Surgical resection is curative for 75% of stage II and 50% of stage III colon cancer patients. The magnitude of benefit of adjuvant chemotherapy in terms of disease-free (DFS) and overall survival (OS) varies according to TNM stage and microsatellite status. Specifically, in patients with stage II microsatellite stable (MSS) tumors and high risk clinical features (i.e. pT4, lymphovascular invasion, perineural invasion, bowel obstruction, positive surgical margins and inadequately sampled lymph nodes) adjuvant therapy with fluoropyrimidines conditioned a modest but significant DFS benefit, while oxaliplatin-based therapy may be offered to patients with poor prognosis such as those with pT4 disease. In patients with stage III disease adjuvant therapy with oxaliplatin and fluoropyrimidine combinations significantly improved DFS and OS in phase 3 randomized trials. However, oxaliplatin is burdened by dose-cumulative and potentially long-lasting neurotoxicity. Therefore, three-month duration of oxaliplatin-based chemotherapy was compared to six-month in six randomized trials including patients with resected stage (II)/III colon cancer. In the pooled analysis of such trials (IDEA Collaboration), the non-inferiority for DFS of three months adjuvant oxaliplatin-based chemotherapy was not formally demonstrated. However, absolute DFS loss with 3- month therapy was clearly unsignificant from a clinical point-of-view and 3-month duration of oxaliplatin-based adjuvant chemotherapy is now recommended in patients with low risk disease (pT3N1) and particularly when adopting a capecitabine-based regimen (CAPOX).~Circulating tumor DNA (ctDNA) detected after surgical resection reflects the presence of micrometastatic disease and pivotal observational studies addressed the prognostic value of ctDNA in the post-surgical setting. Detectable ctDNA after surgery is prognostic for DFS in patients with resected colon cancer with high specificity in predicting recurrence (-100%), reinforcing its promising role for guiding trials on post-surgical intensification strategies, but ctDNA is also endowed with suboptimal sensitivity (70%), thus limiting its potential usefulness to guide the complete omission of adjuvant chemotherapy. Regarding the impact of adjuvant chemotherapy on micrometastatic disease, adjuvant chemotherapy was able to clear ctDNA in individual patients with resected stage II tumors. Moreover, ctDNA clearance after adjuvant chemotherapy was prognostic for better DFS in patients with stage III resected cancers and post-operative positive ctDNA. Collectively, these data highlight that ctDNA may be investigated as a potential real-time surrogate biomarker of the efficacy of adjuvant therapy, but suggest that patients with ctDNA persistence after standard chemotherapy might be molecularly metastatic and may benefit from additional consolidation non-cross resistant strategies aimed at clearing micrometastatic disease.~Temozolomide displayed limited activity (overall response rate [ORR] 9%) in patients with heavily pretreated metastatic colorectal cancer (mCRC) with MGMT promoter methylation assessed by means of a qualitative assay - methylation-specific PCR. However, even if MGMT promoter methylation is found in up to 40% of patients with colorectal cancer, in-silico analyses and translational analyses showed that only a subset of these tumors (- 10% of all comers) display lack of MGMT expression and negative MGMT IHC staining. In keeping with findings, correlative studies of phase 2 trials showed that MGMT immunohistochemical negativity and higher MGMT methylation % by quantitative assays are associated with temozolomide activity. Finally, proficiency of the mismatch repair is needed for alkylators activity. Therefore, temozolomide might be considered a tailored chemotherapy in patients with MGMT silenced tumors (i.e. those with MGMT negative expression and MGMT promoter methylation) and microsatellite stable (MSS) tumors. Significant activity (ORR 26%) and favorable safety profile were reported by the combination of temozolomide and irinotecan (TEMIRI regimen) in patients with pretreated MGMT methylated/MSS mCRC, thus suggesting that the two agents may have synergist activity in line with preclinical data.~Moving from this rationale we designed a phase 2 proof-of-concept trial aimed at evaluating the activity in terms of ctDNA clearance or seroreversion after TEMIRI regimen as a post-adjuvant strategy in patients with MGMT silenced, MSS colorectal cancer (CRC) with positive ctDNA after oxaliplatin-based adjuvant standard chemotherapy.~Eligible patients with MGMT-silenced, MSS, radically resected CRC and detectable ctDNA after standard chemotherapy will be enrolled and will receive 6-month post-adjuvant/consolidation TEMIRI (given for up to 6 monthly cycles).
Surgical resection is curative for 75% of stage II and 50% of stage III colon cancer patients. The magnitude of benefit of adjuvant chemotherapy in terms of disease-free (DFS) and overall survival (OS) varies according to TNM stage and microsatellite status. Standard adjuvant chemotherapy includes fluoropyrimidine and oxaliplatin regimens for up to six months.~Circulating tumor DNA (ctDNA) detected after surgical resection reflects the presence of micrometastatic disease and pivotal observational studies addressed the prognostic value of ctDNA in the post-surgical setting. Adjuvant chemotherapy can promote the clearance of ctDNA, and ctDNA clearance after adjuvant chemotherapy is prognostic for better DFS in patients with stage III resected cancers and post-operative positive ctDNA.~ctDNA may be investigated as a potential real-time surrogate biomarker of the efficacy of adjuvant therapy, but suggest that patients with ctDNA persistence after standard chemotherapy might be molecularly metastatic and may benefit from additional consolidation non-cross resistant strategies aimed at clearing micrometastatic disease.~Temozolomide has modest but non-negligible activity (about 10%) in chemo-refractory patients with MGMT methylated mCRC. The response rate to temozolomide-based therapy in pretreated patients is increased to up to 20% when restricting the focus on those with MGMT IHC-negative/MGMT methylated and MSS cancers Significant activity (ORR 26%) and favorable safety profile were reported by the combination of temozolomide and irinotecan (TEMIRI regimen) in patients with pretreated MGMT methylated/MSS mCRC, thus suggesting that the two agents may have synergist activity in line with preclinical data.~Based on all these considerations, there is a strong rationale for investigating TEMIRI regimen as consolidation non-cross resistant therapy in a liquid-biopsy driven interventional trial.~Eligible patients with MGMT-silenced, MSS, radically resected CRC and detectable ctDNA after standard chemotherapy will be enrolled and will receive 6-month post-adjuvant/consolidation TEMIRI (given for up to 6 monthly cycles).