This study is for people who have stage III colon cancer that has been treated with surgery but has spread to some of the lymph nodes, or who have stage II or stage III colon cancer that has been treated with surgery and has a higher risk of returning based on positive circulating tumor DNA (ctDNA) results. ctDNA is DNA that has been released from tumor cells into the bloodstream. This DNA can be measured using a blood test.
   
The purpose of this study is to find out if ctDNA testing results can be used to determine if the usual chemotherapy approach or another chemotherapy drug combination should be used to prevent colon cancer from returning in patients that are ctDNA positive. Additionally, this study is investigating if the usual approach compared to ctDNA testing every 3 months in ctDNA negative patients should be used to prevent colon cancer from returning.

The usual approach is treatment with chemotherapy drug combinations 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX), or capecitabine and oxaliplatin (CAPOX). The other chemotherapy combination being evaluated in this study is 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX).

These chemotherapy combinations are approved by the U.S. Food and Drug Administration (FDA). The ctDNA test used in this study is not currently FDA approved for determining a type of treatment.  

This study has four study groups., Group 1 and Group 2 are for participants who are ctDNA negative and Group 3 and Group 4 are for participants who are ctDNA positive. Participants will be randomized into one of the two treatment groups that correspond to their ctDNA status. Randomization is like flipping a coin and there is a 50/50 chance of being assigned to a group. 

Group 1 will receive FOLFOX for 3-6 months or CAPOX for 3 months as determined by the study doctor. Group 2 will be monitored with ctDNA testing every 3 months for 3 years. Participants who develop a positive ctDNA test during monitoring will be asked to change to the ctDNA positive group.

Group 3 will receive FOLFOX for 6 months or CAPOX for 6 months, as decided by the study doctor. Group 4 will receive mFOLFIRINOX for 6 months.  

All chemotherapy will be delivered either via a port or intravenously. Total study participation depends on which group each participant is assigned to.