Phase II Pilot Single Arm Prospective Clinical Trial of Rapid Institution of Helical TomoTherapy-based Radiation Therapy for Patients With Painful Osseous Metastatic Disease
Phase: NA
Conditions: Bone Metastases
Sponsor: University of Virginia

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PI: Paul W Read 
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Protocol Title:  A Phase II Pilot Single Arm Prospective Clinical Trial of Rapid 
Institution of Helical TomoTherapy-based Radiation Therapy for Patients with 
Painful Osseous Metastatic Disease 
 
NCT#:  NCT01391234 
 
Protocol version date:  03/25/2013 

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A Phase II Pilot Single Arm Prospective Clinical Trial of Rapid Institution of 
Helical TomoTherapy-based Radiation Therapy for Patients with Painful Osseous 
Metastatic Disease 
 
Principal Investigator: 
 
Paul W. Read, MD PhD 
Professor 
Department of Radiation Oncology  
University of Virginia Medical Center 
Charlottesville, VA 22908 
PO Box 800383 
Phone: 434-924-5191 
Fax: 434-243-9789 
E-mail: pwr3u@hscmail.mcc.virginia.edu 
 
Co-Investigators:  
 
Quan Chen, PhD 
Assistant Professor 
Department of Radiation Oncology, Division of Medical Physics 
University of Virginia Medical Center 
Charlottesville, VA 22908 
PO Box 800383 
Phone: 434-943-0030 
Fax: 434-982-3520 
Email: qc3k@hscmail.mcc.virginia.edu 
  
Lydia L. Handsfield, MS 
Physics Research 
Department of Radiation Oncology, Division of Medical Physics 
University of Virginia Medical Center 
Charlottesville, VA 22908 
PO Box 800383 
Phone: 434-982-1499 
Fax: 434-982-3520 
Email: lll4s@hscmail.mcc.virginia.edu 
 
 
James M. Larner, MD 
Professor and Chairman 
Chairman of the Department of Radiation Oncology  
University of Virginia Medical Center 
Charlottesville, VA 22908 

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PO Box 800383 
Phone: 434-924-5191 
Fax: 434-243-9789 
E-mail: jml2p@hscmail.mcc.virginia.edu 
 
Monica M. Morris, MD 
Associate Professor 
University of Virginia Medical Center 
Charlottesville, VA 22908 
PO Box 800383 
Phone: 434-924-5191 
Fax:  434-243-9789 
E-mail: mmm4u@hscmail.mcc.virginia.eduShiv R. Khandelwal, MD 
Associate Professor of Radiation Oncology 
University of Virginia Medical Center, Culpeper Regional Hospital 
Culpeper, VA 22701 
501 Sunset Lane, PO Box 592  
Phone : 540-982-6278 
Fax : 540-829-4272 
E-mail: srk6v@hscmail.mcc.virginia.edu 
 
 
 
Leslie J. Blackhall, MD 
Associate Professor  
Division of General Medicine, Geriatrics and Palliative Care 
University of Virginia Medical Center, Box 801024 
Charlottesville, VA 22908 
PO Box 800744 
Phone: 434-243-5730 
Fax: 434-243-9282 
E-mail: lb9x@hscmail.mcc.virginia.edu 
 
Geoffrey R. Weis, MD 
Professor and Chief 
Division of Hematology Oncology 
University of Virginia Medical Center 
Charlottesville, VA 22908 
PO Box 800744 
Phone: 434-243-0066 
Fax: 434-243-0064 
E-mail: grw3k@hscmail.mcc.virginia.edu 
 
 
Biostatistician:  
 

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David D. Wilson, MD 
Resident Physician 
Department of Radiation Oncology  
University of Virginia Medical Center 
Charlottesville, VA 22908 
PO Box 800383 
Phone: 434-924-6393 
Fax: 434-243-9789 
E-mail: ddw3m@hscmail.mcc.virginia.edu 
 
 
Clinical Research Coordinator: 
 
Gretchen Watkins, BA 
Senior Clinical Research Coordinator 
Department of Radiation Oncology  
University of Virginia Medical Center 
Charlottesville, VA 22908 
PO Box 800383 
Phone: 434-243-7231 
Fax: 434-243-9789 
Email: gmw7h@hscmail.mcc.virginia.edu 
 
 
Drug Source: Not applicable 
 
Funding Source: 2008 Buchanan Award, Radiation Oncology Departmental Funding, 
UVA Cancer Center and 2012 CMS-1C1-12-0001 from Centers for Medicare and 
Medicaid Services, Center for Medicare and Medicaid Innovation.for Medicare and 
Medicaid Innovation 
 
 
SCHEMA 
 
                               Tx  
 
 
        Follow-Up  
                                    _______  - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -                                                                
               Helical  
  TomoTherapy*: 
      
     Assessments¶:                                                                                                               
                  
                  Week:  0       1             4                8               12                    26                 52 
 
*2-5 Helical TomoTherapy radiation treatments over 1-2 weeks 
¶ Physical Exam (PE) and/or surveys  
       Treatment-related toxicity will be captured during treatment PEs and follow up PEs.  
 

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STUDY OVERVIEW 
• Eligible patients with 1-3 painful osseous metastases will receive a consultation 
and subsequently undergo CT simulation, radiation treatment planning, and their 
first radiation treatment on day 1. 
• Patients will receive a total of 2-5 fractions of high dose palliative radiation 
therapy via helical TomoTherapy consisting of 5-10 Gray (Gy) per fraction with a 
minimum biologic effective dose (BED) of 25 Gy. 
• Standard patient-specific treatment planning quality assurance will be performed 
on a cylindrical phantom with ion chamber and film measurement.   
• Software provided by TomoTherapy Inc.® will be used to measure the radiation 
exiting the patient and recalculate the dose the patient received.  This calculated 
dose will then be compared to phantom measurements and treatment planning 
calculations to validate the ability of this novel radiation dose verification 
software to verify the accurate delivery of radiation.  This will not replace 
standard quality assurance measurements. 
• At the Emily Couric Cancer Center, an in-house developed infrared motion 
tracking system will monitor patients’ positions for any deviation from the 
treatment position.  This is not standard of care but may augment standard safety 
measures with full implementation in the future and does not subject the patient to 
any risks or discomfort. Infrared motion tracking is will be optional and not 
required for patients treated at CRH.  
 
• Contouring (the demarcation of the tumor and critical structures) will be 
performed in the standard manner for treatment planning. 
• Contouring will also be performed in an expedited, experimental manner on 
diagnostic image sets which will then be compared to the standard contours.  
Experimental contouring will not replace standard contouring, nor affect 
treatment planning. 
• Patients will complete questionnaires to capture pain scores of the treated 
lesion(s), analgesic use, patient functional status, patient quality of life, and 
patient satisfaction at 1 week, 4 weeks, 8 weeks, 12 weeks, 6 months, and 12 
months following treatment.  These scores will be compared to questionnaires 
completed pretreatment. 
• Radiation-induced toxicities will be captured during treatment physical 
examinations and at follow-up physical examinations at 4 weeks, 12 weeks, 6 
months, and 12 months. 
 
ELIGIBILITY (see section 3.0) 
• Patient has a biopsy proven diagnosis of cancer.  The osseous metastatic lesions 
do not need to be biopsied. 
• Patients with multiple myeloma are eligible for the study.  
• Patient has 1-3 major painful osseous metastases (target lesions) from any 
primary cancer or unknown primary cancer.  
• Long bone target lesions must have a Mirels fracture score of ≤ 7 (See Appendix 
G). 

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• Patients with spinal cord compression from vertebral body metastases are not 
eligible. 
• Target lesions have not previously been treated with external beam radiation. 
• Radiation oncologist determines that the patient is medically able to undergo 
palliative radiation therapy.  
• Patient has target lesions that are radiographically consistent with metastatic 
disease on CT, MR, or PET CT obtained within 8 weeks of treatment.  
• Persistent distinguishable pain associated with target sites to be treated.  
• Patient average bone pain index (BPI) pain score for last 72 hours at specified 
location is > 3 (0-10 scale)  
• Patients may have additional non-painful or minimally painful osseous metastases 
(if patient has pain from additional sites, the pain from the additional sites must be 
evaluated as being less intense by at least 2 points on the BPI compared to the 
site(s) treated) 
• The patient may have previously been treated with external beam radiation 
therapy to other body sites, but not to the target lesions. 
• The patient may have previously or currently be undergoing chemotherapy or 
bisphosphonate therapy. 
• The patient will be able understand English (or a medical interpreter for their 
native language must be available for all study visits).  
• 18 years of age or older. 
• Life expectancy > 12 weeks. 
• Able and willing to answer simple survey questionnaires.  
• Able and willing to keep a logbook of analgesic use (with or without assistance).  
• Willing to return to clinic for follow-up visits after treatment. 
• Signed study-specific informed consent form 
 
 
 
TREATMENT (see section 4.0):  
• Patients will receive 2 to 5 palliative radiation treatments prescribed to 5-10 Gy 
per treatment with a minimum biologic effective dose (BED) of 25 Gy.  Radiation 
dose will be determined and prescribed by the treating radiation oncologist based 
on tumor volume, proximity and dose to adjacent critical structure limitations, 
tumor radiosensitivity, whether the patient is receiving systemic chemotherapy, 
and the overall performance status of the patient.  
 
CORRELATIVES: 
None 

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TABLE OF CONTENTS [to update TOC use F9, or right click the field] 
1.0 
BACKGROUND AND RATIONALE .................................................................1 
1.1 
Study Synopsis .....................................................................................................1 
1.2 
Disease Background.............................................................................................2 
1.3 
Study Agent(s) Background and Rationale..........................................................4 
1.4  
Preliminary Studies……………………………………………………………13 
1.5 
Rationale for Study Design ..............................................................................145 
1.6 
Correlative Studies .............................................................................................18 
2.0 
STUDY OBJECTIVES ........................................................................................18 
2.1 
Primary Objectives.............................................................................................18 
2.2 
Secondary Objectives.........................................................................................19 
2.3 
Exploratory Objectives ......................................................................................19 
3.0 
PATIENT ELIGIBILITY ...................................................................................18 
3.1 
Inclusion Criteria ...............................................................................................19 
3.2 
Exclusion Criteria ..............................................................................................21 
4.0 
TREATMENT PLAN ..........................................................................................22 
4.1 
Schema ...............................................................................................................22 
4.2 
Treatment Dosage and Administration ..............................................................22 
4.3 
Toxicities and Dosing Delays/Dose Modifications ...........................................24 
4.4 
Concomitant Medications/Treatments ...............................................................25 
4.5 
Other Modalities or Procedures .........................................................................26 
4.6 
Duration of Therapy ...........................................................................................26 
4.7 
Duration of Follow Up .......................................................................................26 

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4.8 
Pregnancy ...........................................................................................................26 
4.9 
Removal of Patients from Protocol Therapy .....................................................27 
4.10 
Expected Adverse Events ..................................................................................27 
5.0 
EVALUATIONS AND ASSESSMENTS ...........................................................28 
5.1 
Time and Events Table ......................................................................................28 
5.5 
Correlative Studies Procedures ..........................................................................28 
5.6 
Final Study Visit ................................................................................................29 
5.7 
Early Termination Visit .....................................................................................29 
6.0 
EVALUATION CRITERIA ...............................................................................29 
6.1 
Response to Palliative Radiotherapy .................................................................29 
6.2 
Toxicity and Safety ............................................................................................30 
7.0 
STATISTICAL CONSIDERATIONS ...............................................................30 
7.1 
Study Design ......................................................................................................30 
7.2 
Sample Size and Accrual ...................................................................................33 
7.3 
Data Analyses Plans ...........................................................................................34 
8.0 
ADVERSE EVENTS AND REPORTING.........................................................35 
8.1 
Definition ...........................................................................................................35 
8.2 
Attribution Assessment ......................................................................................37 
8.3 
Serious or Unexpected Adverse Event Reporting Requirements ......................37 
8.4 
UVA Cancer Center DSMC AE Reporting Requirements ................................37 
8.5 
UVA IRB Reporting Requirements ...................................................................38 
9.0 
DATA SAFETY MONITORING PLAN ...........................................................39 
9.1 
Internal (Investigator) Study Monitoring Plan ...................................................39 

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9.2 
UVA Cancer Center Data Safety Monitoring Committee .................................39 
10.0 
STUDY MANAGEMENT ...................................................................................40 
10.1 
Institutional Review Board (IRB) Approval and Consent .................................40 
10.2 
Registration Procedures .....................................................................................40 
10.3 
Adherence to the Protocol ..................................................................................40 
10.4 
Record Retention ...............................................................................................42 
10.5 
Obligations of Investigators ...............................................................................42 
11.0 
REFERENCES ......................................................... Error! Bookmark not defined. 
12.0 
APPENDICES ......................................................................................................42 
 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Synopsis 
   Background: Osseous metastatic disease causes significant pain, decreased 
functioning, and decreased quality of life. Progressive bone destruction can lead 
to pathologic fractures or spinal cord compression leading to orthopedic surgery, 
paralysis, and/or patients becoming bedridden. Opioids can alleviate pain but have 
neurologic and gastrointestinal side effects that further decrease quality of life. 
Radiation therapy can effectively reduce pain and opioid use and prevent further 
bone destruction, however, its use is limited because the current workflow 
frequently requires one week for planning and two weeks for delivery. 
Additionally, typical palliative radiation plans for osseous metastases lack 
conformality of dose to the tumor volume, and therefore, result in radiation-
induced toxicity to large volumes of adjacent normal tissue.  Recent software and 
hardware advancements provide the opportunity to revolutionize the palliative 
treatment of osseous metastases. We propose to investigate a novel 
TomoTherapy-based workflow, called STAT RT, which includes same day CT 
simulation, treatment planning, and quality assurance measurements coupled with 
highly conformal treatment delivery for patients with osseous metastases in a pilot 
clinical trial.  
   Objective: The overall goal of this STAT RT proposal is to develop a more 
rapid, convenient, and effective palliative radiation approach for patients with 
osseous metastases that is less toxic and less expensive than current treatment 
regimens. We have already optimized the conformality of TomoTherapy-based 
radiation doses for osseous metastases, and we have developed a STAT RT 
workflow that condenses standard of care simulation, planning, quality assurance, 
and treatment delivery into 5-6 hours.  Additional optimization and integration of 
new radiation therapy computing processes will allow for real time simulation, 
planning, and delivery via a novel Scan-Plan-Treat STAT RT workflow that will 
ultimately require only 30 minutes.  In this study we will evaluate the 
effectiveness of the current STAT RT workflow, and we will investigate 
techniques for further optimization that will be needed to create a 30 minute Scan-
Plan-Treat STAT RT workflow.  
   Primary Specific Aim/ Hypothesis:   We will quantify the time for pain relief, 
amount of pain relief, opioid use reduction, functional scores, quality of life, and 
satisfaction of patients treated with STAT RT for osseous metastases.  We 
hypothesize that these patients will have rapid and significant pain relief, 
improved quality of life, and high patient satisfaction.      
   Secondary Specific Aim/ Hypothesis:  We will optimize the integration of 
commercially available and in-development software to develop the Scan-Plan-
Treat STAT RT workflow.  Specifically, we will A) optimize rigid and 
deformable co-registration of pre-contoured diagnostic image sets to MVCT 
simulation scans and compare the accuracy to the same pre-contoured diagnostic 
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kVCT simulation to MVCT scan co-registration, B) optimize CT-detector-based 
exit dose measurement algorithms for quality assurance and compare to standard 
of care phantom-based quality assurance, C) explore the options of including an 
in-house real time infrared tracking system for intrafractional patient position 
monitoring to ensure accurate patient treatment.  We hypothesize that these new 
components will provide effective and efficient methods for treatment planning, 
quality assurance, and patient position monitoring that can be used in a future 30 
minute Scan-Plan-Treat STAT RT workflow.  
   Study design: We will recruit 30 cancer patients with 1-3 painful osseous 
metastatic lesions (target sites) who are candidates for palliative radiation therapy.  
Patients will receive 2-5 fractions of 5-10 Gy (minimum BED of 25 Gy) of 
conformal radiation therapy delivered to the target sites via the Helical 
TomoTherapy system using the STAT RT workflow.  Data will be collected to 
evaluate the effectiveness of our novel image co-registration techniques and CT-
detector-based exit dose calculations.  These novel techniques for image co-
registration, radiation dose calculations, and possible patient position monitoring 
will not alter or replace standard of care techniques. Using validated surveys we 
will record patient pain, analgesic use, function, quality of life, and patient 
satisfaction prior to treatment and at 1 week, 4 weeks, 8 weeks, 12 weeks, 6 
months, and 12 months after therapy.  Radiation-induced treatment related 
toxicities will be captured during treatment and at the above time points.   
1.2 
Disease Background 
1.2.1 Epidemiology of Metastatic Bone Disease 
 
