First-Line Treatment for Metastatic MMR-Proficient Sigmoid Colon Cancer
For metastatic microsatellite stable (pMMR) sigmoid colon cancer with adequate performance status, the recommended first-line treatment is a fluoropyrimidine doublet (FOLFOX or FOLFIRI) combined with bevacizumab, with the choice between oxaliplatin and irinotecan guided by toxicity profiles and patient factors. 1
Primary Treatment Options
Standard Doublet Chemotherapy Plus Bevacizumab
FOLFOX (5-fluorouracil/leucovorin/oxaliplatin) plus bevacizumab is a Level I, Grade A recommendation for first-line therapy in pMMR metastatic colorectal cancer 1
FOLFIRI (5-fluorouracil/leucovorin/irinotecan) plus bevacizumab is equally effective as FOLFOX plus bevacizumab, with both doublets considered equivalent in efficacy 1, 2
The specific FOLFIRI dosing is: irinotecan 180 mg/m² IV over 30-90 minutes day 1, leucovorin 400 mg/m² IV over 2 hours day 1,5-FU 400 mg/m² IV bolus day 1 followed by 1,200 mg/m²/day continuous infusion over 46-48 hours, plus bevacizumab 5 mg/kg IV every 2 weeks 2
Selection Between FOLFOX and FOLFIRI
Choose FOLFOX if you want to avoid early-onset diarrhea or if the patient has risk factors for irinotecan toxicity (Gilbert's disease, elevated bilirubin, UGT1A1*28 homozygosity) 3
Choose FOLFIRI if you want to avoid cumulative peripheral neuropathy or if the patient has pre-existing neuropathy, as FOLFIRI lacks cumulative toxicity and can be continued full-dose until progression 1, 2
For left-sided sigmoid tumors (which this is), both regimens are appropriate; tumor sidedness primarily affects anti-EGFR antibody selection, not chemotherapy backbone choice 1
Triplet Chemotherapy for Selected Patients
FOLFOXIRI (5-FU/leucovorin/oxaliplatin/irinotecan) plus bevacizumab is recommended for highly selected fit patients (ECOG 0-1) without significant comorbidities who require maximal tumor shrinkage 1
This triplet regimen achieves superior response rates and progression-free survival compared to FOLFIRI plus bevacizumab (Level I, Grade B evidence; ESMO-MCBS score: 2) 1
The increased toxicity of FOLFOXIRI limits its use to patients who can tolerate intensive therapy and where aggressive cytoreduction is the goal 1
Why Bevacizumab Over Anti-EGFR Antibodies
Bevacizumab is preferred over anti-EGFR antibodies (cetuximab/panitumumab) for pMMR metastatic colorectal cancer regardless of RAS mutation status, as it can be combined with any chemotherapy backbone and continued through multiple lines 1
Anti-EGFR antibodies are only appropriate for RAS wild-type, BRAF wild-type, left-sided tumors where maximal tumor shrinkage is required, and even then bevacizumab remains a valid alternative 1
For sigmoid (left-sided) tumors that are RAS wild-type, anti-EGFR antibodies combined with chemotherapy doublet achieve ESMO-MCBS scores of 3-4, but bevacizumab offers broader applicability and can be continued beyond first progression 1
Molecular Testing Requirements
Confirm RAS mutation status (KRAS and NRAS exons 2,3, and 4) before considering anti-EGFR therapy, though this does not affect bevacizumab use 1
Test for BRAF V600E mutation, as BRAF-mutant tumors have worse prognosis and may benefit from different strategies in later lines 1
Verify MMR proficiency/MSI status is already established (pMMR/MSS in this case), which excludes immunotherapy as first-line option 1
Treatment Duration and Maintenance
Continue full-dose FOLFIRI plus bevacizumab until disease progression or unacceptable toxicity, as irinotecan lacks cumulative toxicity 1, 2
For FOLFOX-based regimens, after 4-6 months consider maintenance with fluoropyrimidine plus bevacizumab to avoid cumulative oxaliplatin neuropathy (Level I, Grade B) 1
Maintenance with bevacizumab alone (without fluoropyrimidine) is non-inferior to fluoropyrimidine plus bevacizumab but may be less preferable as it provides less disease control time 4
Critical Pitfalls to Avoid
Never use capecitabine plus irinotecan (CAPIRI) on standard 3-weekly dosing, as it has excessive toxicity compared to FOLFIRI; only dose-modified CAPIRI (capecitabine 1600 mg/m²/day × 14 days, irinotecan 200 mg/m² day 1 q3 weeks) is acceptable 1
Never combine bevacizumab with anti-EGFR antibodies (cetuximab or panitumumab) in first-line therapy, as this increases toxicity without improving outcomes 1, 2, 5
Never stop irinotecan early for "maintenance" as you would with oxaliplatin—continue full-dose FOLFIRI until progression due to lack of cumulative toxicity 1, 2
Do not use bolus 5-FU schedules with irinotecan—only infusional 5-FU is appropriate with irinotecan-based regimens 2
Performance Status Considerations
These combination regimens require ECOG performance status 0-2 with adequate organ function 2
For frail or elderly patients unable to tolerate doublet chemotherapy, consider fluoropyrimidine monotherapy plus bevacizumab (Level I, Grade B) 1
Capecitabine (oral) and infusional 5-FU are considered equivalent fluoropyrimidines, with capecitabine offering convenience but requiring dose adjustment for renal impairment 1
Evidence Quality Note
The 2023 ESMO guidelines 1 represent the most current and comprehensive recommendations, superseding the 2014 ESMO guidelines 1. The pMMR population shows clear benefit from chemotherapy plus bevacizumab, with hazard ratios for progression-free survival consistently favoring combination therapy over monotherapy (HR 0.76-0.83 for doublets vs. monotherapy in pMMR patients) 1. The evidence consistently demonstrates that pMMR tumors respond well to standard chemotherapy, unlike dMMR tumors which show poor response to conventional cytotoxic therapy 1.