# Current Management of Locally Advanced Esophageal and Esophagogastric Junction Cancers: Clinical Evidence and Evolving Strategies

## TL;DR

This review discusses current and evolving treatment strategies for locally advanced esophageal and esophagogastric junction cancers, focusing on personalized approaches and biomarkers.

## Contribution

The paper highlights the integration of immunotherapy and biomarker-driven strategies to personalize treatment and improve outcomes in localized esophageal cancers.

## Key findings

- Perioperative chemotherapy with immunotherapy is preferred for adenocarcinomas, while chemoradiotherapy remains standard for squamous cell carcinoma.
- Biomarkers like MSI-H and dMMR identify patients who may benefit from immunotherapy, enabling non-operative management in some cases.
- Circulating tumor DNA and functional imaging are being explored to guide treatment adaptation based on real-time response assessment.

## Abstract

Despite improvements in multimodal therapies, locally advanced esophageal and esophagogastric junction cancers still carry a high risk of recurrence and remain difficult to control long term. This review summarizes current treatment strategies, which are tailored according to tumor type. In adenocarcinomas, perioperative chemotherapy combined with immunotherapy has become the preferred approach following results from recent clinical trials. Meanwhile, chemoradiotherapy remains the mainstay for esophageal squamous cell carcinoma. New strategies are being explored to personalize treatment, including the use of biomarkers like MSI for select patients who might benefit from immunotherapy and organ-preserving approaches for complete responders to reduce unnecessary surgery. This review provides an overview of these advances and the ongoing efforts to improve outcomes in localized disease.

The curative management of localized esophageal and esophagogastric junction (EGJ) cancers has undergone major changes over the past decade, shaped by multimodal strategies integrating chemotherapy, chemoradiotherapy, surgery, and more recently, immunotherapy. For esophageal squamous cell carcinoma (SCC), neoadjuvant or definitive chemoradiotherapy remains the standard of care in Western countries. In contrast, for adenocarcinoma (AC) of the esophagus and EGJ, perioperative chemotherapy has emerged as the preferred strategy. Despite these advances, long-term outcomes remain suboptimal, and recurrence continues to pose a major challenge, highlighting the need to optimize patient selection and treatment sequencing. The integration of immunotherapy in the perioperative or adjuvant setting has recently led to improvements in surrogate endpoints yet overall survival benefit remains under investigation. For patients with tumors harboring microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR), checkpoint inhibitors show exceptional activity, and non-operative management may be feasible in select cases. Conversely, human epidermal growth receptor 2 (HER2)-targeted strategies, although effective in metastatic disease, have not yet translated into practice-changing benefit in the curative setting. The role of circulating tumor deoxyribo nucleic acid (DNA) and functional imaging as real-time tools to assess response and guide treatment adaptation is also being actively explored. This review provides a comprehensive overview of current standards, ongoing developments, and future directions for the treatment of localized esophageal and EGJ cancers, with a focus on emerging personalization strategies and biomarker-driven approaches aimed at improving cure rates and minimizing treatment-related morbidity.