This study is designed as a randomized phase II study. Patients will be randomized between current standard of care treatment (Arm 1) vs. standard of care treatment + SABR (Arm 2) to sites of known disease (Figure ). Patients will be randomized in a 1:2 ratio to Arm 1 vs. Arm 2, respectively. This study has been approved by the Ontario Cancer Research Ethics Board (#11-030), in compliance with the Helsinki Declaration.
Study design. Patients with be randomized in a 1:2 ratio between Arm 1 (Standard of care) vs. Arm 2 (SABR).
The randomized phase II design is required for 3 reasons: First, the randomization will provide an appropriate control group to serve as a comparator for the experimental arm. Historical or contemporaneous non-randomized controls would not be appropriate due to the multitude of biases that could be introduced by patient selection and other confounders. Second, a small sample size will allow for adequate power to assess for an early overall survival difference, quality of life, and to evaluate toxicity in the SABR arm. Third, the results will allow for a decision as to whether a multi-institutional phase III trial is warranted, and inform the design of such a trial.
To assess the impact of a comprehensive oligometastatic SABR treatment program on overall survival and quality of life in patients with up to 5 metastatic cancer lesions, compared to patients who receive standard of care treatment alone.
· Overall Survival
· Defined as time from randomization to death from any cause
· Quality of life
· Assessed with the Functional Assessment of Cancer Therapy: General (FACT-G)
· Assessed by the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4 for each organ treated (e.g. liver, lung, bone)]
· Progression-free survival
· Time from randomization to disease progression at any site or death
· Lesional control rate
· Number of cycles of further chemotherapy/systemic therapy
· 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
· 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), and the total number of metastases must be 5 or less. For example, a patient with two liver metastases and two lung metastases is eligible.
· 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 chemotherapy (cytotoxic or molecularly targeted agents) therapy 4 weeks prior to first fraction of radiotherapy, during radiotherapy, or for two weeks after last fraction. Hormonal therapy is allowed.
· Patients with metastases that have been previously treated (e.g. prior resection, RFA or radiotherapy):
· If that previously treated metastasis is controlled on imaging, the patient is eligible for this study and that site does not need treatment
· 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 ineligibile.
· Patient presented at multidisciplinary tumor board or radiotherapy departmental quality-assurance rounds, with consensus opinion that entry into the study is appropriate.
· 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 MRI.
· Dominant brain metastasis requiring surgical decompression
· Pregnant or lactating women
Evaluation and randomization
Prior to randomization, a complete history and physical examination by the treating radiation oncologist is required. Histologically confirmation of malignancy is required, with metastatic disease detected on imaging. Biopsy of metastasis is preferred, but not required.
Patients must be restaged within 12 weeks prior to randomization, including brain CT or MRI imaging (for tumor sites with propensity for brain metastasis); and CT neck/chest/abdomen/pelvis with bone scan. PET-CT is only required for specific evidence-based indications, as defined by the Ontario Health Insurance Program, and in such cases the CT neck/chest/abdomen/pelvis and bone scan are not required. For other indications, at the discretion of the treating oncologists, PET-CT scans may be done but are not required. MRI spine is required for patients with vertebral or paraspinal metastases.
Patients with liver metastases are also required to have adequate liver function tests (AST, ALT, GGT, alkaline phosphatase). A negative pregnancy test is required for women of child-bearing age.
The study will employ a 1:2 randomization between Arm 1:Arm 2 (Figure ). The sample size allows for one stratification factor at randomization: number of metastatic sites (1-3 vs. 4-5). Randomization will occur in permuted blocks of nine.