sophageal cancer is one of the least studied and deadliest cancers worldwide. During the past three decades, important changes have occurred in the epidemiologic patterns associated with this disease. Recent advances in the diagnosis, staging, and treatment of this neoplastic condition have led to small but significant improvements in survival. These new observations serve as the focus of this review. Cancers arising from the esophagus, including the gastroesophageal junction, are relatively uncommon in the United States, with 13,900 new cases and 13,000 deaths anticipated in 2003. 1 The lifetime risk of this cancer is 0.8 percent for men and 0.3 percent for women. 2 The risk increases with age, with a mean age at diagnosis of 67 years. 2,3 Esophageal cancer is the seventh leading cause of death from cancer among American men, particularly black men, who have a higher incidence of this disease (13 cases per 100,000 persons) than do men in other racial or ethnic groups. 2 Worldwide, esophageal cancer is the sixth leading cause of death from cancer. 4 More than 90 percent of esophageal cancers are either squamous-cell carcinomas or adenocarcinomas. 3 On rare occasions, other carcinomas, melanomas, leiomyosarcomas, carcinoids, and lymphomas may develop in the esophagus as well. Approximately three quarters of all adenocarcinomas are found in the distal esophagus, whereas squamouscell carcinomas are more evenly distributed between the middle and lower third. 3,5 The cervical esophagus is an uncommon site of disease. The pathogenesis of esophageal cancer remains unclear. Data from studies in animals suggest that oxidative damage from factors such as smoking or gastroesophageal reflux, which cause inflammation, esophagitis, and increased cell turnover, may initiate the carcinogenic process. 6 Once cancer develops, it may spread rapidly; 14 to 21 percent of submucosal cancers (T1 lesions) and 38 to 60 percent of cancers that invade muscle (T2 lesions) are associated with spread to lymph nodes. 5,7 At the time of the diagnosis of esophageal cancer, more than 50 percent of patients have either unresectable tumors or radiographically visible metastases. Smoking is associated with an increased risk of both squamous-cell carcinoma and adenocarcinoma of the esophagus (Table 1). 8,9 The ingestion of tobacco condensates is thought to bring tobacco carcinogens, particularly nitrosamines, in contact with the esophageal mucosa. 10 The risk of esophageal cancer correlates directly with the quantity of cigarettes smoked per day and the duration of smoking.

clinicaltrials.gov Identifier: NCT02335411.

PURPOSE Patients with advanced esophageal cancer have a poor prognosis and limited treatment options after first-line chemotherapy. PATIENTS AND METHODS In this open-label, phase III study, we randomly assigned (1:1) 628 patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus, that progressed after one prior therapy, to pembrolizumab 200 mg every 3 weeks for up to 2 years or chemotherapy (investigator’s choice of paclitaxel, docetaxel, or irinotecan). Primary end points were overall survival (OS) in patients with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10, in patients with squamous cell carcinoma, and in all patients (one-sided α 0.9%, 0.8%, and 0.8%, respectively). RESULTS At final analysis, conducted 16 months after the last patient was randomly assigned, OS was prolonged with pembrolizumab versus chemotherapy for patients with CPS ≥ 10 (median, 9.3 v 6.7 months; hazard ratio [HR], 0.69 [95% CI, 0.52 to 0.93]; P = .0074). Estimated 12-month OS rate was 43% (95% CI, 33.5% to 52.1%) with pembrolizumab versus 20% (95% CI, 13.5% to 28.3%) with chemotherapy. Median OS was 8.2 months versus 7.1 months (HR, 0.78 [95% CI, 0.63 to 0.96]; P = .0095) in patients with squamous cell carcinoma and 7.1 months versus 7.1 months (HR, 0.89 [95% CI, 0.75 to 1.05]; P = .0560) in all patients. Grade 3-5 treatment-related adverse events occurred in 18.2% of patients with pembrolizumab versus 40.9% in those who underwent chemotherapy. CONCLUSION Pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients with PD-L1 CPS ≥ 10, with fewer treatment-related adverse events.