A Prospective Randomized Phase II Study of 1 vs 2 Fractions of Palliative Radiation Therapy for Patients With Symptomatic Bone Metastasis
Phase: NA
Conditions: Malignant Neoplasm, Metastatic Malignant Neoplasm in the Bone, Pain
Sponsor: Wake Forest University Health Sciences

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
 
 
 
Principal Investigator: 
Doris R. Brown, MD 
Department of Radiation Oncology 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
 
Co-Investigators: 
 
 
Stefan C. Grant, MD, JD, MBA 
Section on Hematology and Oncology 
Wake Forest School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
Michael D. Chan, MD 
Department of Radiation Oncology 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
Bart Frizzell, MD 
Department of Radiation Oncology 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
Kathryn Greven, MD 
Department of Radiation Oncology 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
Yusuke Shiozawa, M.D., Ph.D. 
Cancer Biology 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
 
Jeffrey Willey, MD 
Department of Radiation Oncology 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
 
 
 
 
A. William Blackstock, MD 
Department of Radiation Oncology 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
Ryan T. Hughes, MD 
Department of Radiation Oncology 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
Biostatistician: 
 
 
Ralph B. D’Agostino Jr, PhD 
Comprehensive Cancer Center of Wake Forest University 
 
 
 
Primary Study Coordinator: 
Angela Howell, RN 
Comprehensive Cancer Center of Wake Forest University 
 
 
 
Regulatory Contact:  
 
Alexandra Bolick 
Comprehensive Cancer Center of Wake Forest University 
 
 
Protocol Editor: 
 
 
Bonny Morris, MSPH, BSN, RN 
Comprehensive Cancer Center of Wake Forest University 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participating Institution: 
 
CCCWFU 
 
 
Version Date: 
 
 
06/04/2019 
01/17/2019 
06/12/2018 
09/26/2017 
03/16/2017 
02/20/2017 
02/07/2017 
10/31/2016 
07/15/2016 
 
 
 
 
 
04/12/2016 
Amended: 
 
 
 
03/12/21 
Confidential

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 3 of 45 
 
Table of Contents 
SCHEMA .............................................................................................................................................................. 5 
1.0Introduction and Background ........................................................................................................................... 6 
1.1 
Rationale for Proposed Treatment Dose and Schedule ........................................................................ 6 
2.0Objectives ........................................................................................................................................................ 6 
2.1 
Primary Objective .................................................................................................................................. 6 
2.2 
Secondary Objectives ........................................................................................................................... 6 
2.3 
Exploratory Objective ............................................................................................................................ 7 
3.0Patient Selection .............................................................................................................................................. 7 
3.1 
Inclusion Criteria ................................................................................................................................... 7 
3.2 
Exclusion Criteria .................................................................................................................................. 8 
3.3 
Inclusion of Women and Minorities ....................................................................................................... 8 
4.0Methods ........................................................................................................................................................... 8 
4.1 
Study Design ......................................................................................................................................... 8 
4.2  
Registration Procedures........................................................................................................................ 9 
4.3 
Data Collection ...................................................................................................................................... 9 
4.4 
Radiation Therapy ............................................................................................................................... 11 
5.0Study Outcomes and Study Measures .......................................................................................................... 12 
5.1 
Primary Outcome ................................................................................................................................ 12 
5.2 
Secondary Outcomes.......................................................................................................................... 12 
5.3 
Exploratory Outcome .......................................................................................................................... 12 
6.0 .................................................................................................................................................................. Treatment Plan
 ............................................................................................................................................................................ 13 
6.1 
Study-Related Activities ...................................................................................................................... 13 
6.2 
Treatment Administration .................................................................................................................... 14 
6.3 
Duration of Therapy ............................................................................................................................ 14 
6.4 
Duration of Follow Up ......................................................................................................................... 14 
7.0  Measurement of Effect ................................................................................................................................. 15 
8.0  Adverse Events List and Reporting Requirements ...................................................................................... 15 
8.1 
Adverse Event List for Radiation Treatment ....................................................................................... 15 
8.2 
Adverse Event Characteristics ............................................................................................................ 16 
8.3 
DSMC SAE Reporting Requirements ................................................................................................. 16 
8.4  
WFUHS IRB AE Reporting Requirements .......................................................................................... 16 
9.0 Blood Collection for Translational Research and Tissue Banking ................................................................ 17 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 4 of 45 
10.0 Data Management ...................................................................................................................................... 18 
11.0Statistical Considerations ............................................................................................................................ 18 
11.1 
Analysis of Primary Objective ............................................................................................................. 18 
11.2 
Analysis of Secondary Objective ......................................................................................................... 18 
11.4 
Estimated Accrual Rate....................................................................................................................... 19 
11.5 
Estimated Study Length ...................................................................................................................... 19 
11.6 
Interim Analysis Plan .......................................................................................................................... 19 
References ......................................................................................................................................................... 23 
Appendix A – Protocol Registration Form ........................................................................................................... 24 
Appendix B – Subject Eligibility Checklist ........................................................................................................... 25 
Appendix C – Race & Ethnicity Verification Form ............................................................................................... 27 
Appendix D – Mandatory DSMC SAE Reporting Guidelines .............................................................................. 28 
Appendix E – Baseline Data Collection Form ..................................................................................................... 34 
Appendix F – Treatment Data Collection Form .................................................................................................. 36 
Appendix G – Patient Questionnaire .................................................................................................................. 37 
Appendix H – Numerical Rating Pain Scale (NRPS) .......................................................................................... 41 
Appendix I – CCCWFU 01416 Adverse Event (AE) Log .................................................................................... 42 
Appendix I – CCCWFU 01416 Adverse Event (AE) Log .................................................................................... 43 
Appendix J – Re-Treatment Data Form .............................................................................................................. 44 
Appendix K – Post-Treatment Imaging ............................................................................................................... 45 
 
 
 
 
 
 
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 5 of 45 
SCHEMA 
 
 
 
 
Consent and pre-study data collection 
Randomization 
Arm A: 8 Gy x 1 fraction for a total dose 
of 8 Gy in a single dose 
Arm B: 8 Gy x 2 fractions for a total dose 
of 16 Gy 3-7 days 
•
Retreatment rate assessed at 6 months post-
treatment completion 
•
Pain and narcotic use assessed at 1, 2, 3, and 6 
months post-treatment completion 
•
Quality of life assessed at 3 and 6  months 
•
Treatment related toxicity assessed at 1, 2, 3, 
and 6 months. 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 6 of 45 
1.0 
Introduction and Background 
 
Bone metastases are not only the most common cause of cancer-related pain, but palliative 
radiotherapy is prescribed most frequently to relieve symptoms. External beam radiotherapy (EBRT) is 
a well-established and efficacious method of palliating painful bone metastases (1). Numerous 
randomized trials have evaluated the potential benefits of certain dose fractionations of EBRT (1–7), yet 
controversy remains over the optimal treatment schedule. For example, RTOG 97-14 randomized 898 
patients with breast or prostate cancer to receive 8 Gy in 1 fraction or 30 Gy in 10 fractions. There was 
no significant difference in complete or partial pain relief at 3 months. Patients in the single dose group 
had a significantly higher retreatment rate at 3 months (18% vs. 9%) but a statistically lower toxicity rate 
(10% vs 17%) (8). An economic analysis of this trial calculated quality-adjusted life year survival to be 
7.3 months vs 9.5 months in the two treatment arms. The authors concluded that single fraction was 
less expensive and more cost-effective (9). Chow et al conducted a systematic review and meta-
analysis of randomized palliative radiotherapy trials comparing single fractions to multiple fractions. 
Twenty-five randomized trials were identified with no significant differences in pain response rates.  The 
likelihood of re-treatment was 2.6-fold higher (95% CI, 1.92-3.47; P < 0.00001) in single fraction EBRT 
arm patients (10). 
1.1 
Rationale for Proposed Treatment Dose and Schedule 
 
The protocol attempts to further define the results of RTOG 97-14, which demonstrated that 8 
Gy x 1 was equal to 30 Gy in 10 fractions for the majority of clinical endpoints. The primary 
exception was the rate of retreatment, where 8 Gy x1 was shown to require additional therapy. 
In this study, we are investigating if a second fraction given within 7 days of the first fraction, 
reduces the retreatment rate or improves pain control.   
2.0 
Objectives 
 
2.1 
Primary Objective 
 
2.1.1 To determine whether 8 Gy x 2 fractions results in lower cumulative re-treatment rates at 
6 months post-treatment completion compared to 8 Gy x 1 fraction in solid tumor 
patients with bone metastases.   
 
2.2 
Secondary Objectives 
 
2.2.1 To determine whether 8 Gy x 2 fractions provides superior pain at 3 and 6 months post-
treatment completion compared to 8 Gy x 1 fraction in solid tumor patients with bone 
metastases. 
 
2.2.2 To determine whether 8 Gy x 2 fractions is associated with improved quality of life at 3 
and 6 months post-treatment completion compared to 8 Gy x 1 fraction in solid tumor 
patients with bone metastases. 
 
 
2.2.3 To determine if 8 Gy x 2 fractions is associated with increased toxicity. 
 
2.2.4 To correlate patient satisfaction, perceived stress, and social support assessed via self-
reported outcomes with treatment outcomes. 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 7 of 45 
2.3 
Exploratory Objective 
 
2.3.1 To determine whether use of a bone strengthening agent is associated with improved 
pain relief, decreased narcotic usage, and re-treatment rates. 
2.3.2  To assess the impact of pain response after radiotherapy on bone structural properties 
such as bone mineral density and cortical thickness 
3.0 
Patient Selection  
 
3.1 
Inclusion Criteria  
 
3.1.1 
Diagnosis of cancer, not including multiple myeloma or lymphoma/leukemia. 
 
3.1.2 
Radiographic evidence* of bone metastases within 8 weeks of study for non-weight bearing 
sites and 4 weeks for weight bearing sites. The patient must have pain which appears to be 
related to the radiographically documented metastasis in the opinion of the treating 
physician, and the decision has been made by the responsible clinician that a course of 
palliative external beam radiation therapy is appropriate treatment. Multiple sites eligible if 
they can be included in no greater than 3 treatment sites and not all identifiable lesions will 
require treatment unless they are painful lesions 
 
 
*This should be one of the following:  Plain Film, Bone Scan, PET scan, CT scan, or MRI. 
 
