This phase III trial compares total ablative therapy and usual systemic therapy to usual systemic therapy alone in treating patients with colorectal cancer that has spread to up to 4 body sites (limited metastatic). The usual approach for patients who are not participating in a study is treatment with intravenous (IV) (through a vein) and/or oral medications (systemic therapy) to help stop the cancer sites from getting larger and the spread of the cancer to additional body sites. Ablative means that the intention of the local treatment is to eliminate the cancer at that metastatic site. The ablative local therapy will consist of very focused, intensive radiotherapy called stereotactic ablative radiotherapy (SABR) with or without surgical resection and/or microwave ablation, which is a procedure where a needle is temporarily inserted in the tumor and heat is used to destroy the cancer cells. SABR, surgical resection, and microwave ablation have been tested for safety, but it is not scientifically proven that the addition of these treatments are beneficial for your stage of cancer. The addition of ablative local therapy to all known metastatic sites to the usual approach of systemic therapy could shrink or remove the tumor(s) or prevent the tumor(s) from returning.

PRIMARY OBJECTIVE:

I. To evaluate and compare overall survival (OS) (measured from time of randomization) in patients with newly diagnosed oligometastatic colorectal cancer (oCRC) treated with total ablative therapy (TAT) in addition to standard of care (SOC) systemic therapy versus SOC systemic therapy.

SECONDARY OBJECTIVES:

I. To evaluate and compare event-free survival (EFS) (measured from time of randomization) between the two treatment arms.

II. To assess the adverse events (AE) profile within each of the two treatment arms.

III. To evaluate the time to local recurrence (TLR) (measured from completion of TAT) in patients with newly diagnosed oCRC treated with TAT + SOC systemic therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients undergo TAT on study, consisting of SABR with or without surgical resection and/or microwave ablation. Patients also receive SOC chemotherapy on study. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) or positron emission tomography (PET)/CT scans throughout the trial.

ARM 2: Patients receive SOC chemotherapy on study. Patients also undergo Patients also undergo CT or MRI or PET/CT scans throughout the trial.

Inclusion Criteria:

• PRE-REGISTRATION (STEP 0): Histologically-confirmed metastatic colorectal adenocarcinoma

• PRE-REGISTRATION (STEP 0): No known microsatellite instable (MSI) tumor

• PRE-REGISTRATION (STEP 0): No known BRAF V600E mutation

• PRE-REGISTRATION (STEP 0): Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. No known peritoneal and/or omental metastases. If radiologic studies suggest the presence of peritoneal disease, a diagnostic laparoscopy is recommended to verify the absence of peritoneal implants

• PRE-REGISTRATION (STEP 0): Primary tumor is already resected OR primary tumor is surgically amenable to resection, as determined by consultation and documentation with surgeon or documentation of discussion in the institutional multi-disciplinary tumor board where a surgeon confirms resectability. Patients with unresectable primary tumors are not eligible

• PRE-REGISTRATION (STEP 0): Four (4) or fewer apparent sites of metastatic disease based on review by local medical team of baseline radiographic imaging obtained prior to initiation of systemic therapy.

  • Sites of metastatic disease must be radiographically evident, but pathologic confirmation is not required.

  • Liver-only metastatic disease is NOT permitted. For patients with liver metastases, there must be at least one other site of metastasis in addition to the liver to be eligible for this study.

  • Metastatic lesions must be amenable to any combination of surgical resection, microwave ablation, and/or stereotactic ablative body radiation therapy (SABR). SABR is required for at least one lesion. Therefore, the patient must be seen by a radiation oncologist in consultation to verify eligibility.

  • Single sites include:

    • Each hemiliver (right and left), each lobe of the lungs, each adrenal gland, lymph nodes amenable to a single resection or treatment in a single SABR field, bone metastases amenable to treatment in a single SABR field

• PRE-REGISTRATION (STEP 0): Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1

• PRE-REGISTRATION (STEP 0): A maximum of 16 weeks (4 months) of systemic therapy may be administered prior to pre-registration

• REGISTRATION (STEP 1): Patients must have no overt evidence of disease progression during systemic therapy prior to registration

• REGISTRATION (STEP 1): Not eligible for hepatic artery infusion pump (HAIP) therapy or benefit of HAIP therapy is undefined

• REGISTRATION (STEP 1): Patients must have measurable disease per RECIST v1.1

• REGISTRATION (STEP 1): Patients must be receiving (or have received) first-line systemic therapy for metastatic disease for a minimum of 16 weeks (4 months) and a maximum of 24 weeks (6 months)

• REGISTRATION (STEP 1): Prior definitive therapy, including adjuvant chemotherapy, must have been completed at least 12 months prior to diagnosis of metastatic disease

• REGISTRATION (STEP 1): Not pregnant and not nursing, because this study involves an agent or treatment that has known genotoxic, mutagenic, and teratogenic effects.

  * Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required

• REGISTRATION (STEP 1): Age >= 18 years

• REGISTRATION (STEP 1): Eastern Cooperative Oncology Group (ECOG) performance status: 0-2

• REGISTRATION (STEP 1): Absolute neutrophil count (ANC) >= 1,500/mm^3

• REGISTRATION (STEP 1): Platelet count >= 50,000/mm^3

• REGISTRATION (STEP 1): Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinine clearance >= 30 mL/min

  * Calculated using the Cockcroft-Gault equation

• REGISTRATION (STEP 1): Total bilirubin =< 1.5 x ULN

• REGISTRATION (STEP 1): Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x ULN

  * In the event of metastatic liver disease, =< 5 x ULN

• REGISTRATION (STEP 1): Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Note: HIV testing is not required for eligibility

• REGISTRATION (STEP 1): No other planned concurrent investigational agents while on study

Exclusion Criteria:

• N/A