Combination of cetuximab with radio-chemotherapy in patients with esophageal cancer: less is more!

A main challenge in the treatment of locally advanced esophageal cancer is to improve efficacy while minimizing treatment-related toxicity. Definitive chemoradiotherapy (CRT) is used to treat patients with locally advanced esophageal cancer who are inoperable for medical reasons, in whom complete R0 resection is unlikely or who decline surgery. However, until recently the data available were predominantly for squamous cell esophageal cancer. Molecular targeted drugs are being evaluated in clinical trials for esophageal, gastric, and gastroesophageal junction cancers. EGFR is overexpressed in 60–86% of gastric or gastroesophageal tumors and in 50–70% of esophageal cancers. Preclinical studies have shown that the chimeric monoclonal antibody cetuximab can overcome an important mechanism of radioresistance, and cetuximab was shown to bear radiosensitizing properties (1). These data led to phase I/II trials evaluating the combination of cetuximab with CRT in locally advanced esophageal squamous cell carcinoma (SCC) and adenocarcinomas with encouraging preliminary results (2,3). However, these trials were of small sample size. One study, reported by Ruhstaller included both, adenocarcinomas and SCC and showed, by adding cetuximab to preoperative CRT a significantly increased histopathologic response rate without elevated toxicity and postoperative mortality (2). Another trial, conducted by Chen and coworkers evaluated a regimen of definitive CRT plus cetuximab in 29 patients with SCC, showing a good clinical response and an acceptable safety profile despite high doses of radiotherapy (59.4 Gy) in Chinese patients (3). Moreover, the addition of EGFR inhibitors to radiotherapy significantly improved the results of radiotherapy alone in patients with SCC of the head and neck. In a landmark study by Bonner and coworkers a nearly doubled median overall survival was achieved in patients allocated to the cetuximab-radiotherapy arm (28 to 54 months) (4). In all, there was clear rationale to test the addition of cetuximab to definitive CRT in a randomized trial in patients with cancer of the esophagus.