Preop vs postop chemo

Background

German CAO/ARO/AIO-94 phase III RCT in 823 patients with clinical stage T3/T4 or node-positive resectable rectal adenocarcinoma, inferior margin <16 cm from the anal verge, comparing preoperative versus postoperative chemoradiotherapy.

Interventions and follow up

Arm A: Preoperative chemoradiotherapy (5-FU 1000 mg/m²/d 120-h infusion weeks 1 and 5 + 50.4 Gy) >> total mesorectal excision >> 4 cycles adjuvant 5-FU bolus 500 mg/m²/d x5d
Arm B: Total mesorectal excision >> postoperative chemoradiotherapy (5-FU + 55.8 Gy) >> 4 cycles adjuvant 5-FU
Primary endpoint: Overall survival
Median follow up: 46 mo

Results

5-yr OS: 76% vs 74% (Arm A vs B), P=.80
5-yr cumulative local relapse: 6% vs 13% (Arm A vs B), P=.006
Sphincter preservation (among those judged to require APR): 39% vs 19%, P=.004

Adverse events

Acute (grade 3-4): 27% vs 40% (Arm A vs B), P=.001
Long-term (grade 3-4): 14% vs 24%, P=.01; long-term GI 9% vs 15%, P=.07
Anastomotic strictures: 4% vs 12%, P=.003

Conclusions

Preoperative chemoradiotherapy reduced local recurrence, lowered acute and long-term toxicity, and improved sphincter preservation compared with postoperative chemoradiotherapy, without affecting overall survival. This established neoadjuvant chemoradiation as the standard for locally advanced rectal cancer.

Key Limitations

No overall survival benefit at the primary endpoint. Used 5-FU rather than modern oxaliplatin-based or total neoadjuvant regimens. About 18% of patients assigned to postoperative therapy were found to have early-stage disease, indicating preoperative clinical overstaging.

Clinical Context

This trial defined neoadjuvant 5-FU chemoradiation plus TME as the standard of care for locally advanced rectal cancer, endorsed by ESMO. Subsequent trials (PRODIGE 23, RAPIDO) have advanced the field toward total neoadjuvant therapy.

References

Sauer R, NEJM, 2004, PMID: 15496622
Long-term: Sauer R et al, JCO, 2012, PMID: 22529255