Although hematologic toxicity and non-hematologic toxicity were relatively low in the docetaxel-plus-nedaplatin combination, these studies included only Asian patients, making it difficult to interpret these results for Caucasians. In addition, RR was still low. Tanespimycin In view of the high activity of DCF-type regimens in first-line treatment, the combination of docetaxel, cisplatin, and 5-FU was investigated in the second-line setting as well.102 While dose reduction of all drugs in the first study resulted in lower RR, increased dose in the second study resulted in a remarkable hematologic toxicity. Finally, only a single non-taxane combination regimen consisting of mitomycin, ifosfamide, and cisplatin was tested.103 Although the toxicity rate was acceptable, the RR was low as well.

Targeted therapy Cetuximab as second line treatment was studied either as monotherapy104,105 or in combination with irinotecan (Cetiri) in patients with AC (Table 4).106 In these studies, both RR and OS time were low. In contrast, there are contradictory results regarding erlotinib activity in AC as second-line monotherapy.107,108 Gefitinib as monotherapy in adenocarcinoma has shown only a minor activity.109,110 However, a recent prospectively randomized Phase III study was able to show that ramucirumab (RAM; IMC-1121B),111 a fully human immunoglobulin (Ig)G1 monoclonal antibody targeting VEGF-receptor (R) 2, significantly improves OS in patients with gastric and GEJ AC (REGARD, Fuchs et al;111 2013 Gastrointestinal Cancers Symposium, LBA5) (Table 4).

Current investigations Regarding locally advanced esophageal cancer, several Phase III studies are now recruiting patients to investigate new chemotherapy combinations, such as S-1/cisplatin, S-1/paclitaxel, cisplatin/paclitaxel, and 5-FU/leucovorin/oxaliplatin/docetaxel (FLOT), as first-line treatment (Table 5). In addition, molecular-targeting compounds as combination partners, such as trastuzumab (monoclonal antibody against ErbB-2), lapatinib (dual EGFR and ErbB-2 tyrosine kinase inhibitor), and cetuximab (monoclonal antibody against EGFR), are studied, too (Table 5). Unfortunately, there is a paucity of Phase III trials investigating second- and third-line treatment. A UK study is currently testing gefitinib (EGFR tyrosine kinase inhibitor); a German study, paclitaxel/RAD 001 (everolimus, mTOR-inhibitor) combination (Table 5).

At least four Phase III trials are investigating new combination partners for radiation in the neoadjuvant setting. Paclitaxel/carboplatin/radiation, paclitaxel/carboplatin/trastuzumab/radiation, Cilengitide navelbine/cisplatin/radiation, and docetaxel/cisplatin/cetuximab/radiation are these regimens (Table 5). Inhibition of angiogenesis through the VEGF-inhibitor bevacizumab is another approach tested in the neoadjuvant setting.