Key Points

• In esophageal and gastroesophageal junction cancer (GEJ), single-agent chemotherapy achieves responses in 10-20% of patients and combination chemotherapy in 35-45% of patients, with a median survival of 10-12 months.
• There are now phase III data to support the addition of an anti-programmed death-1 (PD-1) antibody, nivolumab or pembrolizumab, to a fluoropyrimidine/platinum doublet as first-line therapy for any cancer of the esophagus or GEJ. Combination immunotherapy with ipilimumab, an anti-cytototoxic T lymphocyte antigen-4 (CTLA-4), and nivolumab is also an option for esophageal squamous cell carcinoma (SCC).
• The addition of trastuzumab, a monoclonal antibody against Her2, to first-line chemotherapy has been standard for Her2 positive tumors since 2010. Recent phase III data support the addition of pembrolizumab to trastuzumab and chemotherapy
• In the second-line setting, the anti-vascular endothelial growth factor receptor-2 antibody ramucirumab is active as monotherapy or when combined with paclitaxel chemotherapy.
• Epirubicin was previously routinely added to a fluoropyrimidine/platinum doublet but the lack of randomized data in the metastatic setting and superiority of the docetaxel containing FLOT regimen over epirubicin-containing regimens in the locally advanced setting has led to a significant decline in its use
• For locally advanced esophageal/GEJ adenocarcinoma, uncertainty remains as to whether pre-operative chemoradiation vs. peri-operative chemotherapy is superior.
• For patients with locally advanced esophageal/GEJ adenocarcinoma or SCC who undergo pre-operative chemoradiation and surgerry and with residual disease in the resected tumor, adjuvant nivolumab for 12 months is now a standard-of-care
• Primary concurrent chemoradiation achieves curative potential in patients with squamous cell carcinoma and long-term disease control is also achieved with chemoradiation in a proportion of patients with adenocarcinoma.
• The addition of surgery to primary chemoradiation reduces local recurrence without a clear impact on survival in squamous cell carcinoma patients. Because of lower pathologic complete response to chemoradiation in adenocarcinoma of the esophagus, surgery is more often considered as part of primary management.
• Higher radiation therapy doses above conventional 5,040 cGy or the addition of induction chemotherapy before radiation, do not appear to improve treatment outcome.
• The use of PET scan to guide the choice of chemotherapy with radiation appears to be a promising approach.

Esophageal cancer, an uncommon but highly virulent malignancy in the United States, was responsible for an estimated 16,410 deaths in 2022.[1] The majority of patients who have esophageal cancer die of the disease, which represents the seventh leading cause of cancer death in American men. Although esophageal cancer remains relatively uncommon in the United States, it is a major cause of cancer worldwide, especially in East Asia and other developing countries. Particularly high incidence is observed in northern China[2], the Caspian littoral[3] and the Transkei province of South Africa.[4] The epidemiologic factors responsible for the geographic variability in incidence of esophageal cancer, including potential dietary and environmental carcinogens, remain under active investigation. While other etiologic factors remain unclarified, an association with the abuse of tobacco and alcohol and the development of squamous cell carcinoma (SCC) of the esophagus has been clearly established.[5] Human papilloma virus infection, which is increasingly linked to SCCs of the oropharynx, has not been clearly linked to esophageal SCC in the West.[6]

SCC and adenocarcinoma account for 98% of all cases of esophageal cancer. SCCs typically occur in the proximal two-thirds of the esophagus while adenocarcinomas are found in the distal third and at the gastroesophageal junction (GEJ). While cases of SCC have steadily declined in the U.S. because of a decrease in tobacco and alcohol abuse[5], the incidence of adenocarcinoma of the distal esophagus, GEJ and gastric cardia has increased 4% to 10% per year among U.S. men since 1976 so that it now comprises 75% of all esophageal tumors.[7],[8]

Changing epidemiologic factors account for the increasing incidence of adenocarcinomas, which are now more common because of an increased incidence of gastroesophageal reflux disease (GERD)[9] and obesity.[10] Helicobacter pylori, implicated in peptic ulcer disease and associated with an increased risk of gastric cancer, has not been implicated in the pathogenesis of esophageal adenocarcinoma. In fact, because infection with H. pylori may lead to a reduction in gastric acidity in association with atrophic gastritis, there has been speculation that a decline in the prevalence of H. pylori infection may predispose to an increase in GERD and, therefore, in the incidence of GEJ adenocarcinomas.[11],[12]

For locally advanced esophageal cancer, surgery remains the mainstay of treatment. Various reviews have reported 5-year overall survival (OS) rates from 10% up to 30% to 40% with surgical resection alone.[13],[14] Numerous studies – that have included both adenocarcinoma and SCC histologies and focused on tumors from the esophagus/GEJ and/or stomach – have evaluated pre- and post-operative strategies for locally advanced disease, including chemotherapy or chemoradiation. As a whole, these studies show that some treatment in addition to surgery clearly improves outcomes. The superiority of pre-operative chemoradiation vs. peri-operative chemotherapy remains the subject of ongoing randomized studies.

Approximately 50% of patients with a diagnosis of esophageal cancer present with overt metastatic disease, and chemotherapy is the mainstay of palliation in this setting. With the high likelihood of the development of metastatic disease in patients with initial locoregional cancer, systemic chemotherapy is ultimately required in the majority of patients. This chapter focuses on the use of systemic chemotherapy in the treatment of esophageal cancer, recent advances that incorporate immunotherapy and targeted therapies, and of radiation-based therapy in the primary management of locally advanced esophageal cancer.