American Society of Clinical Oncology updated guideline: Adjuvant chemotherapy for stage II colon cancer

Recommendation 1.1. Adjuvant chemotherapy (ACT) should not routinely be offered to patients with stage II colon cancer (type: evidence-based; harms outweigh benefits; evidence quality: moderate; strength of recommendation: strong).

Recommendation 1.2. ACT should not routinely be offered to patients who are at low risk for recurrence, including patients with stage IIA (T3) tumors with at least 12 sampled lymph nodes of the surgical specimen, tumors without perineural or lymphovascular invasion, poor or undifferentiated tumor grade, clinical intestinal obstruction, tumor perforation, and less than grade BD3 tumor budding (type: evidence-based; harms may outweigh benefits; evidence quality: low; strength of recommendation: weak).

Recommendation 1.4. ACT may be offered to patients with stage IIA (ie, T3) colon cancer with high-risk features, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphovascular invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, and/or grade BD3 tumor budding (≥10 buds) (type: evidence-based; benefits may outweigh harms; evidence quality: low; strength of recommendation: weak).

• The number of risk factors should be considered as part of the shared decision-making process. The presence of more than one risk factor may increase the risk of recurrence; in an exploratory analysis of International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration data, the 5-year disease-free survival (DFS) was 74.8% for stage II patients with two or more risk factors, compared with 87.3% for patients with one risk factor.
• Circulating tumor DNA (ctDNA) was identified as an emerging potential predictive factor; however, insufficient evidence of predictive value of chemotherapy was available to warrant its inclusion in the list of high-risk features within the main recommendation. The Expert Panel anticipates that data on ctDNA will be forthcoming through prospective clinical trials and included in a future version of this guideline.
• The Expert Panel notes that there is controversy around the timing of chemotherapy; data on this topic were not reported in the included observational studies. In the MOSAIC trial of oxaliplatin in addition to fluoropyrimidine-based chemotherapy, patients were required to have started ACT within 7 weeks of surgery. In the QUASAR trial of ACT with fluorouracil and folinic acid, therapy was initiated within 6 weeks of surgery, where possible.

Recommendation 2.1. Adjuvant fluoropyrimidine-only chemotherapy is not routinely recommended for patients with exhibit mismatch repair deficiency (dMMR) or high microsatellite instability (MSI) tumors (type: evidence-based; harms outweigh benefits; evidence quality: moderate; strength of recommendation: strong).

• For patients with dMMR or MSI and T4 tumors and/or other high-risk features (with the exception of poor differentiation), oxaliplatin-containing chemotherapy may be considered (refer to Recommendation 3.1, qualifying statements). This qualifying statement is based on indirect evidence of a DFS benefit with the addition of oxaliplatin in the population of patients with stage II or stage III colon cancer in the MOSAIC trial.
• Poor differentiation is not considered a high-risk prognostic factor in patients with dMMR or MSI tumors.
• Patients with proficient mismatch repair/microsatellite stable (pMMR or MSS) tumors are included within guideline Recommendations 1.1-1.4.

Recommendation 3.1. There is insufficient evidence to routinely recommend the addition of oxaliplatin to fluoropyrimidine-based chemotherapy for patients with high-risk stage II colon cancer (type: evidence-based; benefits may outweigh harms; evidence quality: low; strength of recommendation: weak).

• The Expert Panel notes the significant time to recurrence (TTR) benefit with oxaliplatin-containing ACT in exploratory analyses of the MOSAIC trial. The Panel recommends a shared decision-making approach to guide the choice of therapy that includes discussion of potential for benefit and risks of harm with the addition of oxaliplatin to fluoropyrimidine-based chemotherapy.
• As stated in the qualifying statement to Recommendation 2.1, for patients with dMMR or MSI who have T4 tumors and/or other high-risk features (with the exception of poor differentiation), when shared decision-making results in the choice to proceed with ACT, the Expert Panel recommends oxaliplatin-containing chemotherapy. This statement is based on indirect evidence of benefit in the combined population of patients with stage II and III colon cancer.

Recommendation 4.1. In patients who are candidates for adjuvant doublet chemotherapy, adjuvant oxaliplatin-containing chemotherapy may be offered for a duration of 3 or 6 months, after a discussion with the patient of the potential benefits and risks of harm associated with the options for treatment duration (type: evidence-based; benefits outweigh harms; evidence quality: moderate; strength of recommendation: weak).

• Recommendation 4.1 is based on a subgroup analysis of four randomized trials from the IDEA collaboration. The choice of therapy with capecitabine and oxaliplatin (CAPOX) or fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was non-randomized and made by treating clinicians before random assignment to 3 or 6 months duration of treatment. In high-risk stage II patients, 5-year DFS, the primary study outcome, was 81.7% versus 82.0% (p = 0.09) with 3 versus 6 months of CAPOX, respectively (hazard ratio [HR], 1.02; 80% CI, 0.88 to 1.17). The 5-year DFS was 79.2% versus 86.5% (p = 0.88) with 3 versus 6 months of FOLFOX, respectively (HR, 1.41; 80% CI, 1.18 to 1.68). Among all patients, the prevalence of peripheral neuropathy of grade 2 or higher during treatment was 13% versus 36% with 3 months versus 6 months of treatment, respectively. These findings should be considered during the shared decision-making process.