3.1.3 
The involved bone(s) is/are orthopedically stable and not in need of stabilization via either 
definitive RT, surgical intervention, or both. 
 
3.1.4 
Eligible Treatment Sites Are: 
 
 
Weight bearing sites 
 
 
 
1. pelvis (excluding pubis)  
 
 
 
2. femur 
3. sacrum and/or sacroiliac joints 
4. tibia 
5. up to 5 consecutive cervical, thoracic or lumbar vertebral bodies 
6. lumbosacral spine 
 
Non-weight bearing sites 
7. up to 3 consecutive ribs 
8. humerus 
9. fibula 
10. radius ± ulna 
11. clavicle 
12. sternum 
13. scapula 
14. pubis 
15.  skull 
16.  bones of hands or feet 
 
If multiple sites are treated, the treatment site is included as weight-bearing if any of the 
sites include the pelvis, sacrum, femur or tibia. 
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 8 of 45 
3.1.5 
Pain score of at >5 on a scale of 0 – 10 within a week of enrollment OR pain score < 5 with 
≥ 60 mg of morphine (or equivalent) per day. 
 
3.1.6 
ECOG performance status of 0 - 3. 
 
3.1.7 
Ability to understand and the willingness to sign an IRB-approved informed consent 
document. 
 
3.1.8 
Negative pregnancy test at study registration. 
 
3.1.9 
Life expectancy of at least 12 weeks as deemed by the treating oncologist. 
 
3.1.10 Patients will be eligible for treatment of multiple synchronous osseous sites only if those 
sites can be included in no more than three treatment sites. For patients with painful 
metastases that are contiguous but do not fit into the definition of a site listed above, those 
patients will still be eligible but will be considered to have two treatment sites. For example, 
a patient with a lesion of T4, T7 and T9 would be eligible but would be considered as two 
treatment sites since more than five consecutive vertebral bodies would be treated. These 
lesions could be treated with one field, even though the treatment is coded as two sites. 
 
3.2 
Exclusion Criteria  
 
3.2.1 
Previous radiotherapy or palliative surgery to the painful site that is planned for treatment. 
 
3.2.2 
Spinal cord or cauda equine compression/effacement in vertebral metastases with 
neurological symptoms other than just pain for the lesion that is planned for treatment. 
3.3 
Inclusion of Women and Minorities 
 
Men and women of all races and ethnicities who meet the above-described eligibility criteria are 
eligible to participate in this study.  
 
The study consent form will also be provided in Spanish for Spanish-speaking participants. 
Based on CCCWFU population estimates, we expect approximately 40% of participants to be 
women. Translating this to our sample size estimate of 158, we plan to enroll at least 63 women.  
 
We do not expect the percentage of Hispanic/Latino or racial minority cancer patients eligible for 
this study to be higher than the percentage of Hispanic or racial minority new cancer patients 
seen at CCCWFU (2.2% and 13.3%, respectively); therefore, we plan to enroll at least 21 racial 
minority and 3 Hispanic/Latino patients. 
 
Should we not meet or exceed these estimates, the PI will engage the Cancer Center Health 
Equity Advisory Group to discuss strategies to enhance recruitment in these target populations. 
4.0 
Methods 
 
4.1 
Study Design 
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 9 of 45 
We will use a prospective randomized study design for recruiting patients with painful bone metastasis 
at the CCCWFU. Pain will be assessed prior to randomization. Patients will be randomized between 1 
or 2 fractions of 8 Gy.  The randomization will occur after registration; patients will be randomized 
equally between the two treatment arms.  Treatment needs to begin within 14 days of registration. All 
baseline data needs to be collected before treatment.  Quality control, such as valid values, range 
checks and between-variable consistency will be performed at time of data entry. Data will be kept 
secure with password protection.  
 
4.2  
Registration Procedures 
 
All patients entered on any CCCWFU trial, whether treatment, companion, or cancer control trial, must 
be registered with the CCCWFU Protocol Registrar or entered into ORIS Screening Log within 24 hours 
of Informed Consent. Patients must be registered prior to the initiation of treatment.   
 
You must perform the following steps in order to ensure prompt registration of your patient: 
 
1. Complete the Eligibility Checklist (Appendix B) 
2. Complete the Protocol Registration Form (Appendix A) 
3. Alert the Cancer Center registrar by phone, and then send the signed Informed Consent 
Form, Eligibility Checklist and Protocol Registration Form to the registrar, either by fax or e-
mail. 
 
 
Contact Information: 
Protocol Registrar 
 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu) 
            
*Protocol Registration is open from 8:30 AM – 4:00 PM, Monday-Friday. 
 
 
4. Fax/e-mail ALL eligibility source documents with registration. Patients will not be registered 
without all required supporting documents. 
Note: If labs were performed at an outside institution, provide a printout of the results. Ensure 
that the most recent lab values are sent. 
 
To complete the registration process, the Registrar will:   
 
• 
assign a patient study number 
• 
randomize the patient 
• 
register the patient on the study 
4.3 
Data Collection 
 
At the time of enrollment, a detailed history and physical exam will be performed, including abstraction of 
patient vital signs and also documenting co-morbidities, patient demographics, age, gender, other medical 
conditions, and tumor characteristics. Other variables, such as education level, type of health insurance, and 
marital status (married/single/widowed/divorced/other) will also be obtained.  
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 10 of 45 
Blood Collection: Patients may consent to provide optional blood samples to be used for future genomic 
studies at baseline.  
 
Prior Cancer Therapy:  Information regarding the patient’s history for anti-cancer therapy will be recorded.     
 
Use of Bisphosphonates/Denosumab:  Information regarding the patient’s history for the use of 
biphosphonates will be recorded.  This will include the specific agent, dose, and date treatment started. 
 
Changes in systemic chemotherapy, hormonal therapy, immunotherapy or the use of bisphosphonates for 4 
weeks before and after the delivery of radiotherapy are allowed and will be recorded.   
 
Pain level and Pain Medications:  The patient’s pain level will be assessed using the NRPS (detailed below). 
Information regarding the patient’s history for the use of pain medications will be recorded.  This will include the 
specific agent, dose, and date treatment started.   
 
Nutrition Status, vitals, BMI: At each encounter, height (at baseline only), weight, Body Mass Index 
(BMI=kg/M2), and history of weight loss within three months prior to enrollment until patient’s study completion 
will be recorded and/or extracted from patient records.  
 
ECOG Performance Status 
 
Patient Self-Reported Outcomes (SRO):  
For evaluation of pain relief, the Numerical Rating Pain Scale (NRPS; Jensen 1999) will be used. The NRPS is 
a simple measure of pain on an 11-point scale (0-10). In the study comparing the reliability and validity of 
several measures of pain intensity, the composites of 0-10 ratings have been shown to be useful when 
maximal reliability was necessary in studies with relatively small sample sizes or in clinical settings in which 
monitoring of changes in pain intensity in individuals is needed. This will be performed prior to treatment and 
again at 1, 2, 3, and 6 months. 
 
For patients with a pain score >4 in the treated area at the 3 and 6 month follow-up, imaging (plain film, 
CT, bone scan, MRI) is recommended to assess for bone stability and pathologic fractures. Imaging 
should correlate with other imaging ordered by other treating physicians when possible. Coordination of all 
treatment and imaging should be collaborative to ease patient burden. 
 
We will also include the following psychosocial measures at baseline and again at 3 and 6 months:  
 
• 
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL 
• 
Patient Satisfaction with Cancer Care (11) 
• 
Perceived Stress Scale (12) 
• 
Social Support (13) 
 
Measurement of Treatment-Related Toxicities: Adverse events will be evaluated by the NCI Common 
Terminology Criteria for Adverse Event (CTCAE), v. 4.0. (14). Because of the patient population as well as the 
treatment, emphasis will be placed on gastrointestinal (GI disturbance, esophagitis, diarrhea, nausea, and 
vomiting), hematological (low blood counts or bleeding), spinal (bone fracture, compression fracture, 
insufficiency, or myelitis), and pulmonary toxicities (pneumonitis). However, all adverse events recorded by 
clinical research coordinators will be analyzed. Given the variety of non-protocol related treatment, toxicity will 
be assessed at 30 days after protocol treatment, as per DSMC requirements. These will be documented in 
Appendix I.   
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 11 of 45 
Focused Late AE Assessments: At 2, 3 and 6 months post-treatment, a focused AE assessment 
dependent upon the specific body area treated will be performed. These will be documented in 
Appendix I. Specific AEs to be collected will include the following: 
a) Fistula formation 
a. Abnormal opening in the passageway from mouth to stomach (esophagus), bowels 
or bladder 
b) Scarring of the small or large bowel resulting in a blockage in the bowel that would require 
treatment 
c) Fracture of the bone within the radiotherapy treatment field (Fractures may require surgical 
treatment to prevent permanent disability). 
d) Temporary or permanent damage to the spinal cord, resulting in:  
a. Skin sensations, such as burning, prickling, itching, or tingling  
b. Muscle weakness causing inability to walk (paralysis)  
c. Decreased ability or loss of ability to move a body part or to hold urine or control a 
bowel movement  
 
Imaging: The patient will undergo CT-Simulation prior to treatment. If deemed necessary by the treating 
physician at the time, follow-up imaging is allowed at 3- and 6-months after treatment. These scans, if 
performed, will be as part of standard of care, particularly in the setting of increased pain at post-treatment 
evaluations (see above). Imaging data obtained from these scans will be collected for the purposes of the 
exploratory objective (Section 2.3). 
 
