**1. Introduction**

Gastric cancer (GC) is the fourth (in men) and fifth (in women) most commonly newly diagnosed cancer worldwide and the third (in men) and fifth (in women) leading cause of cancer death [1]. Radical resection remains the only way cure, but cure rates following surgery for resectable GC in the West lag behind those in Japan. In addition, many GC patients will suffer recurrence even after curative resection in approximately 50% of cases [2], which eventually results in a still poor 5-year survival rate of <30% both in the USA [3] and in Europe [4]. Although the 5-year survival rate in Japan is much better than that in the West, there is a global consensus that advanced GC patients need further anticancer therapy.

Currently, five classes of cytotoxic agents (fluoropyrimidines, platinums, taxanes, topoiso‐ merase inhibitors, and anthracyclines) and new molecular targeting agents have been used in GC. Recent randomized controlled trials (RCTs) in the field of treatment for advanced GC have established first-line chemotherapy, although the approach and management for advanced GC varies from region to region so that there is no worldwide consensus on this matter. The most promising regimens are ECF (epirubicin, cisplatin, and 5-fluorouracil) in Europe [5], DCF (docetaxel, cisplatin, and 5-fluorouracil) in the USA (V325 trial) [6], and SP (S-1 and cisplatin) in Japan (SPIRITS trial) [7]. Strikingly, however, the global RCT conducted in the USA (FLAGS trial) failed to exhibit any survival advantage of the SP regimen over the FP (5-fluorouracil plus cisplatin) regimen [8]. Very recently, trastuzumab combined with cisplatin and fluoro‐ pyrimidines has been found to be active for human epidermal growth factor receptor-2 (HER2 or ERBB2)-positive GC (ToGA trial) [9]. Although these regimens are active, the treatment progress is painfully slow [4]. The median time to progression (TTP) or progression free survival (PFS) was 7.4 months by ECF [5], 5.6 months by DCF [6], 6.0 months by Japanese style SP [7], 4.8 months by global style SP [8], and 6.7 months even by adding trastuzumab [9], suggesting that many advanced GC patients experience failure after first-line chemotherapy.

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Figure 1

Interestingly, the median TTP or PFS of these regimens are almost equivalent (5.6-7.4 months) [5-7] while median overall survival times (OS) differ between the studies (Figure 1). The 13 months of median OS by the Japanese SP regimen [7] was apparently longer than those (8.7-9.2 months) by ECF and DCF regimens [5,6] (Figure 1). In addition, even by the use of the SP regimen, the post-progression survival –the survival length difference between median PFS and median OS– differed considerably, being 7 months in the SPIRITS trial [7] and 3.8 months in the FLAGS trial [8] (Figure 1). Such inter-trial differences in post-progression survival are partly attributable to different proportions of subsequent second-line therapy after the failure of first-line chemotherapy, being over 70% in the SPIRITS trial while 30-45% in other trials [6, 8,9]. In this regard, patients who retain good performance status at the time of first-line treatment failure are candidates for second-line therapy. Currently, however, no standard regimens for any second-line therapy hitherto determined suggest an urgent need for the establishment of second-line therapy. Reflecting this urgency, clinical research concerning second-line therapy has been recently commenced. In the era of post first-line chemotherapy, this chapter reviews the next research issues deserving of focus in the field of advanced GC treatment.

**Figure 1.** Median TTP or PFS (white bar) and post-progression free survivals (gray bar) of the previous first-line RCTs. The sum of the white and gray bars indicates median OS. Percentages indicate the proportion of patients receiving further therapy. The reference numbers are expressed in brackets. ECF; epirubicin, cisplatin, and 5-fluorouracil, DCF; docetaxel, cisplatin, and 5-fluorouracil, SP; S-1 and cisplatin. ND; not described.
