Background
Phase III RCT (CROSS — ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study). 366 patients with clinically resectable, locally advanced cancer of the esophagus or esophagogastric junction (cT1N1M0 or cT2-3N0-1M0; 6th edition TNM). 75% adenocarcinoma, 23% squamous cell carcinoma. Eight centers in the Netherlands. This is the long-term outcomes report after minimum 5-year follow-up.
Interventions and follow up
Arm A: Neoadjuvant chemoradiotherapy (carboplatin AUC2 + paclitaxel 50 mg/m² weekly × 5, concurrent with 41.4 Gy in 23 fractions of 1.8 Gy, 5 days/week) followed by esophagectomy
Arm B: Surgery alone
Primary endpoint: Overall survival
mFollow up: Median 84.1 months (surviving patients)
Arm B: Surgery alone
Primary endpoint: Overall survival
mFollow up: Median 84.1 months (surviving patients)
Results
Median OS: 48.6 mo (nCRT+surgery) vs 24.0 mo (surgery alone), HR 0.68 (95% CI 0.53–0.88), P=.003
5-year OS (SCC): 60% vs 24%, HR 0.48, P=.008
5-year OS (adenocarcinoma): ~42% vs ~33%, HR 0.73, P=.038
Pathologic complete response (pCR) rate: 29% overall (47% SCC, 23% adenocarcinoma)
R0 resection rate: 92% (nCRT+surgery) vs 69% (surgery alone)
5-year OS (SCC): 60% vs 24%, HR 0.48, P=.008
5-year OS (adenocarcinoma): ~42% vs ~33%, HR 0.73, P=.038
Pathologic complete response (pCR) rate: 29% overall (47% SCC, 23% adenocarcinoma)
R0 resection rate: 92% (nCRT+surgery) vs 69% (surgery alone)
Adverse events
Main adverse events: Neoadjuvant CRT: hematologic toxicity (leukopenia grade 3-4 in 6%), nausea, fatigue. No significant increase in postoperative mortality (4% vs 4%). Well-tolerated weekly carboplatin/paclitaxel regimen with acceptable toxicity profile. 95% of patients completed the full RT course.
Conclusions
Neoadjuvant chemoradiotherapy with carboplatin/paclitaxel and 41.4 Gy followed by surgery significantly improves OS in resectable locally advanced esophageal cancer compared to surgery alone, with OS benefit seen in both SCC and adenocarcinoma. CROSS is the definitive RCT establishing neoadjuvant CRT as standard of care for resectable esophageal cancer.
Key Limitations
Key Limitations: Dutch single-country trial; surgical expertise may not be generalizable. OS benefit is more pronounced for SCC than adenocarcinoma (HR 0.48 vs 0.73); for adenocarcinoma, perioperative chemotherapy (FLOT4) is an alternative standard. 41.4 Gy is lower than some institutions use (45-50.4 Gy). CROSS regimen (carboplatin/paclitaxel) has not been directly compared to cisplatin/5-FU in a phase III trial. High pCR rates in SCC raise the question of whether surgery can be omitted in complete clinical responders (watch-and-wait strategies being investigated).
Clinical Context
CROSS has become the standard neoadjuvant regimen for resectable esophageal cancer in most Western guidelines (NCCN, ESMO). For adenocarcinoma, FLOT4 (perioperative FLOT chemotherapy, Lancet 2019) is an alternative endorsed by ESMO, particularly for gastric/GEJ adenocarcinoma. The ESOPEC trial (Germany, 2024) compared CROSS vs FLOT in esophageal adenocarcinoma, suggesting FLOT may have superior OS — changing practice in adenocarcinoma.
References