 
4.4 
Radiation Therapy 
 
4.4.1 Treatment Plan 
Arm 1: 8.0 Gy x 1 fraction. 
Arm 2: 8.0 Gy x 2 fractions to 16.0 Gy total dose with 3-7 days in between. 
4.4.2  Patient Positioning and Simulation: Patients must be positioned in a stable supine or 
prone position at the treating physician’s discretion. Any immobilization techniques can 
be used for 3D conformal therapy at the treating physician’s discretion. For cervical 
spine or cervicothoracic junctional areas, a head and neck immobilization device is 
preferred. Simulation of treatment fields is required prior to the treatment.  
4.4.4 3D Treatment CT simulation is required. Non-coplanar beams can be employed. Multiple 
beam directions can be used. Target volume should covered by more than or equal to 
90% of the prescription dose.  
4.4.5 Simulation of treatment fields is required prior to the first treatment. Prior to the first 
treatment, there must be an approved simulation or portal film documenting that the 
treatment site is adequately covered and approved by a radiation oncologist. 
4.4.6  Treatment machine requirements. Treatment must be given using megavoltage 
equipment with 4-20 MV photons or 5-20 MeV electrons. The minimum Source-Axis 
Distance (SAD) shall be 80 cm. 
4.4.7 For spine lesions, treatment volume will include the entire vertebral body(s) of the 
involved spine, plus one vertebral body superior and one vertebral body inferior to the 
index spine. A treatment field margin of 1-2 cm laterally beyond the vertebral body(s) 
can be used based on the treating physician’s discretion.  For non-spine lesion, 
treatment volume will general include the lesion as identified on imaging studies with 1-2 
cm margin.  Final treatment volume will be at treating physician’s discretion.   
4.4.8  Rib metastases may be treated with electrons or with photons. When electrons are used, 
the appropriate energy should be chosen such that the entire lesion is covered by the 
90% (or higher) isodose curve. The dose will be prescribed to the 100% isodose line. 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 12 of 45 
When photons are used, parallel opposed fields may be used, with the depth prescribed 
to the mid thickness. Oblique/tangential fields for rib metastasis are strongly encouraged 
to avoid treatment of underlying structures. A single field may be used to cover the 
lesion, with the depth set at the estimated depth of the rib lesion, and the dose 
prescribed to that level. 
4.4.9 When more than one osseous site is to be included into one treatment field, the treating 
radiation oncologist may use differing field arrangements at her/his discretion, with the 
fields arranged to provide relatively uniform treatment of the target sites with a minimum 
of uninvolved normal tissues. 
4.4.10 For patients who receiving 8 Gy x 2 to an area near or involving either the spinal cord or 
cauda equina, the spinal cord and cauda equina needs to be contoured.  The dose to 
the countered cord/cauda equina this this region will be limited to 107% of the prescribed 
dose.  If needed, the PTV coverage can be lowered to 85%.  If PTV coverage is between 
85% and 80%, a minor deviation should be reported.  If PTV coverage is below 80%, a 
major deviation should be reported.   
 
5.0 
Study Outcomes and Study Measures 
 
5.1 
Primary Outcome 
 
5.1.1 Cumulative re-treatment rates by treatment arm assessed at 6 months post-treatment 
completion. 
5.2 
Secondary Outcomes 
 
5.2.1 Pain, on a 0-10 scale, and narcotic use, in daily oral morphine equivalents, by treatment 
arm assessed at 3 and 6 months post-treatment completion. 
 
5.2.2 Quality of life by treatment arm, assessed by QLQ-C15-PAL at 3 and 6 months post-
treatment completion. 
 
5.2.3 Toxicity by treatment arm, assessed by CTCAE version 4.0. 
 
5.2.4 Association between patient satisfaction, perceived stress, and social support assessed 
via self-reported surveys and treatment outcomes. 
5.3 
Exploratory Outcome 
 
5.3.1 Association of use of a bone strengthening agent with improved pain relief, decreased 
narcotic usage, and re-treatment rates. 
5.3.2 Association of pain response after radiotherapy on bone structural properties such as 
bone mineral density and cortical thickness. 
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 13 of 45 
6.0 
Treatment Plan 
6.1 
Study-Related Activities  
  
Screening/
Baselinea 
Pre-Treatmenth 
At Each 
Treatment 
1 Month Post 
Treatment 
Completionᶠ,g 
2 Months 
Post 
Treatment 
Completionᶠ
,g 
3 Months 
Post-
Treatment 
Completionf,
g 
6 Months 
Post-
Treatment 
Completionf,
g 
Informed Consent 
X 
  
  
  
  
  
  
Demographics: 
age, gender, 
education, health, 
insurance, marital 
status 
X 
  
  
  
  
  
  
Medical history, 
tumor 
characteristics 
X 
  
  
  
  
  
  
Performance 
Status (ECOG) 
X 
  
  
  
  
X 
X 
B-HCGb 
X 
  
  
  
  
  
  
Blood Collection 
(optional) 
  
X 
  
  
  
Xf,ᴵ 
  
Nutritional status, 
BMIᵢ 
X 
  
X 
  
  
X 
X 
Vital Signs 
X 
  
  
  
  
X 
X 
Radiologic 
assessment 
Xc 
  
  
  
  
Xᵉ,m 
Xe,m 
Patient 
Questionnairesd 
  
X 
  
  
  
X 
X 
Concomitant 
Medications 
X 
  
X 
X 
Xᵏ 
Xᵏ 
Xᵏ 
Adverse event 
evaluation 
  
  
X 
X 
Xj 
Xj 
Xj 
 NRPS Pain Scale 
X 
  
  
Xg 
Xg 
Xg 
Xg 
 
a. Pre-study requirements listed in table must be completed within 14 days prior to registration unless otherwise noted. 
b. Serum pregnancy test (women of childbearing potential). 
c. Within 8 weeks of registration for non-weight bearing sites and 4 weeks for weight bearing sites 
d. See Appendix G. 
e. Imaging ordered by the treating physician according to the standard of care, only if indicated. CT scan is not required to be 
performed for study purposes at follow up, but any CT scans obtained as standard of care will be used for purposes of 
reviewing changes in cortical thickness as an exploratory aim.   
f. To be completed 3-6 weeks from final treatment date (1 month visit), 7-9 weeks from final treatment date (2 month visit), 10-18 
weeks from final treatment date (3 month visit) and 20-34 weeks from final treatment date (6 month visit).  
g. For patients who are undergoing additional therapy of any kind and are being followed by another treating physician, the follow-
up visit can be deferred to that treating physician. Schedule of follow-up may be deferred to that treating physician and 
activities will be captured when they fall within visit windows. Toxicity (AEs), pain (NRPS), and patient questionnaire can be 
done over the phone +/- 5 days of said visit. 
h. To be completed any time after consent is signed, but prior to treatment. Not needed for registration. 
i. Height will be captured at the Pre-Study/Baseline visit only. 
j. Focused AE assessment according to those specified in Section 4.3 and outlined in Appendix I (2-, 3- and 6- month assessment). 
k. Focused ConMed assessment; collected medications related to bone pain and bone-strengthening agents only 
(bisphosphonates, RANK-L inhibitors, parathyroid hormone analogs/modulators/agonists). 
l. Optional blood collection for follow-up must occur at 3 months if consented to by the subject (See Section 9.0). 
m. Appendix K to be completed at the time of Data Reconciliation. 
 
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 14 of 45 
6.2 
Treatment Administration 
 
Arm A: 8.0 Gy x 1 fraction to 8.0 Gy total dose. 
Arm B: 8.0 Gy x 2 fractions to 16.0 Gy total dose.  The two fractions will be separated by 3-7 
days. 
 
Simulation of treatment fields is required prior to the first treatment. There must be imaging of 
treatment verification approved by a radiation oncologist. All fields must be treated each day. 
Treatment volume will include the radiographic abnormality with at least a 2 cm margin. 
Treatment of the entire bone is not required. 
 
6.2.1 Retreatment 
 
Previous studies have shown that pain relief from radiotherapy may take several weeks to 
become apparent. Therefore, patients should not be re-irradiated to the same treatment site for 
at least 4 weeks after completion of treatment on this study unless the patient has an increase 
of 2 points on the worst pain score above the nadir or a 25% increase in daily dosage morphine 
equivalent of pain medication. Dose and fractionation schemes are left to the discretion of the 
treating radiation oncologist. Cumulative retreatment occurrence will recorded at the 6 month 
follow-up visit. 
 
6.3 
Duration of Therapy 
 
This is a study of 1 vs. 2 fractions of radiation therapy. For the patients randomized to receive 2 
fractions, the treatment may continue unless one of the following criteria 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. 
 
6.4 
Duration of Follow Up 
 
Given the variety of non-protocol related treatment, toxicity will be assessed at 30 days after 
protocol treatment as it is anticipated that this would be part of standard of care for such 
treatment, and per DSMC requirement.  For patients not receiving any additional treatment, 
additional follow-up visits will occur at 3 and 6 months with follow-up radiologic assessment at 
the discretion of the treating physician if pain score is >4 as such is standard of care for patients 
who receive the treatment. 
 
For patients who are undergoing additional therapy of any kind and are being followed by 
another treating physician, follow-up can be deferred to that treating physician. Toxicity and pain 
can be assessed via chart review and over the phone for these patients at the appropriate study 
time points. Patients will be followed in this same manner if being treated at an outside facility.  
Patients who experience adverse events will be followed every 3-6 weeks until stabilization of 
the adverse event or until 6 months post-treatment, whichever occurs first. 
 
