Benefits and Recommended Regimens of Preoperative Chemotherapy in the FOxTROT Trial for High-Risk Colon Cancer
Preoperative oxaliplatin-fluoropyrimidine chemotherapy for 6 weeks followed by surgery and additional postoperative chemotherapy is recommended for patients with locally advanced colon cancer, as it significantly reduces the risk of residual disease or recurrence within 2 years compared to standard postoperative chemotherapy alone. 1
Benefits of Preoperative Chemotherapy in FOxTROT Trial
- Preoperative chemotherapy for radiologically staged, locally advanced operable primary colon cancer is feasible with acceptable toxicity and perioperative morbidity 2
- Neoadjuvant chemotherapy produces marked tumor downstaging (T and N) and histologic tumor regression (p<0.001) 1
- Resection is more often histopathologically complete with neoadjuvant therapy: 94% vs 89% in the control group (p<0.001) 1
- Fewer patients receiving neoadjuvant chemotherapy had residual or recurrent disease within 2 years (16.9% vs 21.5%; rate ratio 0.72; p=0.037) 1
- Significant reduction in apical node involvement (1% vs 20%, p<0.0001) and resection margin involvement (4% vs 20%, p=0.002) 2
- Histologic tumor regression after neoadjuvant chemotherapy strongly predicts lower postoperative recurrence risk, potentially guiding postoperative therapy decisions 1
Recommended Regimen from FOxTROT Trial
- Primary Regimen: 6 weeks of oxaliplatin-fluoropyrimidine (OxFp) chemotherapy preoperatively, followed by surgery and 18 weeks of additional postoperative chemotherapy 1
- The specific regimen used was OxMdG: oxaliplatin 85 mg/m², l-folinic acid 175 mg, fluorouracil 400 mg/m² bolus, then 2400 mg/m² by 46-hour infusion, repeated at 2-weekly intervals 2
- For patients with RAS wild-type tumors, panitumumab was evaluated but did not enhance the benefit from neoadjuvant chemotherapy 1
Patient Selection for Preoperative Chemotherapy
- Appropriate for patients with radiologically staged locally advanced (T3 with ≥5 mm invasion beyond the muscularis propria or T4) tumors 2
- CT colonography can be used for preoperative local staging of higher-risk colon cancers to identify candidates for neoadjuvant chemotherapy based on FOxTROT criteria 3
- Little benefit was observed in mismatch repair-deficient tumors, suggesting this approach may be less effective for this subgroup 1
Safety and Compliance
- 96% of patients allocated to neoadjuvant chemotherapy started treatment and 87% completed the preoperative course 1
- Grade 3-4 gastrointestinal toxicity occurred in only 7% of patients during preoperative chemotherapy 2
- No significant differences in postoperative morbidity between the preoperative and control groups (14% vs 12% had complications prolonging hospital stay, p=0.81) 2
- Fewer serious postoperative complications were observed in the neoadjuvant group compared to the control group 1
- Only 4.3% of patients allocated to neoadjuvant chemotherapy developed obstructive symptoms requiring expedited surgery 1
Future Directions
- FOxTROT2 will investigate neoadjuvant chemotherapy in older adults and those with frailty, using dose-adapted neoadjuvant OxFp versus straight-to-surgery approach 4
- FOxTROT3 will assess whether intensified triplet neoadjuvant chemotherapy (modified oxaliplatin, 5-fluorouracil and irinotecan) provides additional benefits over OxFp 4
- These trials will establish the FOxTROT platform to optimize the use of neoadjuvant chemotherapy in colon cancer 4
Clinical Implementation Considerations
- Oxaliplatin-based regimens (FOLFOX/CAPEOX) are preferred for neoadjuvant therapy, with duration typically limited to 2-3 months to minimize drug-induced liver damage 5
- During treatment with preoperative chemotherapy, frequent evaluations must be undertaken to optimize timing of surgical intervention 6
- Neoadjuvant chemotherapy allows for earlier treatment of micrometastatic disease and determination of tumor responsiveness to chemotherapy (prognostic value) 5
- Neoadjuvant chemotherapy can be administered more completely and with better compliance before surgery, compared to postoperative adjuvant treatment 5
Potential Pitfalls and Caveats
- Potential disadvantage includes missing the "window of opportunity" for resection due to disease progression or complete response making it difficult to identify areas for resection 6
- Risk of developing liver steatohepatitis and sinusoidal liver injury with oxaliplatin-based regimens, requiring careful monitoring by a multidisciplinary team 6
- Accurate radiological staging is crucial for patient selection - CT colonography shows substantial interreader agreement (κ = 0.68) for classifying high-risk tumors but moderate agreement for nodal staging (κ = 0.44) 3
- Unlike rectal cancer, where neoadjuvant chemoradiotherapy is well-established, colon cancer has traditionally not utilized preoperative therapy, so this represents a paradigm shift in treatment approach 5