What are the guidelines for neoadjuvant chemoradiotherapy (NACTRT) for rectal cancer?

Neoadjuvant Chemoradiotherapy for Rectal Cancer

For locally advanced rectal cancer (stage II/III, cT3-4 or node-positive disease), preoperative chemoradiotherapy with fluoropyrimidine-based chemotherapy (capecitabine or continuous infusion 5-FU) concurrent with radiation therapy is the standard approach, followed by total mesorectal excision surgery and adjuvant chemotherapy. 1

Risk-Stratified Treatment Approach

Good Prognosis ("Good" Tumors)

• cT1-2, N0 tumors: Proceed directly to transanal excision or total mesorectal excision (TME) without neoadjuvant therapy 1
• Upper rectal cancers (>12 cm from anal verge, above peritoneal reflection) should be treated as colon cancer without preoperative radiation 1

Intermediate Risk ("Bad" Tumors)

• cT3 with clear mesorectal fascia (MRF), cN0-1: Either short-course preoperative radiotherapy (SCPRT: 5 × 5 Gy) or standard chemoradiotherapy followed by TME 1
• If clinical complete response (cCR) achieved after CRT, 'watch-and-wait' may be considered in high-risk surgical candidates 1

High Risk ("Ugly" Tumors)

• cT3 with MRF involvement, any cT4a/b, or lateral node-positive disease: Preoperative CRT followed by surgery (TME ± extended resection) 1
• Alternative: SCPRT (5 × 5 Gy) plus FOLFOX with delayed surgery 1
• For fragile/elderly patients or those with severe comorbidity who cannot tolerate CRT: 5 × 5 Gy alone with delayed surgery 1

Chemotherapy Regimens During Radiation

Preferred Options

• Capecitabine: 825 mg/m² orally twice daily on radiation days 1

  • Demonstrated non-inferiority to 5-FU with improved 3-year DFS (75.2% vs 66.6%, p=0.034) 1
  • Superior side effect profile: less weight loss (2.2% vs 17.0%, p=0.00067), less nausea/vomiting (15.4% vs 38.3%, p=0.00045) 2
  • Higher complete tumor regression rates (25.3% vs 13.8%, p=0.049) 2

• Continuous infusion 5-FU: Standard dosing during pelvic radiation 1

Alternative Option

• Bolus 5-FU/leucovorin: Only for patients unable to tolerate capecitabine or infusional 5-FU 1
  • Associated with greater hematologic toxicity compared to infusional regimens 1

NOT Recommended

• Oxaliplatin as radiosensitizer: Not routinely recommended to be added to fluoropyrimidine-based CRT 1
  • May slightly increase pathological complete response rates but enhances acute toxicity without clear long-term oncological benefit 1

Radiation Dosing

Standard Long-Course CRT

• 50.4 Gy in 28 fractions (1.8 Gy per fraction) with optional tumor bed boost of 3 × 1.8 Gy 2
• Recent evidence supports dose escalation to 54 Gy in 25 fractions using VMAT-SIB technique 3
  • Improved pathological complete response (20.6% vs 8.9%, p=0.06) 3
  • Higher sphincter preservation rates (77.8% vs 62.5%) 3
  • Significantly more T0-2 stages and lower overall stages post-operatively (p<0.05) 3

Short-Course RT

• 5 × 5 Gy (25 Gy total) for selected patients 1
• Can be combined with FOLFOX and delayed surgery for advanced disease 1

Timing of Surgery

Surgery should be performed 8-12 weeks after completion of neoadjuvant CRT 1, 4

• Delaying surgery ≥12 weeks is safe and does not increase surgical morbidity, conversion rates, or anastomotic leak rates 4
• Allows for maximal tumor regression and identification of clinical complete responders for potential watch-and-wait approach 1, 4
• No difference in operation time, blood loss, length of stay, or 30-day mortality when surgery delayed beyond 12 weeks 4

Adjuvant Chemotherapy Post-Surgery

All patients with stage II/III rectal cancer should receive adjuvant chemotherapy after neoadjuvant CRT and surgery, regardless of pathological response 1

Regimen Selection Based on Risk

Higher-risk patients (initial cT3-4, N+, threatened CRM):

• FOLFOX or CAPEOX as preferred options 1
• CAO/ARO/AIO-04 trial showed improved 3-year DFS with oxaliplatin addition (75.9% vs 71.2%, p=0.03) 1
• ADORE trial demonstrated higher 3-year DFS with FOLFOX (71.6% vs 62.9%, HR 0.66, p=0.047) 1

Lower-risk patients or those responding well to neoadjuvant 5-FU/capecitabine:

• 5-FU/leucovorin or capecitabine alone are acceptable options 1

Duration and Timing

• Start adjuvant chemotherapy as soon as medically able post-operatively 1
  • Each 4-week delay results in 14% decrease in overall survival 1
• Duration: 4 months when preoperative CRT administered (extrapolated from 6-month MOSAIC trial in colon cancer) 1

Special Consideration: Pathological Complete Response

• Patients achieving pCR after neoadjuvant CRT have excellent outcomes even without adjuvant chemotherapy (5-year DFS 96%, OS 100%) 1
• However, adjuvant chemotherapy is still recommended as NCDB analyses show improved overall survival with adjuvant therapy even in pCR patients 1

Watch-and-Wait Approach

• May be considered in patients achieving clinical complete response (cCR) after CRT, occurring in 10-40% of patients assessed 12 weeks post-treatment 1
• Requires: experienced multidisciplinary team, careful patient selection, vigilant surveillance, and immediate resection capability for recurrences 1
• Assessment methods: digital rectal exam, proctoscopy, and MRI 1
• Caution: Neither FDG-PET, MRI, nor CT can accurately determine pCR; lymph node metastases still present in subset of patients with apparent cCR 1