The American Cancer Society estimates that approximately 1.5 million 
people in the United States will be diagnosed with cancer, and 560,000 will die of 
cancer in 2010 (1). These numbers are projected to increase rapidly in the near 
future due to national demographics with a large number of Americans reaching 
retirement age over the next 15-20 years, resulting in a doubling of projected new 
cancer diagnoses in 2050 to 3 million (2).  Most cancer deaths involve extensive 
locoregional tumors or metastatic disease to brain, lung, liver, or bone causing 
pain, disability, and decreased quality of life.  As treatments for cancer improve, 
patients are living longer with advanced cancer than ever before, and the 
management of metastatic disease is becoming increasingly more multi-
disciplinary and complex with patients treated simultaneously with systemic 
therapy, surgery and radiation.  
 
 
 
The skeleton is one of the most common sites of metastatic disease and is 
often the first site affected by metastases (3, 4).  It was estimated that in 2004, 
250,000 cancer patients were afflicted with metastatic bone disease (3).  Bone 
metastases are most common in patients with multiple myeloma, of whom 90% 
develop bone metastases (5).  Approximately 70% of patients dying of breast and 
prostate cancer have evidence of metastatic bone disease, and bone metastases are 
also common in thyroid, kidney, and lung cancers, occurring in 30-40% of these 
cancers (4).  Metastatic bone disease causes considerable morbidity in patients 

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with cancer, resulting in pain, hypercalcemia, pathologic fractures, compression 
of the spinal cord or cauda equina, and spinal instability (4). 
1.2.2 Standard Palliative Radiotherapy Techniques 
 
Bone metastases are the most common cause of cancer-related pain (4).  It 
is well documented that cancer-related pain is often inadequately controlled in the 
palliative care setting, and both the pain and opioid medication interfere with 
patient function and quality of life (6-8).  Radiotherapy is an important tool for 
the alleviation of pain and suffering for cancer patients, and it is used to prevent 
pathologic bone fractures or palliate tumor-induced obstruction, bleeding, and 
pain that is not well palliated with pharmacologic treatment (9).  Bony metastatic 
lesions in the spine and extra-axial skeleton are often targeted with radiation, 
resulting in prevention of pathologic fractures, reduction in pain, and 
improvement in quality of life (10-13).  
 
 
   a) Lack of Dose Conformality 
 
For 30-40 years, standard palliative radiotherapy treatment techniques 
have utilized simple opposed beam arrangements such as treating a patient with 
parallel opposed anterior and posterior beams.  Although simple to plan and 
deliver, such techniques provide poor conformality, and large volumes of organs 
at risk (OARs) may receive the full prescribed dose depending on the level 
treated. See Figure 1.  These OARs may include (skin, lung, esophagus, trachea, 
stomach, small, bowels, rectum, bladder, or genitals) resulting in cough, 
dysphagia, odynophagia, nausea, vomiting, weight loss, fatigue, diarrhea, dysuria, 
erythema, and pruritus of the skin and genitals (13, 14).  Despite being planned 
and delivered on sophisticated systems, these treatments are frequently only 
modestly effective, and cause significant toxicity to an already ill patient 
population with a limited life expectancy (13).  
 
   b) Slow Workflow for Treatment Planning and Quality Assurance 
 
Conventional simulation and treatment planning is performed over a 
several day process prior to the first delivered treatment.  The patient generally is 
first seen in consultation and scheduled for a CT simulation on a subsequent day.  
During the CT simulation the patient is placed in the position in which they will 
ultimately be treated on a linear accelerator (LINAC) or TomoTherapy unit, and 
immobilization and support devices are fabricated after which they undergo a CT 
scan in the treatment position.  He or she must then wait, sometimes several days, 
for the contouring of the CT simulation images (a process by which the radiation 
oncologist specifies the planning target volume (PTV) of the tumor to be treated 
and the regional organs at risk (OARs) or adjacent tissues that may receive 
radiation resulting in toxicity).  Following the contouring of the CT images, 
radiation treatment planning is performed, during which time medical dosimetrists 
and physicians determine the beam angles and treatment technique to deliver the 
prescribed dose to the PTV while attempting to minimize dose to OARs if 
possible.  Again, for standard osseous metastatic disease palliative techniques 

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tend to be fairly simple.  Following treatment planning, quality assurance 
calculations and/or measurements are performed by medical physicists before 
delivery of the first treatment to ensure accuracy of delivering the planned dose 
and ensure patient safety.   
  
   c) Inconvenient, Modestly Effective Treatments 
 
Although fractionation schedules in Europe are trending toward 
hypofractionation (fewer treatments), the most common palliative dose 
fractionation schedules in the USA for osseous metastases vary between 20 and 
30 Gray (Gy) in 5 -10 fractions delivered over 1 -2 weeks (15).  Conventional 
radiotherapy, regardless of fractionation schedule, has been found to be modestly 
effective in palliation of bone metastases, resulting in an improvement in pain in 
only about 60% of patients (16, 17).  In a retrospective study of end stage cancer 
patients receiving palliative radiotherapy, Gripp et al found that half of the 
patients received treatment for >60% of their final days of life (18).  Thus, these 
often modestly effective treatments subject the patients to repeated visits to the 
treatment center and consume precious time and energy for ill patients and their 
families.  Clearly it is important that we design more effective palliative 
treatments that are more efficient to plan and deliver, minimize acute toxicity, and 
require fewer total treatments.   
1.2.3 Costs of Metastatic Bone Disease 
 
The treatment of metastatic bone disease is costly.  Schulman and Kohles 
estimated that the mean per patient direct cost for cancer patients after diagnoses 
with metastatic bone disease was $75,329 compared to $31,455 for cancer-
matched controls without metastatic bone disease (3).  Using this data, the authors 
estimated that the national cost burden for patients with metastatic bone disease 
was $12.6 billion in 2004, which was 17% of the NIH-reported $74 billion direct 
medical costs for cancer (3).  These costs will clearly increase with our aging 
population and associated increase in cancer prevalence (2).  From a societal 
standpoint, looming Medicare financial constraints will likely result in reduced 
reimbursement for palliative services, driving the economic incentive to develop 
the next generation of more clinically efficient palliative radiotherapy workflows.   
1.3 
Study Agent(s) Background and Rationale  
1.3.1 Stereotactic Body Radiotherapy (SBRT): A more effective, highly 
conformal hypofractionated palliative radiation technique 
 
In the search for more effective and less toxic radiotherapy techniques, 
much attention has been focused on stereotactic body radiotherapy (SBRT).   
SBRT is the use of hypofractionated, highly conformal, high dose radiation 
delivery that has been modeled after intracranial stereotactic radiosurgery (SRS).  
Like SRS, SBRT uses multiple beams that converge on the target volume.  This 
minimizes the volume of tissue receiving high dose to where the beams intersect, 
reducing dose to normal tissue.  This allows for the delivery of ablative doses of 
radiation in a few fractions with acceptable toxicity (19, 20).  SBRT is a proven 

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method for treating lung cancer, yielding excellent rates of local control for non-
small-cell lung cancer and resulting in 5-year survival rates potentially 
comparable to that of surgery (20, 21).  In addition, the treatment of liver 
metastases with SBRT has yielded promising results, achieving local control rates 
at 2 years of approximately 70–90% (22-24).   
 
 
SBRT has also been used in the palliative treatment of bone metastases to 
the spine with remarkable success.  Multiple studies have used SBRT to safely 
deliver high doses of radiation to the spine while significantly limiting dose to the 
spinal cord and achieving local control rates of > 80% at one year (25-29).  
Fractionations in these studies have ranged from 1 to 5 fractions delivering 4- 24 
Gy per individual fraction, with total doses between 10 to 30 Gy (25-29).  In the 
largest prospective study of spine SBRT by Gerszten, 336 cases were treated 
primarily to relieve pain, and they achieved significant pain improvement in 290 
patients (86%).  Nelson, Tsai, Gibbs, and Ryu, have also reported pain reduction 
in greater than 80% of patients in their studies (25-30), much improved over the 
60% in conventional radiotherapy (16, 17).  Not only do more people experience 
pain relief, but the pain relief is more durable.  Gagnon demonstrated statistically 
significant improvement in pain scores lasting throughout all 4 years of follow-up 
(31).  Ryu found the median duration of pain relief to be 13.6 months with SBRT 
(30), which is a dramatic improvement compared to the average 3 to 6 months of 
palliation with conventional therapy (13, 32).  Additionally, spinal SBRT 
treatments have been effective in achieving local control in tumors typically 
resistant to radiotherapy, such as renal cell carcinoma and melanoma, due in part 
to radiation injury to the tumor vasculature (25, 28, 30, 31).   
1.3.2 Adverse Events with SBRT: Minimal Toxicity 
 
Though great success is seen in high dose, hypofractionated therapy, care 
must be taken to avoid incorrectly delivering the high dose radiation to normal 
tissue.  Prevention of damage to normal tissue is ensured through careful patient 
immobilization, co-registration of multiple diagnostic imaging modalities (MRI, 
PET CT, contrast enhanced CT) to the kVCT simulation to accurately define the 
target and OARs, inverse treatment planning with the use of intensity modulated 
radiation therapy (IMRT), patient-specific quality assurance, and CT image 
guidance at the time of treatment delivery.  Nevertheless, common side effects of 
radiotherapy do occur with SBRT as do other adverse events.  However, the 
advantage of conformal radiation is that it spares radiation dose to normal tissue.  
This has been demonstrated by reports of little to no toxicity in many trials using 
SBRT(25, 31), and is reinforced by the findings of McIntosh et al, who compared 
conformal helical TomoTherapy with conventional 3D conformal treatment 
techniques on an anthropomorphic phantom and showed that helical 
TomoTherapy significantly improved conformality and reduced dose to regional 
critical structures(33). 
 

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Most significant adverse events in spinal SBRT have occurred with 
treatments that used extremely high-doses (>20 Gy) in a single fraction.  Gomez 
et al reported odynophagia and dysphagia in 1 patient who had received 22Gy to 
the esophagus in a single dose, and another patient developed an esophageal ulcer 
and necrosis after receiving 24Gy to his esophagus in one fraction (34).  Another 
patient developed bronchial stenosis after receiving 11Gy to a bronchus.  In 
another study with similarly high dose fractionation schedules, 39% of patients 
treated with 18 to 24 Gy in a single dose developed new or progressive vertebral 
fractures (35).  However, their patient selection did not utilize a scoring system to 
identify patients at high risk for pathologic fracture, such as the Mirels scoring 
system (36).  In contrast, Gagnon et al, using mean doses of 26 Gy in 3 fractions 
in 200 patients, only had 2 patients (1%) develop vertebral fractures (31).  Sahgal 
et al reported 5 cases of radiation myelopathy and concluded that for single 
fraction SBRT, up to 10Gy to a maximum point to the thecal sac is safe (37).  
Dose distributions that cause such severe toxicities described above will not be 
used in this study.  Our study will use doses similar to those used by Gagnon for 
his SBRT studies that reported remarkably low toxicities.  Additionally, to 
minimize the number of patients who develop new or progressive fractures, we 
will use the Mirels scoring system to identify patients at high risk of fracture and 
exclude them from the study (36). 
1.3.3 Extrapolation of Spinal SBRT-like Dose Distributions to Non-spine 
Osseous Metastases 
          Given the advances in radiation delivery with SBRT and its success in 
palliation of spine metastases, it is logical to apply these advancements in 
technology to extra-axial bone metastases; however no trials have been published 
to date.  This is due to the fact SBRT is only reimbursed for limited indications 
such as spinal metastases.  It is fair to hypothesize that the extrapolation of SBRT-
like dose distributions to extra-axial bone metastases will improve pain control 
and that rapid institution of radiation will minimize the time patients are in pain 
and on high dose opioids that place them at risk for iatrogenic medical 
complications.  By applying the concepts of spinal SBRT for palliative treatment 
of non-spinal bone metastases, we propose to use highly conformal radiation 
therapy techniques to treat patients that will allow increased dose per fraction and 
fewer total fractions with less toxicity compared to standard non-conformal 
palliative regimens. See Figures 1-2.   
 
 
 
 
 
 
 
 
 

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1.3.4 Relative Biologic Effective Dose: a method to compare different dose 
fractionation schedules 
 
Based on the linear-quadratic equation, one can calculate the biologic 
effective dose (BED) to compare dose delivery of different fractionation 
schedules using the equation: BED = nd [1+d/(alpha/beta)], where n = number of 
fractions and d = dose per fraction.  As seen in Table 1, when compared with 
conventional fractionation schedules for palliative osseous metastases, such as 
30Gy in 10 fractions or 20Gy in 5 fractions, high dose per fraction regimens 
deliver very similar BED to early responding tissues and slightly higher BED to 
late responding tissues.  Our study will deliver a minimum BED of 25 Gy to each 
treatment target. We anticipate that most patients on this trial will receive 2-3 
treatments with 8 Gy delivered per treatment, however, the dose per treatment, 
number of treatments, and total dose will depend on patient-specific factors 
including tumor histology, tumor location and proximity to critical OARs, and 
tumor size.  Relative BED provides a method to compare different dose 
fractionation schedules that can be used to correlate the treatment with patient 
outcomes. 
 
