What is the recommended neoadjuvant chemotherapy regimen for patients with stage II or III rectal cancer?

Neoadjuvant Chemotherapy for Stage II/III Rectal Cancer

For patients with stage II or III rectal cancer, the recommended approach is fluoropyrimidine-based chemotherapy (capecitabine or 5-FU) concurrent with radiation therapy (45-50 Gy), followed by surgery and adjuvant chemotherapy with FOLFOX or CAPEOX for higher-risk patients. 1, 2

Standard Neoadjuvant Chemoradiation Regimen

The cornerstone of treatment combines radiation with concurrent chemotherapy 1:

• Capecitabine is the preferred chemotherapy agent due to its oral convenience and equivalent efficacy to continuous infusion 5-FU, with demonstrated improved 3-year disease-free survival 1, 2
• Continuous infusion 5-FU remains an acceptable alternative, though it carries higher risk of hematologic toxicity 1
• Radiation dose: 45-50 Gy delivered over 25-28 fractions (1.8-2.0 Gy per fraction) 3

Risk-Stratified Treatment Selection

Treatment intensity should be tailored to recurrence risk 3:

Low-Risk Patients (cT3N0-1, MRF−, EMVI−)

• May consider selective neoadjuvant chemotherapy alone with FOLFOX for 5-6 cycles 3
• Surgery plus adjuvant chemotherapy is acceptable for very low-risk tumors (T3a/b with <5mm invasion beyond muscle layer, peritoneum covered) 3

High-Risk Patients (cT4, cN2, MRF+, EMVI+, lateral lymph nodes+)

• Total neoadjuvant therapy (TNT) is recommended: prolonged chemoradiation followed by consolidation chemotherapy with FOLFOX or CAPEOX for 12-16 weeks before surgery 1, 2
• TNT achieves higher pathological complete response rates (up to 27.5% with FOLFOX/RT versus 14% with 5-FU/RT alone) 3, 1

Short-Course Radiotherapy Option

For select patients 3:

• 25 Gy in 5 fractions may be used for cT3 tumors without sphincter preservation requirements
• Surgery should occur within 1 week for low-risk patients 3
• For high-risk patients, add consolidation chemotherapy after short-course RT before surgery 3

Timing Considerations

Critical intervals affect outcomes 3, 1:

• Surgery should occur 5-12 weeks after completing full-dose chemoradiation to allow recovery from toxicity while optimizing pathological response 3
• The GRECCAR6 trial showed that extending the interval to 11 weeks increased morbidity (44.5% vs 32%) and medical complications without improving pathological complete response rates 3
• Optimal interval is 7-8 weeks to balance response optimization with surgical outcomes 1, 2

Adjuvant Chemotherapy (Post-Surgery)

All patients with stage II/III rectal cancer must receive adjuvant chemotherapy regardless of pathological response 1, 4, 2:

• FOLFOX or CAPEOX for 4 months is preferred for higher-risk patients 4
• 5-FU/LV or capecitabine alone is acceptable for lower-risk patients who responded well to neoadjuvant fluoropyrimidine 4
• Total perioperative treatment duration should not exceed 6 months 3, 1

Chemotherapy Without Radiation (Emerging Approach)

For highly selected low/intermediate-risk patients 3, 5:

• FOLFOX alone for 5-6 cycles may be considered for mid-upper rectal cancer without sphincter preservation concerns 3
• The FOWARC trial showed FOLFOX without RT achieved lower pathological complete response (6.6%) compared to FOLFOX/RT (27.5%), but acceptable R0 resection rates (90-100%) 3
• A 2023 study of CAPOX alone in low/intermediate-risk patients achieved 82.6% disease-free survival at median 40-month follow-up 5
• If tumor regression is <20% after 5-6 cycles, add concurrent chemoradiotherapy 3

Critical Pitfalls to Avoid

• Do not omit adjuvant chemotherapy in patients achieving pathological complete response—they still benefit from systemic therapy 4, 2
• Avoid delays in initiating adjuvant chemotherapy—each 4-week delay decreases overall survival by 14% 4
• Monitor for oxaliplatin-induced peripheral neuropathy—it is cumulative and dose-limiting; reduce or discontinue if grade 2-3 neuropathy develops 4
• Only 61.5-76.6% of eligible patients receive recommended adjuvant chemotherapy in real-world practice due to complications, age, and performance status barriers 1, 4

Special Populations

For MSI-H/dMMR stage III rectal cancer, immunotherapy with dostarlimab is preferred over standard total neoadjuvant therapy 4. The UNION phase III trial demonstrated that sequential short-course radiotherapy, immunotherapy, and chemotherapy significantly improved pathological complete response rates in pMMR/MSS patients, though long-term efficacy data are pending 3.