A Trial to Improve Quality of Life With Stereotactic Body Radiotherapy for Patients With Painful Bone Metastases

Study Overview
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Brief Summary
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This is a phase III randomized-controlled, single-blind study comparing the standard schedule for antalgic radiotherapy of a single fraction of 8.0 Gy delivered through three-dimensional conformal radiotherapy (3D-CRT) to a single fraction of 20.0 Gy delivered through stereotactic body radiotherapy (SBRT). The primary aim of this trial is to double the complete response rate. Secondary aims are to compare general response rates, duration of pain response, acute and late toxicity, HRQoL through patient-reported outcome measures (PROMs), pain flare, and re-irradiation need.

Official Title
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A Phase III Randomized-controlled, Single-blind Trial to Improve Quality of Life With Stereotactic Body Radiotherapy for Patients With Painful Bone Metastases

Conditions
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Metastasis to Bone, Radiotherapy, Neoplasm Metastasis

Intervention / Treatment
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* Radiation: Stereotactic body radiotherapy
* Radiation: 3D-conformal radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed malignancy. Pain score ≥ 2 on a scale from 0 to 10. Radiological or (bone) scintigraphic evidence of bone metastasis at the site of pain. Lesions ≤ 5cm in largest diameter. Per lesion no more than 3 consecutive spine segments involved with one unaffected vertebral body above and below. No more than 3 painful lesions needing treatment. Life expectancy estimated at > 3 months. Patients who have received the information sheet and signed the informed consent form. Patients must be willing to comply with scheduled visits, treatment plan, and other study procedures. Patients with a public and/or private health insurance coverage. Exclusion Criteria: Myeloma. Bone metastasis in previously irradiated sites. Previous radioisotope treatment for bone metastases. Complicated bone metastasis, i.e. impending and/or existing pathological fracture, spinal cord compression or cauda equina compression [16]. Patients with significantly altered mental status or with psychological, familial, sociological or geographical condition potential hampering compliance with the study. Individual deprived of liberty or placed under guardianship.

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
Interventional Model Description: All subjects will be randomly assigned in a 1:1 ratio to receive either a single fraction of 8.0 Gy to the painful bone metastasis through 3D-CRT (control arm) or a single fraction of 20.0 Gy to the painful bone metastasis through SBRT (experimental arm).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Single fraction of 8 Gy<br>The current standard treatment will be prescribed, i.e. a 3D-conformal radiotherapy of a single fraction dose of 8.0 Gy to the metastasis with a planning target volume (PTV) margin for set-up and positioning uncertainties of 1 cm. This can be performed at any linear accelerator. | Radiation: 3D-conformal radiotherapy<br>* In the standard setting, 95% of the PTV should receive 95% of the prescribed dose while near maximum dose (Dnear-max) in the PTV should not exceed 107%. Image-guidance will consist of portal images showing the relevant bony anatomy.<br>|
| Experimental: Single fraction of 20 Gy<br>Within the framework of stereotactic body radiotherapy, a single fraction dose of 20.0 Gy will be delivered to the metastasis using a PTV margin of 3-5 mm based on high-precision image-guided radiotherapy (IGRT). Therefore, only linear accelerators with the European Organization for Radiotherapy & Oncology advisory committee on radiation oncology practice (ESTRO-ACROP) specifications for SBRT can be accepted. A risk-adapted approach will be applied, aiming for the highest possible dose no less than 16 Gy, while respecting the tolerances of critical organs at risk (e.g. spinal cord, cauda equina, brainstem etc.). | Radiation: Stereotactic body radiotherapy<br>* Treatment will be prescribed to the periphery of the target, i.e. 80% of the dose should cover 95% of the PTV. The organ at risk (OAR) dose constraints will be in accordance with the recommendations from the report of the American Association of Physicists in Medicine (AAPM) task group 101. Image-guidance will consist of cone-beam CT in combination with 6 degrees of freedom corrections using robotic couch.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain response | Pain response at the treated index site at 1 month after radiotherapy (RT), as defined by the consensus statement. | 4 weeks after RT visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of pain flare | Number of participants with increase in pain score of 2 or more above baseline at the treated site with stable OMED, or an increase of 25% or more in OMED compared with baseline with the pain score stable or 1 point above baseline | 24-48 hours after radiotherapy | 
| Duration of pain response | Time until pain progression (defined as an increase in pain score of 2 or more above baseline at the treated site with stable daily oral morphine equivalent, or an increase of 25% or more in daily oral morphine equivalent (OMED) compared with baseline with the pain score stable or 1 point above baseline) | 2 years after radiotherapy | 
| Re-irradiation need | Need for re-irradiation of the treated lesion | 2 years after radiotherapy | 
| Acute toxicity Measured with CTCAE version 5.0 | Measured with CTCAE version 5.0 | 3 months after radiotherapy | 
| Late toxicity Measured with CTCAE version 5.0 | Measured with CTCAE version 5.0 | 2 years after radiotherapy | 
| Impact of treatment on Quality of Life: EORTC quality of life questionnaire (QLQ) BM22 | Using the EORTC quality of life questionnaire for Bone Metastases (QLQ BM22) to measure impact of bone metastases on QoL [min score 0 - max score 100]. A high score represents a high level of symptomatology. The score is calculated by applying a linear transformation on the scores to each answer of the 22 question-long questionnaire (cfr. EORTC mannual). | 2 years after radiotherapy | 
| Number of Subsequent Serious Skeletal events | Incidence of symptomatic pathologic fractures, radiation or surgery to bone, and spinal cord compression. | 2 years after radiotherapy | 

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