The purpose of this study is to determine if adding ablative local therapy (ALT) to the usual approach of systemic therapy for treatment of metastatic colorectal cancer can lengthen survival and if this approach is better or worse than the usual approach. ALT may be performed by surgery, radiation therapy, heat with microwave ablation, or other methods. This study will use radiation therapy and potentially surgery and/or heat. 

The usual approach for patients who are not in a study is treatment with intravenous (IV, through a vein) and/or oral medications (systemic therapy). These medications help stop the cancer sites from getting larger and the spread of the cancer to additional body sites. ALT can include surgical removal of the tumor, treatment of the tumor with focused intensive radiation called stereotactic ablative radiotherapy (SABR), or heat (microwave ablation) where a needle is temporarily inserted in the tumor and heat is used to destroy the cancer cells.

Participants in this study will get intravenous and/or oral drugs (chemotherapy, biologic therapy at the discretion of your treatment team) for 4-6 months, and then will be randomized to either undergo ALT to all sites of disease with potential additional systemic therapy after, or to continue with systemic therapy alone until their disease gets worse. 

The drug therapy options that may be given in this study are below. All drugs listed are approved by the U.S. Food and Drug Administration (FDA).

• FOLFOX (chemotherapy) given IV
• CAPOX (chemotherapy) given IV and oral medication
• FOLFIRI (chemotherapy) given IV
• FOLFOXIRI (chemotherapy) given IV
• Capecitabine (chemotherapy) given as oral medication
• 5-Fluorouracil (chemotherapy) given IV
• Bevacizumab (biologic therapy) given IV
• Cetuximab (biologic therapy) given IV
• Panitumumab (biologic therapy) given IV

 After participants finish treatment (either ALT or systemic therapy), they will be monitored for side effects and for spread of the cancer or the cancer sites getting larger. The first check will be about 1-2 months after finishing the ALT or systemic therapy, and then will be every 3 months until the disease gets worse or for up to 5 years.

Total study participation will last for 5 years after treatment.