Advancing Esophageal Cancer Treatment: Immunotherapy in Neoadjuvant and Adjuvant Settings

Abstract

Locally advanced esophageal cancer (LAEC) poses a significant and persistent challenge in terms of effective treatment. Traditionally, the primary strategy for managing LAEC has involved concurrent neoadjuvant chemoradiation followed by surgery. However, achieving a pathologic complete response (pCR) has proven to be inconsistent, and despite treatment, roughly half of patients experience locoregional recurrence or metastasis. Consequently, there has been a paradigm shift towards exploring the potential of immunotherapy in reshaping the landscape of LAEC management. Recent research has particularly focused on immune checkpoint inhibitors, investigating their application in both neoadjuvant and adjuvant settings. These inhibitors, designed to block specific proteins in immune cells, are meant to enhance the immune system's ability to target and combat cancer cells. Emerging evidence from these studies suggests the possibility of a mortality benefit, indicating that immunotherapy may contribute to improved overall survival rates for individuals grappling with esophageal cancer. This manuscript aims to meticulously review the existing literature surrounding neoadjuvant and adjuvant immunotherapy in the context of LAEC management. The intention is to thoroughly examine the methodologies and findings of relevant studies, providing a comprehensive synthesis of the current understanding of the impact of immunotherapy on esophageal cancer.

Keywords: LAEC; immune checkpoint inhibitors (ICIs); locally advanced esophageal cancer; neoadjuvant chemoradiation.

Figure 1

Pathogenesis of ESCC and EAC. Major risk factors for ESCC include tobacco and alcohol use. Major risk factors for EAC include GERD and obesity. For ESCC after esophageal injury from smoking or alcohol use, squamous dysplasia may occur and subsequently develop into early ESCC. Left untreated, it will develop into ESCC. For EAC after esophageal injury by gastric acid, metaplasia of nonkeratizing squamous epithelium to nonciliated, mucin-producing columnar cells occurs. Under persistent stress, the metaplasia progresses to EAC.

Figure 2

The tumor microenvironment of EC. DC: dendritic cell, NK: natural killer cell, M2: 2 macrophage, HIF-1: hypoxia-induced factor 1. The TME consists of multiple heterogeneous cells. Dendritic cells process tumor-derived antigens and are impaired from properly functioning in the TME. M2 macrophages lead to pro-survival pathway activation. Transformation of fibroblasts into cancer-associated fibroblasts leads to angiogenesis and remodeling of the extracellular matrix. HIF1 induces angiogenesis. NK cells are inhibited in the TME. The PD1/PDL-1 axis impairs T cell function.

Figure 3

ESMO recommended guidelines for the management of ESCC.