Table 1: Comparison of BED in Different Fractionation Schedules 
 
Total dose # of       
Fractions 
Dose per 
fraction 
(Gy) 
alpha/beta 
BED 
Early 
Responding 
Tissues 
30  
10 
3 
10 
39 
20 
5 
4 
10 
28 
24 
3 
8 
10 
43 
Late 
Responding 
Tissues 
30  
10 
3 
3 
60 
20 
5 
4 
3 
47 
24 
3 
8 
3 
88 
 
20Gy 
10Gy 
0Gy 
20Gy 
10Gy 
0Gy 
Figure 1: Conventional Technique
Figure 2: Conformal Technique

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1.3.5 STAT RT: A Rapid Palliative Radiotherapy Workflow 
 
The University of Virginia Radiation Oncology Department has received 
institutional funding through an institutional  Buchanan Grant  and a CMS 
Innovation Award to fund the technical development of a TomoTherapy-based 
STAT RT program for rapid pain palliation. We have already treated over 30 
patients in the first phase of development of this program with a STAT RT 
workflow that compresses the standard workflow to 6 hours allowing same day 
simulation, treatment planning, and treatment delivery. In the second phase of 
development we will optimize the combination of several recent computing 
advancements to create a Scan-Plan-Treat STAT RT workflow in which CT 
simulation, treatment planning, and treatment delivery with real time quality 
assurance will be performed on a single system in approximately 30 minutes.          
1.3.6 Technologic Rationale For The Choice of The TomoTherapy Platform  
          TomoTherapy delivers highly conformal and homogenous dose 
distributions through modulation of dose from a bank of 64 binary 6.25-mm-wide 
collimator leaves capable of pneumatic opening or closing 51 times per revolution 
as the gantry revolves around the patient See Figure 3.  The system can also treat 
patients with discrete beam angles (i.e. the radiation beam not rotating) in a mode 
called TomoDirect.  Due to increased costs for IMRT, this treatment technique is 
not allowable for the treatment of non-spine bone metastases. Although all 
TomoTherapy treatment delivery is technically IMRT, the treatment planning can 
be done in either a 3D or IMRT mode allowing highly conformal treatments to be 
billed as 3D and thus used in the treatment of all patients with bone metastases.  
In addition, good preliminary data exists to support the use of the fan beam 
MVCT as a CT simulation image set for treatment planning and the use of CT 
detector-based exit dose methodology for quality assurance, making this system 
an excellent platform to pilot this research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3: Helical TomoTherapy Unit 
CT Ion Chamber Detector 

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1.3.7 STAT RT Workflow: Same Day CT Simulation, Treatment Planning, 
Treatment Delivery 
            As previously stated, we have already developed a STAT RT workflow 
for same day palliation that requires approximately 6 hours, and is a highly 
coordinated conventional workflow with kVCT simulation, treatment planning, 
treatment plan quality assurance, and then delivery of conformal hypofractionated 
radiotherapy.  All treatments are planned and delivered on FDA-approved 
systems.  We have treated over 30 patients to date with this workflow, and 
preliminary results reveal rapid and durable palliation with minimal acute 
toxicity.  This workflow allows patients to receive an entire course of palliative 
treatment from start to finish in 1 to 5 days, a process that conventionally takes 3 
weeks.  Since patients are billed for each individual treatment, requiring fewer 
treatments reduces health care costs in addition to being more convenient.  With 
the STAT RT program we are now able to offer a unique workflow that delivers 
rapid, effective, and efficient palliative radiotherapy that is cost effective, less 
toxic, and more convenient for cancer patients and their families.  The dose 
conformality of these treatments is excellent and will not be further optimized.  In 
this pilot clinical trial, for the primary specific aim we will quantify patient 
outcomes following treatment with the current STAT RT workflow in an effort to 
determine its benefits and risks to patients.  As a secondary aim, we will 
systematically evaluate and optimize the software necessary for the clinical 
implementation of the more efficient Scan-Plan-Treat STAT RT workflow. 
1.3.8 Scan-Plan-Treat STAT RT Workflow: A Novel and More Efficient 
STAT RT Workflow 
 
With recent advances in software and technology, we plan to further 
condense the STAT RT workflow into the Scan-Plan-Treat workflow, a 30-
minute process in which all steps (MVCT simulation, diagnostic image co-
registration, treatment planning, and treatment delivery with real time quality 
assurance) are performed on the TomoTherapy unit.  This advanced workflow 
will eliminate the need for the patients to undergo a kvCT simulation on a 
separate unit as well as make it unnecessary for the patient to leave the treatment 
table between the simulation and treatment.  
1.3.9 Secondary Aims: Requirements For Clinical Implementation of the 
Scan-Plan-Treat STAT RT Workflow  
1) MVCT simulation image acquisition (10 minutes) then rigid or deformable 
image co-registration of existing diagnostic image sets with pre-contoured 
target and OAR volumes to the MVCT simulation scan for contour transfer 
(3-5 minutes).  
2) Rapid inverse treatment planning (3-5 minutes). 
3) Monte Carlo secondary dose calculation (2-3 min) 
4) At the Emily Couric Cancer Center location, simple real-time patient motion 
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simulation and treatment delivery (concurrent).   No data for this aim will be 
collected at CRH. 
5) Patient-specific quality assurance using CT detectors during treatment 
delivery (10 minutes). 
   
 
1. New image co-registration workflow 
 
In the conventional workflow, target volumes and OARs are contoured on 
recent diagnostic images (MRI, PET-CT, or diagnostic CT that are already 
available in the patient’s electronic radiology chart).  After the patient undergoes 
a kVCT simulation, the contoured diagnostic images are rigidly or deformably co-
registered to the kVCT simulation images, and the contours are transferred. This 
allows for high resolution diagnostic images to be used for tumor and normal 
tissue identification, which is not always possible to differentiate on CT 
simulation scans due to the resolution of standard wide bore CT simulation 
scanners.  Multiple commercial image processing systems are available for this 
image processing, and we are currently using Velocity® (Atlanta, GA) image 
processing software.  Following treatment planning, the patient then undergoes 
image guided treatment delivery, a process in which a daily MVCT scan is 
obtained on the TomoTherapy unit and co-registered to the planning kVCT scan.  
Patient setup shifts can then be made to ensure accurate patient setup, and the 
patient is treated. Therefore, this is a two image co-registration workflow.  See 
Figure 4. 
 
            A kVCT simulation scan has historically been used for simulation in the 
conventional workflow for both palliative and curative radiation planning. 
Compared to MVCT scans, it has higher resolution and allows the possibility for 
administration of iodinated IV and/or GI contrast, which makes it easier to 
identify soft tissues and bony anatomy for treatment planning. However, contrast 
agents are not generally given for kVCT simulations of patients for palliative 
treatment of osseous metastases since the soft tissue and bone windows are 
adequate. MVCT scan soft tissue and bone windows have quite reasonable 
resolution and can easily be co-registered to higher resolution diagnostic studies 
for contour transfer. MVCT scans are routinely co-registered to kVCT scans for 
image guidance on a daily basis.  Our preliminary data suggests that the 
optimization of this one step image co-registration workflow of diagnostic image 
sets to a MVCT simulation scan is clinically similar to the conventional two 
image co-registration workflow.  
 
 
 
 
 
 
 
 

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 2. Rapid inverse treatment planning on MVCT scans 
            CT image sets are used for radiation treatment planning because the 
electron density of tissues, which is required for calculating dose, is easily 
determined based on the Hounsfield units.  The tissue electron density 
determination is essentially the same for MVCT and kVCT scans.  It has 
previously been reported that as far as the dose calculations are concerned, 
treatment planning on either a kVCT simulation image set or an MVCT 
simulation image set yields treatment plans that are within 1% of each other(38).   
 
           We have recently published that the TomoTherapy STAT RT treatment 
planning module can calculate SBRT and palliative treatment plans in just a few 
minutes(39). The computing speed of radiation treatment planning systems is 
about to take a quantum leap forward with the incorporation of new algorithms 
that will take advantage of the replacement of central processing units with 
graphic processing unit’s whose more rapid and parallel calculating potential can 
improve treatment planning speed by 10-20 times(40, 41).  Real time inverse 
treatment planning of IMRT or 3D TomoTherapy plans has not been a problem 
for patients treated with STAT RT to date.  We will compare planning times for 
current FDA-approved treatment planning systems as well as for newer, in-
development GPU-based algorithms.    
Diagnostic Image 
kVCT 
Simulation 
Scan 
MVCT 
Co-register 
Patient 
Alignment 
Conventional Workflow 
Figure 4: Comparison of Image Co-Registration Workflows 
TREAT 
Co-register 
Contour 
transfer 
PLAN 
Scan-Plan-Treat STAT RT Workflow 
Co-register 
Diagnostic Image 
Contour transfer 
MVCT 
Simulation 
Scan 
PLAN 
and 
TREAT 

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3. Fast Monte Carlo based secondary dose calculation 
 
Most treatments delivered on a traditional linear accelerator undergo a 
secondary dose calculation before the patient is treated.  The secondary 
calculation is compared to the dose calculated by the treatment planning system 
and must be within agreement before the treatment can be administered.  With the 
addition of Quan Chen to the research team, UVa now has access to a very fast 
secondary dose calculation algorithm specifically designed for TomoTherapy. 
Using this Monte Carlo based software, all treatment plans will be second 
checked for dose calculation accuracy. 
 
4. Optical tracking methods for patient intra-fractional motion monitoring 
 
Consistent patient positioning during CT image acquisition and treatment 
is critical to ensure accurate dose delivery.  Physical immobilization devices such 
as external body frames, aquaplast masks and other body molds, and vac-lock 
vacuum bags are commonly used to ensure patient positioning reproducibility.  X-
ray or CT image guidance prior to radiation delivery on the treatment unit is 
routinely employed in the clinic.  Methods for optical tracking of markers on the 
patient surface or of the patient’s skin surface are available to ensure consistent 
patient positioning after image guidance and during treatment, known as intra-
fractional motion (42, 43).  This provides a method without ionizing radiation for 
confirming patient position that can be used real time during the treatment 
process. With this information, treatment can be paused if the patient’s position 
changes during treatment.   At the Emily Couric Cancer Center, we have 
developed an inexpensive in-house optical tracking system to monitor patient 
positioning real time that we will optimize in this protocol. Culpeper Regional 
Hospital does not have this imaging capability and patients treated on this 
protocol at CRH will not have optical surface tracking. 
 
5.  Novel CT-detector-based quality assurance methodology 
 
Current standard of care TomoTherapy quality assurance methodology 
requires that each patient-specific treatment plan be delivered to a cylindrical 
plastic phantom with ion chamber and film measurement or an array of radiation 
detectors to ensure geometric and dose accuracy to within ± 3%.  However, this 
method does not measure the dose that the patient is receiving during treatment or 
provide full 3D dose verification. It causes another delay in delivering the first 
treatment to the patient as it requires approximately 30-40 minutes to complete, 
and is generally done by a medical physicist after clinical patient care is finished.  
A methodology to monitor the patient exit dose in real time would increase 
patient safety through verification of daily treatment accuracy as well as expedite 
the treatment workflow.  Clearly, a real-time quality assurance methodology that 
does not require moving the patient off the TomoTherapy treatment couch for 
phantom measurements is essential for the development of a 30-minute Scan-
Plan-Treat workflow.  Current dose verification methodologies measuring dose at 
the time of patient treatment are limited to point measurements on the patient 
surface (44), which is rarely in the target volume or a critical OAR, or though 

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expensive implanted dosimeters (45, 46) which are not practical for most 
palliative patients.  Since there is not a method to directly measure the three 
dimensional dose in the patient, alternative approaches are being developed and 
tested in academic clinical settings.  These alternative approaches reconstruct the 
delivered three dimensional dose distribution based on the measurement of either 
entrance or exit dose and back-projecting the measurements onto simulation or 
image guidance CT image sets.   
 
 
The opportunity to reconstruct dose from information collected during 
treatment became available with the incorporation of radiation imaging detectors, 
such as electronic portal imaging devices (EPID) on linear-accelerators and CT 
detector arrays on TomoTherapy.  Dose reconstruction using in-line EPID was 
first described by McNutt et al (47, 48).  The EPID, when deployed during 
treatment, collects exit fluence from the patient and then back-projects this to X-
ray fluence before entering the patient; then, the dose in the patient is re-computed 
using this entrance fluence and the planning CT images.  However, there are 
many limitations to EPID-based dose verification.  For example, the EPID was 
originally designed for semi-quantitative portal imaging; and for the purpose of 
dose reconstruction, it suffers from a narrow dynamic range, short life span, non-
linearity in the dose response, ghost artifacts from low temporal resolution, and 
cross-plane scatter photon contribution to the measured fluence (49).  
Investigators are currently working on methods to overcome these challenges.  
 
          The TomoTherapy unit has an in-line source-patient-detector geometry with 
CT ion chamber detectors that are used for daily MVCT scan image guidance for 
accurate patient positioning that remain in place during both imaging and 
treatment. See Figure 3. These CT detectors can also be used to measure the 
patient exit dose fluence and back-project this onto a planning CT scan for 
volumetric or 3D dose reconstruction. Dose verification on TomoTherapy was 
first studied by Kapatoes et al., who calculated the entrance fluence from the exit 
dose using a transfer matrix, which is calculated based on the radiological path 
length from the source to the detector (50, 51).  The use of a CT ion chamber 
array has multiple advantages over EPID for exit fluence measurement.  It is more 
durable, and has a much longer life span.  It has a wider dynamic range and 
doesn’t limit treatment positions.  Finally, it is less sensitive to the noise from 
cross-plane scatter photons that complicate EPID-based dose reconstruction (52). 
Our recently published preliminary data showed that the current TomoTherapy 
CT-detector based algorithm for dose reconstruction is robust with +/- 3-5% 
accuracy which is well within the acceptable range for clinical care (53). We will 
collect clinical data and continue to optimize this in-development software.  
 
