Randomized Trial Comparing Conventional Radiotherapy With Stereotactic Radiotherapy in Patients With Bone Metastases - VERTICAL Study

Study Overview
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Brief Summary
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The purpose of the study is to investigate effectiveness of stereotactic body radiotherapy in patients with bone metastatic disease.

Detailed Description
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Rationale: Bone metastases are a frequent distant manifestation of solid tumours, and many bone metastases are located in the spine. These patients mostly present with severe (back) pain which reduces quality of life. The primary treatment for pain management is a single-fraction low dose external beam radiation therapy (EBRT), effective in achieving pain reduction in around 60% of patients, of whom 0-23% experience complete pain response. Recently, there is growing evidence that Stereotactic Body Radiotherapy (SBRT) achieves a much higher pain response due to the higher dose administered. In retrospective and a few prospective case series, SBRT for spinal, and also non-spinal metastases has been demonstrated to be safe, and efficacious. However, no randomized controlled trials have been performed. Objective: To study whether the pain response after three months in patients with osseous metastatic disease increases after SBRT in comparison to low dose EBRT. Study design: Randomized controlled trial, the VERTICAL study, nested within the PRESENT cohort. Study population: Eligible patients are MRI-compatible patients with radiographic evidence of bone metastases at the radiotherapy department. Fifty-five patients are recruited in both control and intervention arm. Intervention: Patients will undergo MRI-based, cone beam CT-guided SBRT and will receive a single dose of 18 Gray (Gy) on the visible metastasis, and 8 Gy on the bony compartment containing the metastasis (e.g. the affected vertebra or pedicle). Main study parameters/endpoints: The primary endpoint is pain control at three months after radiotherapy. Secondary outcomes are, among others, the occurrence of vertebral compression fracture (VCF) and radiation-induced myelopathy, local tumour control and evaluation of quality of life.

Official Title
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Randomized Controlled Trial Comparing Conventional Radiotherapy With Stereotactic Body Radiotherapy in Patients With Bone Metastases - VERTICAL Study

Conditions
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Spinal Metastases, Bone Metastases

Intervention / Treatment
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* Radiation: Stereotactic Body Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Radiographic evidence of bone metastases For spinal lesions; per lesion no more than 3 consecutive spine segments involved with one unaffected vertebral body above and below No more than 2 painful lesions needing treatment Histologic proof of malignancy No compression of spinal cord No or mild neurological signs (i.e. radiculopathy, dermatomal sensory change, and muscle strength of involved extremity is Medical Research Council (MRC) 4/5 Medically inoperable or patient refused surgery Karnofsky performance score (KPS) > 50 Numeric rating scale (NRS) > 3 Age > 18 years Written informed consent Filling out PRESENT-questionnaires Exclusion Criteria: Lesion in C1 or C2 Radio-sensitive histology such as multiple myeloma, lymphoma, small cell, germ cell Spinal MRI cannot be completed for any reason (in according with the MRI protocol of the Department of Radiology) Impossible to delineate metastasis and organs at risk (OAR) due to artifacts on CT or MRI from previous surgical stabilization Unable to undergo SBRT treatment, according to treating doctor's opinion Epidural disease Severe, worsening or progressive neurological deficit Unstable lesion requiring surgical stabilization Patient with < 3 months life expectancy Previous EBRT or SBRT to same level Chemotherapy or systemic radionuclide delivery within 24 hours before and after SBRT

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stereotactic Body Radiotherapy<br>MRI-based, cone beam CT-guided SBRT delivery of a single dose of 18 Gray (Gy) on the visible metastasis, and 8 Gy on the bony compartment containing the metastasis (e.g. the affected vertebra or pedicle). | Radiation: Stereotactic Body Radiotherapy<br> <br> * Other names: Stereotactic Radiosurgery;|
| No Intervention: Conventional Radiotherapy<br>Delivery of a single fraction of 8 Gy using virtual simulation | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete or partial pain response after radiation, defined according to the International Bone Metastases Consensus Endpoints for Clinical Trials. | The primary endpoint of this study is complete or partial pain response after SBRT or EBRT after three months. Complete and partial response, but also possible pain progression or indeterminate response, will be defined according to the International Bone Metastases Consensus Endpoints for Clinical Trials. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health-Related Quality of Life | Self reported quality of life as measured by the Brief Pain Inventory, European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) C15-PAL, and EORTC QLQ BM22 | at 2, 4, 6, 8 weeks, 3 and 6 months, then every 6 months | 
| Progression free survival | Progression free survival is defined as time between treatment and first sign of progression of disease | up to 3 years | 
| Overall survival | Overall survival is defined as time between treatment and death from any cause | up to 3 years | 
| Occurrence or progression of vertebral compression fracture (VCF) | VCF is defined as new endplate fracture or collapse deformity as compared with before SBRT or EBRT | up to 12 months | 
| Occurrence of radiation-induced myelopathy | Radiation-induced myelopathy is defined as a diagnosis of exclusion and defined as neurological signs and symptoms consistent with radiation damage in the form of necrosis to the segment of the spinal cord irradiated, without MRI evidence of recurrent or progressive tumour affecting the spinal cord. | up to 12 months | 
| Duration of pain relief | Duration of pain relief as measured by the Brief Pain Inventory | at 2, 4, 6, 8 weeks, 3 and 6 months | 
| Determination of rapidity of pain relief | Rapidity of pain relief as measured by the Brief Pain Inventory | at 2, 4, 6, 8 weeks, 3 and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spinal metastases, Spinal metastatic disease, Stereotactic Body Radiotherapy, Response, Bone metastases