Image-Guided Radiosurgery or Stereotactic Body Radiation Therapy in Treating Patients With Localized Spine Metastasis

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00922974
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 399
• Locations: 38
• Arms: 2
• Actual Duration (Months): 125.1
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue.

PURPOSE: This randomized phase II/III trial is studying how well image-guided radiosurgery or stereotactic body radiation therapy works and compares it to external-beam radiation therapy in treating patients with localized spine metastasis.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Cancer; Pain	Radiation: External beam radiation therapy; Radiation: Radiosurgery/SBRT	Phase 2/Phase 3

Detailed Description

OBJECTIVES:

Primary

• Determine the feasibility of successfully delivering image-guided radiosurgery or stereotactic body radiotherapy (SBRT) in patients with spine metastases in a cooperative group setting. (Phase II)

• Determine whether image-guided radiosurgery or SBRT (single dose of 16 Gy) improves pain control as measured by the 11-point Numerical Rating Pain Scale (NRPS) compared to conventional external beam radiotherapy (single dose of 8 Gy). (Phase III)

Secondary

• Determine whether image-guided radiosurgery or SBRT improves the rapidity of pain response and increases the duration of pain response at the treated site(s) compared to conventional external beam radiotherapy, as measured by the NRPS. (Phase III)

• Compare adverse events associated with these treatment regimens, as measured by NCI CTCAE v3.0 criteria. (Phase III)

• Evaluate the long-term effects (24 months) of image-guided radiosurgery or SBRT on the vertebral bone (e.g., compression fracture) and the spinal cord, as measured by MRI. (Phase III)

DETAILS:

This is a multicenter, phase II study followed by a randomized phase III study. Patients enrolled in the phase III portion are stratified according to the number of spine metastases to be treated (1 vs 2-3) and the type of tumor (radioresistant [including soft tissue sarcomas, melanomas, and renal cell carcinomas] vs other).

Phase II patients undergo MRI of the treated spine at baseline and at 3 months; phase III patients undergo MRI at baseline and at 3, 6, 12, and 24 months. Patients enrolled in the phase III portion also complete the Numerical Rating Pain Scale at baseline, at 1, 2, and 3 weeks after randomization, and at 1, 3, 6, 12, and 24 months. Patients are followed after completion of study treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 399 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis
• Actual Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Jan 1, 2018
• Actual Study Completion Date: Apr 6, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radiosurgery/SBRT	Radiation: Radiosurgery/SBRT; Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase II component uses 16 Gy. The phase III component allows 16 or 18 Gy as preferred by the treating physician.; Other Names: stereotactic body radiotherapy SRS stereotactic radiosurgery
Active Comparator: External Beam Radiation Therapy	Radiation: External beam radiation therapy; Single fraction dose of 8 Gy external beam radiation therapy; Other Names: EBRT

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients Receiving Radiosurgery/SBRT Per Protocol or With Minor Variation (Phase II) [The day of protocol treatment]

   Treatment delivery was centrally reviewed by the study chair and medical physics co-chair. Success was defined as having a review of "per protocol" or "minor variation". A 70% success rate was required for continuation to the phase III component. Target volume compliance in is defined as the following levels of target coverage in reference to dose volume: Per protocol: ≥ 90% Minor variation: 80%-90% Major deviation: <80% of of dose volume. Image-Guided Radiotherapy (IGRT) compliance is defined as the following differences in IGRT images between simulation/planning and treatment, as well as at the end of treatment: Per protocol: <2 mm Minor variation: 2mm - 3mm Major deviation: > 3mm

2. Percentage of Patients With Complete or Partial Pain Response at 3 Months (Phase III) [Baseline and 3 months]

   Pain is measured by the Numerical Rating Pain Scale (NRPS) a numerical 11-point scale (0-10) with 0 = no pain, 1-4 = mild, 5-6 = moderate, and 7-10 = severe with 10 the worst pain imaginable. Pain response is calculated as 3 month score - baseline score with a positive value indicating increased pain and a negative value indicating decreased pain. Patients with complete or partial pain response as defined below are considered responders. The index site is the lesion with the highest baseline (day of radiosurgery) pain score. If multiple sites have the same baseline pain score, the index site is the most cephalad lesion. Complete response: post-treatment pain score of 0 at the index site, no increase in narcotic pain medication, and no increase in pain score at the secondary treated site(s). Partial response: post-treatment improvement of at least 3 points at the index site, no increase in narcotic pain medication, and no increase in pain score at the secondary treated site(s).

Secondary Outcome Measures

1. Percentage of Participants With Pain Response Through Two Years (Phase III) [Baseline to two years. NRPS measured at baseline, 1, 2, and 3 weeks, 3, 6, 12, and 24 months.]

   Pain is measured by the NRPS, a numerical 11-point scale from 0=no pain to 10=worst pain imaginable. Magnitude of pain response = post-baseline score - baseline score with a positive value indicating increased pain and a negative value indicating decreased pain. Pain response begins when a patient improves at least 3 points at the index site. (Although pain medication and pain response were part of the protocol definition of pain response, they were unable to be assessed accurately during weeks 1-3 and therefore were not included in the final definition used here.) Pain response time is defined as time from randomization to the date of pain response, last known follow-up (censored), or death (censored). Rates of participants with pain response are estimated using the Kaplan-Meier method. The distributions of pain response times are compared between the arms. Two-year rates are provided.

2. Percentage of Participants With Pain Relapse Through Two Years (Phase III) [Randomization to two years. NRPS measured at baseline, 1, 2, and 3 weeks, 3, 6, 12, and 24 months.]

   Pain is measured by the NRPS, a numerical 11-point scale from 0=no pain to 10=worst pain imaginable. Amount of pain response = post-baseline score - baseline score with a positive value indicating increased pain and a negative value indicating decreased pain. Pain response begins when a patient improves at least 3 points at the index site. Pain response ends when when the pain score increases by 3 points (relapse). (Although pain medication and pain response were part of the protocol definition of pain response, they were unable to be assessed accurately during weeks 1-3 and therefore were not included in the final definition used here.) Pain relapse time is defined as time from randomization to the date of first failure, last known follow-up (censored), or death (censored). Rates of participants with pain relapse are estimated using the Kaplan-Meier method. The distributions of pain relapse times are compared between the arms. Two-year rates are provided.

