Background
CROSS. Phase III RCT enrolled 368 patients with resectable cT1N1 or cT2-3N0-1 cancer of the esophagus or gastroesophageal (GE) junction (75% adenocarcinoma, 23% squamous cell carcinoma).
Interventions and follow up
Arm A: Neoadjuvant chemoradiation — carboplatin AUC 2 + paclitaxel 50 mg/m² on D1, D8, D15, D22, D29 with concurrent RT (41.4 Gy in 23 fractions of 1.8 Gy, 5/week) followed by surgery
Arm B: Surgery alone
Primary endpoint: Overall survival
mFollow up: 45.4 mo (84.1 mo in 2015 long-term update)
Arm B: Surgery alone
Primary endpoint: Overall survival
mFollow up: 45.4 mo (84.1 mo in 2015 long-term update)
Results
mOS (primary): 49.4 mo vs 24.0 mo (arm A vs B); HR 0.657, 95%CI 0.495–0.871, P=.003
mOS (2015 long-term): 48.6 mo vs 24.0 mo; HR 0.68, 95%CI 0.53–0.88; P=.003
SCC mOS: 81.6 mo vs 21.1 mo; HR 0.48, 95%CI 0.28–0.83; P=.008
Adenocarcinoma mOS: 43.2 mo vs 27.1 mo; HR 0.73, 95%CI 0.55–0.98; P=.038
pCR rate (arm A): 29% overall (49% SCC, 23% adenocarcinoma)
mOS (2015 long-term): 48.6 mo vs 24.0 mo; HR 0.68, 95%CI 0.53–0.88; P=.003
SCC mOS: 81.6 mo vs 21.1 mo; HR 0.48, 95%CI 0.28–0.83; P=.008
Adenocarcinoma mOS: 43.2 mo vs 27.1 mo; HR 0.73, 95%CI 0.55–0.98; P=.038
pCR rate (arm A): 29% overall (49% SCC, 23% adenocarcinoma)
Adverse events
Hematologic (arm A): Grade≥3 leukopenia 6%, neutropenia 2%
Non-hematologic (arm A): Grade≥3 anorexia 5%, fatigue 3%
Surgical: No increase in postoperative complications; in-hospital mortality similar (4% vs 4%); one patient died awaiting surgery in arm A
Non-hematologic (arm A): Grade≥3 anorexia 5%, fatigue 3%
Surgical: No increase in postoperative complications; in-hospital mortality similar (4% vs 4%); one patient died awaiting surgery in arm A
Conclusions
Neoadjuvant carboplatin/paclitaxel chemoradiation followed by surgery significantly improved overall survival versus surgery alone in resectable esophageal and GE junction cancer, with greater benefit in squamous cell carcinoma.
Key Limitations
Predominantly lower-third/junctional tumors; relatively low RT dose limits extrapolation to definitive chemoradiation; comparison was surgery alone (no perioperative chemotherapy arm); modest absolute number of SCC patients.
Clinical Context
CROSS established neoadjuvant chemoradiation as a global standard of care for resectable esophageal/GE junction cancer and is endorsed in ESMO and ASCO guidance. The CROSS regimen is the comparator/backbone for subsequent trials (CheckMate 577 adjuvant nivolumab; ESOPEC comparing CROSS vs perioperative FLOT).
References
VanHagen et al, NEJM, 2012, PMID: 22646630
Long-term update: Shapiro J et al, Lancet Oncol, 2015; PMID:26254683
Long-term update: Shapiro J et al, Lancet Oncol, 2015; PMID:26254683