A patient may remain in the study until one of the following criteria applies: 
 
• 
Patient decides to withdraw from the study, or 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 15 of 45 
• 
The patient has completed a minimum of 6 months follow-up.  
• 
Patient enters End of Life Hospice Care and will no longer be followed routinely.  
7.0 
Measurement of Effect 
 
7.1 
Pain Response 
Assessment of pain should be on a scale of 0 to 10, with boundaries of 0 representing no pain 
and 10 representing maximal pain. Pain should be assessed by only the worst pain score for the 
previous 3 days. 
 
Complete response: A pain score of 0 at treated site with no concomitant increase in analgesic 
intake (stable or reducing analgesics in daily oral morphine equivalent. 
 
Partial response: reduction of 2 or more points (0-10 point scale) without analgesic increase OR 
analgesic reduction of 25% in daily oral morphine equivalent without increase in pain. 
 
Pain progression:  
• 
Increase in pain score of 2 or more above the nadir at the treated site with stable daily 
oral morphine equivalent, or  
• 
An increase of 25% or more in daily oral morphine equivalent compared with baseline 
with the pain score stable or 1 point above baseline 
 
Indeterminate response: Any response that is not captured by the complete response, partial 
response, or pain progression definitions 
 
All patients with a pain score > 4 in the treated area at the 3-month follow-up will have plain 
radiographs to assess for bone stability and pathologic fractures. 
 
Any patient with progressive pain in the treated area should have radiographs of the area to 
assess for bone stability and pathologic fracture. 
 
7.2 
Radiation Induced Bone Changes 
 
The patient will undergo standard of care CT simulation prior to treatment. No further imaging is 
required by the protocol. If the patient undergoes CT imaging after treatment for any reason, 
imaging will be analyzed for quantitative assessment of radiation-induced bone changes 
including bone mineral density and cortical. The date and type of imaging (if applicable) will be 
collected if it falls within the timeframes delineated in the follow-up assessment calendar 
(Section 6.1, attention to Footnote f). The scan data will be used for analyses comprising the 
exploratory objective delineated in Section 2.3. These results, if applicable, will be documented 
on Appendix K by the researches after completion of the study.  
 
8.0 
Adverse Events List and Reporting Requirements 
 
8.1 
Adverse Event List for Radiation Treatment 
Expected side effects, depending on the area treated, include nausea, vomiting, diarrhea, skin 
erythema and alopecia in the irradiated area, esophagitis, myelosuppression, urinary urgency 
and frequency, and pneumonitis. 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 16 of 45 
 
8.2 
Adverse Event Characteristics 
 
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will 
be utilized for AE reporting. All appropriate treatment areas should have access to a copy of 
the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP web site (http://ctep.cancer.gov). 
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for 
expedited reporting purposes only.   
 
• 
Attribution of the AE: 
 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
8.3 
DSMC SAE Reporting Requirements 
 
The Data Safety Monitoring Committee (DSMC) is responsible for reviewing SAEs for WFBCCC 
Institutional studies as outlined in Appendix D. All Adverse Events that occur during protocol 
intervention and are coded as either 1) unexpected grade 4, 2) unplanned inpatient hospitalization ≥ 24 
hours (regardless of grade), or grade 5 (death) must be reported to the DSMC using the using the SAE 
console in WISER.  
 
All WFBCCC Clinical Protocol and Data Management (CPDM) staff members assisting a Principal 
Investigator in investigating, documenting and reporting an SAE qualifying for DSMC reporting are 
responsible for informing a clinical member of the DSMC as well as the entire committee via the email 
notification procedure of the occurrence of an SAE.  
 
8.4  
WFUHS IRB AE Reporting Requirements 
 
Any unanticipated problems involving risks to subjects or others and adverse events shall be promptly 
reported to the IRB, according to institutional policy. Reporting to the IRB is required regardless of the 
funding source, study sponsor, or whether the event involves an investigational or marketed drug, 
biologic or device. Reportable events are not limited to physical injury, but include psychological, 
economic and social harm. Reportable events may arise as a result of drugs, biological agents, 
devices, procedures or other interventions, or as a result of questionnaires, surveys, observations or 
other interactions with research subjects. 
 
All members of the research team are responsible for the appropriate reporting to the IRB and other 
applicable parties of unanticipated problems involving risk to subjects or others. The Principal 
Investigator, however, is ultimately responsible for ensuring the prompt reporting of unanticipated 
problems involving risk to subjects or others to the IRB. The Principal Investigator is also responsible 
for ensuring that all reported unanticipated risks to subjects and others which they receive are reviewed 
to determine whether the report represents a change in the risks and/or benefits to study participants, 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 17 of 45 
and whether any changes in the informed consent, protocol or other study-related documents are 
required. 
 
Any unanticipated problems involving risks to subjects or others occurring at a site where the study has 
been approved by the WFUHS IRB (internal events) must be reported to the WFUHS IRB within 7 
calendar days of the investigator or other members of the study team becoming aware of the event. 
 
Any unanticipated problems involving risks to subjects or others occurring at another site conducting 
the same study that has been approved by the WFUHS IRB (external events) must be reported to the 
WFUHS IRB within 7 calendar days of the investigator or other members of the study team becoming 
aware of the event. 
 
Any event, incident, experience, or outcome that alters the risk versus potential benefit of the research 
and as a result warrants a substantive change in the research protocol or informed consent 
process/document in order to insure the safety, rights or welfare of research subjects. 
 
 
9.0 Blood Collection for Translational Research and Tissue Banking 
 
In this study, if the patient consents, plasma and whole blood will be collected at baseline and post-treatment (3 
months). We will explore promising genetic basis biomarkers with regard to of cancer-induced bone pain and 
cachexic syndrome following bone metastatic disease, since much work still remains to be accomplished in this 
area.  
 
The whole blood collected will be utilized for microarray analyses or next generation RNA sequences. The pre-
treatment and post-treatment (3 months) of plasma will be tested for a number of cytokines and proteins (e.g. 
calcitonin-gene related peptide (CGRP), substance P (SP), angiotensin II, Ang 1-7) that are thought to be 
predictive of cancer-induced bone pain and cachexic syndrome following bone metastasis disease.   
 
This may lead to identification of promising new biomarkers with the goals of  
1. Identifying factors predictive of outcome such that patients may be better stratified in future trials; 
2. Developing novel treatment strategies which target the molecular abnormalities identified.  
 
 
1) Blood Sample Preparation 
 
1. Email notification will be sent to 
 
 the day before the 
blood collection. 
 
2. Blood will be collected in green-top lithium-heparin or sodium-heparin vacutainer tubes (1 x 10 ml tube), 
and immediately inverted 8-10 times to prevent coagulation. Attention: Protocol #: CCCWFU # 01416 
should be on the tube 
 
3. Samples will then be sent to Dr. Shiozawa’s lab (Hanes 4013) for research use.  Dr. Shiozawa’s lab 
 
  
  
 
4. Upon receipt, tubes will be centrifuged at 200 x g for 10 mins at room temperature with the break off. 
 
5. Plasma will be removed and placed in 1.5ml Eppendorf tubes and transferred to the Shiozawa lab and 
stored in -80 freezer until further processing.  . 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 18 of 45 
 
6. Buffy coat will be collected and placed in Eppendorf tubes in RNA later and transferred to the Shiozawa 
lab, and stored in -80 freezer until further processing.  
10.0 Data Management 
 
Informed consent document 
Wiser 
Appendix A: Protocol registration form 
Wiser 
Appendix B: Subject Eligibility Checklist 
Wiser 
Appendix C: Race & Ethnicity Verification  
Wiser 
Appendix D: Mandatory DSMC SAE Reporting Guidelines 
Wiser 
Appendix E: Baseline data collection form 
REDCap 
Appendix F: Treatment data collection 
REDCap 
Appendix G: Patient Questionnaire 
REDCap 
Appendix H:  Numerical Rating Pain Scale (NRPS) 
REDCap 
Appendix I: Adverse Events 
Epic/REDCap 
Appendix J:  Retreatment Data Form 
REDCap 
Appendix K: Radiation Induced Bone Changes 
REDCap 
11.0 Statistical Considerations 
11.1 Analysis of Primary Objective 
 
This is a randomized Phase 2 study, with the primary objective to compare the 6-month cumulative 
incidence of re-treatment rates between groups.  Based on previous research, the 8 Gy x 1 fraction 
[8/1] group (control group) had a retreatment rate of 18% (RTOG Study 97-14).    The primary analysis 
will use a one-sided log-rank test statistic to test the null hypothesis that the re-treatment rates are 
equal in each group versus that alternative that the re-treatment rates are lower in the 8 Gy x 2 
fractions [8/2] group.  This analysis will account for competing risks such as death.  Analyses will be 
performed on the patient level, thus if a patient has multiple metastases and any one of these requires 
retreatment then the patient will be considered retreated.  
 
11.2 Analysis of Secondary Objective 
 
There are several secondary outcomes of interest in this study.   Most of these are measured on a 
continuous scale (i.e., quality of life by QLQ-C15-PAL, Patient satisfaction with cancer care, perceived 
stress scale) and thus will be compared between groups using 2-sample t-tests.  In addition, the 
variable for pain response is categorical rather than continuous and will be compared at 3-months 
between groups using a Fisher’s exact test.  Patients categorized as Complete or Partial Responders 
will be compared with those categorized as stable or worsening pain responders. 
 
Groups will also be compared to determine whether there are any differences in the number or severity 
of toxicities.  When comparing severity of toxicities between groups, chi-square tests will be examined.  
The Cochran-Armitage trend test (in SAS Proc Freq) can be used to determine if there is evidence a 
trend in severity of toxicities when comparing groups. 
 
