planned treatment for a pre-existing condition that did not worsen

emergency outpatient treatment for an event not fulfilling the serious criteria outlined above 
and not resulting in inpatient admission

respite care

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Expectedness: Adverse events can be 'Expected' or 'Unexpected.' 

Expected adverse event
o
Expected adverse events are those that have been previously identified as resulting 
from administration of the agent. For the purposes of this study, an adverse event is 
considered expected when it appears in the current adverse event list or is included in 
the informed consent document as a potential risk.  
o
Refer to Section 6.9 for a listing of expected adverse events associated with the 
study agent.

Unexpected adverse event
o
For the purposes of this study, an adverse event is considered unexpected when it 
varies in nature, intensity or frequency from information provided in the current 
adverse event list or when it is not included in the informed consent document as a 
potential risk.  
Attribution

Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows:
o
Definite – The AE is clearly related to the study treatment.
o
Probable – The AE is likely related to the study treatment.
o
Possible – The AE may be related to the study treatment. 
o
Unlikely - The AE is doubtfully related to the study treatment.
o
Unrelated - The AE is clearly NOT related to the study treatment.
PROCEDURES FOR AE AND SAE RECORDING AND REPORTING
Investigators will assess the occurrence of AEs and SAEs at all participant evaluation time points 
during the study. 
All AEs and SAEs whether reported by the participant, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be recorded 
in the participant’s medical record and on the appropriate study-specific case report forms. 
The descriptions and grading scales found in the CTEP Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. The CTEP 
Active Version of the CTCAE is identified and located on the CTEP website at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All appropriate treatment areas should have access to a copy of the CTEP Active Version of 
CTCAE.

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ADVERSE EVENT REPORTING REQUIREMENTS
Serious Adverse Event Reporting
All serious adverse events that occur after the initial dose of study treatment, during treatment, or 
within 30 days of the last dose of treatment must be reported to the DF/HCC Overall Principal 
Investigator on the local institutional SAE form. This includes events meeting the criteria 
outlined in Serious Adverse Event (as above), as well as the following:

Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at least possibly 
related/associated with the intervention.

All Grade 4 (life-threatening or disabling) events that are unexpected or not specifically 
listed in the protocol as not requiring reporting.

All Grade 5 (fatal) events while the participant is enrolled and actively participating in the 
trial OR when the event occurs within 30 days of the last study intervention. 
Note: If the participant is in long term follow up, report the death at the time of continuing 
review. 
Participating investigators must report each serious adverse event to the DF/HCC Overall 
Principal Investigator within 24 business hours of learning of the occurrence. In the event that 
the participating investigator does not become aware of the serious adverse event immediately 
(e.g., participant sought treatment elsewhere), the participating investigator is to report the event 
within 24 hours after learning of it and document the time of his or her first awareness of the 
adverse event. Report serious adverse events by telephone, email or facsimile to:
Tracy Balboni, MD MPH
617-525-6687 or 617-632-4621
TBALBONI@LROC.HARVARD.EDU
Within the following 24-48 business hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the 
event has resolved or continues, if and how the event was treated, and whether the participant 
will continue or discontinue study participation.
Non-Serious Adverse Event Reporting 
Non-serious adverse events will be reported to the DF/HCC Overall Principal Investigator on the 
toxicity Case Report Forms.  
Reporting to the study sponsor: N/A
Reporting to the Institutional Review Board (IRB)
Investigative sites within DF/HCC will report all serious adverse events directly to the DFCI 
Office for Human Research Studies (OHRS).

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Reporting to the Food and Drug Administration (FDA): N/A
Reporting to the NIH Office of Biotechnology Activities (OBA): N/A 
Reporting to the Institutional Biosafety Committee (IBC): N/A
Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any subject safety 
reports or sentinel events that require reporting according to institutional policy.
MONITORING OF ADVERSE EVENTS AND PERIOD OF OBSERVATION
All adverse events, both serious and non-serious, and deaths that are encountered from initiation 
of study intervention through the study intervention period and up to 30 days after the last study 
intervention should be followed to their resolution, or until the participating investigator assesses 
them as stable, or the participating investigator determines the event to be irreversible, or the 
participant is lost to follow-up. The presence and resolution of AEs and SAEs (with dates) 
should be documented on the appropriate case report form and recorded in the participant’s 
medical record to facilitate source data verification. 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately evaluate the 
SAE report (e.g., hospital discharge summary, consultant report, or autopsy report). 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. Participating investigators should notify the DF/HCC 
Overall Principal Investigator of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to 
the study.

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APPENDIX D: SYMPTOM AND PAIN BASELINE ASSESSMENT 

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APPENDIX E: SYMPTOM AND PAIN ASSESSMENT IN THE PAST 24 HOURS

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APPENDIX F: PAIN AND SYMPTOM ASSESSMENT IN THE PAST 7 DAYS (FOLLOW-UP)

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APPENDIX G: SYMPTOM AND PAIN ASSESSMENT IN THE PAST 24 HOURS (LONG-TERM 
FOLLOW-UP)

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