Conformal High Dose Intensity Modulated Radiation Therapy for Asymptomatic Metastatic Disease to the Thoracic and Lumbar Spine
Phase: NA
Conditions: Vertebral Metastasis
Sponsor: Ronald McGarry

 
 
 
 09-RAD-01:  Conformal High Dose Intensity Modulated 
Radiation Therapy for Asymptomatic Metastatic Disease to the 
Thoracic and Lumbar Spine 
 
Version   06/27/2013 
 
 
 
Principle Investigator:  
Ronald C. McGarry, MD, PhD 
 
 
 
Department of Radiation Medicine 
 
 
 
University of Kentucky 
 
Radiation Oncology Co-Investigators:  
 
 
 
William St. Clair MD, PhD 
Jonathan Feddock, MD 
Department of Radiation Medicine 
University of Kentucky 
 
Neurosurgery Co-Investigators: 
 
 
 
Thomas Pittman, MD 
 
 
 
Karin Swartz, MD 
 
 
 
Department of Neurosurgery 
 
 
 
University of Kentucky 
 
Statistical Co-Investigator: 
 
 
 
Brent Shelton, PhD 
 
 
 
Departments of Internal Medicine and Biostatistics 
 
 
 
University of Kentucky Colleges of Medicine and Public   
 
 
 
Health 
 
 
 
 
 
 
 
 
 
 

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Conformal High Dose Intensity Modulated Radiation Therapy for Asymptomatic 
Metastatic Disease to the Thoracic and Lumbar Spine 
 
 
 
Table of Contents 
 
Section 
 
 
 
 
 
Page 
 
1.0 Schema 
 
 
 
 
 
3 
2.0 Background 
 
 
 
 
4 
2.5 Hypothesis 
 
 
 
 
11 
3.0 Objectives  
 
 
 
 
12 
4.0 Eligibility  
 
 
 
 
12 
4.1 Exclusion Criteria  
 
 
 
13 
5.0 Pretreatment Evaluations  
 
 
13 
5.1 Schema 
 
 
 
 
 
14 
6.0 Treatment Plan 
 
 
 
 
14 
7.0 Stereotactic Dose Specifications  
 
17 
7.2 Treatment Planning Volumes 
 
 
17 
8.0 Patient Assessments 
 
 
 
20 
9.0 Criteria for Evaluation 
 
 
 
20 
9.5 Definition of Local Failure 
 
 
22 
10.0 Statistical Considerations 
 
 
22 
11.0 Reporting Toxicity 
 
 
 
23 
12.0 Data and Safety Monitoring Plan 
 
23 
13.0 References 
 
 
 
 
24 
 
 

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1.0 
Schema 
 
 
  Eligible patient1 
 
 
 
 
 
 
 
 
 
 
 
 
Solitary spine metastasis   
≥ 2 Spine metastatses2 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMRT3 
 
 
 
 
 
IMRT3 
 
 
 
 
 
 
 
 
 
Follow-up per clinic standards 
 
Q3 monthly X 12 months 4 
 
 
 
1. Any solid tumor including hormone refractory breast/prostate cancer or lymphoma/myeloma; 
Asymptomatic spine metastasis by MRI/nuclear medicine scan 
2. Single lesion treated at discretion of the treating radiation oncologist, usually the largest lesion 
3. IMRT per protocol 
4. Physical examination, BPI, EORTC QLQC30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.0 Background: Bone and Spinal Metastases 
 
 
Metastatic disease to the bone is a major source of morbidity for patients living 
with cancer.  It is estimated that approximately 85% patients with breast, lung, and 
prostate cancer will develop bone metastases in their lifetime.(4)  Other solid tumor 
malignancies including renal cell carcinoma, thyroid cancer, colorectal cancer, myeloma, 
and lymphoma have also been implicated in the development of bone metastasis.  
Overall, 40% of all bone metastasis will occur within the spinal column, with 5-10% of 
people developing symptomatic spinal cord compression. (11). The most common site 
involved is the lumbar spine. (1, 14)  Untreated, the natural history of an asymptomatic 
spinal metastasis is a progressive development of localized pain, compression fracture, 
spinal cord compression, or a combination and the associated comorbidities that follow.   
 
Traditionally, treatment of spinal metastases has been considered palliative and is 
given to reduce symptoms of disease progression.  The overall prognosis for patients with 
bone metastases remains poor, with the median survival most closely related to the 
primary tumor histology, performance status, and presence of concurrent visceral 
metastases.  For some patients such as those suffering from bone-only metastatic breast 
or prostate cancer, life expectancies can be in excess of 2 to 4 years.(4, 18)  Nowadays 
with improved surgical and radiotherapy techniques, as well as targeted systemic therapy, 
cancer has become more of a chronic disease than a terminal illness.  Arguably, 
eradicating bone metastases before debilitating symptoms develop could provide better 
quality of life independent of a patient’s life expectancy. 
 
2.1 Current Standard of Care 
 
Surgery, radiation, and chemotherapy each play a role in the treatment of 
metastatic spinal disease; however, conventional radiation has historically been the 
mainstay of treatment.  Spinal metastases are generally treated once symptoms develop 
(primarily pain), and are addressed palliatively with the intent of symptomatic control.  
Current standard of care uses broad radiation portals which encompass the involved 
vertebral body level(s), with a margin of normal tissue measuring at least 2cm in all 
directions. (RTOG 97-14).  Clinically, this can equate to including one normal vertebral 
body level superiorly and inferiorly, and approximately 2cm lateral to the transverse 

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processes.  Fractionation schemes vary, but the most commonly used regimens are 4000 
cGy in 200cGy fractions and 300cGy in 300cGy fractions.  Different fractionation 
schemes have been compared extensively in several different trials, with the end result 
being relatively equivalent results in time to pain relief, proportion of partial and 
complete pain improvement, but where they differ is primarily in the duration of 
symptomatic control, with longer control seen with the use of more protracted treatment 
courses.  Documented rates of partial pain improvement are in the range of 70-90%,(9) 
and complete pain relief in approximately 40-50% of patients.   
 