In addition to the primary and secondary analyses described above, analyses will be performed that 
examine whether there are associations between quality of life, patient satisfaction and perceived 
stress measures and treatment outcome (re-treatment rates or amount of pain relief).  In these 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 19 of 45 
analyses, the outcome will be either re-treatment (yes/no) or amount of pain and predictors will include 
treatment arm, patient level measure and the treatment by patient level measure (i.e., QLQ-C15-PAL) 
interaction.  For these analyses, either multiple logistic regression (for binary outcomes) models or 
analysis of covariance (ANCOVA) models for continuous outcomes will be used. 
 
In these multiple logistic regression or ANCOVA models additional characteristics such as gender, 
whether the patient has weight-bearing (yes/no), ECOG performance status, number of lesions, or 
biophosphonates will also be considered as covariates in the models.   
 
For the exploratory outcome of examining the association between the use of a bone strengthening 
agent with pain relief, narcotic use and re-treatment rates either two-sample t-tests (if pain is measured 
on a continuous scale) or Fisher’s exact tests (for categorical measures) will be used.  In addition 
multiple logistic regression or ANCOVA models will be fit to look at the an outcome (i.e., pain relief 
yes/no) and the impact of bone strengthening agents (yes/no), number of metastases (one/more than 
one),  treatment group (8/1 or 8/2) and the treatment by bone strengthening interaction. 
 
   
 
11.3 
Power and Sample Size 
 
Power calculations were performed using PASS 13.  When accounting for competing risks, a one-sided 
logrank test with an overall sample size of 102 subjects (51 in the control group and 51in the treatment 
group) achieves 80% power at a 0.2 significance level to detect a hazard ratio of 0.5251. The study is 
expected to last for 42 months with an accrual (entry) time of 36 months and a follow-up time of 6 
months after the last patient is accrued. The cumulative incidence proportions at time 3 months for the 
event of interest are 0.18 in the control group (8/1) and 0.10 in the treatment group (8/2). The 
cumulative incidence proportions at time 6 months for the competing risk factors are 0.20 in the control 
group and 0.20 in the treatment group. The proportion of subjects lost to follow-up during the entire 
study is conservatively estimated at 0.2. 
 
 
11.4 Estimated Accrual Rate 
 
It is anticipated that 3 patients a month will be accrued to this trial, thus the target of 102 patients 
should be met in approximately 36 months.   .   
 
 
11.5 Estimated Study Length 
 
Since the primary analysis is based on 6 month re-treatment rates and we specify 6-months of follow-
up for all patients, the protocol should be completed in 24months. 
 
 
11.6 Interim Analysis Plan 
 
An interim futility analysis is planned for this study.  After 50 patients are enrolled (25 in each group) a 
test statistic will be calculated for z-test to compare groups using a two-proportion test.  If the test 
statistic has a value of 1.5 (or larger) suggesting that there is evidence that the 8/2 group has a re-
treatment rate that is worse than the 8/1 group, the trial will be considered to be stopped for futility.  The 
conditional power, if this were to occur, would be 3.5%, suggesting the futility index would be 96.5%.  
This calculation was performed using PASS 13.   
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 20 of 45 
 
 
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 21 of 45 
 
 
 
 
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 22 of 45 
 
 
 
 
 
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 23 of 45 
References 
 
1. 
Chow E, Harris K, Fan G, et al. Palliative radiotherapy trials for bone metastases: A systematic review. 
J Clin Oncol 2007;25:1423–1436. 
 
2. 
Cole DJ. A randomized trial of a single treatment versus conventional fractionation in the palliative 
radiotherapy of painful bone metastases. Clin Oncol (R Coll Radiol) 1989;1:59–62. 
 
3. 
Gaze MN, Kelly CG, Kerr GR, et al. Pain relief and quality of life following radiotherapy for bone 
metastases: A randomized trial of two fractionation schedules. Radiother Oncol 1997;45:109–116. 
 
4. 
Nielsen OS, Bentzen SM, Sandberg E, et al. Randomized trial of single dose versus fractionated 
palliative radiotherapy of bone metastases. Radiother Oncol 1998;47:233–240. 
 
5. 
Roos DE, Turner SL, O’Brien PC, et al. Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of 
radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation 
Oncology Group, TROG 96.05). Radiother Oncol 2005;75:54–63. 
 
6. 
Sze WM, Shelley MD, Held I, et al. Palliation of metastatic bone pain: Single fraction versus 
multifraction radiotherapy—a systematic review of randomised trials. Clin Oncol (R Coll Radiol) 2003;15:345–
352. 
 
7. 
Wu JS, Wong R, Johnston M, et al. Meta-analysis of dose fractionation radiotherapy trials for the 
palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 2003;55:594–605. 
 
8.  
Hartsell WF, Scott CB, Bruner DW, Scarantino CW, Ivker RA, et al. Randomized trial of short- versus long-
course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005 Jun 1;97(11):798-804. 
 
9. 
Konski A, James J, Hartsell W, Leibenhaut MH, Janjan N, et al. Economic analysis of radiation therapy 
oncology group 97-14: multiple versus single fraction radiation treatment of patients with bone metastases. Am J 
Clin Oncol. 2009 Aug;32(4):423-8. 
 
10. 
Chow E, Zeng L, Salvo N, Dennis K, Tsao M, Lutz S. Update on the systematic review of palliative 
radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol). 2012 Mar; 24(2): 112-24. 
 
11. 
Jean-Pierre P, Fiscella K, Freund KM, Clark J, Darnell J, Holden A, Post D, Patierno SR, Winters PC; 
Patient Navigation Research Program Group. Structural and reliability analysis of a patient satisfaction with 
cancer-related care measure: a multisite patient navigation research program study. Cancer. 2011 Feb 
15;117(4):854-61. 
 
12. 
Cohen, S. and Williamson, G. Perceived Stress in a Probability Sample of the United States. 
Spacapan, S. and Oskamp, S. (Eds.) The Social Psychology of Health. Newbury Park, CA: Sage, 1988. 
 
13. 
Cohen S, Hoberman, H.M. Positive events and social supports as buffers of life change stress1. 
Journal of applied social psychology. 1983;13(2):99-125. 
 
14. 
Common Terminology Criteria for Adverse Events (CTCAE). 2009; 
4.0:http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, 2010. 
 
15. 
 Jensen, Mark P., Judith A. Turner, Joan M. Romano, and Lloyd D. Fisher. "Comparative Reliability and 
Validity of Chronic Pain Intensity Measures." Pain 83.3 (1999): 157-162. 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 24 of 45 
Appendix A – Protocol Registration Form 
 
DEMOGRAPHICS 
Patient: Last Name: _____________________ First Name: ___________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
Zip code:  
___ ___ ___ ___ ___ 
 
 
Sex:   
  Male      Female 
Ethnicity (choose one):   Hispanic 
Non-Hispanic 
Race (choose all that apply): 
 White           Black            Asian 
 Pacific Islander                 Native American 
Marital status:   Single      Married/Domestic partner      
                         Separated/Divorced      Widowed   
Primary Diagnosis: ____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
 
Education:  High school or less     Some college      College Graduate     
                   Graduate School         Doctorate 
Health Insurance:  Private plan       Medicare      Medicaid      Military     None 
 
Protocol 
Registrar 
can 
be 
contact by 
calling 336-
713-6767 
between 
8:30 
AM 
and 
4:00 
PM, 
Monday 
– 
Friday. 
 
Completed 
Eligibility 
Checklist 
and 
Protocol Registration Form must be hand delivered, faxed or e-mailed to the registrar at 336-7136772 or 
registra@wakehealth.edu. 
 
 
 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to registration) 
 YES   NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by ORIS): 
___ ___ ___ ___ ___ ___ ___ ___ 
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 25 of 45 
Appendix B – Subject Eligibility Checklist 
 
 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria is 
NOT met 
Source Used to Confirm * 
(Please document dates and lab results) 
Diagnosis of cancer, not including multiple 
myeloma or lymphoma/leukemia. 
 
 
 
Radiographic evidence* of bone metastases 
within 8 weeks of study for non-weight bearing 
sites and 4 weeks for weight bearing sites. The 
patient must have pain which appears to be 
related to the radiographically documented 
metastasis in the opinion of the treating physician, 
and the decision has been made by the 
responsible clinician that a course of palliative 
external beam radiation therapy is appropriate 
treatment. Multiple sites eligible if they can be 
included in no greater than 3 treatment sites and 
not all identifiable lesions will require treatment 
unless they are painful lesions. 
 
*This should be one of the following:  Plain Film, 
Bone Scan, PET scan, CT scan, or MRI. 
□ 
□ 
 
 
The involved bone(s) is/are orthopedically stable 
and not in need of stabilization via either definitive 
RT, surgical intervention, or both. 
□ 
□ 
 
Eligible Treatment Sites Are: 
Weight bearing sites: 
1. pelvis (excluding pubis)  
2. femur 
3. sacrum and/or sacroiliac joints 
4. tibia 
5. up to 5 consecutive cervical, thoracic or lumbar 
vertebral bodies 
6. lumbosacral spine 
 
Non-weight bearing sites: 
5. up to 5 consecutive cervical, thoracic or lumbar 
vertebral bodies 
6. lumbosacral spine 
7. up to 3 consecutive ribs 
8. humerus 
9. fibula 
10. radius ± ulna 
11. clavicle 
12. sternum 
13. scapula 
14. pubis 
15. skull 
16. bones of hands or feet 
 
If multiple sites are treated, the treatment site is 
included as weight-bearing if any of the sites 
include the pelvis, sacrum, femur or tibia. 
□ 
□ 
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 26 of 45 
Pain score of at least 5 on a scale of 0 – 10 within 
a week of enrollment OR pain score < 5 with ≥ 60 
mg of morphine (or equivalent) per day. 
□ 
□ 
 
ECOG performance status of 0-3. 
□ 
□ 
 
Ability to understand and the willingness to sign 
an IRB-approved informed consent document. 
□ 
□ 
 
Negative pregnancy test at study registration. 
 
