Capecitabine in the Treatment of Advanced Gastric Cancer

Jae-Lyun Lee; Yoon-Koo Kang

Disclosures

Future Oncol. 2008;4(2):179-198. 

In This Article

Other Oral Fluoropyrimidines

S-1: an Upcoming Competitor to Capecitabine

S-1 is a novel oral fluoropyrimidine originally developed in Japan. S-1 is not a single compound, but a mixture of three compounds, consisting of a 5-FU prodrug, tegafur, together with a DPD inhibitor, 5-chloro-2,4-dihydroxypyridine and an orotate phosphoribosyl transferase inhibitor, potassium oxonate, which suppress the gastrointestinal toxicity of 5-FU ( Table 1 & Figure 2). In two Phase II studies of single-agent S-1 in Japan, 80 mg/m2/day for 4 weeks followed by a 2-week rest resulted in very high ORR (44-49%) ( Table 4 );[86,87] however, this high ORR was not reproduced in a subsequent Korean study.[88] Based on the synergism between S-1 and cisplatin observed in preclinical studies,[89] combination regimens of these two drugs have been developed.[23,90,91,92,93] A Japanese study, in which 19 patients were treated with S-1 80 mg/m2 daily for 3 weeks followed by a 2-week rest, and cisplatin (60 mg/m2) given on day 8 of an every 5-week cycle, resulted in a very high ORR (76%).[91] In a US trial, 42 patients were treated with S-1 50 mg/m2/day for 3 weeks, followed by a 1-week rest, plus cisplatin 75 mg/m2 on day 1 of an every 4-week cycle, resulting in an ORR of 48%, a median PFS of 5.3 months and a median OS of 10.9 months.[23,92,93] To lower the toxicity of this regimen, which usually occurs during the third week of continuous administration, a new dosing schedule was developed, in which S-1 was given for two consecutive weeks of an every 3-week cycle and the dose of cisplatin was 60 mg/m2 In a Korean study using this schedule, the recommended dose (RD) of S-1 was set at 90 mg/m2/day and reduced to 80 mg/m2 to improve feasibility, with cisplatin given on day 1, resulting in an ORR of 48% with a median PFS of 5.3 months.[23] The Phase II results of S-1, alone or in combination with other cytotoxic agents, are shown in Table 1 .[88,94,95,96,97,98]

The results of several Phase III trials of S-1 in AGC were recently reported.[99,100,101] In the Japan Clinical Oncology Group (JCOG) 9912 study, S-1 was found to be noninferior to infusional 5-FU. In the S-1 Plus Cisplatin Versus S-1 in the Treatment for Stomach Cancer (SPIRITS) study, the addition of cisplatin to S-1 significantly improved ORR and survival compared with S-1 alone; therefore, in Japan, combination treatment with S-1 plus cisplatin became a standard regimen for AGC. However, this regimen cannot be a worldwide standard, primarily because the dose of S-1 tolerated by Western patients is much lower than the dose tolerated by Asian patients, which may be associated with the genetic polymorphism of the tegafur-converting enzyme, CYP2A6.[23,92,93,102,103,104,105] In addition, the dose intensity of cisplatin (12 mg/m2/week) in the SPIRITS study was much lower than the doses usually used to treat AGC (20-25 mg/m2/week).[15,17,19,20,21,74] A firm conclusion on the role of S-1 in AGC awaits the results of the recently completed First-Line Advanced Gastric cancer Study (FLAGS) study, which compared the OS of S-1 plus cisplatin versus FP in a Western population. As there are no Phase III trials comparing S-1 and capecitabine, it is hard to determine their relative efficacy and toxicity. In a recent randomized Phase II trial of capecitabine (2500 mg/m2 daily for 2 weeks followed by a 1-week rest) versus S-1 (80 mg/m2 daily for 4 weeks followed by a 2-week rest) monotherapy in elderly patients with AGC; however, the externally reviewed ORRs were comparable (27.2 vs 28.9%).[49] Moreover, with the exception of HFS, which was more common with capecitabine, the incidence of clinically significant toxicities was similar in the two arms.

Other Oral 5-FU Agents

UFT is a 1:4-molar combination of tegafur and competitive DPD inhibitor, uracil. When combined with leucovorin (Figure 2), UFT showed an ORR of 11-26% in AGC.[106,107] Although promising activity was reported (a 57% ORR and median OS of 15 months) when UFT is added to epirubicin and cisplatin combination,[108] further evaluation of UFT was limited with the poor results of UFT plus mitomycin C combination from the JCOG 9205 study.[16] Eniluracil (5-ethynyluracil) is a potent and irreversible inactivator of DPD, and thereby achieves a constant 5-FU plasma concentration by improving the oral bioavailability when coadministered with oral 5-FU. Phase I studies combining eniluracil plus 5-FU have been conducted, and its activity against several malignancies, including colorectal, pancreatic and breast cancer, have been reported. Until now, a Phase II study against AGC has been lacking, as is the case with another DPD-inhibiting oral 5-FU, BOF A-2.[109]

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