Single vs. Multiple Fraction Trial of Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastases/Progression

Study Overview
=================
Brief Summary
-----------------
Stereotactic Ablative Radiotherapy (SABR) is a modern RT technique that delivers high doses of radiation to small tumor targets using highly conformal techniques, while trying to avoid healthy tissues and organs. However, SABR treatment requires increased planning, treatment time, cost and potential for higher toxicity due to the higher dose. The purpose of this study is to compare single fraction (SF) SABR vs. multiple fraction (MF) SABR in regards to toxicities, progression-free survival, quality of life (QoL), and cost-effectiveness. In a subset of patients, we will also compare patient QoL, hospitalization rates, and cost-effectiveness between patients who complete QoL questionnaires, record symptoms and receive healthcare provider-guided intervention vs. patients who complete QoL questionnaires only.

Detailed Description
-----------------
Radiation can be delivered in multiple fractions, or doses, and can take up to several weeks or months of treatment depending on the type of cancer. Radiation can also be offered in a single fraction. Both techniques have evidence for use in clinical care. Multiple fraction is offered to reduce the amount of radiation given at a single time that could reduce late toxicities. However, single fraction radiotherapy is more cost-effective and saves patient time. With this trial, we will compare single fraction vs. multiple fraction in regards to their impact on toxicity, progression-free survival: time from randomization to disease progression at any site or death, lesional control rate: lesion size post-SABR, quality of life and cost-effectiveness. In a subset of sites, we will also investigate the impact of healthcare-provider guided intervention on quality of life. Questionnaires capture various symptoms such as pain, fatigue and information relating to physical, social, and mental wellbeing. This information can help shed light on patient experience and provide a better understanding of the effects of radiation therapy. In this trial, we will compare quality of life questionnaire completion, symptom reporting and healthcare-provider guided intervention vs. quality of life questionnaire completion alone, in regards to patient quality of life. Hospitalization rates and frequency of emergency department visits will also be investigated. Sample size: The total sample size of 598 for this trial was calculated based on the primary endpoint of toxicity for the single vs. multiple fraction SABR randomization. Calculations were performed based on the results of the SABR-5 trial and our clinical judgement. Quality Assurance: Radiation treatments are based on the current phase III SABR-COMET-3 trial and as per recent clinical evidence. All treatments will be planned as per protocol including computed tomography (CT) simulation, organs at risk contouring and undergo a quality assurance process. For the subset of sites involved in the second randomization, training will be provided to patients on the use of Noona, a patient-reported outcome platform.

Official Title
-----------------
Single vs. Multiple Fraction Non-Inferiority Trial of Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligo-metastases/Progression: SIMPLIFY-SABR-COMET

Conditions
-----------------
Oligometastatic Disease, Oligoprogression, Toxicity Due to Radiotherapy, Quality of Life

Intervention / Treatment
-----------------
* Radiation: Single fraction SABR
* Radiation: Multiple fraction SABR
* Other: QoL reporting alone
* Other: QoL reporting, symptom screen and healthcare provider intervention


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1-5 current oligometastatic or oligo-progressive lesions Age 18 years or older Able to provide informed consent Able to complete electronic entry of patient reported outcomes and questionnaires independently or with assistance from a caregiver/family/friend/research staff using electronic methods after providing consent to email use. Life expectancy > 6 months Histologically confirmed malignancy with metastatic disease detected on imaging. Biopsy of metastasis is preferred, but not required. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Controlled primary tumor: defined as at least 3 months since original tumor treated radically, with no progression at primary site (can be considered controlled if no evidence of the primary tumour on imaging [e.g. primary unknown]) A history and physical examination, including ECOG performance status, performed within 6 weeks prior to enrollment Patient has had a CT chest, abdomen and pelvis or PET-CT within 8 weeks prior to enrollment, and within 12 weeks prior to treatment Patient has had a nuclear bone scan (if no positron emission tomography-computed tomography [PET-CT]) within 8 weeks prior to enrollment, and within 12 weeks prior to treatment Patient has had CT or MRI brain imaging if primary has a propensity for brain metastases within 8 weeks prior to enrollment, and within 12 weeks prior to treatment. For patients with known spine metastases, patient has had MRI spine imaging within 8 weeks prior to enrollment, and with 12 weeks prior to treatment. If solitary lung nodule for which biopsy is unsuccessful or not possible, patient has had an FDG (fluorodeoxyglucose) PET scan or CT (chest, abdomen, pelvis) and bone scan within 8 weeks prior to enrollment, and within 12 weeks prior to treatment If colorectal primary with rising Carcinoembryonic antigen (CEA), but equivocal imaging, patient has had an FDG PET scan within 8 weeks prior to enrollment, and within 12 weeks prior to treatment Patient is judged able to: Maintain a stable position during therapy Tolerate immobilization device(s) that may be required to deliver SABR safely Negative pregnancy test for People of Child-Bearing Potential (POCBP) within 4 weeks of RT start date Waivers to inclusion criteria will NOT be allowed. Exclusion Criteria: Concurrent malignant cancer or history of malignant cancers within the past 5 years Lesion in femoral bone requiring surgical fixation No chemotherapy agents (cytotoxic, or molecularly targeted agents) will be used within the period of time commencing 1 week prior to radiation, lasting until 1 week after the last fraction. See section 5.3.3 regarding this criterion. Serious medical comorbidities precluding radiotherapy. These include interstitial lung disease in patients requiring thoracic radiation, Crohn's disease in patients where the gastrointestinal (GI) tract will receive radiotherapy, and connective tissue disorders such as lupus or scleroderma. 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, similar biological effective dose calculations should be used to equate previous doses to the tolerance doses listed below. All such cases should be discussed with the local and study principal investigators (PIs). Current malignant pleural effusion Liver metastases located in the Biliary no fly zone defined for this trial as common biliary track, cystic duct and distal branches (1 cm) + 5 mm. Inability to treat all sites of disease Maximum size of 5 cm for lesions outside the brain, except: Bone metastases over 5 cm may be included, if in the opinion of the local PI it can be treated safely (e.g. rib, scapula, pelvis) Any brain metastasis > 3.5 cm in size or a total volume of brain metastases greater than 30 cc is excluded Clinical or radiologic evidence of spinal cord compression. Patients can be eligible if surgical resection has been performed, but the surgical site counts toward the total of up to 5 metastases. Dominant brain metastasis requiring surgical decompression Surgical resection of all metastases (i.e. no lesion available to be treated with SABR) Pregnant or breast feeding