          One drawback from the dose reconstruction method mentioned 
above is that it relies on the accurate knowledge of the patient geometry and 
attenuation at the time of the treatment.  This information may not be fully 
available nor accurate. This leads to the ambiguity in determining whether a 
discrepancy observed from the dose reconstruction is real (caused by the 
machine) or merely an artifact caused by the patient such as weight loss or 

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positional changes.  To remedy this, we have developed a method to detect if the 
multi-leaf collimator (MLC) is open or close based on the sharp change in the exit 
fluence independent of the patient attenuation (54). In addition, the LINAC output 
and gantry angles during treatment are measured independently for quality 
assurance.  Combining those data, the impact of deviations during the treatment 
delivery can be evaluated through the MCL dose calculation.  The CT detector 
clinical data collected will also be used to optimize this in-development software. 
 
1.4 
Preliminary Studies 
          We have performed significant preliminary research into optimizing each of 
the necessary steps for clinical implementation of the Scan-Plan-Treat STAT RT 
workflow as detailed below. Preliminary clinical data will be collected from 
patients treated with STAT RT on this protocol to optimize the software required 
to develop the more efficient Scan-Plan-Treat STAT RT workflow. A Scan-Plan-
Treat workflow will not be used on this clinical protocol. 
 
1. Preliminary Clinical Outcomes of Patients Treated with STAT RT 
 
We have treated approximately 30 cancer patients with a conformal 
hypofractionated STAT RT treatment regimen for a variety of palliative 
indications.  We have treated patients with IMRT and 3D TomoTherapy planning 
modes and have extensive experience using the TomoTherapy planning systems 
for optimizing conformality of the radiation. Retrospective review of these 
patients shows that the majority of them have had rapid and durable palliation of 
symptoms with minimal toxicity (unpublished data). In general, patients are 
extremely satisfied with the speed at which their treatment is initiated and the 
convenience of the hypofractionated regimens.   
 
2.  Preliminary Studies for Scan-Plan-Treat STAT RT implementation 
 
      a) New image co-registration workflow 
 
FDA-approved imaging software for rigid and deformable co-registration 
and transference of target and OAR contours from diagnostic image sets to either 
kVCT or MVCT images is commercially available. We are using Velocity® 
image processing software.  Our preliminary unpublished data confirms that the 
MVCT scan has sufficient resolution, particularly of bone anatomy, for accurate 
co-registration to contoured diagnostic images and that this one step co-
registration process yields comparable agreement to the conventional two step 
image co-registration workflow with +/- 2-3 mm differences.  See Figure 4. This 
level of agreement is consistent with results reported from image co-registration 
studies performed on a multi-institutional pediatric clinical trial with co-
registration data of 51 patients from 45 institutions using 11 different image 
software systems. They reported an inherent uncertainty of 2 mm for MRI to CT 
co-registration (55).  MVCT image guidance scans and kVCT simulation co-
registration occurs routinely in the clinic and only takes a few seconds, therefore, 

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we do not believe that this will be a rate limiting step in the clinical 
implementation of the Scan-Plan-Treat STAT RT workflow.   
 
   b) Rapid inverse treatment planning on MVCT scans 
 
We have shown that accelerated treatment planning software for Helical 
TomoTherapy provides clinically acceptable dosimetry, with conformality and 
homogeneity that is superior to standard LINAC-based 3D conformal planning 
and is only slightly inferior to standard Helical TomoTherapy dosimetry (33). We 
have also shown that, with planning times of 2-5 minutes, this accelerated 
treatment planning software provides levels of dosimetric conformality, 
heterogeneity, and avoidance of organs at risk for simple SBRT treatments that 
are clinically equivalent to those generated with conventional Helical 
TomoTherapy treatment planning(39). This preliminary data supports that 
treatment planning speed in not likely to be rate limiting in the ultimate clinical 
implementation of the Scan-Plan-Treat STAT RT workflow.  
 
c)  Monte Carlo secondary dose calculation  
 
We have clinically implemented a validated software second dose 
calculation check that reads TomoTherapy treatment plan information exported 
through DICOM and then performs a Monte Carlo dose calculation in a few 
minutes.  Our preliminary results show a 3D-dose distribution can be calculated 
within 2-5 minutes (56).  The software has been used clinically for 8 months on 
all patients treated on TomoTherapy at UVA with excellence results.  
 
 
   d)  Novel CT-detector-based quality assurance methodology  
Our pre-clinical evaluation of the CT-detector based exit radiation dose 
verification algorithm has been retrospectively studied by Sheng et al using in-
development software (53). We compared with planned and delivered doses with 
the conventional phantom quality assurance measurements for 24 patients and 347 
treatment fractions.  The concordance of planned to delivered dose calculated by 
the in-development software was shown to be ± 5% (53). This tolerance is within 
the standard of care of other current clinically available quality assurance 
methods.  We are also using the CT detector exit dose data to measure the MLC 
leaf opening time and comparing this with the calculated leaf opening time as a 
novel quality assurance methodology. 
 
   e) Optical tracking methods for patient intra-fractional motion monitoring 
           At the Emily Couric Cancer Center, we have recently developed an in-
house optical tracking system using multiple OptiTrack FLEX:V100 cameras 
(Natural Point, Corvallis, OR). See Figure 4.  The camera utilizes 26 infrared 
light-emitting diodes (LEDs) and a charge coupled device (CCD) to capture the 
reflective light from markers with special coating.  By using multiple cameras, the 
3D position of each reflective marker can be determined precisely.  Three 
reflective markers are fixed on a rigid body marker base that can vary in size from 
a few centimeters to much larger and create a “trackable” that can easily be placed 
on a patient’s surface to track their motion.  See Figure 5. The x, y, z, yaw, pitch 

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and roll of the trackable can be detected by the camera system.  An in-house C 
program was developed to stream the data and display the position of the 
trackable in real time.  Multiple trackables can be placed on a patient and 
monitored simultaneously.  In the lab, localization precision of 0.1 mm was 
achieved (unpublished data).  Through strategic positioning of the trackables, 
movements of the head, neck, and extracranial locations can be closely monitored.  
This optical tracking technology is unique to ECCCC and is not available at CRH 
and patients treated at CRH will not undergo this experimental aspect of the trial.    
 
 
 
 
 
 
 
 
 
1.5 
Rationale for Study Design 
 
As explained in the previous sections, conventional palliative radiotherapy 
for bone metastases offers only often modestly effective treatments that subject 
the patients to repeated visits to the treatment center and consume precious time 
and energy for ill patients and their families.  With the STAT RT workflow, we 
hypothesize that we can offer more effective palliative treatments that are more 
efficient to plan and deliver, minimize toxicity, and require fewer total treatments.  
We are conducting this investigator initiated prospective pilot clinical trial to 1) 
evaluate the effectiveness and patient satisfaction with STAT RT for patients with 
painful bone metastases, and 2) optimize those components of the workflow 
needed to create a 30 minute Scan-Plan-Treat STAT RT workflow . Further 
development for this workflow has federal funding via a three- year 2012 CMS 
Innovation Challenge Award .    
  
 
Primary specific aim: Quantify the time for pain relief, amount of pain relief, 
opioid use reduction, functional scores, quality of life, and satisfaction of patients 
treated with STAT RT for osseous metastases.   
 
 
 
The objective of palliative treatment is to relieve pain, improve function, 
and improve quality of life. These will be measured before and after treatment 
with the following endpoints: 
Figure 4: OptiTrack Camera 
Figure 5: Trackable 

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• The Brief Pain Inventory (BPI) is a proven survey to evaluate pain levels 
of patient’s with metastatic bone pain and their responses to treatment 
(57). 
• Patients will keep an analgesic use logbook and have their doses converted 
into Oral Morphine Equivalent Doses (OMED).  In this way we can track 
changes in their opiod requirements. 
• Treatment response will be measured by the guidelines set forth by the 
International Bone Metastases Consensus Group (58).  They have 
established a method to measure response to palliative RT accounting for 
opiate use.  These responses are categorized as: Complete Response, 
Partial Response, Pain Progression, Stable Pain.  See Section 6.1.1 for 
details about this categorization.  
• The FACT-G and FACT-BP questionnaires are proven measures of 
quality of life for people with painful bone metastases (59). 
• Karnofsky Performance Score (KPS) is a proven measure of functional 
status. 
 
 
 
We hypothesize that the convenience of the STAT RT workflow will 
result in high patient satisfaction.  The FACIT-TS-BTCSQ survey has been 
shown to be an effective tool in measuring the satisfaction in patients being 
treated for metastatic bone disease (59).  Therefore, we have modified this tool to 
suit our patient population, and we will use this survey to measure patient 
satisfaction at each assessment.  
 
 
 
Toxicity will be assessed by CTCAE Version 4.0 and RTOG Late 
Radiation Morbidity Scoring Criteria.  These are common criteria used to asses 
the toxicity associated with radiation therapy.   The CTCAE will assess acute 
toxicity, and the RTOG Late Radiation Morbidity Scoring Criteria will assess late 
toxicity, which is defined as toxicity that occurs 3 months or more after treatment.  
 
Secondary Specific Aim: Optimize the integration of commercially available and 
in-development software to develop the Scan-Plan-Treat STAT RT workflow.  
 
As described in the background, this optimization will require: 
1) rapid co-registration of diagnostic images onto MVCT simulation images for 
accurate contouring and treatment planning 
2) real-time patient-specific quality assurance using CT detectors during 
treatment delivery  
3) real-time patient motion tracking to ensure accurate patient setup during 
MVCT simulation and treatment delivery.    
 
To implement rapid co-registration of diagnostic images onto MVCT 
simulation images into the workflow, we must first confirm that this image and 
contour-transferring method is just as accurate as the conventional method.  
Again, the experimental method requires rigid and deformable co-registration of 

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pre-contoured diagnostic image sets to MVCT simulation scans; and in the 
conventional method, pre-contoured diagnostic image sets are co-registered to 
kilovoltage CT (kVCT) simulation images, and then kVCT simulation images are 
co-registered to the MVCT scan. See Figure 4.  Contours generated from these 
two different registration flows will be quantitatively compared as described in 
detail in Section 7.1.  
 
 
Earlier we described the advantages of using the CT detector on the 
TomoTherapy unit with dose verification software to provide near real time 3D 
dose verification.  We must confirm that the use of the CT detector and dose 
verification software yields equivalent results to conventional phantom-based 
quality assurance.  Thus, exit radiation dose measurements and back-projected 
dose recalculation verification software will be compared to standard pretreatment 
phantom quality assurance measurements.  If we prove the doses calculated by 
both methods to be equivalent, we could rely on only the CT detector and dose 
verification software for quality assurance in the future, which would further 
streamline the workflow.  
 
As described in the background and preliminary studies, our in-house 
infrared tracking system has been developed to monitor patient positioning during 
simulation and treatment delivery.  This infrared tracking system will be validated 
by 10 healthy volunteers and then used to monitor patient motion during 
treatments at the Emily Couric Cancer Center. The effectiveness of the infrared 
tracking system will be determined by comparing its position calculations with 
the position changes as determined by the position of the treatment set up lasers 
with respect to the patient’s set up skin marks before and after treatment. Patient 
tracking is an additional experimental quality assurance process that in no way 
affects the patient’s treatment and will not be implemented at Culpeper Regional 
Hospital at this time. 
1.6 
Correlative Studies 
Not Applicable 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives   
Our primary objectives are to quantify outcomes of patients with osseous 
metastases treated via the STAT RT workflow.  Specifically, we are plan to: 

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2.1.1 Estimate the response to palliative radiation as defined by International 
Bone Metastases Consensus Group using the BPI and OMED to 
categorize into Complete Response, Partial Response, Pain Progression, 
and Stable Pain after receiving treatment via the STAT RT workflow. 
2.1.2 Estimate the change in the patient’s quality of life and function as scored 
by FACT-BP and KPS after receiving treatment via the STAT RT 
workflow. 
2.1.3 Estimate patient satisfaction with the STAT RT workflow using a 
modified FACIT-TS-BTCSQ survey. 
2.1.4 Report the treatment-related toxicity using CTCAE Version 4 and RTOG 
Late Radiation Morbidity Scoring Criteria after receiving treatment via the 
STAT RT workflow.  
2.2 
Secondary Objectives  
Our secondary objectives are to optimize the integration of commercially 
available and in-development software that are needed to develop a Scan-Plan-
Treat STAT RT workflow.  Specifically, we plan to: 
2.2.1 Optimize CT-detector-based exit dose measurement algorithms for quality 
assurance and compare them to traditional phantom quality assurance 
methods.  
2.2.2 Optimize rigid and deformable co-registration of pre-contoured diagnostic 
image sets to MVCT simulation scans and compare the accuracy to the 
conventional method in which the same pre-contoured diagnostic image sets 
are co-registered to kilovoltage CT (kVCT) simulation images and then 
kVCT simulation is co-registered to the MVCT scan. 
2.2.3 Validate an in-house infrared tracking system and monitor patient motion 
during treatment for all patients treated a ECCCC. 
2.3 
Exploratory Objectives 
Not applicable.  
 
3.0 
PATIENT ELIGIBILITY 

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3.1 
Inclusion Criteria 
3.1.1 Patient has a biopsy proven diagnosis of cancer.  The osseous metastatic 
lesions do not need to be biopsied. 
3.1.2 Patients with multiple myeloma are eligible for the study.  
3.1.3 Patient has 1-3 major painful osseous metastases (target lesions) from any 
primary cancer or unknown primary cancer. 
3.1.4 Long bone target lesions must have a Mirels fracture score of ≤ 7 (See 
Appendix G). 
3.1.5 Radiation oncologist determines that the patient is medically able to 
undergo palliative radiation therapy.  
3.1.6 Patient has target lesions that are radiographically consistent with 
metastatic disease on CT, MR, or PET CT obtained within 8 weeks of 
treatment.  
3.1.7 Persistent distinguishable pain associated with target sites to be treated.  
3.1.8 Patient average BPI pain score for last 72 hours at specified location is > 3 
(0-10 scale)  
3.1.9 Patients may have additional non-painful or minimally painful osseous 
metastases (if patient has pain from additional sites, the pain from the 
additional sites must be evaluated as being less intense by at least 2 points 
on the BPI compared to the site(s) treated) 
3.1.10 The patient may have previously been treated with external beam radiation 
therapy to other body sites, but not to the target sites. 
3.1.11 The patient may have previously or currently be undergoing chemotherapy 
or bisphosphonate therapy. 
 

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3.1.12 The patient will be able to understand English (or a medical interpreter for 
their native language must be available for all study visits).  
3.1.13 18 years of age or older. 
3.1.14 Life expectancy > 12 weeks. 
3.1.15 Able and willing to answer simple survey questionnaires.  
3.1.16 Able and willing to keep a logbook of analgesic use (with or without 
assistance) 
3.1.17 Willing to return to clinic at 4 weeks, 12 weeks, 6 months, and 12 months 
after treatment.  
3.1.18 Signed study-specific informed consent form. 
3.1.19 Women of childbearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control) prior to study 
entry and for the duration of study participation.  Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. 
3.1.20 The radiation oncologist plans to treat the patient’s target lesions with a 
total of 2-5 fractions of high dose palliative radiation therapy consisting of 
5-10 Gy per fraction with a minimum biologic effective dose (BED) of 25 
Gy. 
 