□ 
□ 
 
Life expectancy of at least 12 weeks as deemed 
by the treating oncologist. 
□ 
□ 
 
Patients will be eligible for treatment of multiple 
synchronous osseous sites only if those sites can 
be included in no more than three treatment sites. 
For patients with painful metastases that are 
contiguous but do not fit into the definition of a 
site listed above, those patients will still be eligible 
but will be considered to have two treatment sites. 
For example, a patient with a lesion of T4, T7 and 
T9 would be eligible but would be considered as 
two treatment sites since more than five 
consecutive vertebral bodies would be treated. 
These lesions could be treated with one field, 
even though the treatment is coded as two sites. 
□ 
□ 
 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria is 
present 
Source Used to Confirm * 
(Please document dates and lab results) 
Previous radiotherapy or palliative surgery to the 
painful site that is planned for treatment. 
□ 
□ 
 
Spinal cord or cauda equine 
compression/effacement in vertebral metastases 
with neurologic symptoms other than pain for the 
lesion that is planned for treatment. 
□ 
□ 
 
 
This subject is      
 eligible /  ineligible     for participation in this study. 
 
ORIS Assigned PID: __________________  
 
 
 
 
 
 
 
 
Signature of research professional confirming eligibility:_______________________ Date: _______________ 
 
Signature of Treating Physician**:  _____________________________________ Date:  _______________ 
 
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing the source, 
specifically state which document in the medical record was used to assess eligibility. Also include the date on the 
document. Example: “Pathology report, 01/01/14” or “Clinic note, 01/01/14” 
 
**Principal Investigator signature can be obtained following registration if needed

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 27 of 45 
Appendix C – Race & Ethnicity Verification Form 
 
Thank you so much for helping us to verify your race and ethnicity to ensure the quality of our information. As 
a brief reminder, the information you provide today will be kept confidential. 
 
1. Are you: 
Hispanic or Latino/a 
Not Hispanic or Latino/a 
 
2. What is your race? One or more categories may be selected. 
White or Caucasian 
Black or African American 
American Indian or Alaskan Native 
Asian 
Native Hawaiian or Other Pacific Islander 
Other, Please Specify: ___________________________ 
          
 
 
 
Internal use only: 
 
 
 Name: ____________________ MRN#: ____________________  
 
Was the self-reported race and ethnicity of the participant verified at the time of consent? 
Yes        No 
 
Was a discrepancy found?       Yes         No 
         If yes, please provide what is currently indicated in the EMR:  
 
 
Ethnicity: ____________________ 
 
Race: ____________________ 
Additional comments: __________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 28 of 45 
 
Appendix D – Mandatory DSMC SAE Reporting Guidelines 
 
 
Data and Safety Monitoring 
Committee (DSMC) Serious Adverse 
Event (SAE) Notification SOP 
Date: 02/11/2021 
 
 
Mandatory DSMC SAE Reporting Requirements in WISER 
This document describes reporting requirements of adverse events from WFBCCC Investigator Initiated 
interventional trials to the Data and Safety Monitoring Committee (DSMC). A trial is considered a 
WFBCCC Investigator Initiated interventional trial if the following criteria are met: 
 
1) The Principal Investigator (PI) of the trial is a member of a department at the Wake Forest 
University Baptist Medical Center. 
2) WFBCCC is considered as the primary contributor to the design, implementation and/or 
monitoring of the trial. 
3) The trial is designated as “Interventional” using the Clinical Research Categories 
definitions provided by the NCI in the Data Table 4 documentation. 
(https://cancercenters.cancer.gov/GrantsFunding/DataGuide#dt4) 
 
There are two distinct types of WFBCCC Investigator Initiated interventional trials based on where 
patient enrollment occurs.  These include: 
 
1) Local WFBCCC Investigator Initiated interventional trials defined as trials where all patients are 
enrolled from one of the WFBCCC sites. These include the main outpatient Cancer Center clinics 
(located in Winston-Salem) as well as WFBCCC affiliate sites located in Bermuda Run (Davie 
Medical Center), Clemmons, Lexington, High Point, or Wilkesboro. 
2) Multi-Center WFBCCC Investigator Initiated interventional trials defined as trials where patients 
are enrolled from other sites in addition to WFBCCC sites.   
There are three types of trials that are included in this category: 
a. Trials sponsored by the NCI Community Oncology Research Program (NCORP) that are 
conducted at multiple sites where the PI is a member of a department at the Wake Forest 
University Baptist Medical Center. 
b. Trials sponsored by Industry that are conducted at multiple sites and the PI is a member 
of a department at the Wake Forest University Baptist Medical Center. 
c. Trials sponsored by WFBCCC that are conducted at multiple sites and the PI is a member 
of a department at the Wake Forest University Baptist Medical Center. 
 
All Adverse Events (AEs) and Serious Adverse Events (SAEs) that occur on any patients enrolled on 
WFBCCC Investigator Initiated Interventional trials must be entered into the WISER system. The only 
exception to this requirement is for patients enrolled on NCORP trials at non- WFBCCC sites. AEs and 
SAEs for NCORP patients enrolled at WFBCCC sites must be entered into the WISER system. Once these 
AEs and SAEs are entered in WISER, certain actions must be taken regarding the reporting of specific 
Adverse Events to the DSMC. 
All Adverse Events that occur during protocol intervention (defined below) and are coded as either 1) 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 29 of 45 
 
unexpected grade 4, 2) unplanned inpatient hospitalization > 24 hours (regardless of grade), or grade 5 
(death) must be reported to the DSMC using the using the SAE console in WISER. 
 
A research nurse or clinical research coordinator when made aware that an adverse event meets one of 
the above criteria has occurred on a WFBCCC Investigator Initiated interventional trial, is responsible for 
informing a clinical member of the DSMC by phone (or in-person) about the adverse event. The 
nurse/coordinator should contact the treating physician prior to calling the DSMC clinical member to 
obtain all details of the SAE, as well as all associated toxicities to be recorded along with the SAE. In 
addition, this nurse or coordinator is responsible for entering the adverse event information into the SAE 
console in WISER.  Once the adverse event has been entered into the SAE console an email informing the 
entire DSMC will be generated. 
 
THESE REPORTING REQUIREMENTS APPLY TO any staff member on the study team for a WFBCCC Institutional 
Interventional trial. Ultimately, the protocol PI has the primary responsibility for AE identification, 
documentation, grading and assignment of attribution to the investigational agent/intervention. However, when 
an AE event as described above is observed, it is the responsibility of the person who observed the event to be 
sure that it is reported to the DSMC. 
 
What is considered during protocol intervention? 
During protocol intervention is considered to be the time period while a patient is on study treatment or 
during the time period within 30 days of last study treatment (even if patient begins a new (non-study) 
treatment during the 30 days). This window of 30 days should be the standard window to be used in all 
protocols unless a specific scientific rationale is presented to suggest that a shorter window can be used to 
identify events. If it is a trial sponsored by Industry and the sponsor requires a longer window for 
monitoring of SAEs, then the longer window of time specified by the sponsor should be followed. 
 
What is considered as an Unexpected Grade 4 event? 
Any grade 4 event that was not specifically listed as an expected adverse event in the protocol should be 
considered as unexpected. A grade 4 adverse event can be considered to be unexpected if it is an event that 
would not be expected based on the treatment being received or if it is unexpected based on the health of 
the patient. In either case, if there is any uncertainty about whether a grade 4 adverse event is expected or 
unexpected it should be reported to DSMC. 
 
DSMC notification responsibilities of the person (e.g., nurse) handling the reporting/documenting of the SAE in WISER: 
1. Make a phone call (or speak in person) to the appropriate clinical member of the DSMC according 
to the schedule as listed below (page if necessary). 
2. Enter a new SAE into the SAE module that is located in the Subject>> CRA Console in WISER WITHIN 
24 HOURS of first knowledge of the event. Information can be entered and saved, but the DSMC 
members will not be notified until a date is entered into the  DSMC Notification Date Field. This will 
ensure that all persons that need to be made aware of the event (i.e., PI, study team members and 
DSMC members) will be notified; remember to file a copy of the confirmation. 
3. Document that the appropriate person(s) on the DSMC has been contacted. Indicate the name of 
the DSMC clinician that was contacted and the date and time contacted in the Event Narrative field 
in the SAE console of the particular subject. 
4. Document whether or not the protocol should be suspended based on the discussion with the 
DSMC clinician. This is the major function of the email notification. Enter whether the protocol 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 30 of 45 
 
should be suspended in the Event Narrative Field. 
5. Follow up/update the clinical member(s) of DSMC regarding any new developments or information 
obtained during the course of the SAE investigation and reporting process. 
 
