Stereotactic Body Radiotherapy Followed by Surgical Stabilization in Spinal Metastases

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to assess pain response after combining stereotactic body radiotherapy (SBRT) and pedicle screw fixation in a 48-hour window for the treatment of painful unstable metastases of the thoracic and/or lumbar spine.

Detailed Description
-----------------
Rationale Sixty-five percent of cancer patients with terminal illness have bone metastases, with debilitating pain often as the severe consequence. The spine is the most common location for bone metastases. Standard treatment of unstable vertebral metastases consists of stabilizing surgery, followed by external beam radiotherapy after two weeks. Although this approach is effective in 60-70% of patients, it is has several downsides. Firstly, because of the two weeks interval between surgery and external beam radiotherapy, necessary for sufficient wound healing, it takes time before radiotherapy-induced pain relief is achieved. Moreover, the surgical implants used cause scatter artifacts on planning computed tomography images which prohibits high-resolution imaging and accurate targeting of the lesion. Multiple hospital visits (ranging from 1 to 10) are needed for administration of external beam irradiation, and in about 30-40% of patients no adequate pain response is achieved. An alternative treatment strategy, which would lead to faster pain relief in a higher proportion of patients with less hospital visits, would be highly desirable from the patient's perspective. Secondly, this strategy delays the start of systemic therapy. Objective The main outcome of this study is pain response 4 weeks after start of the treatment. Study design Prospective cohort study nested within the PRESENT cohort being a phase 2b study according to the IDEAL recommendations Study population All patients, male and female, with impending spinal instability requiring surgical intervention and radiotherapy at the University Medical Center Utrecht Intervention The combined treatment of stereotactic body radiotherapy and pedicle screw fixation in a 24 to 48-hour window for the treatment of painful unstable metastases of the cervical, thoracic and/or lumbar spine. Main study parameters/endpoints The main outcome of this study is pain response after 4 weeks Nature and extent of the burden and risks associated with participation, benefit and group relatedness In the preceding BLEND First-in-man study, the investigators have observed no Serious Adverse Events after a median follow-up of 13 months demonstrating the safety and feasibility of this approach.

Official Title
-----------------
Stereotactic Body Radiotherapy Followed by Surgical Stabilization for Patients With Unstable Spinal Metastases: Cohort Study According to the IDEAL Recommendations

Conditions
-----------------
Spinal Neoplasms, Neoplasm Metastasis, Radiosurgery, Surgery

Intervention / Treatment
-----------------
* Other: SBRT followed by surgical stabilization within 24-48 hours


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participation in PRESENT cohort Painful radiosensitive metastases from solid tumors in the cervical, thoracic or lumbar spine needing surgical stabilization Histologic proof of malignancy or radiographic/clinical characteristics indicating malignancy beyond reasonable doubt Radiographic evidence of spinal metastases Fit for (radio)surgery Age > 18 years at the time of given informed consent in the PRESENT cohort. Written informed consent Exclusion Criteria: SBRT cannot be delivered, e.g. in patients who cannot lie on the treatment table because of pain Surgery cannot be performed, e.g. in patients with multiple spinal metastases that cannot be bridged Previous surgery or radiotherapy to index lesion Neurological deficits (ASIA C, B or A) Partial neurological deficits (ASIA D) with rapid progression (hours to days) Non-ambulatory patients Patient in hospice or with < 3 months life expectancy Medically inoperable or patient refused surgery Radiosensitizing systemic treatment that cannot reasonably be stopped (for example immunotherapy and EGFR inhibitors)

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

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SBRT followed by surgical stabilization within 48 hours<br>SBRT and surgical stabilization will be performed within a 24 to 48-hour time window instead of today's standard of care of two weeks between surgical stabilization and conventional radiotherapy. | Other: SBRT followed by surgical stabilization within 24-48 hours<br>* In a first step, patients will undergo SBRT with active sparing of the surgical site. Patients will receive high dose, single to few fractions radiotherapy consisting of a boost to the metastases exclusively. The bony compartment containing the metastatic lesion will receive an elective dose in order to treat subclinical disease. Treatment planning is performed on the pre-treatment CT and MRI data in radiotherapy position that are mutually registered to yield information on all relevant structures for planning. Dose constraints are set for the organ at risks based on institution specific guidelines. All patients will be treated with on online position verification protocol based on institution specific guidelines. Hereafter, surgical intervention will be performed to the standard of care.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain response | Pain response is defined as a decrease in initial worst pain score by at least 2 points on a Numeric Rating Scale (NRS) of 10 at the treated site, without increase in analgesic use, or an analgesic decrease of at least 25% without an increase in pain score | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of pain relief | Duration of pain relief, as measured by the Brief Pain Inventory (BPI) | Through hospital stay, an average of 3 days | 
| Length of hospital stay | Length of hospital stay in days | Through hospital stay, an average of 3 days | 
| 30-day mortality | Mortality after 30 days | 30 days | 
| Neurological status | American Spinal Injury Association (ASIA) scale as measured by physical examination of neurologists or trained ASIA physician | Through hospital stay, an average of 3 days | 
| Neurological deterioration | Defined as a deterioration on the American Spinal Injury Association (ASIA) scale of more than one level | Through hospital stay, an average of 3 days | 
| Adverse events | Adverse events will be scored using a SAVES form | Through hospital stay, an average of 3 days |