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
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: This study is a phase III multicentre randomized trial. All participants will be randomized in a 1:1 ratio between multiple fraction SABR (Arm 1) vs. single fraction SABR (Arm 2). Patients will be stratified by systemic therapy within the last 2 weeks (yes/no); number of sites to be treated (1 vs. multiple) and SABR to the abdominal/pelvic site (yes/no). BC Cancer sites will also participate in the second randomization. Participants will be randomized in a 1:1 ratio to QoL reporting alone via FACT-G and EQ-5D-5L (Arm A) vs. QoL reporting and patient-reported outcome (PRO) symptom screen with healthcare provider intervention (Arm B). Patients will be further stratified by the criteria for the 1st randomization as as well as sex.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Multiple fraction SABR (Arm 1)<br>Participants randomized to this arm will receive multiple fraction SABR | Radiation: Multiple fraction SABR<br>* Participants randomized to this arm will receive MF SABR: Dose/Fractionation are as follows: Lung: Greater than 2 cm from mediastinum or brachial plexus or if mandatory organ-at-risk (OAR) constraints are met: 48 Gy in 4 fractions (12 Gy/#), 54 Gy in 3 fractions (18 Gy/#), daily or every second day Lung: Within 2 cm of mediastinum or brachial plexus 60 Gy in 8 fractions (7.5 Gy/#), 50 Gy in 5 fractions (10 Gy/#), daily Bone: Any bone except spine: 35 Gy in 5 fractions (7 Gy/#), daily Liver: 54 Gy in 3 fractions (18 Gy/#) or 5 fractions (10.8 Gy/#), daily or every second day Spine: 24 Gy in 2 fractions (12 Gy/#) or 35 Gy in 5 fractions (7 Gy/#), daily Adrenal: 40 Gy in 5 fractions (8 Gy/#) or 35 Gy in 5 fractions (7 Gy/#), daily Lymph node/soft tissue: 40 Gy in 5 fractions (8 Gy/#) or 35 Gy in 5 fractions (7 Gy/#), daily Brain - dose per institutional policy for stereotactic lesions (no whole brain RT).<br>|
| Experimental: Single fraction SABR (Arm 2)<br>Participants randomized to this arm will receive single fraction SABR | Radiation: Single fraction SABR<br>* Participants randomized to this arm will receive SF SABR Treatment recommendations are as follows: Lung: Greater than 2 cm from mediastinum or brachial plexus or if mandatory OAR constraints are met: 30 Gy in 1 fraction Lung: Within 2 cm of mediastinum or brachial plexus 20 Gy in 1 fraction Bone, Spine, Adrenal, lymph node/soft tissue: 20 Gy in 1 fraction Liver: 30 Gy in 1 fraction Brain: dose as per institutional policy<br>|
| Active Comparator: Patient-reported outcome (PRO) collection : QoL reporting alone (Arm A)<br>Participants will complete the EuroQoL-5Dimensions-5levels (EQ-5D-5L) and Functional Assessment of Cancer Therapy-General (FACT-G) prior to each scheduled follow-up (FU). | Other: QoL reporting alone<br>* Participants randomized to this arm will complete the EQ-5D-5L and FACT-G at baseline and each follow-up visit<br>|
| Experimental: QoL reporting and healthcare provider (HCP) intervention guided by symptom screen (Arm B)<br>Patients complete EQ-5D-5L and FACT-G prior to each scheduled FU Patient complete online adaptive symptom screen with HCP intervention, prior to each scheduled appointment | Other: QoL reporting, symptom screen and healthcare provider intervention<br>* Participants randomized to this arm will complete the FACT,G, EQ-5D-5L, PRO-CTCAE symptom screen and receive healthcare provider-guided intervention based on their symptom reports.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Occurrences and changes in grade 3 or higher adverse events related to treatment, according to CTCAE v5.0 | At 6 weeks, 3 months, 6 months, 12 months, 24 months, 36 months, 48 months, 60 months | 
| Change in patient-reported quality of life | As measured by the EQ-5D-5L. This questionnaire provides measures for mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. It also includes a numbered scale from 0 to 100 where 100 means the best health one can imagine, and 0 means the worst health one can imagine. | At 6 weeks, 3 months, 6 months, 12 months, 24 months, 36 months, 48 months, 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lesional control rate | Rate is determined based on lesion size post-SABR using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | At 6 weeks, 3 months, 6 months, 12 months, 24 months, 36 months, 48 months, 60 months | 
| Progression-free survival | Time from randomization to disease progression at any site or death | At 6 weeks, 3 months, 6 months, 12 months, 24 months, 36 months, 48 months, 60 months | 
| Overall survival | Time from randomization to death from any cause (exploratory) | Approximately at the end of year 5 of follow-up, at study completion | 
| Resource utilization | Assessed via patient- and provider-reported hospitalization rates, frequency of emergency department visits, number of patients with systemic or radiation therapy post SABR treatment on trial | At 3 months, 6 months, 12 months, 24 months, 36 months, 48 months, 60 months |