3. Percentage of Patients With Adverse Events at 3 Months (Phase III) [Baseline to 3 months]

   Common Terminology Criteria for Adverse Events (version 3.0) grades adverse event (AE) severity from 1=mild to 5=death. Summary data is provided in this outcome measure.; See Adverse Events Module for specific adverse event data.

4. Percentage of Participants With a Vertebral Compression Fracture Through Two Years (Phase III) [From randomization to two years.]

   Failure is defined as a vertebral compression fracture. Failure time is defined as time from randomization to the date of first failure, last known follow-up (censored), or death without compression fracture (competing risk). Failure rates are estimated using the cumulative incidence method. The distributions of failure times are compared between the arms. Two-year rates are provided.

5. Percentage of Participants With Spinal Cord Damage Through Two Years [From randomization to two years]

   Failure is defined as spinal cord damage. Failure time is defined as time from randomization to the date of first failure, last known follow-up (censored), or death without compression fracture (competing risk). Failure rates are estimated using the cumulative incidence method. The distributions of failure times are compared between the arms. Two-year rates are provided.

6. Change in Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at 3 Months (Phase III) [Baseline and 3 months]

   The FACT-G is a validated 27-item measure in which a higher score represents higher quality of life (QOL). Physical, functional, social and emotional well-being subscale scores are added together to form the FACT-G total score. Responses range from 0=Not a lot to 4=Very much. Certain items must be reversed before being added, by subtracting the response from 4. Subscale items are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Total score ranges from 0-108; physical, social and functional subscales from 0-28; emotional subscale from 0-24. Each subscale requires at least 50% of the items to be completed while the overall response rate must be greater than 80%. If items are missing the subscale scores can be prorated. Change at 3 months is calculated as 3 month score - baseline score with a positive change indicating improvement in QOL.

7. Change in Brief Pain Inventory (BPI) Worst Pain Score Through Two Years (Phase III) [Baseline, 3, 6, 12, and 24 months]

   The Brief Pain Inventory Worst Pain score measures self-reported worst pain in the last week. Possible scores range from 0 (no pain) to 10 (worst pain imaginable), with higher scores indicating a worse outcome. Change is calculated as baseline score subtracted from post-baseline score with a positive change indicating more pain.

8. Change in EuroQol 5 Dimension (EQ-5D) Index Score Through Two Years (Phase III) [Baseline, 3, 6, 12, and 24 months]

   The EQ-5D index score measures health status. Possible scores range from 0 (worst health state) to 1 (best health state), with higher scores indicating better health. Change is calculated as baseline score subtracted from post-baseline score with a positive change indicating improved health status.

9. Change in Functional Assessment of Cancer Therapy - General (FACT-G) Total Score Through Two Years (Phase III) [Baseline, 3, 6, 12, and 24 months]

   The FACT-G total score gives a combined score of the four domains of health-related quality of life (HRQOL) in cancer patients: Physical, social, emotional, and functional well-being. Possible total scores range from 0 to 108 with higher scores indicating a better HRQOL. Change is calculated as baseline score subtracted from post-baseline score with a positive change indicating improvement in HRQOL.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. The patient must have localized spine metastasis from the C1 to L5 levels by a screening imaging study [bone scan, positron emission tomography (PET), computerized tomography (CT), or magnetic resonance imaging (MRI)] (a solitary spine metastasis; two separate spine levels; or up to 3 separate sites [e.g., C5, T5-6, and T12] are permitted.) Each of the separate sites may have a maximal involvement of 2 contiguous vertebral bodies. Patients can have other visceral metastasis, and radioresistant tumors (including soft tissue sarcomas, melanomas, and renal cell carcinomas) are eligible. See Figure 1 in Section 3.1.1. of the protocol for a depiction of eligible metastatic lesions: 1) a solitary spine metastasis; 2) two contiguous spine levels involved; or 3) a maximum of 3 separate sites. Each of the separate sites may have a maximal involvement of 2 contiguous vertebral bodies. Epidural compression (arrow) is eligible when there is a ≥ 3 mm gap between the spinal cord and the edge of the epidural lesion (see #10). A paraspinal mass ≤ 5 cm is allowed (see #11).

• There can be multiple small metastatic lesions shown in other vertebral bodies as shown in referenced diagram. The metastatic lesion of each spine should be less than 20% of the vertebral body as opposed to the diffuse vertebral involvement. These small lesions are often seen in the MRI even when bone scan or PET was negative. Most of these lesions are not clinically required to be treated and are therefore not included in the target volume of this protocol. Only the painful spine (pain score≥ 5) is to be treated .

1. Zubrod Performance Status 0-2;

2. Age ≥ 18;

3. History/physical examination within 2 weeks prior to registration;

4. Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential;

5. Women of childbearing potential and male participants who are sexually active must agree to use a medically effective means of birth control;

6. MRI (contrast is not required but strongly recommended) of the involved spine within 4 weeks prior to registration to determine the extent of the spine involvement; an MRI is required as it is superior to a CT scan in delineating the spinal cord as well as identifying an epidural or paraspinal soft tissue component. Note: If an MRI was done as a screening imaging study for eligibility (see Section -1), the MRI can be used as the required MRI for treatment planning.

7. Numerical Rating Pain Scale within 1 week prior to registration; the patient must have a score on the Scale of ≥ 5 for at least one of the planned sites for spine radiosurgery. Documentation of the patient's initial pain score is required. Patients taking medication for pain at the time of registration are eligible.

8. Neurological examination within 1 week prior to registration to rule out rapid neurologic decline; see Appendix III for the standardized neurological examination. Patients with mild to moderate neurological signs are eligible. These neurological signs include radiculopathy, dermatomal sensory change, and muscle strength of involved extremity 4/5 (lower extremity for ambulation or upper extremity for raising arms and/or arm function).