In a retrospective review of 1,304 patients, Rades et al. found in-field recurrences 
of tumor at 2 yrs for different fractionation schemes to be: 24%(1x8Gy), 26%(5x4Gy), 
14%(10x3Gy), 9%(15x2.5Gy), and 7%(20x2Gy), (p=<.001). (14)  This is one of the few 
studies that has separated in-field recurrence from symptomatic recurrence, for which 
multiple studies including the RTOG 97-14 short versus long course comparison study 
have published re-treatment rates for palliation of symptoms in up to 25% for single 
fraction and 7-10% for fractionated regimens.  (9,10,11)  
 
 It is apparent that there are many different fractionation regimens used for 
treatment in radiation oncology. The concept of  biologically equivalent dose (BED) 
based on observed cell killing in vitro, was developed in an attempt to allow radiation 
oncologists to approximate the effects of differing dose fractionation schemes on acute 
and late reacting tissues. The mathematical description of this concept is BED = nd 
(1+d/(α/β)), where n= the number of fractions of radiation given, d=the dose/fraction in 
Gy and the experimentally determined factor α/β described killing for different types of 
tissues. Late responding tissues such as spinal cord are considered to have an α/β of 2 in 
contrast to acute responding tissues such as tumor or bone marrow which have been 
estimated to have an α/β value of approximately 10. In assessing damage to normal 
tissues, Emami et al originally described the radiation tolerance, described as the Toxic 
Dose (TD) 5/5 (the dose associated with the development of tissue toxicity in 5% of 
patients at 5 years) of the spinal cord to be 45-50 Gy delivered in 180-200cGy fractions 
to 5cm length (from above equation with fraction size 2Gy = 90Gy BED2) (5).  Each 
tissue has a defined endpoint such as transverse myelitis in spinal cord.  More recent 
studies have suggested that the true tolerance of the spinal cord to fractionated radiation 

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(180-200cGy) is in the range of 63-70 Gy (18).  Regardless, considering the current 
treatment schemes for palliation of spinal metastases using 3000 cGy in 10 fractions 
(BED2 75 Gy) or 800 cGy in 1 fraction (BED2 40 Gy), the accepted tolerance of the 
spinal cord is met with a single treatment course.  Exceeding spinal cord tolerance places 
a patient at risk for transient or chronic progressive myelopathy.  If spinal cord tolerance 
is met with a single treatment course, there are not many options for retreatment should 
the patient have progression, which from RTOG 97-14 showed us can happen in up to 
25% of cases. 
 
Retreatment of the spinal cord using conventional techniques can be done with 
acceptable results, and sufficient data supports this technique.  Still, long term data 
clearly documenting the true tolerance of the spinal cord is lacking.  One of the current 
areas of increased interest is to use stereotactic body radiation therapy to retreat recurrent 
spinal metastatic disease by effectively avoiding significant dose to the spinal cord as 
much as technically feasible. (17) 
 
2.2 High Dose Conformal Radiation Therapy 
Intensity Modulated Radiation Therapy (IMRT) is a form of radiation therapy treatment 
delivery whereby a radiation treatment is generated in an “inverse planning” method.  
After a patient has undergone a CT simulation procedure, particular structures called 
organs at risk (OAR), such as the parotid glands in the treatment of Head and Neck 
cancers, can be contoured on the treatment planning system.  Maximum dose limits can 
be set for the OARs based on this 3-dimensional contour, and a treatment plan is 
generated that delivers the necessary curative dose of radiation to the tumor, while at the 
same time sparing normal tissues the parotid glands based upon the limits set earlier.  A 
typical IMRT treatment plan will utilize 5, 7, or 9 beams in an effort to gain coverage on 
a tumor and spare OARs.   In contrast, conventional radiation therapy uses fewer beams, 
and utilizes “forward planning.”  A treatment plan is generated with the goals of adequate 
dose coverage to the tumor, with OARs receiving whatever dose of radiation they may 
receive; normal tissue sparing is more difficult to achieve using conventional approaches.     

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One of the principle advantages behind IMRT is its inherent ability to escalate the dose of 
radiation to levels much higher than would be permissible with conventional techniques, 
while at the same time limiting the dose of radiation to OARs.  By definition, Stereotactic 
Body Radiation Therapy (SBRT) refers to the treatment of an isolated cancer in 2-5 
fractions. Often, SBRT can be optimized by the use of IMRT to deliver high doses of 
radiation in a few fractions and utilizes patient immobilization to reduce set-up error and 
patient movement; in contrast to conventional radiation techniques, which delivers 
smaller doses in multiple fractions. Combining the improved conformality of the 
radiation dose distribution using IMRT, and the immobilization of the patient is the only 
safe method for dose escalation and the relative sparing of normal tissues.  This has well 
described as both a safe and effective treatment modality for multiple sites of localized 
disease and most recently trials have begun to evaluate its utility in the treatment of the 
spine.   
 
One of the main advantages of IMRT in the treatment of spinal metastases is the 
ability to sharply delineate dose distributions and spare adjacent structures.  Ryu et al. 
and Yamada et al. demonstrated that by using a margin of 5mm between the treatment 
volume and the structure of interest (ie the spinal cord), high dose SBRT delivered using 
IMRT can be given safely with single fraction disease of up to 18 Gy (BED = 180Gy, 
α/β=2) without significant toxicity.  (16, 20, 21). In a recent study in female Yucatan pigs 
(considered a good human analog), Medin et al (unpublished) showed not only recovery 
of cord tolerance over a 3 year period to pre-irradiation tolerance but that re-irradiation 
with a 16 Gy single fraction irradiation produced no toxicity. Additionally, in contrast to 
full circumferential irradiation of cord, partial thickness cord irradiation has higher dose 
tolerance in experiments in progress.   
 
2.3 Radiation Prescription Dose 
 
In a review of the linear quadratic model of cell killing by radiation, it is apparent 
that large fractions of radiation kill cells on the “linear” portion of the curve and by 
definition are very effective especially in being less influenced by factors such as hypoxia 
or cell cycle. The difficulty with large fractions (>600-800cGy) is maintaining normal 
tissue toxicity to an acceptable level. As a palliative modality, considerations of 

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fractionation include the symptoms to be palliated (“oncologic control”) vs. toxicity to 
normal tissues. Ideally, one would like to achieve high local control with low toxicity 
with a radiation regimen delivered in the shortest possible time.  
 
Improved local control rates in brain, lung, liver, and pancreas cancers have been 
seen with the use of high dose, single fraction IMRT.  Prostate, lung, and breast tumors 
are responsible for up to 90% of bone metastases.  Multiple dose escalation studies have 
been carried out for these sites demonstrating that higher tumor doses equate to improved 
cell killing.  Onishi et al. in a Japanese trial of hypo-fractionated high dose radiation for 
primary lung cancers, demonstrated an improved 5yr Progression Free Survival (PFS) 
and Overall Survival (OS) for patients who received a BED10>100Gy. (13)  Similarly, the 
MRC Prostate trials comparing 64Gy vs 74Gy, the Dutch Prostate trials comparing 68Gy 
vs 78Gy, and MD Anderson trials comparing 70Gy vs 79Gy have all shown improved 
disease free survivals on long term follow-up with higher doses of radiation.  Comparing 
radiation doses to an intact primary tumor compared to a metastatic bone lesion, it is not 
surprising that the RTOG documents recurrence rates and the need for retreatment in up 
to 10% and 25% of cases treated palliatively.   
 
Ideally, if enough of the spinal cord can be spared from the radiation dose, higher 
effective doses could be directed to the site of disease that would both palliate symptoms 
and eradicate tumor.  Gertzen et al. treated 393 patients with 500 verified symptomatic 
spinal metastases (excluding neurologic deficits or spinal cord compression) using single 
fractionated SBRT with doses of 12.5 to 25 Gy (BED 90.625 Gy and 337.5 Gy 
respectively), and found response rates of pain improvement in 86% and long-term tumor 
control of 88% at median follow-up of 21 months.  Local control rates of 90% at median 
follow-up of 15 months were also found by Yamada et al. (20)   in a series of 93 
previously irradiated patients, now treated for recurrence at Memorial Slone Kettering 
with single fraction radiotherapy using doses of 18-24 Gy.  
 
For the majority of cases of toxicity that have occurred using single fraction high 
dose radiation to treat spinal lesions, these occurred during dose escalation studies or 
were attributed to extenuating patient circumstances that were likely contributory.  
However, apparently safe limits have been published by Ryu et al. (16) who described the 
treatment of recurrent spinal metastases in patients previously treated with conventional 

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radiation therapy.  This trial has established a minimum partial tissue tolerance of the 
spinal cord to hypofractionated radiation therapy of 10Gy to 10% volume defined by 
involved area of disease plus a 6mm craniocaudal margin.  In this study, there was a 
statistically significant difference in pain symptoms for doses in excess of 14 Gy.  
Additional data suggests that the spinal cord can tolerate a maximum point dose of 13-14 
Gy in a single fraction. (6-8) Multiple studies have demonstrated that single fraction 
high dose radiation to the spine can be administered safely with a complication rate of 
<1%. (17, 20).  No cases of spinal cord injury were documented in the series from 
Germany published by Gertzen. (6-8)  Yamada et al. also demonstrated no cases of 
radiculopathy or myelopathy, although grade 1/2 esophagitis and skin toxicity were 
observed in 3 patients, and acute compression fracture occurred in 3 patients.  (20)  In the 
study by Ryu et al, one patient developed radiation-induced cord injury 13 months 
following treatment of single fraction RT of dose 16Gy, with max point dose 14.2Gy, and 
dose to 10% volume 9.6Gy.  The patient incidentally was treated with additional 
chemotherapy with Carboplatin/Taxol.  After administration of steroids, the patient had a 
complete symptomatic resolution.  Overall, high dose single fraction radiation to the 
spine appears to be safe when dose restraints to the spinal cord are met. 
 
In summary, there is accumulating data to support the concept that a single 
fraction RT using IMRT to deliver a minimum conformal dose of 14Gy (BED = 116Gy, 
α/β=2) can palliate symptoms of vertebral spinal metastases, control disease locally, and 
maintain low radiation doses to spinal cord that would not preclude a patient from 
receiving additional therapy in the future. 
 
2.4 Health Related Quality of Life and Utilities 
 
Skeletal related events (SREs), defined in this study as a pain attributable to bone 
metastasis, pathological bone fracture, spinal cord compression, surgery to bone, or 
radiation to bone, have important and significant effects on measures of health-related 
quality of life. 
 

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2.4.1 The Brief Pain Inventory (BPI)  
 
The BPI, developed by Daut et al., was modeled after the McGill Pain 
Questionnaire.  The BPI is a seventeen-item patient self rating scale assessing 
demographic data, use of medications, as well as sensory, and reactive components of 
pain.  Respectable reliability has been demonstrated over short intervals using test retest 
item correlation; worst pain, (r = 0.93); usual pain, (r = 0.78); and pain now, (r = 0.59).  
Evidence of validity of the BPI comes from several sources.  The relationship between 
use of pain medications and overall pain ratings was examined.  The percentage of 
patients taking pain medications increased with high pain ratings.  Significance was 
demonstrated between increased medication use and high pain ratings for bother narcotic 
(x = 28.17, df = 3, p < 0.002) and non-narcotic (x = 23.75, df = 3, p < 0.002) for pain 
relievers.  Validity of the BPI was also supported by the moderate correlation between 
worst pain intensity ratings and ratings of interference with six areas of activity and mood 
(r = 0.245 to 0.478, p < 0.02 for all but social relationships were p < 0.05).  And finally, 
there is a logical pattern in the differences in inter-correlations among various pain and 
activity interference measures for different diseases. 
 
The BPI includes items that will address components of sensory pain including 
severity, location, chronicity, and degree of relief due to therapy.  The BPI also has items 
that address reactive pain components including depression, suffering, and perceived 
availability of relief.  The BPI’s ease of translation (validated in 12 languages) and brief 
administration have made it a frequently used tool in clinical trials in which reduction or 
prevention of pain are primary or secondary outcome measures, and it is considered the 
FDA standard for a pain assessment tool.   
 
2.4.2 EORTC Quality of Life Questionnaire (QLQ-C30) 
 
 
In 1986, the EORTC initiated a research program to develop an integrated, 
modular approach for evaluating the QoL of patients participating in international cancer 
clinical trials.  This research resulted in the development of a core questionnaire which is 
referred to as the EORTC QLQ-C30 (Aaronson et al., 1993).  The EORTC QLQ-C30 
incorporates nine multi-item scales: five functional scales (Physical, Role, Cognitive, 

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Emotional, and Social Functioning); three symptom scales (Fatigue, Pain, and 
Nausea/Vomiting); and Global Health Status/QoL scale.  Six single item scales are also 
included (Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, and Financial 
Difficulties).  The psychometric properties of the questionnaire were tested and in 
conclusion it was found to possess the required standards such as validity (measuring 
what it is intended to measure), reliability (measuring with sufficient precision), and 
sensitivity (ability to detect changes) (Aaronson et al,. 1993; Osoba et al., 1994; Kaasa et 
al., 1995).  The questionnaire was initially tested in a population of lung cancer patients 
(Aaronson et al., 1993) and subsequently in a variety of cancer patient groups.  A 
bibliography is contained in the EORTC QLQ-C30 Scoring Manual (Fayers et al., 2001). 
 
There is a continuing program of development for the EORTC QLQ-C30.  There 
have been four versions of the questionnaire: the QLQ-C30 version 1.0, the interim 
version QLQ-C30 (+3), which introduced new questions for the Role Functioning and 
Global Health Status/QoL scales, the QLQ-C30 version 2.0, which was released after 
validation of the new questions, and the current version 3.0 of the QLQ-C30.  Version 3.0 
differs from version 2.0 only in that it has four-point scales for the first five items 
comprising the physical functioning scale.  Data from all four versions are used in this 
manual, but only the current versions of the Global Health Status/QoL, Physical 
Functioning and Role Functioning scales are reported: this means that available sample 
sizes for these three scales will generally be lower.  In previous publications the 
abbreviations QL2, RF2, and PF2 are often used to distinguish the revised versions of 
these scales from the original versions but in this manual QL, RF, and PF will instead be 
used to denote the current versions.  The remaining 12 scales have remained unchanged 
throughout the history of the questionnaire. 
 
2.5 Hypothesis 
Given the high rates of vertebral metastasis from many cancers, the primary objective of 
the study is that up front treatment of metastatic lesions will alter the time to progression 
and development of associated symptoms.   
 

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3.0 Objectives 
Primary 
1. Time to any skeletal related event most commonly symptomatic recurrence or 
progression with pain/neurologic impairment with evidence of radiographic 
progression.  
Secondary 
2. Safety and toxicity. Patients will be monitored for minimum of one year for both 
acute and late effects including non-malignant compression fracture, progression 
of pain, and Quality of Life. 
 
4.0 Eligibility 
1. Histological confirmation of malignancy (non-small cell lung cancer, breast 
cancer (hormone refractory), prostate cancer  (hormone refractory), lymphoma, 
renal cell carcinoma, myeloma by either biopsy or cytology of the primary or 
metastatic lesion. 
2. Patients must have radiological documentation of metastatic disease to the 
thoracic or lumbar spine which may include computer assisted tomography (CAT 
scan), positron emitted tomography (PET) or nuclear medicine bone scan 
(NMBS).  Magnetic resonance imaging (MRI) is required prior to treatment 
planning to confirm the extent of the disease and is used for defining the target for 
the radiation. 
3. Patient with ≥1 asymptomatic spinal metastases of the thoracic spine OR ≥1 
asymptomatic spinal metastases of the lumbar spine may be included.  Patients 
with spinal metastases to multiple vertebral levels may be included at the 
discretion of the investigator; however, only one vertebral level will be treated. 
4. Spinal metastatic lesion being treated must be ≤ 6cm in greatest dimension. 
5. Tumor to be treated should not directly abut the spinal cord, and should have at 
least 5mm separation from the spinal cord.  For patients with tumors closer than 
5mm, inclusion is permissible at the discretion of the treating radiation oncologist 
such that dosimetric review demonstrates that the total dose to spinal cord is 
within tolerable range of <10Gy to 10% partial volume or max point dose 18 Gy. 

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6. Patients must be able to fit into either the Civco stereotactic immobilization or the 
Elekta Stereotactic BodyFix immobilization device. 
7. Must be ≥ 18 years of age. 
8.   ECOG status 0-2. 
8. Women of childbearing potential and male participants must use an effective 
contraception method. (Until at least 60 days following treatment.) 
9. Negative urine pregnancy test within one week before starting treatment in 
women of child-bearing potential. 
10. Patients must sign a study-specific informed consent form. 
 
 
4.1 Exclusion Criteria 
1. Patients with evidence of spinal instability OR neurologic deficit resulting from 
bony compression of neurologic structures. 
2. Patients with other systemic illness, or have not recovered adequately from their 
primary treatment or who have evidence of progression of their current cancer 
prior to therapy that, in the investigator’s opinion, would preclude their inclusion. 
3. Patient may not receive concomitant cytotoxic anti-neoplastic therapy during 
treatment. Patients may be allowed to use hormonal suppression therapy or 
bisphosphonates for hypercalcemia. 
4. Pregnant or lactating women. 
5. Any patient with symptoms of pain, compression fracture, neurologic deficit 
attributable to spinal metastases will not be included. 
6. Patients previously treated with radiation therapy to the thoracic or lumbar spinal 
levels of involved disease will not be included. 
 
5.0 Pretreatment Evaluations 
(All lab tests and radiographic studies should be obtained within 4 weeks of study entry) 
5.0.1 Complete history, physical examination, and evaluation of Zubrod Performance 
Status. 
5.0.2  Pathological (biopsy) or cytologically proven malignancy  

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5.0.3 NMBS, CT, or PET and MRI demonstrating findings consistent with metastatic 
disease. 
5.1 Schema 
Patients will be accrued and distributed into one of two strata: 
1. Patients with a single confirmed spinal metastasis within the thoracic or lumbar spinal 
levels. These patients will be treated to the single metastatic lesion.   
2. Patients with ≥2 confirmed spinal metastases within the thoracic or lumbar spinal 
levels. These patients will have a single lesion selected at the discretion of the treating 
radiation oncologist for treatment, usually the largest lesion while respecting dosimetric 
limits.  The remainder of the spinal metastases will serve as internal controls, and further 
treatment will be withheld unless symptoms of progression are identified.   
 
6.0 Treatment Plan 
All radiation therapy must be planned and delivered with IMRT-based delivery system.  
Non-contrast CT images will be obtained in 2.5mm slices, and fused with the patients 
pre-study entry MRI T2 or 1 weighted images depending on the method yielding best 
resolution of the tumor upon fusion with the treatment planning CT scan.  Tomotherapy 
is allowed. 
 
6.1 Volume and ICRU Point Definitions 
The definitions of volumes are in accordance with the 1993 ICRU Report#50:45 
Prescribing, Recording and Reporting Photon Beam Therapy.  At the time of CT 
simulation, the patient’s most recent MRI T1 weighted post-contrast axial images will be 
fused with the non-contrast CT simulation films.   
6.1.1 Gross Tumor Volume (GTV) is defined by the physician as all known gross disease 
as defined by the planning CT and clinical information.  Gross tumor includes the 
primary tumor as defined on planning CT corresponding to the contrast-enhancing area 
on MRI T1 weighted images. 
6.1.2 Clinical Target Volume (CTV) will have no additional margin for microscopic 
extension and will be the same as the GTV. 

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6.1.3 Planning Target Volume (PTV) is defined by the physician as known gross disease 
as defined by planning CT expanded to include the entire vertebral body and pedicles.  
When there is a paraspinal or epidural component, the involved spine and the gross 
visible tumor will be included in the target volume. 
6.1.4 The ICRU Reference Point is to be located in the central part of the PTV.  
Typically, this point should be located on the beam axis or at the intersection of the beam 
axes (isocenter). 
  
6.2  3-D Planning  
6.2.1 Planning Volume: The PTV is to be treated with any combination of coplanar or 
noncoplanar 3-dimensional beams optimized with IMRT or with tomotherapy-based 
IMRT shaped to deliver the specified dose while restricting the dose to the normal 
tissues.   
 
6.2.2 Dose Specification:  
Field arrangements will be devised under the discretion of the treating physician, and all 
patients will be treated at 14-16 Gy single fraction dosing using 6MV photons.  While it 
is expected that single fraction of high dose radiation will be delivered, for difficult 
geometry the treatments may be fractionated to up to 3 fractions providing critical organ 
tolerances are maintained.  All attempts are to be made to cover the contoured GTV by a 
minimum of 95% prescribed dose. 
6.2.3 All patients will have 3-Dimensional CT Planning with attention to dose limiting 
organs.  Complete dose volume histograms must be provided and include (at a minimum) 
spinal cord, heart (where applicable), lung (where applicable), and esophagus (where 
applicable), gross tumor volume (contoured gross disease), planning target volume 
(involved vertebral body(s) and spinal cord). 
 
6.3 Normal Tissue Volume and Tolerances 
6.3.1  Efforts will be made to maintain dose limits as described below, and total dose 
received by partial volumes of  5%, 15%, 25%, and 50% will also be recorded for further 
dose tolerance evaluation. The treating radiation oncologist will assess the treatment 

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parameters to ensure dose-limiting organs remain within the commonly accepted levels 
considered relatively safe.  It is expected that most patients will be treated with 
Tomotherapy. This technology uses arc-based IMRT to deliver rotational therapy to the 
PTV. Dose limitations will be defined in the IMRT-based plan as per Table 6.3.1 taking 
into account any previous radiation delivered. In a static IMRT plan using a minimum of  
7 beams, each will contributing only approximately 200cGy of the total prescribed dose 
of 14-16 Gy.  If any beam traverses a critical organ, the dose delivered will be considered 
and a maximum point dose to any organ considered as well.  Table 6.3.1 lists common 
maximum dose limits to a point or volume within several critical organs to be considered 
when stereotactic radiotherapy is used.  Size of fraction delivered to each organ during 
each conformal treatment must be considered, since not all beams will either enter or exit 
through a structure.  All attempts will be made to keep entrance and exit doses of each 
fraction traversing a critical organ to as close to a maximum of 200 cGy as possible to 
help estimate critical structure doses.  All critical organs will be contoured and doses 
calculated in a standard fashion.  Composite plans incorporating the initial radiotherapy 
and the high dose IMRT plan must be created to accurately assess tolerances. 
 
Table 6.3.1  
Serial Tissue 
Volume 
Volume Max (Gv) 
Endpoint( Grade 3) 
 
 
 
 
Spinal Cord 
Less than or equal 
to 0.35cc
10 Gy 
myelitis 
AND 
Spinal Cord 
Less than or equal 
to 10% of the partial 
spinal cord
10 Gy 
myelitis 
AND 
Spinal Cord 
Less than or equal 
to 0.03cc
14 Gy 
myelitis 
Cauda Equina 
<0.03 cc 
<5 cc
16 Gy 
14 Gy
neuritis 
Sacral Plexus 
<0.03 cc 
<5 cc
18 Gy 
14.4 Gy
neuropathy 
Esophagus* 
<0.03 cc 
<5 cc
16 Gy 
11.9 Gy
stenosis/fistula 
Ipsilateral Brachial Plexus 
<0.03 cc 
<3 cc
17.5 Gy 
14 Gy
neuropathy 
Heart/Pericardium 
<0.03 cc 
<15 cc
22 Gy 
16 Gy
pericarditis 
Great vessels* 
<0.03 cc 
<10 cc
37 Gy 
31 Gy
aneurysm 

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Trachea* and Larynx 
<0.03 cc 
<4cc
20.2 Gy 
10.5 Gy
stenosis/fistula 
Skin 
<0.03 cc 
<10 cc
26 Gy 
23 Gy
ulceration 
Stomach 
<0.03 cc 
<10 cc
16 Gy 
11.2 Gy
ulceration/fistula 
Duodenum* 
<0.03 cc 
<5 cc
16 Gy 
11.2 Gy
ulceration 
Jejunum/Ileum* 
<0.03 cc 
<5 cc
. 15.4 Gy 
11.9 Gy
enteritis/obstruction 
Colon* 
<0.03 cc 
<20 cc
18.4 Gy 
14.3 Gy
colitis/fistula 
Rectum* 
<0.03 cc 
<20 cc
18.4 Gy 
14.3 Gy
proctitis/fistula 
Renal hilum/vascular trunk 
<2/3 volume
10.6 Gy 
malignant hypertension
Parallel Tissue 
Critical Volume (cc)
Critical Volume 
Dose Max (Gv) 
Endpoint ( Grade 3) 
Lung (Right & Left) 
1000 cc 
7.4 Gy 
Pneumonitis 
Renal cortex (Right & Left) 
200 cc
8.4 Gy
Basic renal function 
 
7.0 Stereotactic Dose Specifications 
7.1.1 Stereotactic Targeting and Treatment 
Civco Stereotactic positioning system or Elekta Body Fix System will be used for patient 
setup. 
 

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7.1.2 Patient Positioning 
The patient’s position must be accurately reproducible from treatment to treatment in the 
supine position. Within the immobilization system, the patient will be positioned on Vac-
loc pillows to conform to patient’s external contours. 
7.1.3 Inhibition of Effects of Internal Organ Motion 
Abdominal compression to the maximum as tolerated by the patient will be used to 
minimize the effect of internal organ motion at the discretion of the treating physician. 
Ideally, compression will produce damping of the diaphragmatic movement to 0.5-1.0 cm 
as determined by fluoroscopy (conventional) or alternatively by the creation of maximum 
intensity projection (MIP) CT images to determine respiratory excursion of the target 
vertebral body.  
7.1.4 Localization 
Immediately before each treatment, mV (Tomotherapy) or kV cone beam CT 
(conventional linac) isocentre localization will be done on the treatment unit to ensure 
proper accurate targeting of the tumor volume. 
 
7.2 Treatment Planning/Target Volumes 
7.2.1 Image Acquisition 
Treatment planning will utilize computed tomography (CT).  The planning CT will be 
obtained with the patient in the body frame to allow simultaneous view of the patient’s 
anatomy and fiducial system.  3mm thick axial slices will be obtained with the gantry 
angle at 0 degrees.  The CT images will be fused with the patient’s pre-treatment T1 
Weighted Post contrast axial images by an appropriately trained Dosimetrist.  Contouring 
of the GTV will be accomplished using CT Bone windowing or soft tissue windows with 
contrast, with verification of the fused T1 MRI images.  Only abnormal density on CT 
consistent with gross tumor will be included in the GTV.  No margin or enlargement will 
be permitted for presumed microscopic extension (ie GTV = CTV).  The PTV will 
include an expansion of the GTV to include the remainder of the vertebral body(s) 
involved, with greatest diameter dimension not to exceed 6cm. 
 
 
 

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7.2.2 Dosimetry 
Each case will have Tomotherapy or conventional IMRT arrangements designed to 
deliver highly conformal prescription dose distributions per the UK institutional standard.  
The isocenter will be defined as the common point of gantry and couch rotation for the 
treatment unit.  The isocenter in stereotactic coordinates will be determined from system 
fiducials and translated to the treatment record.  The field aperture size and shape will 
correspond nearly identically to the projection of the PTV along a beam’s eye view, 
except when observing the minimum field dimension of 3.5cm in the treatment of small 
lesions.  Hotspots will be manipulated to occur within the target and not within adjacent 
normal tissue.  
 
7.2.3 Dose Fractionation 
The prescription dose of 14-16 Gy for a single fraction or 8Gy for three fractions (24 Gy 
total) will be delivered to the margin of the PTV covering a minimum of 95% of the 
PTV.  Three fractions will be used in cases where the GTV is in close proximity to the 
spinal cord such that fractionation will provide improved spinal cord sparing at the 
discretion of the treating radiation oncologist.  Planning will include correction for dose 
inhomogeneity (e.g. air, bone) 
 
7.3 Technical Factors 
7.3.1 Physical Factors 
Treatment will consist of photon (x-ray) beams produced by a linear accelerator including 
Tomotherapy.  6MV energies will be used under most circumstances, with energies of 
15-18MV used only in a limited number of beams (maximum 2) that must travel a 
cumulative distance of more than 10cm through soft tissue (not lung) to reach the 
isocenter. 
7.3.2 Minimum Field Aperture 
A minimum field dimension of 3.5cm is required for any field used from treatment 
delivery.  If the minimum fields exceeds the technical requirements for small lesions 
(<2.5cm axial GTV dimensions or <1.5cm cranio-caudal GTV dimensions), the 
prescription dose is still prescribed to the edge of the defined PTV. 

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8.0 Patient Assessments 
 
Assessments 
Pre-Study 
Entry 
1mo (+/- 3days) 
Post SBRT 
3mo (+/- 7days) 
Post SBRT 
Follow-Upa,b
 
History/Physical 
X 
X 
X 
X 
Pregnancy testc 
X 
 
 
 
MRI of T/L Spine  
X 
 
 
Xd 
Full body PET, CT 
spine and/or NMBS 
X 
 
 
Xd 
Pathology Review 
X 
 
 
 
Toxicity Eval 
 
X 
X 
X 
BPI & 
EORTC QOL Evals 
X 
X 
X 
X 
a:  Follow-up intervals as per institutional standards (recommended approximately q3month). 
b:  Follow-up period of 1 year. 
c:  As indicated. 
d: As clinically indicated 
 
8.1 Baseline Documentation of Metastatic Lesions 
Patient will be required to have imaging of the thoracic or lumbar spine including PET, 
CT and/or NMBC prior to study enrollment.  In addition, MRI corresponding to the areas 
of involvement must be obtained prior to treatment planning.  Attempts will be made to 
quantify maximum tumor dimensions based upon the largest diameter (LD) measurable 
on pre-treatment MRI images.  This will be reported as the baseline LD, and will be used 
if applicable, for comparison in order to document radiographic disease progression.   
 
9.0 Criteria for Evaluation 
The endpoints for this study are to determine time to symptomatic recurrence in 
asymptomatic patients. In other words, we will assess the levels of pain perceived by the 
patients and overall quality of life as follows: 
 
9.1 Brief Pain Inventory 
This scale was developed in 1983 and has been validated in multiple national clinical 
trials. It is intended to obtain estimates of pain prevalence and severity. Ratings are on a 
scale of 0-10. It is a 10 item scale evaluating: 
 
1. Demographic data 
 
2. Use of Medication 

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3. Components of Sensory pain: 
 Severity 
 Chronicity 
 Location 
 Degree of relief relative to therapy 
 
4. Reactive components of pain: 
 Depression 
 Suffering 
 Perceived availability of relief 
9.2 EORTC QLQ-C30 
 
 
Developed by the EORTC Quality of life study group and consists of 9  
 
 
multi-item scales measuring: 
 5 functional scales (physical, emotional, role, cognitive and social) 
 Global QOL 
 3 symptom scales (fatigue, pain, nausea and vomiting) 
  
 
It has been validated in over 2200 registered studies.  
 
9.3 Symptom Development  
Patients will be followed as per schema for one year. The first symptoms of tumor 
recurrence are expected pain and/or neurological changes localizable to the treated area. 
If symptoms are noted, an MRI or PET scan will be done as per standard of care.  
 
9.4 Radiographic Response Criteria 
9.4.1 Evaluation of Metastatic Lesions 
Patients will undergo repeat imaging as clinically indicated. For patients in whom disease 
progression or recurrence is suspected, additional imaging in the form of CT scan or MRI 
may be obtained.  An attempt to define extent of disease progression/recurrence can 
include, but is not limited to, comparison of maximum tumor diameter with pre-treatment 
imaging; evaluation for abnormal NMBS tracer uptake; evaluation for pathological 
enhancement of CT/MRI contrast material; or other radiographic documentation of 
progression. 

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9.5 Definition of Local Failure 
Refers to the primary treated tumor after protocol treatment and corresponds to 
meeting the following criteria:  
1. Evidence of symptomatic tumor progression (ie pain, compression fracture, or 
neurologic deficits such that radiation toxicity cannot be attributed).  
AND 
2. Radiographic evidence of disease progression/recurrence with corresponding 
activity on PET/CT or NMBS, or contrast enhancement on MRI.  
 
10.0 Statistical Considerations 
10.1 Sample size and power. 
 
 The primary endpoint of this study is to determine the feasibility of using 
stereotactic radiotherapy for treatment of asymptomatic spinal metastases to decrease the 
recurrence rate of pain/neurologic impairment and/or radiologic recurrence/progression 
within a 24 month follow-up period.  Our hypothesis is that without treatment, 
approximately 75% or more of these patients will become symptomatic from their spinal 
metastasis within one year from identification.  With treatment, there is sufficient 
literature to suggest a local control rate of 80-100%.  As a feasibility study, we propose to 
enroll 26 patients evaluable-for-outcome, equally divided between the two strata. In 
comparison to literature-derived data, this will provide 80% power to detect a null 
hypothesis rate of 60% or higher versus an alternative (treated) rate of 35% or less.  This 
equates to being able to detect at least a 42% reduction in progression, or local control 
rate of those patients whom we would expect to progress to symptoms. 
We anticipate that progression rates may very well differ with respect to cancer site (eg. 
lung vs prostate).  With our enrollment of 26 patients total, we anticipate obtaining at 
least 5 non-small cell lung cancer patients, at least 5 prostate (hormone refractory) cancer 
patients, and 5 breast (hormone refractory) cancer patients.   Within each of these sub-
groups, we have precisely 83.5% power to detect a null hypothesis rate of 75% or greater 
versus an alternative (treated) rate of 15% or lower, which equates to being able to detect 
an 80% or greater reduction in progression.  