3.2 
Exclusion Criteria 
3.2.1 Inability to lie flat on table for treatment 
3.2.2 Patient with < 12 weeks life expectancy 
 
3.2.3 Systemic therapeutic radionuclide delivery within 30 days prior to 
treatment 
3.2.4 Epidural compression of spinal cord or cauda equine 
3.2.5 Long bone target lesions must have a Mirels fracture score of ≤ 7 
3.2.6  Spinal canal compromise > 25% 
 
3.2.7 Unstable spine requiring surgical stabilization 

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3.2.8 Target lesions have previously been treated with external beam radiation. 
3.2.9 PTV located within 5mm of spinal cord or cauda equina. 
 
3.2.10 A serious uncontrolled medical disorder that, in the opinion of the 
Investigator, would impair the ability of the patient to receive protocol 
therapy. 
3.2.11 Pregnant and breastfeeding women are excluded from this study. 
 
4.0 
TREATMENT PLAN 
 
4.1 
Schema 
 
 
         Tx  
 
 
        Follow-Up  
                                    _______  - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -                                                                
               Helical  
  TomoTherapy*: 
      
     Assessments¶:                                                                                                               
                  
                  Week:  0       1             4                8               12                    26                 52 
 
*1-5 helical TomoTherapy radiation treatments over 1-2 weeks 
¶ Physical Exam (PE) and/or surveys  
       Treatment-related toxicity will be captured during treatment PEs and followup PEs.  
 
• This is an investigator-initiated, prospective, non-randomized, multi-centered 
pilot phase II trial.  The clinical trial will be open to accrual at UVA and CRH 
only.  
• We anticipate that it will take approximately 24 months to accrue 30 patients to 
this pilot study, and each patient will plan to undergo 1 year follow-up.  
4.2 
Treatment Dosage and Administration: Radiation Therapy 
• Approved and consented patients will receive radiotherapy using the STAT 
RT workflow.   
• The patients will receive Helical TomoTherapy using the Hi Art system 
(TomoTherapy Inc).   
• Patients will receive a total of 2-5 fractions of high dose palliative radiation 
therapy consisting of 5-10 Gy per fraction with a minimum biologic effective 
dose (BED) of 25 Gy. 

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• Dose specifications:  The planning target volume (PTV) will be prescribed a 
minimum BED of 25 Gy.  The maximum dose prescribed will be a BED of 72 
Gy.  
• Variations of dose prescription: There is a wide acceptable range of doses 
delivered to bone metastases in the palliative setting.  The appropriate dose will 
be determined by tumor histology (whether the tumor is radiosensitive or 
radioresistant) and location of critical structures (to prevent radiation-induced 
toxicity to adjacent organs at risk).  Dose prescription will be at the discretion of 
the treating radiation oncologist, however will have to be at least a BED= 25 Gy. 
o Beam Energy 6 MV (TomoTherapy only has one beam energy) 
o Beam Shaping  All treatments will be delivered with conformal delivery 
with multi-leaf collimator beam modulation. 
• Localization, Simulation and Immobilization:   All patients will undergo non-
contrast enhanced kVCT simulations with standard immobilization devices:  
aquaplast masks for head, neck, upper thoracic PTVs, Vac-Lok cushions or 
custom headrests, body-fix immobilization system for spinal tumors are all 
permissible. Diagnostic contrast enhanced CT scans, PET CT scans, or MRIs 
from the patient’s PACS chart will be used to guide target and OAR contouring. 
The diagnostic images will be rigidly (MRI, contrast enhanced CT, PET CT) or 
deformably (contrast enhanced CT, PET CT) co-registered to the kVCT 
simulation in Velocity.  Following contour transfer to the kVCT simulation image 
set, the images will be reviewed and approved by a physician and then transferred 
to the TomoTherapy treatment planning station.   
• An experimental contouring plan will be created to compare to the conventional 
treatment plan but will not be used in treatment planning.  We will experimentally 
co-register the contoured diagnostic images directly to the MVCT scan and 
generate the PTV and OAR contours using only the MVCT scan without the 
kVCT intermediate.  Contours generated by both methods will then be compared.  
• Treatment planning/Target Volumes: Dose will be prescribed to a PTV which 
will be a gross target volume (GTV) expanded by 0-10 mm depending on critical 
adjacent structures.  
• Treatment Planning: TomoHelical (rotational beam delivery) and TomoDirect 
(fixed beam delivery) techniques in either the IMRT and 3D planning modes are 
permissible. 

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• Critical Structures 
The following are dose limitations to critical structures.   These are accepted dose 
limitations that have been used in multiple clinical trials of radiotherapy (20, 60). 
 
Table 2: Critical Structures Dose Constraints 
 
Organ 
Volume 
Total Dose 
Spinal cord  
Any point 
18 Gy maximum 
Esophagus 
Any point 
27 Gy maximum 
Ipsilateral brachial plexus 
Any point 
24 Gy maximum 
Heart 
Any point 
30 Gy maximum 
Trachea and ipsilateral 
bronchus 
Any point 
30 Gy maximum 
Right and left lung 
<10% of volume 
20Gy or greater   
Liver  
>700 cc normal liver 
<15 Gy 
Single kidney 
> 66% of volume 
<15 Gy 
Total Kidney Volume 
(L+R) 
< 35% of volume 
<15 Gy  
Stomach 
Any point 
30 Gy maximum 
Bowel 
Any point 
30 Gy maximum 
 
• Documentation requirements:  We will provide a dosimetry form that specifies 
the dosemetric criteria for the PTVs and OARs have been met for each study 
subject.  This will ensure dosimetric compliance with PTV and OAR 
specifications.  The treating radiation oncologist must sign this form for the study 
to continue.   
• RT Quality Assurance: Standard quality assurance will be performed with all 
treatment plans.  This involves the placement of a phantom with an array of 
radiation detecting ion chambers called OmniPro Matrixx on the couch of the 
TomoTherapy unit.  The planned treatment is then delivered to theMatrixx 
phantom, and the ion chamber array ensures that the correct point dose and 
geometry is delivered.  This ensures that the patient will get the dose as it was 
planned.  Then, while the phantom and then the patient are irradiated, the fluence 
of the radiation exiting the patient will be measured by the CT detector.  The exit 
dose verification software will then back-project this data collected by the CT 
detector onto the planning CT scan for volumetric or 3D dose reconstruction.  
This calculated 3D doses delivered will then be compared to the measured dose 
recorded by the phantom and also compared to the planned dose.     
4.3 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity.  
Each patient will be assessed periodically for the development of any toxicity 

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according to the Time and Events table (Section 5.1).  Toxicity will be assessed 
according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE) 
Version 4.0 and the RTOG Late Radiation Morbidity Score (See Appendix F). 
 
Radiation Adverse Events 
 
Table 3: Non-hematological Toxicity: Modifications for Recurrent Toxicity 
 
NCI CTCAE Version 4 Grade 
Conformal Radiotherapy 
0-2 
No change from original starting dose  
3  
Hold until resolved to < Grade 2, then resume treatment. 
Second episode of grade 3 or 4 toxicity 
Hold until resolved to < Grade 2, then resume treatment.  
Third episode of grade 3 or 4 toxicity 
Remove subject from trial 
 
 
Table 4: Non-hematological Toxicities: Modifications for Various Expected 
Toxicities 
 
Non-hematological Toxicity Dose Reductions for Conformal 
Radiotherapy 
Event 
Action 
Nausea 
Grade 1-2 
None 
Grade 3 
Hold until resolved to < Grade 2, then resume treatment. 
Grade 4 
Hold until resolved to < Grade 2, then resume treatment. 
Vomiting 
Grade 1-2 
None 
Grade 3 
Hold until resolved to < Grade 2, then resume treatment. 
Grade 4 
Hold until resolved to < Grade 2, then resume treatment. 
Mucositis 
Grade 1-2 
None 
Grade 3 
Hold until resolved to < Grade 2, then resume treatment. 
Grade 4 
Hold until resolved to < Grade 2, then resume treatment. 
Esophagitis 
Grade 1-2 
None 
Grade 3 
Hold until resolved to < Grade 2, then resume treatment. 
Grade 4 
Hold until resolved to < Grade 2, then resume treatment. 
Fatigue 
Grade 1-2 
None 
Grade 3 
Hold until resolved to < Grade 2, then resume treatment. 
Grade 4 
Hold until resolved to < Grade 2, then resume treatment. 
Dermatitis 
Grade 1-2 
None 
Grade 3 
Hold until resolved to < Grade 2, then resume treatment. 
Grade 4 
Hold until resolved to < Grade 2, then resume treatment. 
 
4.4 
Concomitant Medications/Treatments 
Not applicable. 

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4.5 
Other Modalities or Procedures 
Not applicable.  
4.6 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue 
for 2 to 5 fractions depending of the clinical situation.  We expect most patients to 
receive treatments for less than 1 week, however, all treatments will be completed 
within 21 days.  Receiving treatment for > 21 days will be a major protocol 
violation.    Remaining fractions will be discontinued if: 
• Inter-current illness that prevent further administration of treatment 
• Unacceptable adverse events 
• The 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. 
4.7 
Duration of Follow Up 
After removal from study, patients will be followed for 12 months after treatment 
was initiated or until death, whichever occurs first.  Patients removed from study 
for treatment-related adverse events will be followed until resolution or 
stabilization of the adverse event.  
4.8 
Pregnancy 
Women of childbearing potential (WOCBP) includes any female who has 
experienced menarche and who has not undergone successful  surgical  
sterilization  (hysterectomy,  bilateral  tubal  ligation  or  bilateral oophorectomy) 
or is not postmenopausal [defined as amenorrhea  ≥ 12 consecutive months;  or 
women on hormone replacement therapy  (HRT) with documented serum follicle  
stimulating  hormone (FSH)  level  > 35 mIU/mL].  Even women who are using 
oral, implanted or inject able contraceptive hormones or mechanical products 
such as an intrauterine  device  or  barrier methods (diaphragm, condoms, 
spermicides) to prevent pregnancy or practicing abstinence or where partner is 
sterile (e.g., vasectomy), should be considered to be of child bearing potential. 
 
WOCBP  must  have  a  negative  serum  or  urine  pregnancy  test  (minimum  
sensitivity25 IU/L or equivalent units of HCG, or in accordance with local 
regulations, whichever is more sensitive) within 7 days prior to the start of study 
treatment or in accordance with local regulations, whichever is of shorter 
duration. 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an 
unintentional pregnancy.   
 

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All WOCBP MUST have a negative pregnancy test within 7 days prior to first 
receiving study treatment.  If the pregnancy test is positive, the patient must not 
receive investigational product and must not be enrolled in the study. 
 
In addition, all WOCBP should be instructed to contact the Investigator 
immediately if they suspect they might be pregnant (e.g., missed or late 
menstrual period) at any time during study participation. 
 
Male subjects who are actively trying to conceive will be counseled to wait for 6 
months following radiation therapy to allow spermatogenesis to recover.  
4.9 
Removal of Patients from Protocol Therapy 
Patients will be removed from study when any of the criteria listed in Section 4.6 
apply.  Notify the Principal Investigator, and document the reason for study 
removal and the date the patient was removed in the Case Report Form.   The 
patient should be followed-up per protocol.     
4.10 
Expected Adverse Events 
Depending on the site of treatment, potential / expected treatment toxicities 
include Grade 1 to 3 toxicity of the following symptoms, with Grade 3 occurring 
in no more than the following percentages of patients: 
 
Dermatitis  
20% 
Nausea  
20% 
Fatigue 
20% 
Vomiting 
20% 
Diarrhea 
20% 
Mucositis 
20% 
Esophagitis 
20% 

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5.0 
EVALUATIONS AND ASSESSMENTS 
5.1 
Time and Events Table 
 
 
Pre-
treatment 
During 
treatment 
Week 1 
Week 4 
Week 8 
Week 12 
6-Month 
12-Month 
Informed Consent 
X 
 
 
 
 
 
 
 
History and PE 
X 
 
 
X 
 
X 
X 
X 
Karnofsky 
Performance 
Status 
X 
 
 
X 
X 
X 
X 
X 
X 
Toxicity  
Evaluations 
 
X 
X 
X 
X 
X 
X 
X 
Opiod Logbook 
Evaluation 
X 
X 
X 
X 
X 
X 
 
 
Brief Pain 
Inventory 
X 
 
X 
X 
X 
X 
X 
X 
FACT-BP and 
FACT-G surveys 
X 
 
X 
X 
X 
X 
X 
X 
Satisfaction and 
Convenience 
Survey 
X 
 
X 
X 
X 
X 
X 
X 
Quality Assurance 
X 
 
 
 
 
 
 
 
Diagnostic 
Imaging 
(CT/MRI/PET CT) 
X 
 
 
 
 
 
 
 
Pathology 
X 
 
 
 
 
 
 
 
Pregnancy test (< 
7 days) 
X 
 
 
 
 
 
 
 
Radiotherapy 
Delivery 
 
X 
 
 
 
 
 
 
Exit Radiation 
Dose Verification 
 
X 
 
 
 
 
 
 
Intrafractional 
Motion 
Monitoring 
 
X 
 
 
 
 
 
 
Conventional and 
Expedited Image 
Registration Flow 
 
X 
 
 
 
 
 
 
 
 
5.2 
Correlative Studies Procedures 
Not applicable.  

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5.3 
Final Study Visit 
The final study visit will occur at the 12 month visit.  See the Time and Events 
Table for assessments that will be performed.  Patients removed from study for 
treatment-related adverse events will be followed until resolution or stabilization 
of the adverse event 
5.4 
Early Termination Visit 
Subjects may withdraw voluntarily from participation in the study at any time.   
At the time of withdrawal, the subject will be requested to provide their opioid 
logbook and complete the following surveys: BPI, FACT-BP/FACT-G, and 
Satisfaction survey.  
 
Subjects may also withdraw voluntarily from receiving the study intervention for 
any reason.  If that is the case, they will be encouraged to continue regular follow-
up evaluations according to the Time and Events table.  
 
As all of these patients have metastatic cancer and a limited life expectancy, it is 
likely that a reasonable percentage of study participants will choose hospice care 
before the completion of their follow-up. 
 
6.0 
EVALUATION CRITERIA 
6.1 
Response to Palliative Radiotherapy 
6.1.1 Response Criteria According to the International Bone Metastases 
Consensus Group 
Complete Response (CR): 
Pain reduction to zero AND OMED* 
stable or reduced  
 
Partial Response (PR): 
Pain reduction by two scores or more 
AND OMED* stable or reduced.                       
 