9. Patients with epidural compression are eligible provided that there is a ≥ 3 mm gap between the spinal cord and the edge of the epidural lesion.

10. Patients with a paraspinal mass ≤ 5 cm in the greatest dimension and that is contiguous with spine metastasis are eligible.

11. Patients must provide study specific informed consent prior to study entry.

Exclusion Criteria:

1. Histologies of myeloma or lymphoma;

2. Non-ambulatory patients;

3. Spine instability due to a compression fracture;

4. 50% loss of vertebral body height;

5. Frank spinal cord compression or displacement or epidural compression within 3 mm of the spinal cord;

6. Patients with rapid neurologic decline;

7. Bony retropulsion causing neurologic abnormality;

8. Prior radiation to the index spine;

9. Patients for whom an MRI of the spine is medically contraindicated;

10. Patients allergic to contrast dye used in MRIs or CT scans or who cannot be premedicated for the use of contrast dye.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Cancer Center at UC Health Sciences Center	Aurora	Colorado	United States	80045
2	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado	United States	80933
3	George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus	New Britain	Connecticut	United States	06050
4	CCOP - Christiana Care Health Services	Newark	Delaware	United States	19713
5	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
6	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois	United States	60611-3013
7	OSF St. Francis Medical Center	Peoria	Illinois	United States	61637
8	Cancer Center at Ball Memorial Hospital	Muncie	Indiana	United States	47303-3499
9	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky	United States	40536-0093
10	James Graham Brown Cancer Center at University of Louisville	Louisville	Kentucky	United States	40202
11	St. Agnes Hospital Cancer Center	Baltimore	Maryland	United States	21229
12	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan	United States	48202
13	Butterworth Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
14	William Beaumont Hospital - Royal Oak Campus	Royal Oak	Michigan	United States	48073
15	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
16	Billings Clinic - Downtown	Billings	Montana	United States	59107-7000
17	Nebraska Medical Center	Omaha	Nebraska	United States	68198
18	Payson Center for Cancer Care at Concord Hospital	Concord	New Hampshire	United States	03301
19	Seacoast Cancer Center at Wentworth - Douglass Hospital	Dover	New Hampshire	United States	03820
20	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756-0002
21	Capital Health Regional Cancer Center	Pennington	New Jersey	United States	08534
22	Stony Brook University Cancer Center	Stony Brook	New York	United States	11794-9446
23	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
24	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210-1240
25	Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
26	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania	United States	19107-5541
27	UPMC - Shadyside	Pittsburgh	Pennsylvania	United States	15213-2582
28	UPMC Cancer Center at UPMC Presbyterian	Pittsburgh	Pennsylvania	United States	15213
29	Lankenau Cancer Center at Lankenau Hospital	Wynnewood	Pennsylvania	United States	19096
30	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57701
31	Huntsman Cancer Institute at University of Utah	Salt Lake City	Utah	United States	84112
32	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Madison	Wisconsin	United States	53792-6164
33	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin	United States	53226
34	All Saints Cancer Center at Wheaton Franciscan Healthcare	Racine	Wisconsin	United States	53405
35	Ottawa Hospital Regional Cancer Centre - General Campus	Ottawa	Ontario	Canada	K1Y 4E9
36	Hopital Notre-Dame du CHUM	Montreal	Quebec	Canada	H2L 4M1
37	McGill Cancer Centre at McGill University	Montreal	Quebec	Canada	H2W 1S6
38	Tel-Aviv Sourasky Medical Center	Tel Aviv		Israel	64239

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: Samuel Ryu, MD, Josephine Ford Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 23, 2016

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00922974
• Other Study ID Numbers: RTOG-0631; CDR0000646803; NCI-2009-01687
• First Posted: Jun 18, 2009
• Last Update Posted: May 19, 2021
• Last Verified: Apr 1, 2021

• Keywords provided by Radiation Therapy Oncology Group: spinal bone metastases; pain
• Additional relevant MeSH terms: Neoplasm Metastasis

Study Results

Participant Flow

Arm/Group Title	Radiosurgery/SBRT	External Beam Radiation Therapy
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase II component uses 16 Gy. The phase III component allows 16 or 18 Gy as preferred by the treating physician.	Single fraction dose of 8 Gy external beam radiation therapy
Period Title: Phase II Component
STARTED	46	0
Eligible	44	0
Eligible and Started Treatment	39	0
Eligible, Treated, Adverse Event Data	34	0
COMPLETED	39	0
NOT COMPLETED	7	0
Period Title: Phase II Component
STARTED	217	136
Eligible	209	130
Eligible With 3 mo. NRPS Data	139	76
Eligible With 3 mo. FACT-G Data	87	58
Eligible With Adverse Event Data	202	117
Eligible, Treated, Adverse Event Data	148	83
Eligible and Consented to Quality of Life Participate in Quality of Life (QOL) Study Component	152	100
COMPLETED	209	130
NOT COMPLETED	8	6

