Adjuvant Treatment for Colon Cancer with Mismatch Repair Deficiency
For a patient with colon cancer who has undergone right hemicolectomy and has mismatch repair (MMR) gene mutation (deficient MMR/dMMR), observation without adjuvant chemotherapy is recommended for stage II disease, while stage III disease warrants adjuvant chemotherapy with FOLFOX or similar regimens despite the dMMR status.
Stage-Specific Treatment Algorithm
Stage II Colon Cancer with dMMR
Observation is the preferred approach for stage II dMMR colon cancer, as these patients have excellent prognosis and do not benefit from 5-fluorouracil-based adjuvant therapy 1.
The ASCO guideline explicitly states there is very low-quality evidence (with considerable heterogeneity) showing uncertainty whether adjuvant chemotherapy improves or worsens disease-free survival (DFS) or overall survival (OS) for patients with dMMR or MSI-high tumors 1.
dMMR tumors have approximately half the recurrence risk of proficient MMR (pMMR) tumors and demonstrate relatively higher survival rates, making the risk-benefit ratio of chemotherapy unfavorable 1.
Stage II MSI-high patients may have good prognosis and do not benefit from 5-FU adjuvant therapy 1.
Stage III Colon Cancer with dMMR
FOLFOX (5-FU/leucovorin/oxaliplatin) is recommended for stage III dMMR colon cancer, as the 2015 MOSAIC study update demonstrated benefit even in dMMR tumors 2.
The hazard ratios for DFS and OS benefit with FOLFOX in stage II-III dMMR patients were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively 2.
Distant recurrences were reduced by 5-FU-based adjuvant treatment in dMMR stage III tumors (11% vs 29%; P = .011) 3.
The updated MOSAIC 10-year survival data support the use of FOLFOX in patients with stage III disease, including those with dMMR 2.
High-Risk Stage II Disease Exception
Consider adjuvant chemotherapy for stage II dMMR tumors with T4 stage (including perforation), as T4 tumors were identified as independent prognostic factors for survival even in dMMR patients 4.
Other high-risk features include: lymph node sampling <12, high-grade tumor, vascular invasion, lymphatic invasion, perineural invasion, bowel obstruction, or high preoperative CEA levels 1.
For high-risk stage II dMMR patients who receive chemotherapy, fluoropyrimidine monotherapy without oxaliplatin is reasonable, as there is insufficient evidence to routinely recommend oxaliplatin addition in stage II disease 1.
Recommended Regimen Details
FOLFOX is the preferred regimen for stage III disease: oxaliplatin 85 mg/m² IV over 2 hours on Day 1, leucovorin 200 mg/m² IV over 2 hours on Days 1-2, fluorouracil 400 mg/m² IV bolus followed by 600 mg/m² as 22-hour continuous infusion on Days 1-2, repeated every 2 weeks 5.
Treatment duration is 6 months (12 cycles) for adjuvant therapy or until unacceptable toxicity 5.
Alternative regimens include FLOX or CapeOx (capecitabine plus oxaliplatin) 1.
Critical Caveats and Pitfalls
Do not use bevacizumab, cetuximab, panitumumab, or irinotecan in the adjuvant setting outside of clinical trials 1, 6.
Confirm MMR status by immunohistochemistry (detecting loss of MLH1, MSH2, MSH6, or PMS2 expression) or by PCR assays for microsatellite instability 1.
Rule out Lynch syndrome: MSH2 and/or MSH6 loss indicates suspicion of Lynch syndrome, while MLH1 and PMS2 loss requires further investigation with BRAF mutation or MLH1 promoter hypermethylation testing 1.
Monitor for oxaliplatin-specific toxicities: peripheral sensory neuropathy (reduce dose to 75 mg/m² for persistent Grade 2, discontinue for Grade 3-4), myelosuppression, and hypersensitivity reactions 5.
The benefit of oxaliplatin in patients age 70 and older has not been proven, and grade 3-4 diarrhea is considerably higher with FLOX than FOLFOX 1.
Prognostic Context
dMMR is independently associated with improved outcomes: delayed time to recurrence (HR 0.72,95% CI 0.56-0.91, P=.005), improved DFS (P=.035), and improved OS (P=.031) compared to pMMR tumors 3.
Five-year recurrence rates are significantly lower for dMMR versus pMMR tumors (22% vs 33%; P<.001) 3.
dMMR tumors have fewer distant recurrences (12% vs 22%; P<.001) compared to pMMR tumors 3.