Targeted Therapies with Chemoradiation in Esophageal Cancer: Development and Future Directions

Human Epidermal Growth Factor Receptor 2 (HER2) HER2, epidermal growth factor receptor, and vascular endothelial growth factor pathways have been most extensively studied in esophagogastric cancers. Neoadjuvant and definitive chemoradiation are effective. This review will first focus on 3 of the most widely studied targeted therapies, trastuzumab (anti-HER2), bevacizumab (anti-vascular endothelial growth factor [anti-VEGF]), and cetuximab (anti-epidermal growth factor receptor [anti-EGFR]) Trastuzumab HER2 overexpression has been found in esophagogastric cancer at rates similar to breast cancer. In a large multi-institutional series. In a study, of patients with HER2-positive gastric or GE cancer were randomized to either trastuzumab and chemotherapy or chemotherapy alone. Median survival was improved with the addition of trastuzumab to chemotherapy from 11.1 to 13.5 months. If the tumor is found to be HER2 positive, patients are randomized to concurrent and maintenance trastuzumab in addition to chemoradiation. Chemoradiation consists of a dose of 50.4 Gy along with weekly carboplatin (AUC 2) and paclitaxel (50 mg/m2). Bevacizumab phase II study, Shah et al12 added bevacizumab to cisplatin and irinotecan and observed a response rate of 65% and a median survival of 12.3 months. In another phase II study, Shah et al13 evaluated bevacizumab in combination with docetaxel, cisplatin, and 5-FU. This regimen yielded a response rate of 67% and an impressive median survival of 16.8 months. Ilson et al18 reported results of preoperative chemoradiation with cisplatin, irinotecan, and bevacizumab. A pathologic complete response was seen in 4 of 33 patients (12%). Progression-free survival and overall survival were 14 and 30 months, respectively. Shows some promise in certain stages of cancer, (i.e. t3n1). Cetuximab / Panitumumab In esophagogastric cancer, variable rates of EGFR overexpression have been noted, ranging from 30% to 90%. phase III study. Patients with inoperable/metastatic esophageal, gastric, or GE junction cancer were randomized to receive EOC (epirubicin, oxaliplatin, capecitabine) with or without panitumumab. An early planned interim analysis showed that the panitumumab arm was statistically inferior after 553 (76%) patients were enrolled. Given the negative results of most trials, lack of efficacy with cetuximab, it is unlikely that anti-EGFR strategies will be further developed in the United States in unselected patients. Known Targets/New Agents HER2: Trastuzumab emtansine (T-DM1) International phase II/III trial in second-line advanced esophagogastric cancer will open randomizing between T-DM1 versus a taxane. Antiangiogenesis: Sorafenib Targets several kinases, including VEGFR1, VEGFR2, VEGFR3, Raf-1, Braf, and PDGFR1, for r use in renal cancer and hepatocellular. Hepatocyte growth factor/Mesenchymal epithelial transition factor (Hgf/Met) The cell surface receptor c-MET (mesenchymal–epithelial transition factor [MET]) and its ligand hepatocyte growth factor (HGF) are potential therapeutic targets in esophagogastric cancer. crizotinib is an orally bioavailable potent small-molecule inhibitor of MET. Rilotumumab is a human monoclonal antibody to HGF Heat shock protein 90 (Hsp90) is a chaperone protein that binds to the nucleotide-binding site and promotes the release of client proteins. Inhibition of Hsp90 is believed to cause these client proteins to adopt aberrant conformations, which are then targeted for ubiquitination and hence subsequent degradation. further understanding of potential synergy with radiation must be demonstrated before clinical trials ref- Theodore S. Hong, Jennifer Y. Wo, Eunice L. Kwak, Targeted Therapies with Chemoradiation in Esophageal Cancer: Development and Future Directions, Seminars in Radiation Oncology, Volume 23, Issue 1, January 2013, Pages 31-37, ISSN 1053-4296, 10.1016/j.semradonc.2012.09.004. (http://www.sciencedirect.com/science/article/pii/S1053429612000847)