Baseline Characteristics

Arm/Group Title	Radiosurgery/SBRT (Phase II)	Radiosurgery/SBRT (Phase III)	External Beam Radiation Therapy	Total
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase II component uses 16 Gy.	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase III component allows 16 or 18 Gy as preferred by the treating physician.	Single fraction dose of 8 Gy external beam radiation therapy	Total of all reporting groups
Overall Participants	44	209	130	383
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63	63	63	63
Sex: Female, Male (Count of Participants)
Female	18 40.9%	95 45.5%	60 46.2%	173 45.2%
Male	26 59.1%	114 54.5%	70 53.8%	210 54.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 6.8%	10 4.8%	7 5.4%	20 5.2%
Not Hispanic or Latino	40 90.9%	194 92.8%	118 90.8%	352 91.9%
Unknown or Not Reported	1 2.3%	5 2.4%	5 3.8%	11 2.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.3%	1 0.5%	0 0%	2 0.5%
Asian	0 0%	12 5.7%	3 2.3%	15 3.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	1 0.8%	1 0.3%
Black or African American	5 11.4%	20 9.6%	20 15.4%	45 11.7%
White	38 86.4%	169 80.9%	101 77.7%	308 80.4%
More than one race	0 0%	1 0.5%	1 0.8%	2 0.5%
Unknown or Not Reported	0 0%	6 2.9%	4 3.1%	10 2.6%
Zubrod performance status (Count of Participants)
0	13 29.5%	51 24.4%	34 26.2%	98 25.6%
1	25 56.8%	112 53.6%	83 63.8%	220 57.4%
2	6 13.6%	46 22%	13 10%	65 17%
Baseline Numerical Rating Pain Scale (NRPS) (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	7	7	7	7
Number of Spine Metastases (Count of Participants)
1	36 81.8%	160 76.6%	100 76.9%	296 77.3%
2-3	8 18.2%	49 23.4%	30 23.1%	87 22.7%
Location of Index Spine Metastasis (Count of Participants)
C-1 to C-7	4 9.1%	9 4.3%	11 8.5%	24 6.3%
T-1 to T-6	6 13.6%	36 17.2%	19 14.6%	61 15.9%
T-7 to T-12	15 34.1%	65 31.1%	50 38.5%	130 33.9%
L-1 to L-5	19 43.2%	99 47.4%	50 38.5%	168 43.9%
Location of Spine Metastasis #2 (Count of Participants)
C-1 to C-7	1 2.3%	0 0%	3 2.3%	4 1%
T-1 to T-6	2 4.5%	5 2.4%	5 3.8%	12 3.1%
T-7 to T-12	1 2.3%	14 6.7%	9 6.9%	24 6.3%
L-1 to L-5	4 9.1%	30 14.4%	13 10%	47 12.3%
Location of Spine Metastasis #3 (Count of Participants)
T-1 to T-6	0 0%	1 0.5%	2 1.5%	3 0.8%
T-7 to T-12	0 0%	3 1.4%	5 3.8%	8 2.1%
L-1 to L-5	1 2.3%	2 1%	3 2.3%	6 1.6%
Taking Pain Medication (Count of Participants)
No	2 4.5%	28 13.4%	15 11.5%	45 11.7%
Yes	42 95.5%	181 86.6%	115 88.5%	338 88.3%
Type of Tumor (Count of Participants)
Radioresistant	29 65.9%	15 7.2%	44 33.8%
Other	180 409.1%	115 55%	295 226.9%
Intended Radiosurgery/SBRT Dose (Count of Participants)
16 Gy	44 100%	115 55%	76 58.5%	235 61.4%
18 Gy	0 0%	94 45%	54 41.5%	148 38.6%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients Receiving Radiosurgery/SBRT Per Protocol or With Minor Variation (Phase II)
Description	Treatment delivery was centrally reviewed by the study chair and medical physics co-chair. Success was defined as having a review of "per protocol" or "minor variation". A 70% success rate was required for continuation to the phase III component. Target volume compliance in is defined as the following levels of target coverage in reference to dose volume: Per protocol: ≥ 90% Minor variation: 80%-90% Major deviation: <80% of of dose volume. Image-Guided Radiotherapy (IGRT) compliance is defined as the following differences in IGRT images between simulation/planning and treatment, as well as at the end of treatment: Per protocol: <2 mm Minor variation: 2mm - 3mm Major deviation: > 3mm
Time Frame	The day of protocol treatment

Outcome Measure Data

Analysis Population Description

Patients enrolled in the phase II component who were eligible and had treatment review information.

Arm/Group Title	Radiosurgery/SBRT (Phase II)
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase II component uses 16 Gy.
Measure Participants	39
Target volume	39 88.6%
IGRT	37 84.1%

2. Primary Outcome

Title	Percentage of Patients With Complete or Partial Pain Response at 3 Months (Phase III)
Description	Pain is measured by the Numerical Rating Pain Scale (NRPS) a numerical 11-point scale (0-10) with 0 = no pain, 1-4 = mild, 5-6 = moderate, and 7-10 = severe with 10 the worst pain imaginable. Pain response is calculated as 3 month score - baseline score with a positive value indicating increased pain and a negative value indicating decreased pain. Patients with complete or partial pain response as defined below are considered responders. The index site is the lesion with the highest baseline (day of radiosurgery) pain score. If multiple sites have the same baseline pain score, the index site is the most cephalad lesion. Complete response: post-treatment pain score of 0 at the index site, no increase in narcotic pain medication, and no increase in pain score at the secondary treated site(s). Partial response: post-treatment improvement of at least 3 points at the index site, no increase in narcotic pain medication, and no increase in pain score at the secondary treated site(s).
Time Frame	Baseline and 3 months

Outcome Measure Data

Analysis Population Description

Eligible participants randomized in the phase III component with both baseline and 3 month NRPS scores

Arm/Group Title	Radiosurgery/SBRT (Phase III)	External Beam Radiation Therapy
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase III component allows 16 or 18 Gy as preferred by the treating physician.	Single fraction dose of 8 Gy external beam radiation therapy
Measure Participants	139	76
Number (95% Confidence Interval) [percentage of participants]	40.3 91.6%	57.9 27.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	Based on the one-sided exact binomial test with α=0.025 and a 2:1 randomization, 228 patients would be required to detect a 40% improvement in the response rate from 51% (external beam radiation therapy) to 70% (Radiosurgery/SBRT) with a statistical power of 0.80.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.99
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Percentage of Participants With Pain Response Through Two Years (Phase III)
Description	Pain is measured by the NRPS, a numerical 11-point scale from 0=no pain to 10=worst pain imaginable. Magnitude of pain response = post-baseline score - baseline score with a positive value indicating increased pain and a negative value indicating decreased pain. Pain response begins when a patient improves at least 3 points at the index site. (Although pain medication and pain response were part of the protocol definition of pain response, they were unable to be assessed accurately during weeks 1-3 and therefore were not included in the final definition used here.) Pain response time is defined as time from randomization to the date of pain response, last known follow-up (censored), or death (censored). Rates of participants with pain response are estimated using the Kaplan-Meier method. The distributions of pain response times are compared between the arms. Two-year rates are provided.
Time Frame	Baseline to two years. NRPS measured at baseline, 1, 2, and 3 weeks, 3, 6, 12, and 24 months.

