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

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

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.

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.

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 10 weeks prior to enrollment, and within 13 weeks prior to treatment

• Patient has had a nuclear bone scan (if no positron emission tomography-computed tomography [PET-CT]) within 10 weeks prior to enrollment, and within 13 weeks prior to treatment

• Patient has had CT or MRI brain imaging if primary has a propensity for central nervous system metastases (if deemed appropriate by the treating investigator) within 10 weeks prior to enrollment, and within 13 weeks prior to treatment.

• For patients with known spine metastases, patient has had MRI spine imaging within 10 weeks prior to enrollment, and with 13 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 10 weeks prior to enrollment, and within 13 weeks prior to treatment

• If colorectal primary with rising Carcinoembryonic antigen (CEA), but equivocal imaging, patient has had an FDG PET scan within 10 weeks prior to enrollment, and within 13 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

Exclusion Criteria:

• Uncontrolled concurrent malignant cancer

• 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 oligometastatic or oligoprogressive disease

• Presence of brain metastases as the sole site 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

• Patients with spine instability as judged by a Spinal Instability Neoplastic Score (SINS) of >12

• Dominant brain metastasis requiring surgical decompression

• Surgical resection of all metastases (i.e. no lesion available to be treated with SABR)

• Complete response to systemic therapy, defined as the absence of visible disease on imaging

• Pregnant or breast feeding