Stage III colorectal cancer (CRC) patients are currently treated with three- or sixmonths of adjuvant chemotherapy (ACT) using fluoropyrimidines and oxaliplatin depending on the risk subgroup (low vs high).In stage II CRC patients ACT is still controversial: combination of fluoropyrimidines and oxaliplatin may be considered in the case of at least one major risk factor (i.e. pT4 stage, lymph nodes sampling less than 12 and clinical presentation with intestinal perforation) or in presence of multiple risk factors. However identifying CRC patients who will benefit from ACT remains an open question. Post-surgery circulating tumor (ct-DNA) seems a promising marker of minimal residual disease (MRD) and a clinically relevant marker of poor prognosis.Also the persistence of detectable ct-DNA at the end of the adjuvant treatment predicts high risk of recurrence.Drawing from these considerations, we designed the present study, including two phaseII randomized trials:1) Part 1: resected stage III and high-risk stage II colon cancer patients with positive ct-DNA after surgery will be randomized to receive FOLFOX for 12 cycles or CAPOX for 8 cycles (at investigator choice) versus FOLFOXIRI for 12 cycles;2) Part 2: resected stage III and high-risk stage II colon cancer patients with positive ct-DNA after the end of a fluoropyrimidine and oxaliplatin-based adjuvant therapy – either in the frame or outside of Part 1 – will be randomized to receive observation or trifluridine/tipiracil for 6 cycles.

Both Part 1 and 2:– Histologically confirmed stage III or high-risk stage II adenocarcinoma of colon including intraperitoneal rectal cancer.– adequate hematopoietic, liver and renal function.Part 1– no evidence of metastatic disease at post-operative CT scan.– Positive ct-DNA after surgery (central assessment). The blood sample should be collected 2-6 weeks after the surgery.Part 2– Fluoropyrimidine and oxaliplatin-containing adjuvant treatment for at least 3 months.– no evidence of metastatic disease at post-adjuvant CT scan.– Positive ct-DNA after the end of adjuvant treatment (central assessment).

The primary objectives of this study are to determine whether an intensified adjuvant regimen of FOLFOXIRI could increase the percentage of cases with undetectable ct-DNA following chemotherapy (Part 1) and whether an additional adjuvant regimen of FTD/TPI could do the same (Part 2) in a population at high risk of relapse.