 
 
 
 
 
 
 
 
OR 
 
 
 
 
 
 
Stable pain AND OMED* reduction 
by 25% or more 
 
Pain Progression (PP): 
Pain increase by two scores or more 
AND OMED* stable or increased. 
 
 
 
 
 
 
 
 
OR 
 
 
 
 
 
 
 
No change in pain AND OMED* 
increased by 25% or more (or start of 
morphine use after the baseline or 
epidural pain treatment at follow-up) 
 
 
 
 
 
 
 
 
Stable Pain (SP): 
Stable pain AND stable OMED* 

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OMED = Oral Morphine Equivalent Dose 
* The total OMED intake over the most recent 72 hours will be 
calculated at each evaluation.  
6.1.2 Duration of Response 
Duration of overall response:  The duration of overall 
response is measured from the time measurement criteria 
are met for Complete Response or Partial Response 
(whichever is first recorded) until the first date that Stable 
Pain or Pain Progression is objectively documented. 
 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date 
that Partial Response is objectively documented. 
 
 
Duration of stable pain:  Stable Pain is measured from the 
start of the treatment until the criteria for Pain Progression 
are met, taking as reference the baseline measurements 
recorded just prior to treatment. 
6.1.3 Response Review 
The endpoints in this study are all quantitative based on 
validated surveys and pain scores that are reported by the 
patients.  Thus, we do not feel that a review by an expert 
independent of the study is necessary or valuable.  
6.2 
Toxicity and Safety 
All patients who receive treatment on this protocol will be evaluable for toxicity 
using the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4 and the RTOG Late Radiation Morbidity 
Scoring Criteria at time points indicated in the Time and Events table in Section 
5.1.  
7.0 
STATISTICAL CONSIDERATIONS 
7.1 
Study Design 
 
This is an investigator-initiated, prospective, non-randomized, single-
centered phase II clinical trial.  This clinical trial will have a primary aim of 
determining outcomes of patients treated with a conformal hypofractionated 
STAT RT treatment utilizing widely accepted surveys and questionnaires and 
clinical examinations.  The secondary aim is to collect clinical data to optimize 
software integration to develop the Scan-Plan-Treat STAT RT workflow that will 
make the entire process much quicker and efficient for the patient and clinic.  The 
University of Virginia diagnoses almost 3000 cancers annually and we treat 

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approximately 80 patients with osseous metastases each year in the Department of 
Radiation Oncology. We anticipate it will take approximately 18 months to accrue 
30 patients to this pilot study.  
 
1) Primary Aim: Evaluation of Outcomes of Patients with Osseous 
Metastases Treated with STAT RT  
 
We will recruit 30 cancer patients with 1-3 painful osseous metastatic 
lesions (target sites) requiring opioid medication who are candidates for palliative 
radiation therapy.  Patients will receive 2-5 fractions of 5-10 Gy (minimum BED 
of 25 Gy) of conformal radiation therapy delivered to the target sites via the 
Helical TomoTherapy system using the STAT RT workflow.  Patient pain, 
analgesic use, function, quality of life, and satisfaction will be recorded prior to 
treatment, at 1 week, 4 weeks, 8 weeks, 12 weeks, 6 months, and 12 months after 
therapy using the following measures:  
a) The Brief Pain Inventory (BPI)  
b) Patients will keep an analgesic use logbook and have their doses converted 
into Oral Morphine Equivalent Doses (OMED).   
c) Treatment response will be measured by the guidelines set forth by the 
International Bone Metastases Consensus Group as described in Section 
6.1.1.   
d) The FACT-BP and FACT-G questionnaires  
e) Karnofsky Performance Scale (KPS)  
f) Patient Satisfaction will be measured by a modified FACIT-TS-BTCSQ 
survey.  
       
 
Radiation-induced treatment related toxicities will be captured during 
treatment and at the above time points and graded using the CTCAE Version 4.0 
and the RTOG Late Radiation Morbidity Score Criteria. 
 
2) Secondary Aim: Optimization of Software Integration for Scan-Plan-
Treat Workflow 
Several secondary investigational aims will be studied that will not be 
used in direct patient care but are essential in further streamlining the STAT RT 
workflow.  These components will not subject the patient to any additional 
inconvenience or risk.  Standard patient-specific quality assurance will be 
performed on a Matrixx ion chamber array. 
 
a)  Optimization of Novel Image Co-registration Workflow 
           The standard two step image co-registration process of contoured 
diagnostic images to kVCT simulation scans and then kVCT simulation scans to 
MVCT image guidance scans will be used to treat all patients. We will then 
experimentally co-register the contoured diagnostic images directly to the MVCT 
scan, and the PTV and OAR contours generated onto the MVCT scan by both 
methods will then be compared. 
To evaluate the conventional and the experimental image registration 
flows, the two registration flows will be compared in the following manner: 

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• Gross tumor volumes (GTVs) will be generated from both the 
conventional and experimental image registration flows. The differences 
in volume and the distances between the two centers of the GTVs will 
used to evaluate the similarity of the two GTV contours.  
• Spinal cord contours will also be generated from both registration flows. 
The point of the spinal cord that has the shortest distance to the center of 
the GTV will be identified for each contour.  The distance between the 
points from the two registration flows will be used to evaluate the 
similarity of the two cord contours. The volumes of the two cords will also 
be compared.  
• Quantitative evaluation of the contours will be performed using the Dice 
index.  Dice index is defined as the overlapping volume of two structures 
divided by the average volume of the two.  Clearly, Dice index is 1 if the 
two structures are identical and 0 if they do not share any voxel.  Dice 
index will be calculated in Velocity for contours generated on 
conventional and experimental image registration flows.  Dice indices of 
0.8 or higher are acceptable based on literature (61). 
 
b) Treatment Planning Speeds 
          We will determine the speed of radiation treatment planning with our 
current clinical system and compare this to the speed of planning with newer in-
development algorithms running on next generation computers with graphic 
processing units (GPUs).  Since highly conformal radiation treatments must be 
routinely calculated in a few minutes for the Scan-Plan-Treat STAT RT 
workflow, we will determine if the treatment planning with GPUs is fast enough 
for clinical implementation (i.e. can be done in approximately 5 minutes).  If not, 
we will optimize the planning process in collaboration with TomoTherapy, Inc to 
increase the speed of planning. 
 
c) Exit Radiation Dose Verification 
         In-development software provided by TomoTherapy Inc.®  will be used to 
measure the exit dose fluence, backproject this fluence as entrance fluence, and 
then calculate the patient dose on the MVCT scan.  This software will be further 
optimized and refined on this clinical trial.  All patients’ radiation treatment plans 
will undergo standard of care phantom-based quality assurance measurements.  
The phantom exit dose will also be calculated via this software in this 
optimization process.  By comparing the values obtained with the software to the 
calculated treatment plan and phantom measurements, we hope to optimize this 
novel radiation dose verification software to +/- 3% calculated to delivered dose. 
Preliminary data shows that we are already at +/- 5% calculated to delivered dose 
(53).  
 
d) Infrared Motion Tracking System (UVA patients only) 
       An in-house developed infrared motion tracking system will be optimized at 
the Emily Couric Cancer Center.  The system will initially be validated on 10 

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healthy volunteers who will be instructed to lie still on the couch for 10 minutes. 
Following that, a small couch motion of 1-5 mm will be introduced in the x, y and 
z directions and compared with the motion detected by the infrared cameras.  
After the system is validated with the healthy volunteers, it will then be used to 
monitor the intra-fractional motion of patients treated on this protocol during 
treatment.  We anticipate having to modify/edit the software code during clinical 
implementation.   
 
All patients undergoing treatment at UVA will have “set up” skin marks 
placed as is standard of care for laser alignment of the patient prior to MVCT scan 
image guidance, which is then used for finer (generally millimeter) adjustments of 
internal target volumes.  Following scanning we will note the position of the 
lasers with respect to the set up skin marks, and at the completion of treatment we 
will again measure the location of the set up marks to the lasers.  With this data 
we can determine if the patient had moved after the image guidance MVCT or 
during treatment, and we will compare this with data from the infrared tracking 
system.  This system does not utilize ionizing radiation, add additional burdens or 
constraints, cause any discomfort or side effects, and is completely noninvasive.  
In reality, an additional layer of safety is added to the STAT RT treatment as any 
unexpected patient motion will be monitored and reported.  We anticipate that this 
system will be able to accurately track patients with +/- 2-3 mm of motion 
accurately.  
 
Stopping Rules: 
 
 
The study will be suspended for a safety review if 5 or greater “Probable” 
or “Definite” Serious Adverse Events occur or greater than 5 unexpected 
toxicities of > Grade 3 occur.  
7.2 
Sample Size and Accrual 
We performed calculations to detect a change in patients’ BPI pain scores 
before and after treatment using the Wilcoxon signed-rank test.  Using the 
software G*Power 3.1.2 (University Kiel, Germany) the following calculations 
were made.  To detect a mean change of 2 units on the BPI scale with a standard 
deviation of 3, and achieve a 2-sided alpha of 0.05 with 80% power, a sample size 
of 21 is needed.  Most studies report a mean improvement in pain scores of about 
3.5.  (32).  Thus we anticipate an improvement by at least 3 on the BPI in our 
study, which should be adequately powered with 30 patients.  
 
 
Since we have had accrual from prior studies of about 20 patients a year 
and this is a pilot study, we thought that a sample size of 30 subjects would be 
realistic for accrual and provide the necessary patient data for optimization of the 
software systems.  We treat approximately 30 patients with osseous metastases 
annually at UVA with palliative radiotherapy.  We anticipate an accrual rate of 20 
cases per year over 18 months.  Since the power analysis requires a sample size of 

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21, accrual of 30 subjects would allow for dropouts and still have sufficient 
power.   
7.3 
Data Analyses Plans 
 
Treatment response as defined by International Bone Metastases 
Consensus Group will be determined for each patient.  As described in Section 
6.1.1, pain intensity as defined by the BPI and opiate use as quantified by the 
OMED will be used to categorize patients as having: Complete Response, Partial 
Response, Pain Progression, Stable Pain.  At each evaluation, the patient’s BPI 
and OMED at that visit will be compared to the pre-treatment levels.  The “Worst 
Pain” score from the patient’s BPI will be used to evaluate for treatment response.  
Patient response does not require a statistical analysis.  The percentage of patients 
in each response category at each evaluation will be reported.  
 
 
Patient pain will be recorded using the BPI before treatment and at 
designated evaluations after treatment.  Pain scores before and after treatment will 
be compared using a Wilcoxon signed ranks test to determine if there is a 
statistically significant difference.  Example: Pre-treatment vs. 1 week, Pre-
treatment vs. 4 weeks, etc. 
 
 
Analgesic use will be recorded by requiring each patient to keep a logbook 
of their analgesic intake.  Their opiate intake for the last 72 hours will be 
converted to OMED at each evaluation and used in the categorization of treatment 
response.  The difference between their OMED before and after treatment will be 
compared using paired two-sample t-tests.   
 
 
Patients’ functional status will be determined using the Karnofsky 
Performance Scale at each evaluation.  The difference between the KPS before 
and after treatment will be compared using a Wilcoxon signed ranks test. 
 
 
Patients’ quality of life will be measured using FACT-BP and FACT-G 
scores at each evaluation.  The difference between the FACT scores before and 
after treatment will be compared using a Wilcoxon signed ranks test.   
 
 
Patient satisfaction will be measured using a modified version of FACT - 
TS – BTCSQ.   No statistical analysis will be required for reporting the results.  
The average scores from the satisfaction survey will be reported.  
 
 
To evaluate the CT detector dose calculations, the delivered radiation dose 
obtained using the phantom quality assurance will be compared to the exit 
radiation dose quality assurance calculation.  The calculated dose and delivered 
dose for each patient will be compared using a paired two-sample t-test, and the 
% difference in dose will be reported. 
 

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Contours generated from the conventional and experimental image 
registration flows will be compared in a variety of ways as described in Section 
7.1.  All comparisons of the contouring measures, including the Dice indices, will 
be performed using paired two-sample t-tests. 
 
 
 
Toxicity will be recorded using CTCAE 4.0 criteria and RTOG Late 
Radiation Morbidity Scoring Criteria.  The incidences of grade 3 or more 
toxicities will be reported.   
 
 
The effectiveness of the infrared tracking system will be determined by 
comparing its position calculations with the position of the patient as determined 
by the position of the lasers with respect to the set up skin marks before and after 
treatment.  The position changes calculated by each method will be compared 
using paired two-sample t-tests.   
 
 
The average treatment planning speed of radiation treatment planning with 
our current clinical system will be calculated and compared the average speed of 
planning with newer in-development algorithms running on next generation 
computers with graphic processing units.  These means will be compared with 
two-sample t-tests.  
8.0 
ADVERSE EVENTS AND REPORTING 
The treating physician is required to notify the UVA Data Safety Monitoring 
Board (DSMB), and the UVA Institutional Review Board (IRB-HSR) of any of 
any serious adverse event (SAE).   
8.1 
Definition 
8.1.1 Adverse Event 
An adverse event is any undesirable medical experience occurring to a 
subject who has been given an investigational product, whether or not 
related to the study treatment(s). Medical conditions present before 
starting the investigational treatment/intervention will be considered 
adverse events only if they worsen after starting study treatment. The 
following are adverse events: 
 
 
• All unfavorable, harmful or pathological changes in the 
general condition of a patient. 
• Subjective or objective symptoms (spontaneously offered by 
the patient and/or observed by the Investigator or the study 
nurse). 
• All intercurrent events or exacerbation of pre-existing diseases 
which occurred after the administration of the study treatment. 
• All clinically significant changes in laboratory abnormalities. 

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• Any undesirable and unintended effect of research occurring 
in human subjects as a result of the collection of identifiable 
private information under the research. 
 