Elements needed to complete the SAE form in the Subject Console in WISER (see Screen Shot 3): 
1. Event Date 
2. Reported Date 
3. Reported by 
4. If Grade 5, enter Death Date 
5. If Grade 5, enter Death occurred: within 30 days 
6. Event Narrative: Brief description (include brief clinical history relevant to this event, including 
therapies believed related to event). Begin narrative with the DSMC clinician who was notified and 
Date/Time notified. In addition, state attribution by DSMC clinician as either “Unrelated”, “Unlikely”, 
“Possibly”, “Probably”, or “Definitely”.  Always include the following here: 
i. DSMC clinician name, date/time contacted and comments 
ii. Date of last dose before the event 
iii. Is suspension of the protocol needed? Y/N 
7. Treating Physician comments 
8. PI comments, if available 
9. Protocol Attribution after discussion with DSMC clinician 
10. Outcome (Fatal/Died, Intervention for AE Continues, Migrated AE, Not Recovered/Not Resolved, 
Recovered/Resolved with Sequelae, Recovered/Resolved without Sequelae, Recovering and 
Resolving) 
11. Consent form Change Required? Y/N 
12. SAE Classification *This is required in order for the email notification to be sent* 
13. Adverse Event Details – Enter all details for each AE associated with the SAE. 
a. Course start date 
b. Category 
c. AE Detail 
d. Comments 
e. Grade/Severity 
f. Unexpected Y/N 
g. DLT Y/N 
h. Attributions 
i. Action 
j. Therapy 
k. Click ADD to attach the AE Detail to the SAE. 
14. Enter Date Notified DSMC -- *This is required for the email notification to be sent* 
15. Click Submit. The auto-generated notification email will disseminate within 5 minutes. If you do not 
receive an email within 5 minutes, check that you have entered the “Date Notified DSMC” and the 
“SAE Classification”. If these have been entered and the email still has not been received, take a 
screen shot of the SAE in WISER and immediately email it out to all of the DSMC members listed in 
this SOP. In the subject line, indicate that this is a manual transmission of the SAE in lieu of the auto-
generated email. It is required that a notification goes to the DSMC members immediately so that 
their assessment can be obtained within the 24 hour period requirement. Contact the Cancer Center 
Programmer/Analyst to alert that there is an issue with the auto-generated email. 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 31 of 45 
 
 
The Clinical Members of DSMC to Notify by Phone or Page: 
 
Monday 
Tuesday 
Wednesday Thursday 
Friday 
Saturday Sunday 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
 
  
 
 
 
 
 
 
 
Definition of Unavailable: 
As a general guideline if the first clinician that is contacted does not respond to the phone call or page 
within 30 minutes, then initiate contact with the next DSMC clinician listed in the table above on the 
particular day the SAE is being reported. Allow up to 30 minutes for the new DSMC clinician to respond to a 
phone call or page before contacting the next member in the table. These times (30 minutes) are a general 
guideline. Best judgment as a clinical research professional should be used giving considerations of the time 
of day, severity of the SAE, and other circumstances as to when it is appropriate to contact backup 
clinicians. If the event occurs near the end of day, then leave messages (voice or email) as appropriate and 
proceed with submitting the DSMC notification form. It is important to take reasonable steps and to 
document that some type of contact has been initiated to one or more of the clinical members of DSMC. 
 
DSMC CLINICAN RESPONSIBILITY: 
It is the responsibility of the DSMC clinician to review all reported events, evaluate the events as they are 
reported; and communicate a response to the Investigator, event reporter and the members of DSMC. The 
review will include but not be limited to the information reported; there may be times when additional 
information is needed in order for an assessment to be made and further communication directly with the 
investigator may be warranted. DSMC reserves the right to disagree with the Investigator's assessment. If 
DSMC does not agree with the Investigator, DSMC reserves the right to suspend the trial pending further 
investigation. If there is any immediate danger or harm that could be present for a future patient based on 
the information provided in the DSMC report then an immediate suspension of enrollment should be 
considered. 
 
 
AMENDMENTS TO PREVIOUS REPORTS 
If all pertinent information is unavailable with the initial submission, once the additional information is 
available do not submit a new report. Rather, go to the original email that was sent to the DSMC and using 
that email “reply to all”. Entitle this new email “Amendment for (list date of event and patient ID)” this will 
avoid duplications of the same event. List the additional information being reported. This information 
needs to be entered into WISER as well. To do this, go to the Subject console and click SAEs on the left 

 
A Prospective Randomized Phase II Study of 1 vs 2 Fractions of  
Palliative Radiation Therapy for Patients with Symptomatic Bone Metastasis  
Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU # 01416 
Protocol version date 03/12/21 
 
                          Page 32 of 45 
 
column. Click on the appropriate SAE number that needs updating. Then click Update. This will allow 
additional  information to be added. 
 
Acronyms 
AE – Adverse Event 
DSMC-Data and Safety Monitoring Committee 
SAE-Serious Adverse Event 
WFBCCC – Wake Forest Baptist Comprehensive Cancer Center 
NCI-National Cancer Institute 
WISER –Wake Integrated Solution for Enterprise Research 
 
Screen Shots: 
The following screen shots come from the SAE Console within the Subject Console in WISER. 
Screen Shot 1: 
 
Screen Shot 2:
 

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 33 of 45 
 
Screen Shot 3: 
 
 
 
Screen Shot 4: 
 
 
 
 
 
 
 
 
 
 
 
 

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 34 of 45 
 
 
Appendix E – Baseline Data Collection Form 
 
1. Medical history (check all that apply): 
 Myocardial infarction 
 Congestive heart failure 
 Peripheral vascular disease 
 Cerebrovascular disease 
 Dementia 
 Chronic pulmonary disease 
 Connective tissue disease 
 Peptic ulcer disease 
 Liver disease – 
 mild 
 moderate 
 severe 
 Diabetes – end organ damage? Yes 
 
No 
 
 Hemiplegia 
 Other cancer – specify ___________________ 
 AIDs 
 Other medical condition – specify _______________________ 
 
Other sites of metastases: Yes 
 
No 
 N/A  
  
 
If yes: 
a. Brain:  Yes 
 
No 
  
b. Liver:   Yes 
 
No 
  
c. Other: _______ 
 
2. Medications (including pain meds): 
Concurrent medications: 
a. Name:________  
  Dose:________     Frequency:________   Date started:_______ 
b. Name:________  
  Dose:________     Frequency:________   Date started:_______ 
c. Name:________  
  Dose:________     Frequency:________   Date started:_______ 
d. Name:________  
  Dose:________     Frequency:________   Date started:_______ 
e. Name:________  
  Dose:________     Frequency:________   Date started:_______ 
f. 
Name:________  
  Dose:________     Frequency:________   Date started:_______ 
 
Currently using bisphosphonates/Denosumab? Yes 
      No 
        
If yes:  
Name:________  
   Dose:________     Frequency:________ 
 Started:_________Prior Cancer Therapy: 
a. Name:________  
 
Treatment Regimen:_______________________ 
b. Name:________  
 
Treatment Regimen:_______________________ 
c. Name:________  
 
Treatment Regimen:_______________________ 
 
Change in systemic chemotherapy in past 4 weeks? Yes 
 No 
    N/A 
 
 
Change in hormonal therapy in past 4 weeks?    Yes 
 
No 
    N/A 
 
 
Change in use of bisphosphonates in past 4 weeks? Yes 
 No 
    N/A 
 
 
 
 
Change in immunotherapy  in past 4 weeks? Yes 
 No 
    N/A 
 
 
 
3. Performance Status (check one): 

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 35 of 45 
 
 
ECOG PERFORMANCE STATUS 
GRADE 
Description 
   0 
Fully active, able to carry on all pre-disease performance without restriction 
   1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
   2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
   3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
   4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
   5 
Dead 
 
4.  Nutrition status: 
a.  Height: _______ 
b. Weight: _______ 
c. BMI (kg/M2)______ 
d. History of weight loss: (within the last three months prior to enrollment)  Yes 
 
No 
  
If yes, date of weight loss:__/__/__ 
If yes, amount of weight loss: ____ 
5. Vital signs: 
a. HR______ 
b. BP___/___ 
c. RR____ 
d. Temp (oF)____ 
 
6. Physical Exam 
 
Derm – 
 WNL 
 Abnormal, specify ______________________________ 
HEENT – 
 WNL 
 Abnormal, specify ______________________________ 
CV – 
 WNL 
 Abnormal, specify ______________________________ 
Pulm – 
 WNL 
 Abnormal, specify ______________________________ 
GI – 
 WNL 
 Abnormal, specify ______________________________ 
Other – 
 Abnormal, specify ____________________________ 
 
7. Documentation of negative pregnancy test for women of child-bearing potential? 
 
 
Yes 
  
 
No 
, reason_ _____________       Not applicable
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 36 of 45 
 
 
Appendix F – Treatment Data Collection Form 
 
Time point of assessment: 
 
 Treatment administration   
Tx #1  
 
Tx #2  
 
 
 
  3 months post treatment  
  6 months post treatment 
 
 
1. Nutrition status: 
a. Weight: _______ 
b. BMI (kg/M2)_____ 
c. History of weight loss: (since last assessment)  Yes 
 
No 
  
If yes, date of weight loss:__/__/__ 
If yes, amount of weight loss: ____ 
2. Vital signs: 
a. HR______ 
b. BP___/___ 
c. RR____ 
d. Temp (oF)___ 
 
 
 
 

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 37 of 45 
 
Appendix G – Patient Questionnaire 
 
 
Time point of assessment: 
 
 Baseline  
  3 months post treatment  
  6 months post treatment  
 
 
 
 
 

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 38 of 45 
 
 
 
 
We are interested in knowing about the stresses you are experiencing with your treatment.  Please 
answer each question regarding how you have perceived stress in the past week on a scale from 1 = 
“Never” to 5 = “Very Often”.   
 
 
Never 
Almost 
Never 
Sometimes 
Fairly 
Often 
Very 
Often 
In the last month, how often have you been upset 
because of something that happened unexpectedly? 
1 
2 
3 
4 
5 
In the last month, how often have you felt that you 
were unable to control the important things in your 
life? 
1 
2 
3 
4 
5 
In the last month, how often have you felt nervous 
and “stressed”? 
1 
2 
3 
4 
5 
In the last month, how often have you felt confident 
about your ability to handle your personal problems? 
1 
2 
3 
4 
5 
In the last month, how often have you felt that things 
were going your way? 
1 
2 
3 
4 
5 
In the last month, how often have you found that you 
could not cope with all the things that you had to do? 
1 
2 
3 
4 
5 
In the last month, how often have you been able to 
control irritations in your life? 
1 
2 
3 
4 
5 
In the last month, how often have you felt that you 
were on top of things? 
1 
2 
3 
4 
5 
In the last month, how often have you been angered 
because of things that were outside your control? 
1 
2 
3 
4 
5 
In the last month, how often have you felt difficulties 
were piling up so high that you could not overcome 
them? 
1 
2 
3 
4 
5 
 
 

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 39 of 45 
 
We are interested in knowing about your support network.  Please read the statements and answer how 
true or false each is for you.  The answers range from 1= “Definitely False for you” to 4 = “Definitely 
True for you”. 
 
