Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic Tumors (SABR-COMET)

Study Overview
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Brief Summary
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Stereotactic Ablative Radiotherapy (SABR) is a new radiation treatment that delivers high-dose, precise radiation to small tumors in 1-3 weeks of treatment. This new technique can potentially allow radiation treatments to be focused more precisely, and delivered more accurately than with older treatments. This improvement could help by reducing side effects and by improving the chance of controlling the cancer by more precisely treating the cancer. The purpose of this study is to compare SABR with current approaches of chemotherapy and conventional radiotherapy to assess the impact on overall survival and quality of life.

Detailed Description
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TREATMENT PLAN 6.0.1 Standard Arm (Arm 1) Radiotherapy for patients in the standard arm should follow the principles of palliative radiotherapy as per the individual institution, with the goal of alleviating symptoms or preventing imminent complications. Patients in this arm should not receive stereotactic doses or radiotherapy boosts. Treatment recommendations are as follows: Brain: Whole brain radiotherapy i.e. 20 Gy in 5 fractions, 30 Gy in 10 fractions Lung: Palliative radiotherapy as per 2011 consensus guidelines.15 i.e. 8 Gy in 1 fraction, 20 Gy in 5 fractions, 30 Gy in 10 fractions Bone: Palliative radiotherapy as per 2011 consensus guidelines.16 i.e. 8 Gy in 1 fraction (most common), 20 Gy in 5 fractions, 30 Gy in 10 fractions Liver: 20 Gy in 5 fractions if standard institutional practice 6.0.2 Treatment Planning for Standard Arm Treatment planning is to be done using CT simulation or conventional simulation (fluoroscopy) as per individual institutional practice. Simple beam arrangements, such as parallel opposed beams, are favored wherever possible. 6.1 Experimental Arm (Arm 2) All treatments in this study are based on current protocols in clinical use at the LRCP and VUmc for treatment of lung,17 liver,18 brain,19,20 and spinal cord21 metastases. The guiding principle for radiotherapy is to achieve disease control but to minimize any potential adverse impact on quality of life. Concurrent chemotherapy or targeted therapy at the time of radiotherapy is not permitted within the 4 weeks prior to SABR. Hormone therapy is permitted. 6.1.1 Dose/Fractionation Lung- tumors 3 cm or less surrounded by lung parenchyma, 54(Gy) in 3 fractions Abutting chest wall or >3 cm, 55(Gy)in 5 fractions, every second day Within 2 cm of mediastinum or brachial plexus, 60(Gy),8* fractions, every second day Bone -Any bone except femur,35(Gy), in 5 fractions,daily vertebral body,16-20(Gy)in 1 fraction, single dose, or 30Gy in 3 fractions, every second day Brain - Non-radiosurgical,40(Gy) to metastases, in 5 fractions,daily If whole brain treated, then simultaneous boost to each lesion,20 Gy whole brain (optional), in 5 fractions, daily Radiosurgical, ≤1 cm, 22-24(Gy), in 1 fraction, >1 and ≤2 cm, 22-24(Gy) in 1 fraction >2 and ≤ 3 cm, 18-20(Gy) in 1 fraction Optional whole brain to follow (see text) Liver-LRCP site: Dose is based on calculated normal tissue probability of <5%,Every second day other sites 45-60(Gy), in 3-8 fractions, every second day Adrenal, 60 (Gy), in 8 fractions, every second day (If whole brain treated, then simultaneous boost to each lesion) 6.1.2 Immobilization Treatment will be setup using reproducible positioning, verified using an on-line protocol, for all patients in this study. Immobilization may include a custom immobilization device, such as thermoplastic shell or vac-lok bag, as per individual institutional practice when delivering SABR. Some centers do not use immobilization devices and have demonstrated high degrees of accuracy; this is acceptable in this study. 6.1.3 Imaging/Localization/Registration All patients in Arm 2 will undergo planning CT simulation. 4-dimensional CT will be used for tumors in the lungs or liver. Axial CT images will be obtained throughout the region of interest. For centres using stereotactic radiosurgery platforms, real-time tumor tracking and orthogonal imaging systems are permitted. Any center which is not yet experienced in lesions at any specific sub-site (e.g. adrenal metastases) shall be eligible to participate by including only patients with lesions at other pre-specified sites It is strongly recommended that the doses to organs at risk are not to be exceeded - in some specific cases, this may require lower doses or higher fractionations than listed here. Such changes in dose will require approval of one of the local principal investigators. (see section 6.2)