AEs should be followed to resolution or stabilization, and reported as 
SAEs if they become serious (see below, definition of SAE).  This also 
applies to patients experiencing AEs that cause interruption or 
discontinuation of investigational product, or those experiencing AEs that 
are present at the end of their participation in the study.  Such patients 
should receive post-treatment follow-up as appropriate.  AEs will be 
collected up to 30 days post last dose of study treatment in all cases 
including early study termination.  If an ongoing AE changes in its 
severity or in its perceived relationship to study treatment, a new AE entry 
for the event should be completed. 
8.1.2 Unexpected Adverse Event 
An unexpected adverse event is any adverse treatment experience where 
the specificity or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure for an unapproved 
investigational product or package insert/summary of product 
characteristics for an approved product). 
8.1.3 Serious Adverse Event  
A serious adverse event or experience (SAE) or serious adverse drug 
reaction (ADR) is any adverse event temporally associated with the 
subject’s participation in research that meets any of the following criteria: 
 Death; 
 Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
 Requires inpatient hospitalization or prolongation of existing 
hospitalization;* 
 Results in congenital anomaly/birth defect; 
 Results in a persistent or significant disability/incapacity; 
 Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in the definition.  For reporting purposes, also consider the occurrences 
of pregnancy as an event which must be reported as an important 
medical event. 
 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis 

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interventional therapy, resection of primary tumor, or elective surgery, 
will not be considered serious adverse events. 
8.2 
Attribution Assessment 
The Principal Investigator will evaluate all AEs and assess their toxicity and 
attribution, if any, to study treatment.  The following criteria will define the 
attribution: 
 
Definite:  The AE is clearly relation to the investigational agent. 
Probable: The AE is likely related to the investigational agent. 
Possible: The AE may be related to the investigational agent. 
Unlikely: The AE is doubtfully related to the investigational agent. 
Unrelated: The AE is NOT related to the investigational agent. 
8.3 
Serious or Unexpected Adverse Event Reporting Requirements 
This section may need revision if Sponsor or Funding Source of study has specific 
reporting requirements for trial, and/or if study is conducted under an IND. 
 
 
For any serious or unexpected event which occurs to any patient in the course of 
their treatment on this study or within 30 days following cessation of treatment, 
the UVA Study Coordinator must inform: 
• The Principal Investigator verbally within 24 hours. 
• Written report to the UVA Office of Clinical Research, DSMC, 
and IRB within 7 days. 
 
Collection of complete information concerning SAEs is extremely important.  
Thus, follow-up information which becomes available as the SAE evolves, as 
well as supporting documentation (e.g., hospital discharge summaries and autopsy 
reports), should be collected subsequently, if not available at the time of the initial 
report, and immediately sent using the same procedure as the initial SAE report. 
8.4 
UVA Cancer Center DSMC AE Reporting Requirements 
All adverse events will be recorded on appropriate case report forms. In addition, 
AE Reporting will occur via the UVA Cancer Center clinical trials reporting 
system, C3TO (TABLE Below).  
Therapeutic Medium Risk Phase II Studies 
Reporting requirements for AEs that occur within 30 days of the last dose of protocol specified treatment 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 & 5 
 
Expected 
and 
unexpected 
 Expected 
 Unexpected 
Expected 
 
Unexpected 
 Expected 
 Unexpected 
Without 
hospitalization 
With 
hospitalization 
Without 
hospitalization 
With 
hospitaliz
ation 
Unrelated 
Unlikely 
Not required 
Not 
required 
Not required 
C3TO 
30 days 
C3TO 
15 days 
C3TO 
30 days 
C3TO 
15 days 
C3TO 
15 days 
C3TO 
15 days 
Possible 
Probable 
C3TO 
30 days 
C3TO 
30 days 
C3TO 
15 days 
C3TO 
30 days 
C3TO 
15 days 
C3TO 
15 days 
C3TO 
15 days 
C3TO 
15 days 
C3TO 
(24-hrs)* 

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8.5 
UVA IRB Reporting Requirements 
Reporting to the UVA HSR-IRB will follow the institutional plan as outlined in 
the table below. In addition, DSMC reports will be furnished to the IRB within 15 
calendar days of study team’s receipt of report.  
 
Type of Event 
To whom will it 
be reported: 
Time Frame for 
Reporting 
How reported? 
Any internal event resulting in 
death that is deemed 
DEFINITELY related to 
(caused by) study participation 
(Note:  An internal event is 
one that occurs in a subject 
enrolled in a UVa protocol.) 
IRB-HSR 
Within 24 hours 
IRB Online and phone call 
 
www.irb.virginia.edu/ 
 
Internal, Serious, Unexpected 
adverse event  
 
Only for events as outlined in 
section 8.0. 
IRB-HSR 
Within 7 calendar days 
from the time the study 
team received 
knowledge of the 
event. 
 
Timeline includes 
submission of signed 
hardcopy of AE form. 
IRB Online 
 
www.irb.virginia.edu/ 
 
 
Unanticipated Problems that 
are not adverse events or 
protocol violations  
 
IRB-HSR 
 
 
Within 7 calendar days 
from the time the study 
team received 
knowledge of the 
event.  
Unanticipated Problem report form.  
http://www.virginia.edu/vprgs/irb/HSR
_docs/Forms/Reporting_Requirements
-Unanticipated_Problems.doc ) 
 
Protocol Violations (Note the 
IRB-HSR only requires that 
MAJOR violation be reported, 
unless otherwise required by 
your sponsor, if applicable.) 
 
Or  
 
Enrollment Exceptions 
 
IRB-HSR 
 
 
 
Within 7 calendar days 
from the time the study 
team received 
knowledge of the 
event.  
 
Protocol Violation and Enrollment 
Exception Reporting Form 
 
 
http://www.virginia.edu/vprgs/irb/hsr_
forms.html 
 
 
Definite 
7 days 
 
*Enter into Cancer Center database within 24 hours if unexpected and definitely related to protocol specified treatment 
Hospitalization defined as an inpatient hospital stay or prolongation of a hospital stay equal to or greater than 24 hours 

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Data Breach 
The UVa Corporate 
Compliance and 
Privacy Office 
 
 
 
 
ITC: If breach 
involves electronic 
data. 
 
 
 
UVa Police if breach 
incluces such things 
as stolen computers.  
As soon as possible 
and no later than 24 
hours from the time 
the incident is 
identified.  
 
 
As soon as possible 
and no later than 24 
hours from the time 
the incident is 
identified. 
 
 
IMMEDIATELY 
UVa Corporate Compliance and Privacy Office: 
Phone 924-9741 
 
 
 
 
 
ITC: Information Security Incident Reporting 
Procedure, 
http://www.itc.virginia.edu/security/reporting.ht
ml 
 
 
 
Phone – (434) 924-7166 
 
 
9.0 
DATA SAFETY MONITORING PLAN 
The Principle Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the UVA Data Safety Monitoring Committee 
(DSMC). 
9.1 
Internal (Investigator) Study Monitoring Plan 
The University of Virginia Data Safety Monitoring Committee (DSMC) requires 
the Principal Investigator to review all patient data at least monthly and to provide 
a semi-annual report.  Review of adverse events assessment will be performed by 
the Principal Investigator with study personnel. Minutes of these meetings will be 
maintained and provided to the DSMC with the semiannual review. At these 
meetings the following will be discussed: 
 Participant safety (AE reporting) 
 Data validity, integrity, and completeness 
 Enrollment and retention 
 Protocol adherence 
 
In addition, the DSMC requires semi-annual auditing by the Vice President of 
Research and Graduate Studies (VPRGS) compliance monitors. The VPGRS 
monitor’s semi-annual audit will be reviewed by the Principal Investigator and the 
DSMC Chair  
9.2 
UVA Cancer Center Data Safety Monitoring Committee 
 The University of Virginia Cancer Center Data and Safety Monitoring Committee 
(DSMC) will provide oversight of the conduct of this study.  The CC DSMC will 
report to the UVA Protocol Review Committee (PRC). 
 
 
The DSMC will review the following: 
• All adverse events 
• Audit results 

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• Application of study designed stopping/decision rules 
• Whether the study accrual pattern warrants continuation/action 
• Protocol violations 
 
The CC DSMC will meet every month for aggregate review of AE data.  Tracking 
reports of the meetings are available to the PI for review.  Issues of immediate 
concern by the DSMC are brought to the attention of the PI (and if appropriate to 
the PRC and IRB) and a formal response from the PI is requested.   Per the 
Cancer Center NIH approved institutional plan this study will be audited 
approximately every 6 months.  
10.0 STUDY MANAGEMENT 
10.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
10.2 
Registration Procedures 
All patients must be registered with the C3TO at the University of Virginia 
Cancer Center before enrollment to study.   
10.3 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   

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10.3.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB-HSR 
approval/favorable opinion.   
 
For any such emergency modification implemented, a UVA IRB modification 
form must be completed by study Personnel within five (5) business days of 
making the change.   
10.3.2 Single Patient/Subject Exceptions 
Any request to enroll a single subject who does not meet all the eligibility criteria 
of this study requires the approval of the Principal Investigator and the IRB.  
10.3.3 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the 
Principal Investigator and the IRB.   
 
Protocol Deviations: A protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
CRC of record will record the deviation, and report to any sponsor or data and 
safety monitoring committee in accordance with their policies.  Deviations should 
be summarized and reported to the IRB at the time of continuing review. 
 
 
Protocol Violations: An unplanned protocol variance is considered a violation if 
the variance: 
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
Violations should be reported by CRC of record to the IRB within one (1) week 
of the investigator becoming aware of the event.  

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10.4 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
10.5 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered onto the Case 
Report Forms. Periodically, monitoring visits will be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification 
of proper entry of data. At the completion of the study, all case report forms will 
be reviewed by the Principal Investigator and will require his/her final signature 
to verify the accuracy of the data. 
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43. Wiersma RD, Wen Z, Sadinski M, Farrey K, Yenice KM. Development of a 
frameless stereotactic radiosurgery system based on real-time 6D position 
monitoring and adaptive head motion compensation. Phys Med Biol. 2010 Jan 
21;55(2):389-401.  
44. Essers M, Mijnheer BJ. In vivo dosimetry during external photon beam 
radiotherapy. Int J Radiat Oncol Biol Phys. 1999 Jan 15;43(2):245-59.  
45. Beyer GP, Scarantino CW, Prestidge BR, Sadeghi AG, Anscher MS, Miften M, 
et al. Technical evaluation of radiation dose delivered in prostate cancer patients as 
measured by an implantable MOSFET dosimeter. Int J Radiat Oncol Biol Phys. 
2007 Nov 1;69(3):925-35.  
46. Scarantino CW, Ruslander DM, Rini CJ, Mann GG, Nagle HT, Black RD. An 
implantable radiation dosimeter for use in external beam radiation therapy. Med 
Phys. 2004 Sep;31(9):2658-71.  
47. McNutt TR, Mackie TR, Paliwal BR. Analysis and convergence of the iterative 
convolution/superposition dose reconstruction technique for multiple treatment 
beams and tomotherapy. Med Phys. 1997 Sep;24(9):1465-76.  
48. McNutt TR, Mackie TR, Reckwerdt P, Papanikolaou N, Paliwal BR. Calculation 
of portal dose using the convolution/superposition method. Med Phys. 1996 
Apr;23(4):527-35.  
49. Mijnheer B. State of the art of in vivo dosimetry. Radiat Prot Dosimetry. 
2008;131(1):117-22.  

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50. Kapatoes JM, Olivera GH, Balog JP, Keller H, Reckwerdt PJ, Mackie TR. On 
the accuracy and effectiveness of dose reconstruction for tomotherapy. Phys Med 
Biol. 2001 Apr;46(4):943-66.  
51. Kapatoes JM, Olivera GH, Ruchala KJ, Smilowitz JB, Reckwerdt PJ, Mackie 
TR. A feasible method for clinical delivery verification and dose reconstruction in 
tomotherapy. Med Phys. 2001 Apr;28(4):528-42.  
52. Siewerdsen JH, Jaffray DA. Cone-beam computed tomography with a flat-panel 
imager: Magnitude and effects of x-ray scatter. Med Phys. 2001 Feb;28(2):220-31.  
53. Sheng K, Jones R, Yang W, Schneider B, Chen Q, Sobering G, et al. 3D dose 
verification using tomotherapy CT detector array. Int.J.Radiat.Oncol.Biol.Phys. 
2010 Submitted and under review.  
54. Chen Q, Westerly D, Fang Z, Sheng K, Chen Y. TomoTherapy MLC verification 
using exit detector data. Med Phys. 2012 Jan;39(1):143-51.  
55. Ulin K, Urie MM, Cherlow JM. Results of a multi-institutional benchmark test 
for cranial CT/MR image registration. Int J Radiat Oncol Biol Phys. 2010 Aug 
1;77(5):1584-9.  
56. Chen Q, Ding K, Levinson L, Read P, Benedict S. SU‐E‐T‐32: The use of monte 
carlo method as an independent dose verification calculation tool for TomoTherapy. 
Med Phys. 2012;39(6):3709.  
57. Wu JS, Beaton D, Smith PM, Hagen NA. Patterns of pain and interference in 
patients with painful bone metastases: A brief pain inventory validation study. J 
Pain Symptom Manage. 2010 Feb;39(2):230-40.  
58. Chow E, Wu JS, Hoskin P, Coia LR, Bentzen SM, Blitzer PH. International 
consensus on palliative radiotherapy endpoints for future clinical trials in bone 
metastases. Radiother Oncol. 2002 Sep;64(3):275-80.  
59. Broom R, Du H, Clemons M, Eton D, Dranitsaris G, Simmons C, et al. Switching 
breast cancer patients with progressive bone metastases to third-generation 
bisphosphonates: Measuring impact using the functional assessment of cancer 
therapy-bone pain. J Pain Symptom Manage. 2009 Aug;38(2):244-57.  
60. Schefter TE, Kavanagh BD, Timmerman RD, Cardenes HR, Baron A, Gaspar 
LE. A phase I trial of stereotactic body radiation therapy (SBRT) for liver 
metastases. Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1371-8.  
61. Zhang T, Chi Y, Meldolesi E, Yan D. Automatic delineation of on-line head-and-
neck computed tomography images: Toward on-line adaptive radiotherapy. Int J 
Radiat Oncol Biol Phys. 2007 Jun 1;68(2):522-30.  
 

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12.0 APPENDICES 
 
APPENDIX A 
 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4 
 
An electronic copy of the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4 
can be obtained from the World Wide Web CTEP site.  The web address is:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 

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APPENDIX B 
 
FACT-G (Version 4) 
Below is a list of statements that other people with your illness have said are 
important. Please circle or mark one number per line to indicate your 
response as it applies to the past 7 days. 
PHYSICAL WELL-BEING 
Not at 
all 
A 
little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of energy ..................................................... 0 
1 
2 
3 
4 
GP2 
I have nausea .................................................................... 0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family .......................................
0 
1 
2 
3 
4 
GP4 
I have pain ........................................................................ 0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment ....................... 0 
1 
2 
3 
4 
GP6 
I feel ill ............................................................................. 0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ...................................... 0 
1 
2 
3 
4 
 
SOCIAL/FAMILY WELL-BEING 
 
Not at 
all 
A 
little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GS1 
I feel close to my friends .................................................. 0 
1 
2 
3 
4 
GS2 
I get emotional support from my family .......................... 0 
1 
2 
3 
4 
GS3 
I get support from my friends .......................................... 0 
1 
2 
3 
4 
GS4 
My family has accepted my illness .................................. 0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness ...............................................................................
0 
1 
2 
3 
4 
GS6 
I feel close to my partner (or the person who is my 
main support) ...................................................................
0 
1 
2 
3 
4 

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Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
I feel sad .............................................................................. 0 
1 
2 
3 
4 
I am satisfied with how I am coping with my illness .......... 0 
1 
2 
3 
4 
I am losing hope in the fight against my illness .................. 0 
1 
2 
3 
4 
I feel nervous ....................................................................... 0 
1 
2 
3 
4 
I worry about dying ............................................................. 0 
1 
2 
3 
4 
I worry that my condition will get worse ............................ 0 
1 
2 
3 
4 
 
 
 
FUNCTIONAL WELL-BEING 
Not 
at 
all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
I am able to work (include work at home) .......................... 0 
1 
2 
3 
4 
My work (include work at home) is fulfilling ..................... 0 
1 
2 
3 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer 
it, please mark this box           and go to the next section. 
 
