Updates for esophageal cancer

Esophageal and gastroesophageal cancers are a major global health problem, with an estimated 604,000 new cases and 544,000 deaths in 2020. It is the sixth leading cause of cancer-related mortality. In the United States, an estimated 21,560 cases were diagnosed in 2023. The incidence of adenocarcinoma appears to be rising, while the squamous cell cancers appear to be stable. The 5-year survival rates are low, at 21.6%.¹ 

For adenocarcinoma, the majority of the cases are either locally advanced or metastatic at the time of diagnosis. There have been a number of advances in the treatment of esophageal cancer and the following is a brief summary:

Locally advanced/resectable esophageal adenocarcinoma

Combined modality therapy has been the mainstay and the most common approach, according to the CROSS trial, which utilized preoperative weekly low-dose carboplatin/Taxol and XRT followed by surgery.² However, this showed poor long-term results as the combined modality therapy did not improve the 10-year survival as compared to surgery.^{3, 4}

The CALGB 80803 trial showed improved outcomes with FolFox + RT followed by surgery as compared to the CROSS regimen.⁵

The ESOPEC trial commenced in 2016 and is a Phase 3 randomized controlled trial (RCT) comparing a perioperative FLOT regimen with surgery to CROSS-based chemotherapy and radiation therapy (chemo/RT) and surgery. The results were presented at the plenary session of ASCO 2024 and published in January 2025⁶ and show OS advantage for the perioperative FLOT regimen, HR for death 0.70, p=0.01 for the perioperative chemotherapy arm.⁶ Therefore, the new standard of care for locally advanced/resectable E/GEJ adenocarcinoma is perioperative chemotherapy with FLOT and surgery.⁶

The ESOPEC trial did not address the question of adjuvant immunotherapy. The CHECKMATE 577 study showed a PFS advantage for adjuvant nivolumab when given to patients who received combined chemo/RT and had T+ or N+ disease.⁷

Therefore, the standard of care for locally advanced/resectable esophageal adenocarcinoma is now perioperative FLOT/surgery. Combined chemo/RT is the standard if the patients decline/defer, or cannot have surgery. The patients who are non-path CR post-chemo/RT should receive adjuvant nivolumab for one year.⁷

Metastatic esophageal adenocarcinoma

The management of metastatic disease is essentially biomarker-driven and based on the results of tissue NGS testing; optimal combination therapy can be utilized. The most important targets have been Her2Neu, MSI/MMR, PDL-1, TMB and additionally, NTRK, BRAF V600E, RET and FGFR are also helpful.

For tumors that are PDL-1 positive, combination chemotherapy and I/O therapy with nivolumab/pembrolizumab have proven effective.^{8, 9}

In March 2024, the FDA approved tislelizumab-jsgr (Tevimbra) in combination with chemotherapy for first-line treatment of HER2-negative, PDL-1-positive esophageal/GEJ/gastric adenocarcinoma and esophageal squamous cell cancer. The approval was based on the Phase 3 RATIONALE 306 trial, which showed OS improvement to 17.2 mo for chemotherapy+ tislelizumab vs. 10.6 mo for chemotherapy alone – HR 0.66, p=.0001.¹⁰

More recently, a new target, CLDN18.2, has been identified in esophageal and gastric malignancies, and a new antibody has been developed to target CLDN18.2. It is zolbetuximab (Vyloy), and it received FDA approval in October 2024, based on the SPOTLIGHT and GLOW trials. Combination of chemotherapy (FOLFOX/CAPOX) and zolbetuximab showed statistically significant improvement in the PFS/OS in locally advanced/metastatic esophageal/GEJ/gastric adenocarcinoma.^{11, 12}

Conclusion

Over the last few years, there have been a number of treatment advances for esophageal cancer. For surgically resectable esophageal/GEJ adenocarcinoma, perioperative chemotherapy and surgery are the preferred treatment options; combined chemotherapy/RT also remains an option, perhaps for non-surgical candidates, and the role of adjuvant immunotherapy with nivolumab also remains an option for non-pathologic CR post-therapy. For metastatic esophageal cancer, there are a number of effective biomarker-driven systemic therapies. Additional immunotherapy with tislelizumab and novel CLDN18.2-targeted agents, such as zolbetuximab, has expanded treatment options. 

Learn more about esophageal cancer treatment at Northside Hospital Cancer Institute.

References:

1. Bray, F., J. Ferlay, I. Soerjomataram, et al. 2018. “Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.” CA: A Cancer Journal for Clinicians 68: 394–424.
2. Van Hagen, P., et al. 2012. “Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer.” New England Journal of Medicine 366: 2074–2084.
3. Oppediijk, V., et al. 2014. “Patterns of Recurrence after Surgery Alone versus Preoperative Chemoradiotherapy and Surgery in the CROSS Trials.” Journal of Clinical Oncology 32: 385–391.
4. Eyck, B. M., et al. 2021. “Ten-Year Outcome of Neoadjuvant Chemoradiotherapy plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial.” Journal of Clinical Oncology 39: 1995–2004.
5. Goodman, K., et al. 2021. “Randomized Phase II Study of PET-Adapted CMT for Esophageal Cancer: Mature Results of the CALGB 80803 Trial.” Journal of Clinical Oncology 39 (25): ASCO 2021.
6. Hoeppner, J., et al. 2025. “Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer (ESOPEC Trial).” New England Journal of Medicine 392: 323–335.
7. Kelly, R., A. Ajani, et al. 2021. “Adjuvant Nivolumab in Resected Esophageal or GEJ Cancer.” New England Journal of Medicine 384: 1191–1203.
8. Janjigian, Y. Y., et al. 2024. “First-Line Nivolumab plus Chemotherapy for Advanced Gastric, GEJ, and Esophageal Adenocarcinoma: Three-Year Follow-up of the Phase III CheckMate 649 Trial.” Journal of Clinical Oncology 42 (17).
9. Shah, M., et al. 2024. “First-Line Pembrolizumab plus Chemotherapy for Advanced Esophageal Cancer: Five-Year Outcomes from the Phase 3 KEYNOTE-590 Study.” Journal of Clinical Oncology 42 (3): GI ASCO.
10. Xu, J., et al. 2023. “Tislelizumab plus Chemotherapy versus Placebo plus Chemotherapy as First-Line Treatment for Advanced/Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-306): A Global Randomized Placebo-Controlled Phase 3 Study.” The Lancet Oncology 24: 483–95.
11. Shitara, K., et al. 2024. “Final Overall Survival Results from Phase 3 SPOTLIGHT Study Evaluating Zolbetuximab plus mFOLFOX6 as First-Line Treatment for Patients with CLDN18.2+, HER2-, Locally Advanced Unresectable or Metastatic Gastric or GEJ Adenocarcinoma.” Journal of Clinical Oncology 42 (16), suppl 4036 (ASCO).
12. Xu, R., et al. 2023. “Zolbetuximab plus CAPOX in First-Line Claudin 18.2+/HER2- Locally Advanced/Metastatic Gastric or GEJ Adenocarcinoma: Primary Phase 3 Results from GLOW.” Journal of Clinical Oncology 41 (36), suppl 405736, GI ASCO.