**2. Rationale for second-line therapy**

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.

104 Updates on Cancer Treatment

Figure 1

4.8

docetaxel, cisplatin, and 5-fluorouracil, SP; S-1 and cisplatin. ND; not described.

SP

30%

Ajani et al.[8]

Koizumi et al.[7]

Van Cutsem et

al.[6]

Waters et al.[5]

74%

32%

ND

SP

DCF

ECF

6

3.8

0 2 4 6 8 10 12 14

Survival time (months)

**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;

3.6

1.3

7

5.6

7.4

The significance of second-line therapy after disease progression by first-line chemotherapy has been evaluated by several randomized comparisons of survival times between second-line therapy and best supportive care (BSC) or placebos. Various kinds of agents have been investigated in the RCTs of second-line therapy, such as chemotherapy drugs [10-12] and molecular targeting agents [13-15]. Some of these trials have demonstrated significantly improved survival times by second-line therapies as compared with BSC or a placebo (Table 1).

The AIO conducted a RCT to compare irinotecan (21 patients) with BSC (19 patients) [10]. Although this study was closed prematurely due to poor patient accrual, irinotecan could significantly (p=0.012) prolong median OS (4.0 months) as compared to those by BSC (2.4 months). The second RCT conducted in Korea [11] assigned patients in a ratio of 2:1 to chemotherapy (docetaxel or irinotecan) plus BSC (133 patients) or BSC alone (69 patients). Choice of chemotherapy drugs was left to the discretion of the investigators. Median OS of the chemotherapy arm (5.3 months) was significantly (p=0.007) longer than those of the BSC arm (3.8 months). This survival difference may be partly ascribed to the significantly (p=0.02) greater number of patients receiving further chemotherapy (third-line chemotherapy) in the chemotherapy arm (40%) than in the BSC arm (22%) because median OS was longer (8.0 months) for patients who received subsequent treatment than those who did not (3.76 months), regardless of treatment arm. Of note, the lack of any difference in median OS between docetaxel use (5.2 months) and irinotecan use (6.5 months) implies that both agents are equally active, although bias for patient allocation can not be denied. In the third RCT conducted in the UK [12], 168 patients were allocated to either docetaxel plus active symptom control or active symptom control alone (84 patients each). The median OS in the docetaxel group (5.2 months) was significantly longer (p=0.01) than that in the active symptom control alone group (3.6 months). Measurements of disease specific quality of life showed benefits for docetaxel in reducing dysphagia and abdominal pain.

The efficacy of molecular targeting agents as a second-line setting has been investigated by three other RCTs [13-15]. First, a GRANITE-1 trial [13] randomly assigned 656 patients at a 2:1 schedule either to everolimus (n=439) or a matching placebo (n=217). Significantly longer median PFS by everolimus (1.7 months, p<0.0001) than that by placebo (1.4 months) did not reflect a difference in median OS (5.4 months in the everolimus arm versus 4.3 months in the placebo arm, p=0.12). Such a discrepancy, namely a significant PFS difference and nonsigni‐ ficant OS difference, could be ascribed to the fact of the similar or even longer median OS (4.3 months) in the placebo arm in this study as compared to those (2.4-3.8 months) of BSC arms in other second-line RCTs [10-12]. Therefore, one should remember that the longer survival length in the control arm might diminish any statistical significance even when the experi‐ mental regimen is effective. Subsequently, a global REGARD trial [14] was able for the first time to demonstrate that ramucirumab, a monoclonal antibody of vascular endothelial growth factor receptor (VEGFR)-2, was significantly superior to placebo with regard to median OS (5.2 months versus 3.8 months, p=0.047) and median PFS (2.1 months versus 1.3 months, p<0.0001), respectively. In addition, more patients receiving ramucirumab experienced stable or im‐ proved QOL than those in the placebo arm. Finally, apatinib, a tyrosine-inhibitor agent targeting VEGFR with an anticipated anti-angiogenesis effect, has been now tested in a clinical trial (NCT 01512745) [15]. This study aims to determine whether apatinib can improve PFS or OS compared to placebos.

Subsequently, a metaanalysis has very recently elucidated a 36% reduction in the risk of death (p<0.0001) by second-line therapy [16], suggesting that second-line therapy is effective and should be considered in some segments of GC patients refractory to first-line therapy.
