Spine SABR - Dose-escalated Stereotactic Ablative Body Radiotherapy (SABR) for Solid Tumour Spine Metastases

Study Overview
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Brief Summary
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This study will look at treatment for patients that have already been diagnosed with cancer, but develop a new tumor(s) in the spine. Patients who are not recommended for surgery are usually treated with 5-10 sessions of radiotherapy to manage symptoms. For patients with a longer life expectancy (>6 months), it is better to give a higher dose of treatment to potentially improve the duration of pain relief, cancer control and potentially survival. Higher doses of radiotherapy, however, may also cause worse toxicity and side effects. This study will look at delivering higher doses of radiation in 2 sessions rather than 5-10, using a more modern, targeted technique called image-guided Stereotactic Ablative Body Radiotherapy (SABR). This method requires special equipment and expertise compared to the traditional radiotherapy and this has limited availability in Ireland. This study aims to find out the highest dose that is safe to be given to patients and carefully examine the side effects. These results will help create national and international guidelines to benefit all cancer patients. Patients will be monitored closely during treatment and for 2 years afterwards. Patients have been involved in developing the treatment protocol and the patient information leaflet. Patients will also be asked to fill in quality of life (QOL) questionnaires at certain timepoints during the study. It is anticipated that this study will support the delivery of high quality SABR to all cancer patients in Ireland, resulting in potentially better quality of life, symptom and tumor control.

Official Title
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Spine SABR - Dose-escalated Stereotactic Ablative Body Radiotherapy (SABR) for Solid Tumour Spine Metastases

Conditions
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Solid Tumor Spine Metastases

Intervention / Treatment
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* Radiation: Radiation: image guided dose escalated SABR using a simultaneous integrated boost (SIB)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained prior to any study-related procedures ≥ 18 years of age Life expectancy > 6 months ECOG (Eastern Cooperative Oncology Group) performance status (PS) 0-2 Histological diagnosis of malignant primary disease (excluding haematologic, seminomatous or small cell subtype) Diagnosis of oligometastatic disease (OMD) or oligoprogressive disease (OPD) defined as: OMD where there are 1 to 5 metastatic lesions, with a controlled primary tumor being optional, but where all metastatic sites must be safely treatable (can be synchronous or metachronous to primary tumor diagnosis) with curative intent OR OPD with 1 to 5 lesions progressing on a background of widespread but stable metastatic disease OR Systemic therapy-induced OMD where there are 1 to 5 persistent lesions after systemic therapy, all safely treatable with SABR Single spinal level from C1 to L5 to be treated for the purpose of the study (co-existing lesion(s) on non-consecutive spinal level(s) may receive RT at Investigator discretion, if deemed unlikely to interfere with study treatment and assessment of outcomes). Stable spine assessed by Spinal Instability Neoplastic Score (SINS) (SINS 0-6, or SINS 7-12 and not for surgical intervention). Bilsky Grade 0-1a (i.e. minimal (epidural impingement, without deformation of thecal sac) or no epidural disease) as confirmed by Radiation Oncologist Able to lie flat in the treatment position for radiotherapy for up to 60 minutes Females of childbearing potential must not be pregnant or lactating, and must be prepared to take adequate contraception methods during treatment. Males whose female partners are of childbearing potential must be prepared to take adequate contraception methods during treatment. Examples of effective contraception methods are a condom or a diaphragm with spermicidal jelly, or oral, injectable or implanted birth control Exclusion Criteria: Previous radiotherapy or surgery to the proposed SABR treatment site which is likely to interfere with treatment or assessment of outcomes (for radiotherapy, this includes prior thoracic radiotherapy to the lung or oesophagus which would result in overlap of fields if a T spine lesion will be treated) Patients with symptomatic spinal cord compression or cauda equina syndrome, resulting in bony compression or epidural compression of the spinal cord or cauda equine, respectively Patients with syndromes or conditions associated with increased radiosensitivity Patients with radiosensitive histologies, e.g. myeloma or lymphoma Contraindication to MRI, e.g. MRI-incompatible personal pacemaker in situ Patients with pre-existing osteoporotic fractures of the spine Prior treatment with any radionuclide within 30 days prior to registration Patients who have received chemotherapy within 1 week prior to administration of protocol RT or who are expected/planned to receive chemotherapy during RT or within 1 week after completing protocol RT Uncontrolled intercurrent illness that is likely to interfere with treatment or assessment of outcomes, or psychiatric illness/social situations that would limit compliance with study requirements Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study, or if it is felt by the research / medical team that the patient may not be able to comply with the protocol and follow-up schedule due to psychological, familial, sociological or geographical conditions Significant or progressive neurological deficit such that emergency surgery or radiation required