Outcome Measure Data

Analysis Population Description

Eligible participants randomized in the phase III component with pain response data

Arm/Group Title	Radiosurgery/SBRT (Phase III)	External Beam Radiation Therapy
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase III component allows 16 or 18 Gy as preferred by the treating physician.	Single fraction dose of 8 Gy external beam radiation therapy
Measure Participants	209	130
Number (95% Confidence Interval) [percentage of participants]	19.2 43.6%	19.2 9.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.38
	Comments
	Method	Stratified log rank
	Comments	One-sided significance level = 0.025.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference level = Radiosurgery/SBRT

4. Secondary Outcome

Title	Percentage of Participants With Pain Relapse Through Two Years (Phase III)
Description	Pain is measured by the NRPS, a numerical 11-point scale from 0=no pain to 10=worst pain imaginable. Amount of pain response = post-baseline score - baseline score with a positive value indicating increased pain and a negative value indicating decreased pain. Pain response begins when a patient improves at least 3 points at the index site. Pain response ends when when the pain score increases by 3 points (relapse). (Although pain medication and pain response were part of the protocol definition of pain response, they were unable to be assessed accurately during weeks 1-3 and therefore were not included in the final definition used here.) Pain relapse time is defined as time from randomization to the date of first failure, last known follow-up (censored), or death (censored). Rates of participants with pain relapse are estimated using the Kaplan-Meier method. The distributions of pain relapse times are compared between the arms. Two-year rates are provided.
Time Frame	Randomization to two years. NRPS measured at baseline, 1, 2, and 3 weeks, 3, 6, 12, and 24 months.

Outcome Measure Data

Analysis Population Description

Eligible participants randomized in the phase III component who experienced partial or complete pain response

Arm/Group Title	Radiosurgery/SBRT (Phase III)	External Beam Radiation Therapy
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase III component allows 16 or 18 Gy as preferred by the treating physician.	Single fraction dose of 8 Gy external beam radiation therapy
Measure Participants	140	80
Number (95% Confidence Interval) [percentage of participants]	91.7 208.4%	96.9 46.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.29
	Comments
	Method	Stratified log rank
	Comments	One-sided significance level = 0.025
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.73
	Confidence Interval	(2-Sided) 95%; 0.24 to 12.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Significance level = Radiosurgery/SBRT

5. Secondary Outcome

Title	Percentage of Patients With Adverse Events at 3 Months (Phase III)
Description	Common Terminology Criteria for Adverse Events (version 3.0) grades adverse event (AE) severity from 1=mild to 5=death. Summary data is provided in this outcome measure.; See Adverse Events Module for specific adverse event data.
Time Frame	Baseline to 3 months

Outcome Measure Data

Analysis Population Description

Eligible participants randomized in the phase III component with adverse event information

Arm/Group Title	Radiosurgery/SBRT (Phase III)	External Beam Radiation Therapy
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase III component allows 16 or 18 Gy as preferred by the treating physician.	Single fraction dose of 8 Gy external beam radiation therapy
Measure Participants	202	117
Treatment-related AE	7.4 16.8%	7.7 3.7%
Any AE	43.6 99.1%	36.7 17.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	Percentage of patients with treatment-related adverse events.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments	Two-sided significance level = 0.05
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	Percentage of patients with any adverse events.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments	Two-sided significance level = 0.05
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Percentage of Participants With a Vertebral Compression Fracture Through Two Years (Phase III)
Description	Failure is defined as a vertebral compression fracture. Failure time is defined as time from randomization to the date of first failure, last known follow-up (censored), or death without compression fracture (competing risk). Failure rates are estimated using the cumulative incidence method. The distributions of failure times are compared between the arms. Two-year rates are provided.
Time Frame	From randomization to two years.

Outcome Measure Data

Analysis Population Description

Eligible participants randomized in the phase III component

Arm/Group Title	Radiosurgery/SBRT (Phase III)	External Beam Radiation Therapy
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase III component allows 16 or 18 Gy as preferred by the treating physician.	Single fraction dose of 8 Gy external beam radiation therapy
Measure Participants	209	130
Number (95% Confidence Interval) [percentage of participants]	19.5 44.3%	21.6 10.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.59
	Comments	Two-sided significance level = 0.05
	Method	Gray's test
	Comments

7. Secondary Outcome

Title	Percentage of Participants With Spinal Cord Damage Through Two Years
Description	Failure is defined as spinal cord damage. Failure time is defined as time from randomization to the date of first failure, last known follow-up (censored), or death without compression fracture (competing risk). Failure rates are estimated using the cumulative incidence method. The distributions of failure times are compared between the arms. Two-year rates are provided.
Time Frame	From randomization to two years

Outcome Measure Data

Analysis Population Description

Eligible participants randomized in the phase III component

Arm/Group Title	Radiosurgery/SBRT (Phase III)	External Beam Radiation Therapy
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase III component allows 16 or 18 Gy as preferred by the treating physician.	Single fraction dose of 8 Gy external beam radiation therapy
Measure Participants	209	130
Number (95% Confidence Interval) [percentage of participants]	3.6 8.2%	1.7 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.38
	Comments	Two-sided significance level = 0.05
	Method	Gray's test
	Comments

8. Secondary Outcome

Title	Change in Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at 3 Months (Phase III)
Description	The FACT-G is a validated 27-item measure in which a higher score represents higher quality of life (QOL). Physical, functional, social and emotional well-being subscale scores are added together to form the FACT-G total score. Responses range from 0=Not a lot to 4=Very much. Certain items must be reversed before being added, by subtracting the response from 4. Subscale items are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Total score ranges from 0-108; physical, social and functional subscales from 0-28; emotional subscale from 0-24. Each subscale requires at least 50% of the items to be completed while the overall response rate must be greater than 80%. If items are missing the subscale scores can be prorated. Change at 3 months is calculated as 3 month score - baseline score with a positive change indicating improvement in QOL.
Time Frame	Baseline and 3 months

Outcome Measure Data

Analysis Population Description

Eligible patients randomized in the phase III component who consented to QOL having both baseline and 3 month FACT-G total score.

