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

Study Overview
=================
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.

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.

Official Title
-----------------
Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis

Conditions
-----------------
Metastatic Cancer, Pain

Intervention / Treatment
-----------------
* Radiation: External beam radiation therapy
* Radiation: Radiosurgery/SBRT


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 . Zubrod Performance Status 0-2; Age ≥ 18; History/physical examination within 2 weeks prior to registration; Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential; Women of childbearing potential and male participants who are sexually active must agree to use a medically effective means of birth control; 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. 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. 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). 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. Patients with a paraspinal mass ≤ 5 cm in the greatest dimension and that is contiguous with spine metastasis are eligible. Patients must provide study specific informed consent prior to study entry. Exclusion Criteria: Histologies of myeloma or lymphoma; Non-ambulatory patients; Spine instability due to a compression fracture; > 50% loss of vertebral body height; Frank spinal cord compression or displacement or epidural compression within 3 mm of the spinal cord; Patients with rapid neurologic decline; Bony retropulsion causing neurologic abnormality; Prior radiation to the index spine; Patients for whom an MRI of the spine is medically contraindicated; Patients allergic to contrast dye used in MRIs or CT scans or who cannot be premedicated for the use of contrast dye.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiosurgery/SBRT<br> | Radiation: Radiosurgery/SBRT<br>* 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.<br>* Other names: stereotactic radiosurgery;|
| Active Comparator: External Beam Radiation Therapy<br> | Radiation: External beam radiation therapy<br>* Single fraction dose of 8 Gy external beam radiation therapy<br>* Other names: EBRT;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Receiving Radiosurgery/SBRT Per Protocol or With Minor Variation (Phase II) | 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 | The day of protocol treatment | 
| Percentage of Patients With Complete or Partial Pain Response at 3 Months (Phase III) | 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). | Baseline and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Pain Response Through Two Years (Phase III) | 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. | Baseline to two years. NRPS measured at baseline, 1, 2, and 3 weeks, 3, 6, 12, and 24 months. | 
| Percentage of Participants With Pain Relapse Through Two Years (Phase III) | 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. | Randomization to two years. NRPS measured at baseline, 1, 2, and 3 weeks, 3, 6, 12, and 24 months. | 
| Percentage of Patients With Adverse Events at 3 Months (Phase III) | 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. | Baseline to 3 months | 
| Percentage of Participants With a Vertebral Compression Fracture Through Two Years (Phase III) | 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. | From randomization to two years. | 
| Percentage of Participants With Spinal Cord Damage Through 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. | From randomization to two years | 
| Change in Functional Assessment of Cancer Therapy - General (FACT-G) Total Score at 3 Months (Phase III) | 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. | Baseline and 3 months | 
| Change in Brief Pain Inventory (BPI) Worst Pain Score Through Two Years (Phase III) | 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. | Baseline, 3, 6, 12, and 24 months | 
| Change in EuroQol 5 Dimension (EQ-5D) Index Score Through Two Years (Phase III) | 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. | Baseline, 3, 6, 12, and 24 months | 
| Change in Functional Assessment of Cancer Therapy - General (FACT-G) Total Score Through Two Years (Phase III) | 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. | Baseline, 3, 6, 12, and 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
spinal bone metastases, pain