Official Title
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Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic Tumors (SABR-COMET): A Randomized Phase II Trial

Conditions
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Metastatic Tumors

Intervention / Treatment
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* Radiation: Stereotactic ablative radiotherapy
* Radiation: palliative radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 or older Willing to provide informed consent Histologically confirmed malignancy with metastatic disease detected on imaging. Biopsy of metastasis is preferred, but not required. ECOG performance status 0-1 Controlled primary tumor a. defined as: at least 3 months since original tumor treated definitively, with no progression at primary site All sites of disease can be safely treated based on criteria below Maximum 3 metastases in any single organ system (i.e. lung, liver, brain, bone) Life expectancy >6 months Not a candidate for surgical resection at all sites: surgery to all sites not recommended by multidisciplinary team, or unfit or declining surgery Prior chemotherapy allowed but no systemic therapy 4 weeks prior to first fraction of radiotherapy, during radiotherapy, or for two weeks after last fraction Patients with metastases that have been previously treated (e.g. prior resection, Radiofrequency Ablation (RFA) or radiotherapy): a. If that previously treated metastasis is controlled on imaging, the patient is eligible for this study and that site does not need treatment a. If that previously treated metastasis is NOT controlled on imaging: If the previous treatment was surgery, the patient is eligible if that site can be treated by SABR If the previous treatment was radiotherapy or RFA, the patient is ineligible. Patient presented at multidisciplinary tumor board or quality-assurance rounds. Exclusion Criteria: Serious medical comorbidities precluding radiotherapy Bone metastasis in a femoral bone Patients with 1-3 brain metastasis and no disease elsewhere (these patients should not be randomized but treated with stereotactic radiotherapy as per results of randomized trials) Prior radiotherapy to a site requiring treatment Complete response to first-line chemotherapy (i.e. no measurable target for SABR) Malignant pleural effusion Inability to treat all sites of active disease Clinical or radiologic evidence of spinal cord compression OR tumor within 3 mm of spinal cord on Magnetic Resonance Imaging (MRI). Dominant brain metastasis requiring surgical decompression Pregnant or lactating women

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 |
| --- | --- |
| Active Comparator: Standard arm<br>Standard of care, palliative radiotherapy, and chemotherapy at the discretion of the treating medical oncologist | Radiation: palliative radiotherapy<br>* Investigators should follow the principles of palliative radiotherapy as per the individual institution. Treatment recommendations are as follows: Brain: Whole brain radiotherapy i.e. 20 Gy in 5 fractions, 30 Gy in 10 fractions Lung: Palliative radiotherapy as per 2011 consensus guidelines.15 i.e. 8 Gy in 1 fraction, 20 Gy in 5 fractions, 30 Gy in 10 fractions Bone: Palliative radiotherapy as per 2011 consensus guidelines.16 i.e. 8 Gy in 1 fraction (most common), 20 Gy in 5 fractions, 30 Gy in 10 fractions Liver: 20 Gy in 5 fractions if standard institutional practice<br>|
| Experimental: Stereotactic arm<br>Stereotactic ablative radiotherapy, and chemotherapy at the discretion of the treating medical oncologist | Radiation: Stereotactic ablative radiotherapy<br>* Total dose and number of fractions will depend on the site of disease. Treatment will be given daily, or every other day, over 1 -3 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | At approximately end of year 4 (study completion) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life: Assessed with the Functional Assessment of Cancer Therapy: General (FACT-G) |  | At approximately end of year 2, and end of year 4 (study completion) | 
| Toxicity: Assessed by the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4 for each organ treated (e.g. liver, lung, bone) |  | At approximately the end of years 1, 2, 3, and 4 (study completion) | 
| Progression-free survival |  | At approximately end of year 2, and end of year 4 (study completion) | 
| Lesional control rate |  | At approximately end of year 2, and end of year 4 (study completion) | 
| Number of cycles of further chemotherapy/systemic therapy |  | At approximately end of year 2, and end of year 4 (study completion) |