A Randomized Phase III Trial of Stereotactic Ablative Radiotherapy for Patients With Up to 10 Oligometastases and a Synchronous Primary Tumor.

Study Overview
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Brief Summary
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This study is a phase III multi-institutional randomized trial. Patients will be randomized in a 1:2 ratio between current standard of care treatment (Arm 1) vs. standard of care treatment + SABR (Arm 2) to sites of known disease. Patients will be stratified by two of the strongest prognostic factors, based on a large multi-institutional analysis3: histology (Group 1: hormone-sensitive prostate cancer, breast, or renal; Group 2: all others), and number of metastases (Group 1: 1-3; Group 2: 4-10).

Official Title
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A Randomized Phase III Trial of Stereotactic Ablative Radiotherapy for Patients With Up to 10 Oligometastases and a Synchronous Primary Tumor.

Conditions
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Metastatic Tumor

Intervention / Treatment
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* Radiation: Palliative Radiotherapy
* Drug: Chemotherapy
* Drug: Hormone therapy
* Drug: Immunotherapy
* Drug: Targeted Systemic Therapy
* Other: Observation
* Radiation: Stereotactic Ablative Radiotherapy
* Procedure: Surgery
* Other: Radiofrequency Therapy (RFA)
* Radiation: Fractionated Radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Willing to provide informed consent Karnofsky performance status > 60 Life expectancy > 6 months Histologically confirmed malignancy with metastatic disease detected on imaging. Biopsy of metastasis is preferred, but not required. Total number of metastases 1-10 at the time of enrollment, with a primary tumor also present Restaging completed within 12 weeks prior to randomization (see section 5.1) For patients receiving thoracic radiotherapy, the enrolling physician must confirm there are no computed tomography (CT) changes suggestive of fibrotic interstitial lung disease (ILD) (i.e. reticular changes, traction bronchiectasis, or honeycombing) reported on any prior CT scans. If any are present, the patient must be assessed by a respirologist to rule out ILD prior to enrollment. Exclusion Criteria: Serious medical comorbidities precluding radiotherapy. These include ILD in patients requiring thoracic radiation, Crohn's disease in patients where the gastrointestinal (GI) tract will receive radiotherapy, or ulcerative colitis where the bowel will receive radiotherapy and connective tissue disorders such as lupus or scleroderma. For patients with liver metastases, moderate/severe liver dysfunction (Child Pugh B or C); please see the Child-Pugh score calculator. Substantial overlap with a previously treated radiation volume. Prior radiotherapy in general is allowed, as long as the composite plan meets dose constraints herein. For patients treated with radiation previously, biological effective dose calculations should be used to equate previous doses to the tolerance doses listed in Appendix 1. All such cases must be discussed with a member of the study steering committee. Malignant pleural effusion Inability to treat all sites of disease Brain metastasis > 3 cm in size or a total volume of brain metastases greater than 30 cc. Metastasis in the brainstem Clinical or radiologic evidence of spinal cord compression Metastatic disease that invades any of the following: GI tract (including esophagus, stomach, small or large bowel), or skin 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 (Arm 1)<br>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. | Radiation: Palliative Radiotherapy<br>* 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. Recommended dose fractionations in this arm will include 8 Gy in 1 fraction, 20 Gy in 5 fractions, and 30 Gy in 10 fractions.<br>Drug: Chemotherapy<br>* Pre-specified based on the standard of care approach for that patient.<br>* Other names: Cytotoxic Systemic Therapy;Drug: Hormone therapy<br>* Pre-specified based on the standard of care approach for that patient.<br>* Other names: Hormonal Systemic Therapy;Drug: Immunotherapy<br>* Pre-specified based on the standard of care approach for that patient.<br>Drug: Targeted Systemic Therapy<br>* Pre-specified based on the standard of care approach for that patient.<br>Other: Observation<br>* Pre-specified based on the standard of care approach for that patient.<br>|
| Experimental: Experimental Arm (Arm 2)<br>Consists of treatment to the primary tumor and metastases, with SABR preferred, but other options all allowable (e.g. surgery, RFA, fractionated radiation, chemoradiation) if those are deemed to be preferable by the treating oncologists. | Radiation: Palliative Radiotherapy<br>* 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. Recommended dose fractionations in this arm will include 8 Gy in 1 fraction, 20 Gy in 5 fractions, and 30 Gy in 10 fractions.<br>Drug: Chemotherapy<br>* Pre-specified based on the standard of care approach for that patient.<br>* Other names: Cytotoxic Systemic Therapy;Drug: Hormone therapy<br>* Pre-specified based on the standard of care approach for that patient.<br>* Other names: Hormonal Systemic Therapy;Drug: Immunotherapy<br>* Pre-specified based on the standard of care approach for that patient.<br>Drug: Targeted Systemic Therapy<br>* Pre-specified based on the standard of care approach for that patient.<br>Other: Observation<br>* Pre-specified based on the standard of care approach for that patient.<br>Radiation: Stereotactic Ablative Radiotherapy<br>* The primary tumor may be treated with SABR or with other local modalities at the discretion of the treating team and/or the local multidisciplinary tumor board. Preferred doses are 20 Gy in 1 fraction, 30 Gy in 3 fractions (every second day), and 35 Gy in 5 fractions (daily).<br>Procedure: Surgery<br>* Treatment to the primary tumor and metastases, with SABR preferred, but other options all allowable if those are deemed to be preferable by the treating oncologists. The primary tumor may be treated with SABR or with other local modalities at the discretion of the treating team and/or the local multidisciplinary tumor board. Because of the convenience in using SABR for all lesions, non-SABR modalities should only be used if they are likely to provide a benefit over SABR.<br>Other: Radiofrequency Therapy (RFA)<br>* Treatment to the primary tumor and metastases, with SABR preferred, but other options all allowable if those are deemed to be preferable by the treating oncologists.<br>Radiation: Fractionated Radiation<br>* Treatment to the primary tumor and metastases, with SABR preferred, but other options all allowable if those are deemed to be preferable by the treating oncologists. Tumors in the esophagus, stomach, small intestine or colon should be treated with either fractionated radiation or a lower SABR dose (e.g. 25 Gy in 5 fractions) to minimize the risk of perforation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from randomization to death from any cause, or date of last follow-up, whichever occurs first. | Approximately end of year 6 (Study Completion) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of Life (QOL) assessed with the Functional Assessment of Cancer Therapy: General (FACT-G). |  | Quality of Life outcomes to be collected for the first 2 years (3, 6, 12, 18, 24 months) | 
| Quality of Life (QOL) assessed with the Functional Assessment of Cancer Therapy: The EuroQol 5-Dimension 5-Level (EQ-5D-5L). |  | Quality of Life outcomes to be collected for the first 2 years (3, 6, 12, 18, 24 months) | 
| Toxicity assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) version 5 for each organ treated (e.g. liver, lung, bone). |  | Toxicity outcomes to be collected for the first 2 years (Last week of treatment, in 6 weeks, in 3, 6, 12, 18, 24 months) | 
| Time to next systemic therapy | The time from randomization until commencement of any systemic anti-cancer therapy, or date of last follow-up, whichever occurs first. | From randomization to year 6 (study completion). | 
| Receipt of additional radiation during follow-up | Will be collected for SABR (as a binary endpoint; yes/no), and non-SABR (yes/no). | During year 6 (follow-up year). |