Arm/Group Title	Radiosurgery/SBRT (Phase III)	External Beam Radiation Therapy
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase III component allows 16 or 18 Gy as preferred by the treating physician.	Single fraction dose of 8 Gy external beam radiation therapy
Measure Participants	87	58
Mean (Standard Deviation) [score on a scale]	2.4 (16.0)	5.2 (14.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	Assuming that the data are normally distributed, the two sample t-test assuming equal variances will be used to test the hypothesis at the one-sided 0.025 significance level. A mean difference of 7 points represents a clinically meaningful change (CMC). A difference of less than 7 points between the treatment arms will not be considered meaningful, even if it has statistical significance.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	t-test, 2 sided
	Comments

9. Secondary Outcome

Title	Change in Brief Pain Inventory (BPI) Worst Pain Score Through Two Years (Phase III)
Description	The Brief Pain Inventory Worst Pain score measures self-reported worst pain in the last week. Possible scores range from 0 (no pain) to 10 (worst pain imaginable), with higher scores indicating a worse outcome. Change is calculated as baseline score subtracted from post-baseline score with a positive change indicating more pain.
Time Frame	Baseline, 3, 6, 12, and 24 months

Outcome Measure Data

Analysis Population Description

Questionnaires were not completed by all eligible participants randomized in the phase III component who consented to QOL. Therefore, the number of participants reported below are the number with the relevant questions answered at baseline and the given time point on each arm.

Arm/Group Title	Radiosurgery/SBRT (Phase III)	External Beam Radiation Therapy
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase III component allows 16 or 18 Gy as preferred by the treating physician.	Single fraction dose of 8 Gy external beam radiation therapy
Measure Participants	152	100
3 months	-1.9 (2.9)	-2.0 (3.3)
6 months	-2.3 (2.9)	-2.8 (2.9)
12 months	-2.2 (3.7)	-2.3 (2.9)
24 months	-1.4 (3.3)	-2.1 (3.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with BPI Worst Pain Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Treatment Arm (External Beam Radiation Therapy vs. Radiosurgery/SBRT) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4313
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with BPI Worst Pain Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Age (< 63 years vs. ≥ 63 years) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8707
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with BPI Worst Pain Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Gender (female vs. male) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1549
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with BPI Worst Pain Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Race (Other vs. while) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0193
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with BPI Worst Pain Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Zubrod performance status (0 vs. 1,2) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0016
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with BPI Worst Pain Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Taking pain medication (No vs. Yes) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with BPI Worst Pain Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Tumor type (radioresistant vs. other) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6371
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

10. Secondary Outcome

Title	Change in EuroQol 5 Dimension (EQ-5D) Index Score Through Two Years (Phase III)
Description	The EQ-5D index score measures health status. Possible scores range from 0 (worst health state) to 1 (best health state), with higher scores indicating better health. Change is calculated as baseline score subtracted from post-baseline score with a positive change indicating improved health status.
Time Frame	Baseline, 3, 6, 12, and 24 months

Outcome Measure Data

Analysis Population Description

Questionnaires were not completed by all eligible participants randomized in the phase III component who consented to QOL.. Therefore, the number of participants reported below are the number with the relevant questions answered at baseline and the given time point on each arm.

Arm/Group Title	Radiosurgery/SBRT (Phase III)	External Beam Radiation Therapy
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase III component allows 16 or 18 Gy as preferred by the treating physician.	Single fraction dose of 8 Gy external beam radiation therapy
Measure Participants	152	100
3 months	0.09 (0.19)	0.09 (0.23)
6 months	0.08 (0.23)	0.12 (0.25)
12 months	0.09 (0.21)	0.03 (0.25)
24 months	-0.02 (0.26)	-0.02 (0.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with EQ-5D Index Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Treatment Arm (External Beam Radiation Therapy vs. Radiosurgery/SBRT) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0218
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with EQ-5D Index Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Age (< 63 years vs. ≥ 63 years) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9437
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with EQ-5D Index Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Gender (female vs. male) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0696
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with EQ-5D Index Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Race (Other vs. while) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1140
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with EQ-5D Index Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Zubrod performance status (0 vs. 1,2) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with EQ-5D Index Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Taking pain medication (No vs. Yes) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with EQ-5D Index Score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Tumor type (radioresistant vs. other) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7732
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

11. Secondary Outcome

Title	Change in Functional Assessment of Cancer Therapy - General (FACT-G) Total Score Through Two Years (Phase III)
Description	The FACT-G total score gives a combined score of the four domains of health-related quality of life (HRQOL) in cancer patients: Physical, social, emotional, and functional well-being. Possible total scores range from 0 to 108 with higher scores indicating a better HRQOL. Change is calculated as baseline score subtracted from post-baseline score with a positive change indicating improvement in HRQOL.
Time Frame	Baseline, 3, 6, 12, and 24 months

Outcome Measure Data

Analysis Population Description

Questionnaires were not completed by all eligible participants randomized in the phase III component who consented to QOL.. Therefore, the number of participants reported below are the number with the relevant questions answered at baseline and the given time point on each arm.

