What are the standard hospital‑based medication regimens for rectal adenocarcinoma in the neoadjuvant, adjuvant, and metastatic settings?

Hospital Medication Regimens for Rectal Adenocarcinoma

Neoadjuvant Setting (Before Surgery)

For locally advanced rectal cancer (stage II/III), the standard neoadjuvant approach is fluoropyrimidine-based chemoradiation with either capecitabine or continuous infusion 5-FU, followed by surgery and adjuvant chemotherapy. 1, 2

Standard Neoadjuvant Chemoradiation Regimens

Preferred concurrent chemotherapy options during radiation (45-50 Gy):

• Capecitabine 825 mg/m² twice daily, 5-7 days/week during radiation 3, 1, 2

  • This is the preferred option due to convenience and equivalent efficacy to infusional 5-FU 1

• Continuous infusion 5-FU 225 mg/m² over 24 hours, 7 days/week during radiation 3, 1

• Bolus 5-FU 400 mg/m² IV + leucovorin 20 mg/m² IV for 4 days during weeks 1 and 5 of radiation 3

Critical caveat: Do not add oxaliplatin to concurrent chemoradiation—multiple trials show increased grade 3/4 toxicity without significant DFS or OS benefit 3. The NCCN explicitly states oxaliplatin is not recommended with concurrent radiation 3.

Total Neoadjuvant Therapy (TNT) for High-Risk Disease

For high-risk patients (cT4, EMVI+, threatened mesorectal fascia, or cN2), TNT is the preferred approach, achieving pathologic complete response rates up to 27.5% versus 14% with standard therapy. 3, 1

TNT regimens include:

• FOLFIRINOX (6 cycles) → capecitabine/radiation → surgery 3

  • FOLFIRINOX: oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², 5-FU 400 mg/m² bolus, then 2400 mg/m² over 46 hours every 2 weeks 3

• Short-course radiation (5 × 5 Gy) → FOLFOX (6-9 cycles) → surgery 3, 1

  • FOLFOX: oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-FU 400 mg/m² bolus, then 2400 mg/m² over 46 hours every 2 weeks 3

• CAPOX (4 cycles) → short-course radiation → surgery 3

  • CAPOX: oxaliplatin 130 mg/m² day 1, capecitabine 1000 mg/m² twice daily days 1-14, every 3 weeks 3

Surgery should occur 7-8 weeks after completing chemoradiation to optimize pathologic response. 1

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Adjuvant Setting (After Surgery)

All patients with stage II/III rectal cancer must receive adjuvant chemotherapy after neoadjuvant chemoradiation and surgery, regardless of pathologic response, including those with pathologic complete response. 1, 2, 4

Adjuvant Chemotherapy Regimens

For higher-risk patients (ypN+, inadequate response, or high-risk features):

• FOLFOX for 4 months (8 cycles) 4

  • Oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-FU 400 mg/m² bolus, then 2400 mg/m² over 46 hours every 2 weeks 3

• CAPOX for 4 months (6 cycles) 4

  • Oxaliplatin 130 mg/m² day 1, capecitabine 1000 mg/m² twice daily days 1-14, every 3 weeks 3

For lower-risk patients or those with good response to neoadjuvant fluoropyrimidine:

• 5-FU 500 mg/m² IV bolus + leucovorin 500 mg/m² IV over 2 hours, once weekly for 6 weeks × 3 cycles 3, 4

  • Each cycle = 6 weeks on, 2 weeks off 3

• Capecitabine 1250 mg/m² twice daily days 1-14 every 3 weeks for 6 months total perioperative therapy 3, 4

Critical timing: Start adjuvant chemotherapy as soon as medically able after surgery—each 4-week delay decreases overall survival by 14% 4. Total perioperative treatment duration should not exceed 6 months 1, 4.

Common pitfall: Only 61.5-76.6% of eligible patients receive adjuvant chemotherapy in real-world practice 4. Factors preventing completion include postoperative complications, advanced age, and poor performance status 4, 5.

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Metastatic Setting (Stage IV)

For metastatic rectal cancer, combination chemotherapy with FOLFOX, FOLFIRI, or CAPOX ± biologic agents is standard, with regimen selection based on KRAS/RAS mutation status and resectability of metastases. 3

First-Line Metastatic Regimens

For potentially resectable metastases:

• FOLFOX or FOLFIRI or CAPOX for 2-3 months, then re-evaluate for conversion to resectable disease every 2 months 3

• FOLFOX or FOLFIRI or CAPOX + bevacizumab 3

  • Bevacizumab requires ≥6 week interval before elective surgery due to wound healing concerns 3

• FOLFOX or FOLFIRI or CAPOX + cetuximab (KRAS/RAS wild-type only) 3

For unresectable metastases:

• FOLFIRI: irinotecan 180 mg/m², leucovorin 400 mg/m², 5-FU 400 mg/m² bolus, then 2400 mg/m² over 46 hours every 2 weeks 3

• FOLFOX: oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-FU 400 mg/m² bolus, then 2400 mg/m² over 46 hours every 2 weeks 3

• CAPOX: oxaliplatin 130 mg/m² day 1, capecitabine 1000 mg/m² twice daily days 1-14, every 3 weeks 3

Critical caveat: FOLFIRINOX is not recommended in the metastatic rectal cancer setting 3. For synchronous metastases, consider staged or synchronous resection of both primary and metastatic disease 3.

Targeted therapy selection: Check KRAS/RAS mutation status before adding cetuximab or panitumumab—these agents are only effective in wild-type tumors and increase toxicity without benefit in mutated tumors 3.