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Oesophageal adenocarcinoma is currently the most rapidly increasing cancer in the US and Western Europe.1,2 This type of tumour is frequently detected at an advanced stage and requires multimodal treatment. Despite improvements in its detection, surgical resection and neoadjuvant therapy, the overall survival of oesophageal cancer remains lower than that of other solid tumours.3 In fact, a recent meta-analysis by Greer et al., analysing 21 randomised trials of neoadjuvant radiochemotherapy prior to surgery for patients with oesophageal cancer, showed a non-significant improvement in overall survival.4 In the last few years, there has been an exponential growth in our understanding of the cellular and molecular events associated with cell-cycle regulation, programmed cell death, angiogenesis and tumour growth. The discovery and characterisation of growth factor receptors – agents that stimulate or inhibit angiogenesis, cell-cycle regulatory proteins and other compounds that regulate cellular function – led to the possibility that biologic therapy could be used to prevent or treat neoplasia. Oncologists are currently investigating several novel targets, both as single agents or in combination with chemotherapy, to assess the potential for increased efficacy. Pre-clinical and clinical studies have described potential tumour targets in oesophageal cancer, including cyclo-oxgenase-2 (COX-2), epidermal growth factor receptor (EGFR) and vascular endolethial growth factor (VEGF).5 The goal of this article is to provide an update of the most recent data of targeted therapy against these three factors in oesophageal cancer.
COX-2 and the isoform COX-1 are rate-limiting enzymes in the conversion of arachidonic acid to prostaglandins. It is well-known that COX-2 participates in the regulation of a broad range of cellular processes, including proliferation, angiogenesis and resistance to apoptosis. Pre-clinical studies have shown that COX-2 is sequentially increased in the metaplastic–dysplastic sequence leading to oesophageal adenocarcinoma.6–8 In addition, epidemiological studies have revealed that regular Aspirin® use is associated with a decreased risk of oesophageal cancer, an effect that was also observed with selective COX-2 inhibitors in a case-control study.9,10 These findings implied that the inhibition of COX-2 is an effective strategy in the prevention and treatment of oesophageal adenocarcinoma. In fact, preliminary data from several phase I/II trials assessing the potential of combining COX-2 inhibitors and concurrent chemoradiotherapy for locally advanced oesophageal cancer are already available. In a phase II trial, Enziger et al. analysed the efficacy of neoadjuvant therapy with cisplatin, irinotecan, concurrent radiation therapy and celecoxib, a selective COX-2 inhibitor, in patients with locally advanced oesophageal cancer.11 In their preliminary analysis, 25 out of 36 patients had completed chemoradiation and surgery, of whom 11 had a complete pathological response. Govindan et al. reported the first results of a phase II study conducted by the Hoosier Oncology Group (HOG) in patients with potentially resectable oesophageal cancer receiving cisplatin, 5-fluorouracil, celecoxib and radiation therapy.12 Of the 31 patients included in the study, five had a complete pathological response. In a clinical study by Altorki et al., an overall response rate of 57% was observed in patients with oesophageal cancer receiving pre-operative paclitaxel/carboplatin and celecoxib followed by adjuvant celecoxib.13
Finally, Dawson et al. demonstrated in a phase I/II trial of celecoxib with chemotherapy and radiotherapy in the treatment of patients with locally advanced oesophageal cancer that the regimen was well tolerated, with a radiological response rate of 54%.14 The results of these pilot studies are encouraging; however, further follow-up is necessary to determine the continued safety of celecoxib and its impact on disease progression and overall survival in patients with oesophageal cancer.