Targeted Therapy

Since current therapy is both largely ineffective against esophageal cancer and highly toxic, research interest has turned to the potential of targeted therapy to improve outcomes.15 Esophageal cancer develops when sustained damage from GERD, smoking, alcohol, or other irritants leads to mutations that activate or inhibit specific signaling pathways.15 Targeted therapy is directed against signaling pathways that promote cell growth, cell division, increased cell motility, evasion of apoptosis, or sustained angiogenesis—the key characteristics of cancer.15 Several agents have now reached phase 2 or 3 trials for treatment of esophageal cancer.

Anti-HER2 Therapies Overexpression of human epidermal growth factor receptor 2 (HER2), a tyrosine kinase receptor that promotes cell growth, has been found in a subset of esophageal cancers and may provide an opportunity for targeted therapy.16

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Trastuzumab, the monoclonal antibody that targets HER2 and is approved for use in HER2-positive breast cancer17, was investigated in the ToGA trial. The ToGA trial randomized 106 patients with gastroesophageal cancer and 478 with gastric cancer whose tumors overexpressed HER2 to treatment with standard chemotherapy (capecitabine plus cisplatin or fluorouracil plus cisplatin every 3 weeks for 6 cycles) or chemotherapy plus trastuzumab (8 mg/kg on day 1 of the first cycle followed by 6 mg/kg every 3 weeks) until disease progression or unacceptable toxicity occurred.17 Median survival was 13.8 months (95% confidence interval [CI] 12, 16) in the trastuzumab plus chemotherapy group and 11.1 months (95% CI 10, 13) in the chemotherapy alone group, relating to a 26% reduction in the death rate.17 The beneficial effect of trastuzumab was greatest in patients with high expression of HER2.17 The adverse events profiles were similar in the two study groups.17 Although the results were not analyzed according to cancer location, results of the ToGA trial suggest a role for trastuzumab in gastroesophageal cancers expressing HER2.

Anti-EGFR Therapy EGFR is a tyrosine kinase receptor with effects on apoptosis, cell proliferation, and angiogenesis.16 Overexpression of EGFR, which is seen in as many as 30% to 90% of esophageal cancer tumors, is associated with a worse outcome.16

Cetuximab, a partially humanized murine IgG1 monoclonal antibody that binds to EGFR and initiates immune-mediated cytotoxicity16, was well tolerated but ineffective as monotherapy in patients with previously treated esophageal or gastric adenocarcinoma.18 A phase 2 trial of 72 patients with advanced, unresectable adenocarcinoma of the stomach or gastroesophageal junction evaluated cetuximab in an initial dose of 400 mg/m2 followed by weekly doses of 250 mg/m2 combined with cisplatin 75 mg/m2 plus docetaxel 75 mg/m2 on day 1 every 3 weeks for a maximum of 6 cycles, followed by cetuximab alone in patients with complete or partial response or stable disease.19 Complete response was seen in one patient and partial response in 27; the overall response rate was 41.2% (95% CI 29.5%, 52.9%).19 The disease control rate was 76.5%, the median time to progression was 5 months (95% CI 3.7, 5.4), and the median overall survival was 9 months (95% CI 7, 11).19 Grade 3 or 4 neutropenia occurred in 32 patients and febrile neutropenia in 14.19

In a phase 2 trial of 63 patients who had failed first-line therapy for gastroesophageal adenocarcinoma, cetuximab 500 mg/m2 and irinotecan 180 mg/m2 were administered every other week.20 Six patients had a partial response (overall response rate, 11%) and 19 patients had stable disease (disease control rate, 48%).20 Progression-free survival was 2.8 months and median overall survival was 6.1 months.20 The 1-year survival rate was 17%; neutropenia occurred in 11% of patients and febrile neutropenia in 2%.20

Gefitinib is an EGFR tyrosine kinase inhibitor that has been shown to down-regulate oncogenes associated with tumor progression, but which provided only modest benefit when used as monotherapy in patients with advanced, inoperable esophageal adenocarcinoma.21,22