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Unresectable Disease

Unfortunately, up to one third of patients with gastric cancer will have unresectable disease at the time of diagnosis.305 Chemotherapy for locally advanced gastric cancer without distant metastases can result in shrinking of the tumor to the point where successful curative resection is possible.387,388 Even when curative surgery is not possible, chemotherapy has been shown both to improve survival as well as quality of life compared to best supportive care in this group of patients.389

A meta-analysis by Wagner and colleagues390 demonstrated a small but significant survival benefit for combination chemotherapies, with a median survival of 8.3 months with combination regimens and 6.7 months for single-agent therapies. As expected, toxicity was increased in the combination schedules, and thus, combination chemotherapy should only be considered in patients with good performance status. Although there is no single standard of care in advanced gastric cancer, there is some evidence coming from metaanalyses. Drugs related to increased survival in phase III trials are cisplatin, docetaxel and trastuzumab, a monoclonal antibody that interferes with the HER2/neu receptor. HER2 is amplified and is a key driver of tumorigenesis in 7% to 34% of gastric cancers. In the ToGA phase III multicenter randomized study, patients with gastric cancer and HER2 overexpression received chemotherapy and trastuzumab, resulting in a median overall survival of 13.8 months, compared with 11.1 months in those treated with chemotherapy alone.391 Further manipulation of this pathway using the novel anti-HER2– directed agents pertuzumab and T-DM1, in addition to dual EGFR/HER2 blockade with lapatinib, may yield positive results. As a consequence, tumor assessment for HER2 overexpression should be performed, and the addition of trastuzumab to palliative chemotherapy should be considered for every patient with HER2+ gastric adenocarcinoma. In contrast, targeting of the EGFR pathway in combination with chemotherapy in unselected patients has not been fruitful to date. Other new targeted agents, such as panitumumab, a human immunoglobulin (Ig)G-2 monoclonal antibody that blocks the EGFR receptor, are currently under investigation. Similarly, use of the anti-angiogenic monoclonal antibody bevacizumab was not successful in a large global randomized trial.392-396 Careful selection of patient subsets will become a key factor in future clinical trials as novel targeted agents such as those targeting the MET/HGF and FGFR axes move forward into clinical development.

Several randomized clinical trials have demonstrated efficacy of multidrug cisplatin-based regimens.397,398 A newer clinical trial using the EOX regimen (epirubicin, oxaliplatin, and capecitabine [Xeloda]) was found to be non-inferior to cisplatin-based regimens, and had a median survival of 11.2 months.399 The benefit of the EOX regimen is the substitution of oxaliplatin and capecitabine for cisplatin and 5FU, respectively, resulting in greater convenience, ease of administration, and potentially fewer side effects.

Second-line chemotherapy may also be superior to best supportive care, but again no standard regimens have been defined. Monotherapy with docetaxel or irinotecan has been shown to be superior to best supportive care,400-402 and a recent study showed no superiority of irinotecan over weekly paclitaxel. Thus, monotherapy with irinotecan or taxanes such as paclitaxel can be considered an option in advanced gastric cancer patients as a second-line treatment.403

Patients with advanced gastric cancer of the distal antrum or pylorus are at risk for developing gastric outlet obstruction. Traditionally, surgical gastrojejunostomy was performed for relief of symptoms and to allow continued enteral nutrition. With the advent of endoscopic stents, duodenal stenting across the obstructing tumor has emerged as a nonsurgical alternative for palliation. The results of a literature review of studies evaluating gastrojejunostomy versus stenting found no differences in rate of technical success (96% to 100%), early and late complications, and persistent symptoms.404 Recurrent obstructive symptoms were more common with stenting. Both gastrojejunostomy and endoscopic stenting are acceptable options for the relief of malignant gastric outlet obstruction. The decision should be based on the individual clinical scenario as well as the availability of appropriate surgical or endoscopic expertise.