Ablative Radiotherapy to Restrain Every Metastasis Safely Treatable (ARREST-2): A Randomized Phase II/III Trial

Inclusion Criteria:

• Age 18 or older

• willing and able to provide informed consent

• ECOG performance status 0-2

• Life expectancy > or equal to 6 months

• Histologically confirmed malignancy with evidence of metastatic disease on imaging

• All sites of disease can be safely treated on a preliminary radiation plan

• > or equal to 11 metastases (the primary tumor does not have to be controlled andcan be included as a target if it can feasibly and safely be treated with SABR. Ifthe primary tumor is treated, a minimum of 12 targets are required0 at least 11metastases are required in addition to the primary tumor.)

• Investigations required within 12 weeks of enrollment:

• Brain: MRI is required for all patients with known untreated or previously treatedbrain metastases. MRI is strongly recommended for all tumor sites with a propensityto develop brian metastases.

• Body: 18-FDG PET/CT imaging is recommended, except for tumors where FDG uptake isnot expected (e.g. prostate, renal cell carcinoma). PSMA-PET or choline-PET isrecommended for prostate cancer. In situations where a PET scan is unavailable, orfor tumors that do not take up radiotracer, a CT neck/chest/abdomen/pelvis and bonescan are required.

• Liver: For patients with liver metastases, a diagnostic or simulation MRI isrequired to confirm the total number of metastases.

• No plans for systemic therapy (i.e. chemotherapy, targeted agent, immunotherapy) for 3 months from the time of enrolment. Reasons may include: a break from systemictherapy is desired by the patient and medical oncologist, the patient declines nextline of systemic therapy, or no further systemic therapy options are available.Exceptions include hormone therapy for breast cancer or prostate cancer, which maybe continued.

• SABR or palliative radiotherapy should commence no later than 2 weeks afterrandomization.

• For patients with brain metastases that are going to be treated regardless of thestudy arm, there must be additional extracranial disease present that will betreated with SABR on Arm 2 and not treated with SABR on Arm 1.

Exclusion Criteria:

• Serious medical comorbidities precluding radiotherapy. These include interstitiallung disease in patients requiring thoracic radiation, Chrohn's disease in patientswhere the GI tract will receive radiotherapy, ulcerative colitis where the bowelwill receive radiotherapy and connective tissue disorders such as lupus orscleroderma.

• For patients with liver metastases, moderate/severe liver dysfunction (Child-Pugh Bor C)

• Substantial overlap with a previously treated radiation volume. Prior radiotherapyis allowed, as long as the composite plan meets dose constraints herein. Forpatients treated with radiation previously, biologically effective dose calculationsshould be used to equate previous doses to the tolerance doses listed in Appendix 1.All such cases must be discussed with the study PI.

• Inability to treat all sites of disease. Any brain metastasis >3 cm in size or atotal volume of brain metastases greater than 30 cc.

• Solitary or dominant brian metastasis requiring surgical decompression.

• Radiologic evidence of spinal cord compression.

• Disseminated disease, including leptomeningeal metastases, peritonealmetastases/carcinomatosis, malignant pleural effusion, and lymphangitiscarcinomatosis.

• Pregnant or lactating women.