Esophageal / GEJ Cancer: Treatment by Histology

Esophageal / GEJ Cancer: Treatment by Histology: overview

This algorithm covers esophageal and gastroesophageal junction (GEJ) cancer and branches first on extent of disease, then on histology and biomarkers.

For localized, resectable disease, neoadjuvant chemoradiation followed by surgery is supported by CROSS, which improved overall survival over surgery alone, with greater benefit in squamous cell carcinoma. Patients with residual disease after this approach receive adjuvant nivolumab, based on CheckMate-577, which doubled disease-free survival versus placebo. For adenocarcinoma, perioperative FLOT chemotherapy (FLOT4) is an alternative. Advanced adenocarcinoma is treated by biomarker: nivolumab plus chemotherapy for PD-L1 CPS 5 or higher (CheckMate-649), trastuzumab plus chemotherapy plus pembrolizumab for HER2-positive disease (KEYNOTE-811), and a chemotherapy doublet for biomarker-negative tumors. Advanced squamous cell carcinoma is treated with pembrolizumab plus chemotherapy (KEYNOTE-590), or with nivolumab plus chemotherapy or nivolumab plus ipilimumab (CheckMate-648), both of which improved overall survival over chemotherapy.

Step by step

• Localized, resectable: neoadjuvant chemoradiation, then surgery (CROSS).
• Residual disease after neoadjuvant chemoradiation and surgery: adjuvant nivolumab (CheckMate-577).
• Localized adenocarcinoma: perioperative FLOT chemotherapy as an alternative (FLOT4).
• Advanced adenocarcinoma, PD-L1 CPS 5 or higher: nivolumab plus chemotherapy (CheckMate-649).
• Advanced adenocarcinoma, HER2 positive: trastuzumab plus chemotherapy plus pembrolizumab (KEYNOTE-811).
• Advanced adenocarcinoma, biomarker negative: chemotherapy doublet.
• Advanced squamous cell carcinoma: pembrolizumab plus chemotherapy (KEYNOTE-590), or nivolumab plus chemotherapy or nivolumab plus ipilimumab (CheckMate-648).

Trials behind this algorithm

• CROSS Trial VanHagen et al, NEJM, 2012, PMID: 22646630
• Checkmate 577 Kelly et al. NEJM, 2021 PMID: 33789008
• Checkmate 649 trial Janjigian et al. , Lancet, 2021, PMID: 34102137
• KEYNOTE-811 trial Janjigian YY et al, Nature, 2021; PMID: 34912120
• KEYNOTE-590 Sun J-M et al, Lancet, 2021; PMID: 34454674
• CheckMate 648 Doki Y et al, NEJM, 2022; PMID: 35108470

Background reading: Esophageal and gastric cancer board review notes.