Arm/Group Title	Radiosurgery/SBRT (Phase III)	External Beam Radiation Therapy
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase III component allows 16 or 18 Gy as preferred by the treating physician.	Single fraction dose of 8 Gy external beam radiation therapy
Measure Participants	152	100
3 months	2.4 (16.0)	5.2 (14.1)
6 months	5.7 (16.6)	5.0 (15.8)
12 months	0.9 (16.6)	2.9 (20.0)
24 months	-3.8 (16.7)	-2.1 (14.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with FACT-G total score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Treatment Arm (External Beam Radiation Therapy vs. Radiosurgery/SBRT) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5198
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with FACT-G total score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Age (< 63 years vs. ≥ 63 years) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1197
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with FACT-G total score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Gender (female vs. male) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0306
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with FACT-G total score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Race (Other vs. while) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7903
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with FACT-G total score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Zubrod performance status (0 vs. 1,2) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with FACT-G total score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Taking pain medication (No vs. Yes) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0026
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Radiosurgery/SBRT (Phase II), External Beam Radiation Therapy
	Comments	A general linear mixed-effect model was run with FACT-G total score (baseline, 3, 6, 12, and 24 months) as the outcome of interest. Age, gender, race, Zubrod performance status, pain medication, tumor type, time, and treatment arm were the covariates considered in each model. Tumor type (radioresistant vs. other) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3282
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately. (Time and intercept estimates are not shown.)

