What is the preferred initial treatment approach between neoadjuvant chemoradiotherapy (NACTRT) and short-course radiotherapy (SCRT) for patients with locally advanced rectal cancer?

Treatment Selection Between NACTRT and SCRT for Locally Advanced Rectal Cancer

For most patients with locally advanced rectal cancer, long-course neoadjuvant chemoradiotherapy (NACTRT) is preferred over short-course radiotherapy (SCRT) when radiation is included in the treatment plan, primarily due to superior long-term local control. 1

Risk-Stratified Treatment Algorithm

High-Risk Features (TNT with Long-Course CRT Strongly Recommended)

Patients with ANY of the following high-risk features should receive total neoadjuvant therapy (TNT) with long-course chemoradiotherapy rather than SCRT: 1, 2

• Low rectal tumors (particularly those requiring potential abdominoperineal resection) 1, 2
• T4 tumors 1, 2
• Extramural vascular invasion (EMVI) positive 1, 2
• Tumor deposits identified on MRI 1, 2
• Threatened mesorectal fascia (MRF+) 1, 2
• Threatened intersphincteric plane 1
• cN2 disease 1, 2
• Enlarged lateral lymph nodes 1, 2

Evidence Supporting Long-Course CRT Over SCRT

The RAPIDO trial's 5-year follow-up data revealed a critical finding: short-course RT-based TNT resulted in 10% locoregional failure compared to 6% with standard long-course chemoradiotherapy (RR 1.45,95% CI 0.97-2.17). 1, 2 While this difference did not reach statistical significance, the numerically higher failure rate with SCRT is clinically meaningful, particularly for patients where local control is paramount. 1

Long-course chemoradiotherapy followed by consolidation chemotherapy is the preferred TNT regimen because it provides superior local control while maintaining the systemic benefits of total neoadjuvant therapy. 1, 2

When SCRT May Be Considered

SCRT followed by consolidation chemotherapy may be a viable alternative in specific circumstances: 1

• Logistical constraints where initiating radiation therapy is significantly delayed compared to chemotherapy 1
• Lower-risk T3 tumors without high-risk features, particularly when surgery is planned within 1 week of completing SCRT 1
• Patient preference after thorough discussion of the trade-offs between treatment duration and local control outcomes 1

However, even in these scenarios, the Chinese Society of Clinical Oncology recommends that high-risk patients (cT4a/b, EMVI+, cN2, MRF+, positive lateral lymph nodes) should receive consolidation chemotherapy after SCRT rather than immediate surgery. 1

Critical Pre-Treatment Assessment Requirements

Before making the NACTRT versus SCRT decision, ALL patients must undergo: 1, 2

• High-resolution pelvic MRI with dedicated rectal sequence assessing tumor relation to anal verge, sphincter complex, mesorectal fascia, EMVI status, tumor deposits, and lymph nodes 1, 2
• Standardized synoptic MRI reporting to ensure consistent risk stratification 1
• MSI/MMR status assessment (MSI-H/dMMR patients should receive immunotherapy instead) 1, 2

Outcomes Comparison

TNT with long-course CRT demonstrates superior survival outcomes compared to standard neoadjuvant CRT alone: 1

• 5-year overall survival: HR 0.78 (95% CI 0.62-0.97), translating to 158 deaths per 1,000 patients versus 198 per 1,000 with standard CRT 1
• Pathologic complete response: 22.4% with TNT versus 14.3% with standard CRT (RR 1.74,95% CI 1.45-2.10) 1
• 5-year disease-related treatment failure: HR 0.79 (95% CI 0.63-1.00) 1

Toxicity Considerations

Long-course chemoradiotherapy has a more favorable acute toxicity profile compared to SCRT-based TNT: 1

• Grade 3+ toxicity during neoadjuvant therapy: 35.9% with TNT versus 23% with standard CRT (RR 1.56,95% CI 1.18-2.07) 1
• Most common severe toxicities with TNT: neutropenia (20.3%), pain (3.1%), hypertension (2.9%) 1
• Grade 1-2 neuropathy at 6 months: 33.4% with TNT versus 22% with standard CRT (RR 1.52,95% CI 1.19-1.95) 1

SCRT-specific toxicity includes higher rates of grade 2 proctitis (27% in one series), though this is generally manageable. 3

Common Pitfalls to Avoid

Do not select treatment based solely on radiographic nodal assessment (cN stage) as clinical lymph node staging has limited accuracy. 1 Instead, use the constellation of MRI risk factors listed above. 1

Do not use SCRT for patients seeking organ preservation/watch-and-wait approaches. 1 Long-course chemoradiotherapy is more appropriate when the goal is achieving clinical complete response for potential non-operative management. 1, 2

Do not prescribe concurrent targeted agents with SCRT. 1 The Chinese guidelines explicitly recommend against concurrent use of chemotherapy drugs and targeted drugs with short-course radiotherapy. 1