0 
1 
2 
3 
4 
GS7 
I am satisfied with my sex life ......................................... 0 
1 
2 
3 
4 

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I am able to enjoy life ......................................................... 0 
1 
2 
3 
4 
I have accepted my illness .................................................. 0 
1 
2 
3 
4 
I am sleeping well ............................................................... 0 
1 
2 
3 
4 
I am enjoying the things I usually do for fun ...................... 0 
1 
2 
3 
4 
I am content with the quality of my life right now ............. 0 
1 
2 
3 
4 
 

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APPENDIX C 
 
FACT-BP 
QUALITY OF LIFE MEASUREMENT IN PATIENTS WITH BONE PAIN 
 
Please answer the following questions about your bone pain. Sometimes it is not easy to 
tell whether a pain you might have is bone pain or some other type of pain. Please do the 
best you can to answer these questions about your bone pain in particular. By circling one 
(1) number per line, please indicate how true each statement has been for you during the 
past 7 days. 
 
 
 
In how many places in your body have you felt bone 
pain? .................................................................................
0 
1 
2 
3 
4+ 
 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
I am content with the quality of my life right now…… 
0 
1 
2 
3 
4 
I have certain parts of my body where I experience 
significant pain………………………………………... 
0 
1 
2 
3 
4 
 
     I have bone pain………………………………………. 
0 
1 
2 
3 
4 
It hurts when I put weight or pressure on the place 
where I have bone pain .....................................................
0 
1 
2 
3 
4 
   I have bone pain even when I sit or lie still...................
 
 
0 
1 
2 
3 
4 
I need help doing my usual activities because of bone 
pain ................................................................................... 0 
1 
2 
3 
4 
  I am forced to rest during the day because of bone pain
 
 
0 
1 
2 
3 
4 
  I have trouble walking because of bone pain………….
 
 
0 
1 
2 
3 
4 
Bone pain interferes with my ability to care for myself 
(bathing, dressing, eating, etc.) ......................................... 0 
1 
2 
3 
4 
Bone pain interferes with my social activities…………..
 
 
0 
1 
2 
3 
4 

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    Bone pain wakes me up at night………………………...
 
0 
1 
2 
3 
4 
I am frustrated by my bone pain ......................................... 0 
1 
2 
3 
4 
I feel depressed about my bone pain ................................... 0 
1 
2 
3 
4 
   I worry that my bone pain will get worse……………….
 
 
0 
1 
2 
3 
4 
   My family has trouble understanding when my bone         
   pain interferes with my activity .......................................... 0 
1 
2 
3 
4 
 

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APPENDIX D 
 
Bone Treatment Convenience and Satisfaction Questionnaire 
FACIT-TS-BTCSQ – Baseline (Modified) 
 
For each statement, please choose the response that best describes your 
expectation of this treatment. 
 
"Treatment for bone disease" means the radiation you receive to treat your bone 
disease only, NOT your other cancer treatments. 
 
Treatment for Bone Disease Expectations 
Not  at 
All 
A little 
bit 
Some-
what 
Quite a 
bit 
Very 
much 
 
I believe that my treatment for bone disease will 
cause me physical pain ..............................................
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
I believe that receiving treatment for bone disease 
will be inconvenient. .................................................
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
I worry that my treatment for bone disease will 
not be effective. .........................................................
 
 
 
0 
 
 
1 
 
 
 
2 
 
 
3 
 
 
4 
 
I believe that treatment for bone disease will be 
harmful to me. ...........................................................
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
I believe that my treatment schedule for bone 
disease will be stressful to me. ..................................
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
I believe that my treatment schedule for bone 
disease will be stressful to my family ........................
 
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
I believe that I will be bothered by side effects of 
treatment for bone disease .........................................
 
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 

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APPENDIX E 
 
Bone Treatment Convenience and Satisfaction Questionnaire 
FACIT-TS-BTCSQ – On Treatment (Modified) 
 
The following to be completed by patient. 
 
The following is a list of statements that people receiving bisphosphonate 
therapy have commented are important. For each statement, please choose 
the response that best describes your expectation of this treatment. 
 
 
"Treatment for bone disease" means the drug(s) you receive to treat your bone 
disease only, NOT your other cancer treatments.  
 
Treatment for Bone Disease Expectations 
Not  at 
All 
A little 
bit 
Some-
what 
Quite a 
bit 
Very 
much 
 
Treatment for bone disease takes up my time ...........
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
My treatment for bone disease takes up my 
family’s time. .............................................................
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
I worry about side effects from treatment for bone 
disease.. ......................................................................
 
 
 
0 
 
 
1 
 
 
 
2 
 
 
3 
 
 
4 
 
My treatment for bone pain causes me physical 
pain ............................................................................
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
Receiving treatment for bone disease is 
inconvenient. .............................................................
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
I worry that my treatment for bone disease will 
not be effective. .........................................................
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 

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Treatment for bone disease seems harmful to me. ....
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
My treatment schedule for bone disease is 
stressful to me. ...........................................................
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
My treatment schedule for bone disease is 
stressful to my family ................................................
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
I am bothered by side effects of treatment for 
bone disease. 
………………………………………… ...................
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
  
Considering your experience with treatment for bone disease to date, please 
respond to the following questions. 
 
 
No, not 
at all 
Yes, to 
some 
extent 
Yes, for 
the most 
part 
Yes, 
completely 
 
Are you satisfied with the results of the treatment for 
your bone disease so far? ................................................
 
 
 
0 
 
 
1 
 
 
2 
 
 
3 
 
 
 
 
 
No 
Maybe 
Yes 
Would you recommend this treatment for bone 
disease to others with your illness? .................................
 
 
0 
 
1 
 
2 
 
Would you choose this treatment for bone disease 
again? ..............................................................................
 
 
 
0 
 
 
1 
 
 
2 
Time Used for Hospitalizations and Outpatient Medical Visits 
 
 

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1) How many times and for how long did you have a hospital stay or an outpatient visit 
during the past 4 weeks?   
     (Please complete the table below.) 
 
 
Total 
Number  
of Visits 
 Average 
Length  
of Visit 
 
Hospital Admissions 
 
 
 
days 
Family Practice Visits 
 
 
 
hours 
Specialist Visits 
 
 
 
hours 
Emergency Visits 
 
 
 
hours 
Other Visits 
 
 
 
hours 
 
 
2) We would like to know the cost incurred by you or by someone helping you with 
transportation to and from the above visits during the past 4 weeks.  
     (Please complete the table below.) 
 
 
Total 
Number 
of Trips 
Average 
Kilometers 
per Trip 
Average Time of Trip 
Average 
Cost 
Ambulance 
 
 
 
hours 
 
mins 
 
Private Vehicle 
 
 
 
hours 
 
mins 
 
Public 
Transport/Taxi 
 
 
 
hours 
 
mins 
 
 
3) During the past 4 weeks, how much total time did you or someone helping you miss 
from work or leisure time due to actual visits and travel time?  (Please complete the 
table below) 
 
Time Missed from Work/Leisure 
Days 
Hours 
Total time missed by patient  
 
 
 
Total time missed by someone helping 
patient  
 
 
 
 
 

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APPENDIX F 
 
RTOG Late Radiation Morbidity Scoring Table 
ORGAN 
TISSUE 
0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
5 
SKIN 
None 
Slight atrophy 
Pigmentation change 
Some hair loss 
Patch atrophy; 
Moderate 
telangiectasia; Total 
hair loss 
Marked atrophy; Gross telangiectasia 
Ulceration 
D 
E 
A 
T 
H 
 
D 
I 
R 
E 
C 
T 
L 
Y 
 
R 
E 
L 
A 
T 
E 
D 
 
T 
O 
 
R 
A 
D 
I 
A 
T 
I 
O 
N 
 
L 
A 
T 
E 
 
E 
F 
F 
E 
C 
T 
S 
SUBCUTANEOUS 
TISSUE 
None 
Slight induration 
(fibrosia) and loss of 
subcutaneous fat 
Moderate fibrosis but 
asymptomatic 
Slight field contracture 
<10% linear reduction 
Severe induration and loss of subcutaneous 
tissue 
Field contracture 
>10% linear measurement 
Necrosis 
MUCOUS 
MEMBRANE 
None 
Slight atrophy and 
dryness 
Moderate atrophy and 
telangiectasia 
Little mucous 
Marked atrophy with complete dryness 
Severe telangiectasia 
Ulceration 
SALIVARY 
GLANDS 
None 
Slight dryness of mouth 
Good response on 
stimulation 
Moderate dryness of 
mouth 
Poor response on 
stimulation 
Complete dryness of mouth 
No response on stimulation 
Fibrosis 
SPINAL CORD 
None 
Mild L'Hermitte's 
syndrome 
Severe L'Hermitte's 
syndrome 
Objective neurological findings at or below 
cord level treated 
Mono, para 
quadraplegia 
BRAIN 
None 
Mild headache 
Slight lethargy 
Moderate headache 
Great lethargy 
Severe headaches 
Severe CNS dysfunction (partial loss of 
power or dyskinesia) 
Seizures or paralysis 
Coma 
EYE 
None 
Asymptomatic cataract 
Minor corneal 
ulceration or keratitis 
Symptomatic cataract 
Moderate corneal 
ulceration 
Minor retinopathy or 
glaucoma 
Severe keratitis 
Severe retinopathy or detachment 
Severe glaucoma 
Panopthalmitis/ 
Blindness 
LARYNX 
None 
Hoarseness 
Slight arytenoid edema 
Moderate arytenoid 
edema 
Chondritis 
Severe edema 
Severe chondritis 
Necrosis 
LUNG 
None 
Asymptomatic or mild 
symptoms (dry cough) 
Slight radiographic 
appearances 
Moderate symptomatic 
fibrosis or pneumonitis 
(severe cough) 
Low grade fever 
Patchy radiographic 
appearances 
Severe symptomatic fibrosis or pneumonitis 
Dense radiographic changes 
Severe respiratory 
insufficiency/ 
Continuous O2/ 
Assisted ventilation 
HEART 
None 
Asymptomatic or mild 
symptoms 
Transient T wave 
inversion & ST changes 
Sinus tachycardia >110 
(at rest) 
Moderate angina on 
effort 
Mild pericarditis 
Normal heart size 
Persistent abnormal T 
wave and ST changes 
Low ORS 
Severe angina 
Pericardial effusion 
Constrictive pericarditis 
Moderate heart failure 
Cardiac enlargement 
EKG abnormalities 
Tamponade/ Severe 
heart failure/ Severe 
constrictive 
pericarditis 
ESOPHAGUS 
None 
Mild fibrosis 
Slight difficulty in 
swallowing solids 
No pain on swallowing 
Unable to take solid 
food normally 
Swallowing semi-solid 
food 
Dilatation may be 
indicated 
Severe fibrosis 
Able to swallow only liquids 
May have pain on swallowing 
Dilation required 
Necrosis/ Perforation 
Fistula 
SMALL/LARGE 
INTESTINE 
None 
Mild diarrhea 
Mild cramping 
Bowel movement 5 
times daily 
Slight rectal discharge 
or bleeding 
Moderate diarrhea and 
colic 
Bowel movement >5 
times daily 
Excessive rectal mucus
or intermittent 
bleeding 
Obstruction or bleeding 
requiring surgery 
Necrosis/ Perforation 
Fistula 
LIVER 
None 
Mild lassitude 
Nausea, dyspepsia 
Slightly abnormal liver 
function 
Moderate symptoms 
Some abnormal liver 
function tests 
Serum albumin normal 
Disabling hepatitic insufficiency 
Liver function tests grossly abnormal 
Low albumin 
Edema or ascites 
Necrosis/ Hepatic 
coma or 
encephalopathy 
KIDNEY 
None 
Transient albuminuria 
Persistent moderate 
Severe albuminuria 
Malignant 

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No hypertension 
Mild impairment of 
renal function 
Urea 25-35 mg% 
Creatinine 1.5-2.0 mg% 
Creatinine clearance 
>75% 
albuminuria (2+) 
Mild hypertension 
No related anemia 
Moderate impairment 
of renal function 
Urea>36-60 mg% 
Creatinine clearance 
(50-74%) 
Severe hypertension 
Persistent anemia (<10g%) 
Severe renal failure 
Urea >60 mg% 
Creatinine >4.0 mg% 
Creatinine clearance <50% 
hypertension 
Uremic coma/Urea 
>100% 
BLADDER 
None 
Slight epithelial atrophy 
Minor telangiectasia 
(microscopic hematuria) 
Moderate frequency 
Generalized 
telangiectasia 
Intermittent 
macroscopic hematuria 
Severe frequency and dysuria 
Severe generalized telangiectasia (often with 
petechiae) 
Frequent hematuria 
Reduction in bladder capacity (<150 cc) 
Necrosis/ Contracted 
bladder (capacity 
<100 cc) 
Severe hemorrhagic 
cystitis 
BONE 
None 
Asymptomatic 
No growth retardation 
Reduced bone density 
Moderate pain or 
tenderness 
Growth retardation 
Irregular bone 
sclerosis 
Severe pain or tenderness 
Complete arrest of bone growth 
Dense bone sclerosis 
Necrosis/ 
Spontaneous fracture 
JOINT 
None 
Mild joint stiffness 
Slight limitation of 
movement 
Moderate stiffness 
Intermittent or 
moderate joint pain 
Moderate limitation of 
movement 
Severe joint stiffness 
Pain with severe limitation of movement 
Necrosis/ Complete 
fixation 
 
 

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APPENDIX G 
 
Mirels Fracture Score 
 
Variable 
Score 
1 
2 
3 
Pain 
Mild 
Moderate 
Severe 
Location 
Upper 
Extremity 
Lower 
Extremity 
Peritrochanteric 
Size* 
 
Less than 
1/3 
1/3 to 2/3 
Greater than 2/3 
Nature 
Blastic 
Mixed 
Lytic 
 
*Size =  The degree of cortex taken up by the lesion (<1/3, 1/3-2/3, >1/3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX H 
Brief Pain Inventory 
 
 
 
 
 
 
 
 
 
 
 
 
 

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