Adverse Events

Time Frame	Collected at 1, 3, 6, 12, and 24 months from randomization.
Adverse Event Reporting Description	All-cause mortality reported for all enrolled patients. Adverse events reported for eligible patients who started protocol treatment and have adverse event data. This data was updated when 24 month secondary outcome measures were entered.
Arm/Group Title	Radiosurgery/SBRT (Phase II)		Radiosurgery/SBRT (Phase III)		External Beam Radiation Therapy
Arm/Group Description	Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase II component uses 16 Gy.		Single fraction dose image-guided radiosurgery / stereotactic body radiotherapy (SBRT). The phase III component allows 16 or 18 Gy as preferred by the treating physician.		Single fraction dose of 8 Gy external beam radiation therapy
All Cause Mortality
	Radiosurgery/SBRT (Phase II)		Radiosurgery/SBRT (Phase III)		External Beam Radiation Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/46 (2.2%)		144/217 (66.4%)		80/136 (58.8%)
Serious Adverse Events
	Radiosurgery/SBRT (Phase II)		Radiosurgery/SBRT (Phase III)		External Beam Radiation Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/34 (14.7%)		19/196 (9.7%)		10/117 (8.5%)
Blood and lymphatic system disorders
Blood disorder	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Hemoglobin decreased	1/34 (2.9%)		0/196 (0%)		2/117 (1.7%)
Cardiac disorders
Pericardial effusion	0/34 (0%)		0/196 (0%)		1/117 (0.9%)
Gastrointestinal disorders
Abdominal pain	0/34 (0%)		0/196 (0%)		1/117 (0.9%)
Duodenal obstruction	0/34 (0%)		0/196 (0%)		1/117 (0.9%)
Duodenal ulcer	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Lower gastrointestinal hemorrhage	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Mucositis oral	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Oral pain	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
General disorders
Chills	1/34 (2.9%)		1/196 (0.5%)		0/117 (0%)
Disease progression	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Fatigue	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Fever	2/34 (5.9%)		0/196 (0%)		0/117 (0%)
General symptom	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Infections and infestations
Catheter related infection [with unknown ANC]	0/34 (0%)		0/196 (0%)		1/117 (0.9%)
Pneumonia [with unknown ANC]	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Soft tissue infection [with unknown ANC]	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Stoma site infection [with normal or Grade 1-2 ANC]	0/34 (0%)		0/196 (0%)		1/117 (0.9%)
Injury, poisoning and procedural complications
Fracture	0/34 (0%)		0/196 (0%)		1/117 (0.9%)
Investigations
Alanine aminotransferase increased	1/34 (2.9%)		0/196 (0%)		0/117 (0%)
Aspartate aminotransferase increased	1/34 (2.9%)		0/196 (0%)		0/117 (0%)
Hyperbilirubinemia	1/34 (2.9%)		0/196 (0%)		0/117 (0%)
INR increased	1/34 (2.9%)		0/196 (0%)		0/117 (0%)
Lymphopenia	1/34 (2.9%)		0/196 (0%)		0/117 (0%)
Neutrophil count decreased	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Platelet count decreased	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Metabolism and nutrition disorders
Dehydration	0/34 (0%)		0/196 (0%)		1/117 (0.9%)
Hypercalcemia	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Hyperglycemia	1/34 (2.9%)		0/196 (0%)		0/117 (0%)
Hypoalbuminemia	1/34 (2.9%)		0/196 (0%)		0/117 (0%)
Hypocalcemia	1/34 (2.9%)		0/196 (0%)		1/117 (0.9%)
Hyponatremia	1/34 (2.9%)		2/196 (1%)		0/117 (0%)
Musculoskeletal and connective tissue disorders
Back pain	2/34 (5.9%)		5/196 (2.6%)		2/117 (1.7%)
Bone pain	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Muscle weakness	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Muscle weakness upper limb	0/34 (0%)		0/196 (0%)		1/117 (0.9%)
Neck pain	1/34 (2.9%)		0/196 (0%)		0/117 (0%)
Pain in extremity	0/34 (0%)		0/196 (0%)		1/117 (0.9%)
Nervous system disorders
Cognitive disturbance	1/34 (2.9%)		0/196 (0%)		0/117 (0%)
Ischemia cerebrovascular	0/34 (0%)		0/196 (0%)		1/117 (0.9%)
Psychiatric disorders
Confusion	0/34 (0%)		0/196 (0%)		1/117 (0.9%)
Renal and urinary disorders
Urinary incontinence	1/34 (2.9%)		0/196 (0%)		0/117 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Dyspnea	0/34 (0%)		1/196 (0.5%)		1/117 (0.9%)
Pleural effusion	0/34 (0%)		1/196 (0.5%)		3/117 (2.6%)
Respiratory disorder	0/34 (0%)		1/196 (0.5%)		1/117 (0.9%)
Vascular disorders
Hypotension	0/34 (0%)		1/196 (0.5%)		0/117 (0%)
Other (Not Including Serious) Adverse Events
	Radiosurgery/SBRT (Phase II)		Radiosurgery/SBRT (Phase III)		External Beam Radiation Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/34 (88.2%)		141/196 (71.9%)		76/117 (65%)
Blood and lymphatic system disorders
Hemoglobin decreased	3/34 (8.8%)		39/196 (19.9%)		16/117 (13.7%)
Gastrointestinal disorders
Abdominal pain	0/34 (0%)		27/196 (13.8%)		6/117 (5.1%)
Constipation	4/34 (11.8%)		32/196 (16.3%)		13/117 (11.1%)
Diarrhea	0/34 (0%)		22/196 (11.2%)		14/117 (12%)
Dysphagia	4/34 (11.8%)		8/196 (4.1%)		1/117 (0.9%)
Nausea	5/34 (14.7%)		42/196 (21.4%)		22/117 (18.8%)
Vomiting	1/34 (2.9%)		22/196 (11.2%)		8/117 (6.8%)
General disorders
Chest pain	0/34 (0%)		12/196 (6.1%)		3/117 (2.6%)
Edema limbs	2/34 (5.9%)		22/196 (11.2%)		7/117 (6%)
Fatigue	3/34 (8.8%)		63/196 (32.1%)		31/117 (26.5%)
Fever	0/34 (0%)		14/196 (7.1%)		6/117 (5.1%)
General symptom	2/34 (5.9%)		6/196 (3.1%)		4/117 (3.4%)
Pain [NOS]	2/34 (5.9%)		11/196 (5.6%)		6/117 (5.1%)
Pain [other]	2/34 (5.9%)		15/196 (7.7%)		12/117 (10.3%)
Injury, poisoning and procedural complications
Fracture	0/34 (0%)		10/196 (5.1%)		4/117 (3.4%)
Investigations
Alanine aminotransferase increased	1/34 (2.9%)		17/196 (8.7%)		9/117 (7.7%)
Alkaline phosphatase increased	3/34 (8.8%)		24/196 (12.2%)		9/117 (7.7%)
Aspartate aminotransferase increased	2/34 (5.9%)		19/196 (9.7%)		10/117 (8.5%)
Creatinine increased	0/34 (0%)		10/196 (5.1%)		5/117 (4.3%)
Hyperbilirubinemia	0/34 (0%)		10/196 (5.1%)		5/117 (4.3%)
Leukopenia	2/34 (5.9%)		23/196 (11.7%)		8/117 (6.8%)
Lymphopenia	1/34 (2.9%)		20/196 (10.2%)		9/117 (7.7%)
Platelet count decreased	2/34 (5.9%)		24/196 (12.2%)		9/117 (7.7%)
Weight loss	1/34 (2.9%)		13/196 (6.6%)		10/117 (8.5%)
Metabolism and nutrition disorders
Anorexia	1/34 (2.9%)		28/196 (14.3%)		10/117 (8.5%)
Dehydration	0/34 (0%)		11/196 (5.6%)		2/117 (1.7%)
Hyperglycemia	2/34 (5.9%)		32/196 (16.3%)		12/117 (10.3%)
Hypoalbuminemia	1/34 (2.9%)		30/196 (15.3%)		8/117 (6.8%)
Hypocalcemia	2/34 (5.9%)		29/196 (14.8%)		10/117 (8.5%)
Hypokalemia	2/34 (5.9%)		17/196 (8.7%)		9/117 (7.7%)
Hyponatremia	2/34 (5.9%)		17/196 (8.7%)		8/117 (6.8%)
Musculoskeletal and connective tissue disorders
Back pain	14/34 (41.2%)		60/196 (30.6%)		30/117 (25.6%)
Bone pain	5/34 (14.7%)		7/196 (3.6%)		7/117 (6%)
Joint pain	2/34 (5.9%)		16/196 (8.2%)		3/117 (2.6%)
Muscle weakness	1/34 (2.9%)		23/196 (11.7%)		7/117 (6%)
Muscle weakness lower limb	1/34 (2.9%)		12/196 (6.1%)		3/117 (2.6%)
Musculoskeletal disorder	2/34 (5.9%)		11/196 (5.6%)		4/117 (3.4%)
Neck pain	3/34 (8.8%)		13/196 (6.6%)		2/117 (1.7%)
Pain in extremity	3/34 (8.8%)		24/196 (12.2%)		12/117 (10.3%)
Nervous system disorders
Dizziness	0/34 (0%)		13/196 (6.6%)		4/117 (3.4%)
Headache	3/34 (8.8%)		12/196 (6.1%)		5/117 (4.3%)
Peripheral motor neuropathy	2/34 (5.9%)		4/196 (2%)		3/117 (2.6%)
Peripheral sensory neuropathy	6/34 (17.6%)		17/196 (8.7%)		8/117 (6.8%)
Psychiatric disorders
Anxiety	1/34 (2.9%)		11/196 (5.6%)		3/117 (2.6%)
Confusion	0/34 (0%)		10/196 (5.1%)		8/117 (6.8%)
Renal and urinary disorders
Urinary retention	2/34 (5.9%)		0/196 (0%)		4/117 (3.4%)
Urogenital disorder	1/34 (2.9%)		11/196 (5.6%)		2/117 (1.7%)
Respiratory, thoracic and mediastinal disorders
Cough	2/34 (5.9%)		17/196 (8.7%)		12/117 (10.3%)
Dyspnea	1/34 (2.9%)		32/196 (16.3%)		12/117 (10.3%)
Hypoxia	0/34 (0%)		10/196 (5.1%)		4/117 (3.4%)
Pleural effusion	2/34 (5.9%)		10/196 (5.1%)		6/117 (5.1%)
Skin and subcutaneous tissue disorders
Hand-and-foot syndrome	2/34 (5.9%)		0/196 (0%)		0/117 (0%)
Pruritus	3/34 (8.8%)		1/196 (0.5%)		1/117 (0.9%)
Rash desquamating	2/34 (5.9%)		6/196 (3.1%)		3/117 (2.6%)
Vascular disorders
Hypotension	2/34 (5.9%)		13/196 (6.6%)		1/117 (0.9%)
Thrombosis	1/34 (2.9%)		13/196 (6.6%)		4/117 (3.4%)

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor