Systemic Treatment of Esophageal Cancer

Abstract

Esophageal cancer poses a significant global burden, ranking seventh in terms of incidence and sixth in cancer-related mortality. This article provides a comprehensive review of the systemic treatment approaches for esophageal cancer, focusing on both localized and metastatic disease. The histologic subtypes of esophageal cancer, squamous cell carcinoma (SCC), and adenocarcinoma (AC) are influenced by different risk factors, including smoking, alcohol consumption, obesity, and gastroesophageal reflux disease (GERD). Common clinical manifestations include progressive dysphagia and weight loss, prompting the need for accurate diagnosis and staging. For patients with early-stage disease (T1N0), surgical or endoscopic resection remains the treatment of choice. However, the optimal approach for clinical T2N0 disease is still debated. Neoadjuvant therapy, such as chemoradiotherapy or chemotherapy, has shown significant benefits in improving overall survival and R0 resection rates. Notable trials, including the CROSS and MAGIC trials, have established new treatment standards by demonstrating the effectiveness of combined therapies. Metastatic esophageal cancer requires palliative systemic chemotherapy to alleviate symptoms, improve quality of life, and extend survival. Platinum-based regimens, such as cisplatin and 5-fluorouracil, have been widely used, while immunotherapies, such as pembrolizumab and nivolumab, have shown promising results, particularly in patients with squamous cell carcinoma and high PD-L1 expression. Furthermore, the management of metastatic esophageal adenocarcinoma parallels that of gastric adenocarcinoma, with trastuzumab and ramucirumab demonstrating survival benefits in HER2-positive and antiangiogenic settings, respectively. This chapter emphasizes the importance of comprehensive genomic profiling and the need for patients to participate in clinical trials to further advance treatment strategies for esophageal cancer. Continued research and collaboration are essential for optimizing therapeutic outcomes and enhancing the management of this challenging malignancy. © 2025 Elsevier B.V., All rights reserved.