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10.2 Analysis 
NCSS PASS was used to perform the aforementioned power calculations.  A one-sided 
binomial hypothesis test with a target significance level of 0.05 was employed to assess 
power and sample size and will be used to assess the rate of progression for the 26 
enrolled patients as well as sub-groups where the sample size is larger than 5. 
 
11.0 Reporting Toxicity 
All patients will be assessable for toxicity, and those with measurable disease will be 
assessable for response.  All grade 4 or grade 5 toxicities that are attributable to radiation 
therapy will be reported to the DSMB and Institutional Review Board within 24 hours of 
discovery.  The stereotactic radiotherapy will be given in a one, or three day prescription 
with a minimum 40 hours between doses.  Definitions of acute versus late effects will be 
used as below.  Monitoring of late effects (most notably for Chronic Progressive 
Myelopathy) of radiation therapy will continue for the duration of the 12 month follow-
up period. 
 
11.1 Acute Radiation Toxicity: Acute (≤ 90 days from RT start) side effects of radiation 
therapy will be documented using the NCI Common Toxicity Criteria version 3.0.  A 
copy of the CTCAE version 3.0 can be downloaded from the CTEP homepage 
(http://ctep.info.nih.gov) 
 
11.2 Late Radiation Toxicity: Late (> 90 days from RT start) side effects will be 
documented using the NCI Common Toxicity Criteria version 3.0 
 
11.3 Death from any cause while the patient is receiving protocol treatment and up to 30 
days after the last protocol treatment, will be reported directly to the DSMB and IRB. 
 
12.0 Data and Safety Monitoring Plan 
 
DSM committee will meet every 6 months to review patient safety and toxicity 
reports. 
 

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13.0 References 
 
1. Adsourian et al . (1990) The Pattern of Vertebral Involvement in Metastatic Vertebral 
 
Breast Cancer. Clin Orthop Relat Res. V250, 165-170. 
 
2. Chang et al. (2004) Phase I Clinical Eval of Near-Simultaneous CT Image-Huided 
 
SBRT For Spinal Metastases. IJROBP. V59, N5: 1288-1294. 
 
3. Chang et al. (2007) Phase I/II Study of Sterotactic Body Radiotherapy for Spinal 
 
Metastasis and its Pattern of Failure. J Neurosurg Spine. V7, 151-160. 
 
4. Coleman RE. (1997) Skeletal Complications of Malignancy. Cancer. V80, 1588-1594. 
 
5. Emami et al. (1991) Tolerance of Normal Tissue to Therapeutic Irradiation. IJROBP. 
 
V29, 109-122. 
 
6. Gertzen et al. (2007) Radiosurgery for spinal metastases: Clinical experience in 500 
 
cases from a single institution. Spine. V32. 193-99.  
 
7. Gertzen et al. (2005) Single Fraction Radiosurgery for the treatment of Spinal Breast 
 
Masses. Cancer. V104, N10: 2244-2254. 
 
8. Gertzen et al. (2005) Spinal Radiosurgery for Spinal Mets from Renal Cell Carcinoma. 
 
J Neurosurg. Spine. V3, N4: 288-295. 
 
9. Hartsell WF, J Natl Cancer Inst. 2005 Jun 1;97(11):798-804 (RTOG 9714) 
 
10. Kaasa S, Radiother Oncol. 2006 Jun;79(3):278-84. 
 
11. Klimo P Jr, Schmidt MH. (2004) Surgical Management of Spinal Mets. Oncologist. 
 
V9: 188-196. 2004. 
 
12. Milker-Zabel S, Int J Radiat Oncol Biol Phys. 2003 Jan 1;55(1):162-7 
 
 
13. Onishi et al. (2007) Hypofractionated Stereotactic Radiosurgery for Stage I Non-
small Cell Lung Cancer. J Thoracic Oncol. V2, N7: S94-S100. 
 
14. Steinmetz et al. (2001) Management of Metastatic Tumors of the Spine: Strategies 
 
and Operative Indications. NS Focus. V11, e2.  
 
15. Rades et al. (2005) Evaluation of Five Radiation Fractionation Schedules and 
 
Prognostic Facotrs for Metastatic Spinal Cord Compression. JCO. V23,N15: 
 
3366-3375. 
 
16. Rock et al. (2004) The Evolving Role of Sterotactic Radiosurgery and Stereotactic 
 
Radiation Therapy for Patients with Spine Tumors. J Neuro Oncol. V69. 319-334. 

09-RAD-01 v. 27-JUN-2013 
25
 
17. Ryu et al. (2006) Partial Volume Toleran e of the Spinal Cord and Complications of 
 
Single-Dose Radiosurgery. Cancer. V109, N3: 628-636. 
 
18. Singh et al. (2004) Is There a Favorable Subset of Patients with Prostate Cancer who 
 
develop Oligometastases? IJROBP. V58, 3-10. 
 
19. Van Der Kogel. (1993) Retreatment Tolerance of the Spinal Cord. IJROBP.v26. 715. 
 
20. Wai MS, Cochrane Database Syst Rev. 2004;(2):CD004721 
 
21. Yamada Y, Int J Radiat Oncol Biol Phys. 2005 May 1;62(1):53-61 
 
22. Yamada et al. (2008) High-Dose, Single Fraction Image-Guided Intensity Modulated 
 
Radiation Therapy for Metastatic Spinal Lesions. Int J Rad Oncol Bio Phys. V71, 
 
N2: 484-490.