 
Definitely 
false for 
you 
Probably 
false for 
you 
Probably 
true for 
you 
Definitely 
true for 
you 
If you wanted to go on a trip for a day (for example, the 
country or mountains), you would have a hard time 
finding someone to go with you. Would you say this is… 
1 
2 
3 
4 
You feel that there is no one you can share your most 
private words and here’s what. Would you say this is… 
1 
2 
3 
4 
If you were sick, you could easily find someone to help 
you with your daily chores. Would you say this is… 
1 
2 
3 
4 
There is someone you can turn to for advice about 
handling problems with your family. 
1 
2 
3 
4 
If you decide one afternoon that you would like to go to a 
movie that evening, you can easily find someone to go 
with you. 
1 
2 
3 
4 
When you need suggestions on how to deal with a 
personal problem, you know whoyou can turn to. 
1 
2 
3 
4 
You don’t often get invited to do things with others. 
1 
2 
3 
4 
If you had to go out of town for a few weeks it would  be 
difficult to find someone who would look after your house 
or apartment (the plants, pets, garden, etc.). 
1 
2 
3 
4 
And if you wanted to have lunch with someone, you 
could easily find someone to join you. 
1 
2 
3 
4 
If you were stranded 10 miles from home, there is 
someone you could call who would come and get you. 
1 
2 
3 
4 
If a family crisis arose, it will be difficult to find someone 
who could give you good advice about how to handle it. 
1 
2 
3 
4 
If you needed some help in moving to a new house or 
apartment, you would have a hard time finding someone 
to help you. 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 40 of 45 
 
We are interested in knowing about the satisfaction you are experiencing with your treatment.  Please 
answer each question regarding your satisfaction with your treatment in the past week on a scale from 
1 = “Strongly Agree” to 5 = “Strongly Disagree”.   
 
 
Strongly 
Agree 
Agree 
Neither 
Disagree 
Strongly 
Disagree 
I felt that my health concerns were understood. 
1 
2 
3 
4 
5 
I felt that I was treated with courtesy and respect. 
1 
2 
3 
4 
5 
I felt included in decisions about my health. 
1 
2 
3 
4 
5 
I was told how to take care of myself. 
1 
2 
3 
4 
5 
I felt encouraged to talk about my personal health 
concerns. 
1 
2 
3 
4 
5 
I felt I had enough time with my doctor. 
1 
2 
3 
4 
5 
My questions were answered to my satisfaction. 
1 
2 
3 
4 
5 
Making an appointment was easy. 
1 
2 
3 
4 
5 
I knew what the next step in my care would be. 
1 
2 
3 
4 
5 
I feel confident in how I deal with the health care 
system. 
1 
2 
3 
4 
5 
I was able to get the advice I needed about my 
health issues. 
1 
2 
3 
4 
5 
I knew who to contact when I had a question. 
1 
2 
3 
4 
5 
I received all the services I needed. 
1 
2 
3 
4 
5 
I am satisfied with the care I received. 
1 
2 
3 
4 
5 
The doctors seemed to communicate well about my 
care. 
1 
2 
3 
4 
5 
I received high quality care from my regular doctor. 
1 
2 
3 
4 
5 
I received high quality care from my specialists. 
1 
2 
3 
4 
5 
My regular doctor was informed about the results of 
the tests I got. 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
 
 
 
 

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 41 of 45 
 
 
Appendix H – Numerical Rating Pain Scale (NRPS) 
 
Time point of assessment: 
 
 
 
 Screening/Baseline  
 
 
 
 
 
 1-month post treatment 
 
 
 2-months post treatment 
 
 
 3 months post treatment 
 6 months post treatment 
 
 
 
Please rate your pain by circling the one number that best describes your pain at its WORST in  the past 3 
days. 
 
 
 
 
 
Site of Pain: _____________________________________________________________________ 
 
Toxicity Evaluation: 
 
Did the patient report any adverse events or toxicities? 
Y 
/ 
N 
/ 
N/A 
 
If Yes, Describe and add to AE Log:  
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________
________________________________________________________________________________________ 
 
Any changes to the patient’s medications?  
Y 
/ 
N 
/ 
N/A 
 
 
If yes,  Name:________  
  Dose:________     Frequency:________   Date started:_______ 
 
 
Name:________  
  Dose:________     Frequency:________   Date started:_______ 
 
 
Name:________  
  Dose:________     Frequency:________   Date started:_______ 
 
 
Name:________  
  Dose:________     Frequency:________   Date started:_______ 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Pain 
 
 
 
 
 
 
Worst possible pain 

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 42 of 45 
 
 
Appendix I – CCCWFU 01416 Adverse Event (AE) Log 
 
PI: _______________ 
 
PID: _________________ 
 
MRN: ________________ 
 
 
 
Start Date: _____________ 
End Date: _______________ 
 
Time Point (choose 
one)  
1 month 
 
 
 
Adverse Event CTC 
Term 
Value (-5 if 
nonnumeric) 
Grade 
(0-5) 
per CTC 
Start 
Date 
Attribution 
1=Related 
2=Probably 
3=Possible 
4=Unlikely 
5=Unrelated 
Treating MD 
Initials/Date 
End 
Date 
Expected 
1=Yes      
0=No 
Serious 
Adverse 
Event 
(SAE)   
1=Yes 
0=No 
Dose 
Limiting 
Toxitity 
(DLT) 
1=Yes 
0=No 
Action 
Taken 
1=None     
2=Tx 
withheld 
3=Tx D/C   
4=Tx 
adjusted 
5=Other 
Reportable?   
(1-IRB 2-
STRC, 3-FDA 
4-Sponsor) 
Nausea 
  
  
  
  
  
  
1 
  
  
  
  
Vomiting 
  
  
  
  
  
  
1 
  
  
  
  
Diarrhea 
  
  
  
  
  
  
1 
  
  
  
  
Skin erythema 
  
  
  
  
  
  
1 
  
  
  
  
alopecia 
  
  
  
  
  
  
1 
  
  
  
  
 esophagitis 
  
  
  
  
  
  
1 
  
  
  
  
myelosuppression 
  
  
  
  
  
  
1 
  
  
  
  
 Urinary urgency 
  
  
  
  
  
  
1 
  
  
  
  
 Urinary frequency 
  
  
  
  
  
  
1 
  
  
  
  
 pneumonitis 
  
  
  
  
  
  
1 
  
  
  
  
Pain (increased from 
baseline) 
 
 
 
 
 
 
 
 
 
 
 
Serious Adverse Event: Hospitalization; Disability; Birth Defect; Life-threatening; Death. 
CTCAE Version 4 - http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
 
 

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 43 of 45 
 
Appendix I – CCCWFU 01416 Adverse Event (AE) Log 
 
PI: _______________ 
PID: _________________ 
MRN: ________________ 
Start Date: _____________ 
End Date: _______________ 
Time point (choose one):        
 
2 months   3 months 6 months 
 
 
 
OTHER Adverse 
Events 
Value       
(-5 if non-
numeric) 
Grade(0-
5) per 
CTC 
Start Date 
Attribution 
1=Related 
2=Probably 
3=Possible 
4=Unlikely 
5=Unrelated 
Treating 
MD 
Initials/Date 
End Date 
Expected 
1=Yes 
0=No 
Serious 
Adverse 
Event 
(SAE)  
1=Yes 
0=No 
Action Taken  
1=None        
2=Tx withheld 
3=Tx D/C      
4=Tx adjusted 
5=Other 
Reportable?    (1-
IRB 2-STRC, 3-FDA 
4-Sponsor) 
Fistula formation 
  
  
  
  
  
  
  
  
  
  
 Bowel 
obstruction 
  
  
  
  
  
  
  
  
  
  
 Bowel 
perforation 
  
  
  
  
  
  
  
  
  
  
 Fracture of the 
bone 
  
  
  
  
  
  
  
  
  
  
 Damage to spinal 
cord (myelitis) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 44 of 45 
 
 
Appendix J – Re-Treatment Data Form 
 
 
1) Did re-treatment occur? Yes 
 No 
  
 
a. If yes, when was the first re-treatment?   __/___/___ 
 
 
 
 

CCCWFU # 01416 
Patient ID:__________ 
Date of completion: _________ 
Protocol version date 03/12/21 
 
                          Page 45 of 45 
 
 
 
Appendix K – Post-Treatment Imaging 
 
DATA COLLECTION FORM 
 
PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 Date Completed: ___ ___ / ___ ___ / ___ ___ 
 
 
PI: Doris Brown, M.D. 
 
 
Study Number:___CCCWFU 01416_________ 
 
 
To be completed by study staff: 
 
To be completed by study staff: 
Time Point 
Type of Imaging (CT, X-ray, etc.)b 
Date of Imagingb 
3 Monthsa 
 
 
6 Monthsa 
 
 
 
To be completed by the investigators (Dr. Willey): 
 
Cortical Bone Thickness (mm)b 
Bone Mineral Density (mg HA/cc)b 
3 Monthsa 
 
 
6 Monthsa 
 
 
 
 
a10-18 weeks from final treatment date (3-month) and 20-34 weeks from final treatment date (6-month visit). 
bNA if none