Esophageal cancer treatment advances

Esophageal and gastroesophageal cancers remain a major global health challenge. In 2022, an estimated 511,000 new cases and 445,000 deaths were reported worldwide, and the disease continues to rank among the leading causes of cancer-related mortality globally.

In the United States, approximately 22,530 new cases are estimated in 2026. The incidence of adenocarcinoma continues to rise, while squamous cell carcinoma rates remain stable. Despite treatment advances, the five-year survival rate remains low at 21.6%.

Locally advanced and resectable esophageal adenocarcinoma

For patients with locally advanced or resectable esophageal adenocarcinoma, combined modality therapy has long been the standard approach. The CROSS trial established preoperative weekly low-dose carboplatin and paclitaxel with radiation therapy followed by surgery as a widely used regimen. However, long-term follow-up showed no significant improvement in 10-year survival compared with surgery alone.

The CALGB 80803 trial demonstrated improved outcomes using FOLFOX plus radiation therapy followed by surgery compared with the CROSS regimen.

More recently, the ESOPEC trial, a phase 3 randomized controlled trial launched in 2016, compared perioperative FLOT chemotherapy plus surgery with CROSS-based chemoradiation followed by surgery. Results presented at the American Society of Clinical Oncology (ASCO) 2024 meeting and published in 2025 showed an overall survival benefit with perioperative FLOT (hazard ratio for death, 0.70; P = .01).

As a result, the current standard of care for locally advanced, resectable esophageal or gastroesophageal junction (GEJ) adenocarcinoma is perioperative FLOT chemotherapy followed by surgery.

The ESOPEC trial did not address adjuvant immunotherapy. However, the CheckMate 577 study demonstrated improved progression-free survival with adjuvant nivolumab in patients with residual disease following chemoradiation and surgery.

In summary:

• Preferred approach: Perioperative FLOT chemotherapy plus surgery
• Alternative option: Chemoradiation for patients who are not surgical candidates
• Adjuvant therapy: One year of nivolumab for patients without a pathologic complete response after chemoradiation

Metastatic esophageal adenocarcinoma

Treatment of metastatic esophageal cancer is increasingly biomarker-driven, guided by next-generation sequencing (NGS) and molecular testing. Key biomarkers include HER2, MSI/MMR, PD-L1 and tumor mutational burden (TMB), along with less common targets such as NTRK, BRAF V600E, RET and FGFR.

For PD-L1-positive tumors, combination chemotherapy and immunotherapy with nivolumab or pembrolizumab has demonstrated significant benefit.

In March 2024, the U.S. Food and Drug Administration approved tislelizumab-jsgr (Tevimbra) in combination with chemotherapy for first-line treatment of HER2-negative, PD-L1-positive esophageal, GEJ and gastric cancers, as well as esophageal squamous cell carcinoma. This approval was based on the phase 3 RATIONALE 306 trial, which showed improved overall survival (17.2 months vs. 10.6 months; hazard ratio, 0.66; P = .0001).

Another emerging target is CLDN18.2, identified in esophageal and gastric cancers. Zolbetuximab (Vyloy), a monoclonal antibody targeting CLDN18.2, received FDA approval in October 2024 based on the SPOTLIGHT and GLOW trials. When combined with chemotherapy (FOLFOX or CAPOX), zolbetuximab significantly improved progression-free and overall survival in patients with locally advanced or metastatic disease.

Conclusion

Recent advances have significantly expanded treatment options for esophageal and gastroesophageal cancers.

For resectable disease, perioperative chemotherapy with FLOT followed by surgery is now the preferred standard of care, with chemoradiation remaining an option for select patients. Adjuvant nivolumab provides additional benefit for patients with residual disease after treatment.

For metastatic disease, biomarker-driven therapy continues to improve outcomes. The addition of immunotherapy agents such as tislelizumab and targeted therapies like zolbetuximab has further broadened treatment strategies and offers new hope for patients.

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