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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Treatment will consist of image guided dose escalated SABR using a simultaneous integrated boost (SIB) delivered in two fractions adhering to organ at risk dose-volume histogram constraints. There will be three dose levels delivered to the Planning Target Volume_1 (PTV_1) in each treatment arm as follows: 28 Gy (14 Gy per fraction), 30 Gy (15 Gy per fraction) and 32 Gy (16 Gy per fraction). A lower dose of 20 Gy (10 Gy per fraction) will be delivered to the PTV_2 which will be defined according to international consensus guidelines (Cox et al., 2012). The dose to PTV_2 will remain the same through all dose levels. All doses are prescribed to the target volume.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low baseline VCF risk<br>All of: No VCF Predominantly sclerotic lesion (as determined by the Investigator based on MRI) Normal spinal alignment <50% vertebral body involvement | Radiation: Radiation: image guided dose escalated SABR using a simultaneous integrated boost (SIB)<br>* Treatment will consist of image guided dose escalated SABR using a simultaneous integrated boost (SIB) delivered in two fractions adhering to organ at risk dose-volume histogram constraints. There will be three dose levels delivered to the Planning Target Volume_1 (PTV_1) in each treatment arm as follows: 28 Gy (14 Gy per fraction), 30 Gy (15 Gy per fraction) and 32 Gy (16 Gy per fraction). A lower dose of 20 Gy (10 Gy per fraction) will be delivered to the PTV_2 which will be defined according to international consensus guidelines (Cox et al., 2012). The dose to PTV_2 will remain the same through all dose levels. All doses are prescribed to the target volume.<br>|
| Experimental: High baseline VCF risk<br>Any of: Pre-existing VCF Predominantly lytic lesion (as determined by the Investigator based on MRI) Spinal deformity ≥50% vertebral body involvement | Radiation: Radiation: image guided dose escalated SABR using a simultaneous integrated boost (SIB)<br>* Treatment will consist of image guided dose escalated SABR using a simultaneous integrated boost (SIB) delivered in two fractions adhering to organ at risk dose-volume histogram constraints. There will be three dose levels delivered to the Planning Target Volume_1 (PTV_1) in each treatment arm as follows: 28 Gy (14 Gy per fraction), 30 Gy (15 Gy per fraction) and 32 Gy (16 Gy per fraction). A lower dose of 20 Gy (10 Gy per fraction) will be delivered to the PTV_2 which will be defined according to international consensus guidelines (Cox et al., 2012). The dose to PTV_2 will remain the same through all dose levels. All doses are prescribed to the target volume.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The establishment of the MTD of 2-fraction spine SABR in patients with oligometastatic or oligoprogressive solid tumor metastases of the spine, by the number of patients experiencing DLTs within six months after treatment. | DLT rate will be calculated as the proportion of evaluable patients (along with the 95% CI) experiencing a DLT, among the total evaluable patients. All evaluable patients will be used in the DLT analysis which will be performed after they have been potentially followed for the 6-months observation period. Patients not evaluable will be reported separately. For each such patient, the reason for exclusion, protocol treatment received, and toxicities reported during the first year will be listed. | From start of treatment to 6 months post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate local progression-free survival at 1 and 2 years post-treatment, using Magnetic Resonance Imaging (MRI). | Post treatment response and outcomes using MRI at 3, 6, 9, 12, 15, 18, and 24 months post-RT will be evaluated. The same patients used for DLT analysis will be used in these analyses. Radiation site (treated per study protocol) PFS (i.e. local PFS) at 1 year will be considered the key efficacy endpoint. Local progression is progression within the radiation site treated per study protocol, as identified on serial imaging. When local progression is suspected, two or three MRI scans 6-8 weeks apart are recommended per Investigator discretion (in line with international consortium (SPINO guidelines) (Thibault et al., 2015)). Local control may be defined as the absence of progression within the radiation site treated per study protocol on serial imaging (MRI). Any new or progressive tumor within the epidural space Neurological deterioration attributable to pre-existing epidural disease with equivocal increased epidural disease dimensions on MRI | Up to 2 years post treatment | 
| Estimate 6-month, 1-year and 2-year post-treatment overall survival rates. | The Kaplan-Meier method will be used to estimate overall survival at each dose level. Cox proportional hazards regression will be used to characterise overall survival rate as a function of dose. Overall survival will be measured from the date of study registration until the date of death due to any cause or censoring. | Up to 2 years post treatment | 
| Estimate the pain flare incidence 1 week post-treatment (i.e. 1 week after 2nd SABR fraction) using the Numeric Pain Rating Scale (NPRS) 0-10. | Pain score (including acute pain flare) at the radiation site treated per study protocol (assessed by numerical pain rating score, 0-10) (time frame: 1 week post treatment). [with secondary endpoint 4:] The changes in raw scores and percent change will be assessed over time using the Wilcoxon Signed rank test. | 1 week post treatment | 
| Pain score at radiation site (treated per study protocol) at 4 weeks, 3 months, 6 months, 1 year and 2 years post-treatment, using the NPRS. | Pain score (including acute pain flare) at the radiation site treated per study protocol (assessed by numerical pain rating score, 0-10) (time frame: 1 week post treatment). The changes in raw scores and percent change will be assessed over time using the Wilcoxon Signed rank test. | Up to 2 years post-treatment | 
| Acute toxicity profiles of ≥Grade 2 toxicities at 1- and 4-weeks post treatment, and at 3 months post-treatment using NCI CTCAE V5 | Counts and frequencies will be provided for the worst grade toxicity experienced by the patient. Acute toxicity profiles of ≥Grade 2 toxicities and their relatedness to study RT will be calculated, summarised and presented in tabular format with proportions, plus 95% confidence intervals where appropriate, at 1 and 4 weeks post treatment and at 3 months post-treatment using NCI CTCAE V5. | Up to 3 months post-treatment | 
| Late toxicity profiles of ≥Grade 2 toxicities and DLTs at 6, 9, 12, 15, 18 and 24 months post-treatment using NCI CTCAE V5. | Counts and frequencies will be provided for the worst grade toxicity experienced by the patient. Late toxicity profiles of ≥Grade 2 toxicities at 6, 9, 12, 15, 18 and 24 months post treatment completion, will be calculated, summarised and presented in tabular format with proportions, plus 95% confidence intervals where appropriate, using NCI CTCAE V5. | Up to 2 years post-treatment | 
| Estimates of time to onset of ≥ Grade 2 and ≥ Grade 3 acute toxicities. | Time-to-event analyses will be conducted for time to onset of the worst grade ≥2 and grade ≥3 acute toxicities separately. Kaplan-Meier curves will be presented and median point estimates (with 95% Cis) will be reported. Patients free of an event at the time of analysis will be censored at last available toxicity assessment. Time to toxicity will be measured from treatment start date. Patients alive and free of event at the time of analysis and patients lost to follow-up will be censored at the last available assessment. | Up to 3 months post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumor Spine Metastases, Dose-Escalated Stereotactic Ablative Body Radiotherapy