27and sixteenth patients were randomized and efficacy and toxicity
profile were similar with capecitabine or 5FU when combined with
cisplatin. The median progression-free survival and overall survival
for cisplatin/capecitabine and cisplatin/5FU were 5.6 and 10.3,
and 5.0 and 9.3 months, respectively.
S-1 is a fourth generation oral fluoropyrimidine and it contains
tegafur/gimeracil/oteracil potassium in a molar ratio of 1:0.4:1.
Gimeracil prolongs half-life of fluorouracil and oteracil improve
gastrointestinal tolerability via enzymatic inhibition [ 31 , 32 ]. The
JCOG 9912 study has shown the noninferiority of S-1 to 5FU in
terms of overall survival. Since then S-1 represents the standard
therapy for advanced gastric cancer in Japan [ 33 ]. Subsequently,
the SPIRITS study that randomized 305 patients to S-1 versus S-1
plus cisplatin in 38 canters in Japan has reported a significant
reduction in the risk of death by 23% with doublet combination.
There was absolute improvement of 2 months in both median
overall survival (13 months vs. 11 months) and progression-free
survival (6 months vs. 4 months) [ 34 ]. As opposed to Japanese
studies, efficacy of S-1 in the Western countries appeared less con-
vincing. Cisplatin with 5FU or S-1 were compared in the phase III
randomized FLAGS study but did not detect a significant improve-
ment in overall survival (8.6 months vs. 7.9 months; p = 0.20).
Improved safety profile was the only positive findings in the study
[ 35 ]. Meta-analysis of S1-based versus capecitabine-based chemo-
therapy as first-line treatment for metastatic gastric cancer has
demonstrated similar overall response rate, time-to-tumor progres-
sion, overall survival as well as toxicity profiles though less hand-
foot- skin reaction has been consistently reported. However, studies
included in the meta-analysis were mostly small phase II studies
with limited information on quality of life [ 36 ]. The XParTS II
study is the only head-to-head comparison between cisplatin and
S-1 (SP) and cisplatin and capecitabine (PX) in a randomized phase
II setting. Preliminary results in the 109 eligible patients showed
equivalence in major study endpoints but pre-planned subgroup
analysis showed superiority of SP for progression free survival in
diffuse type gastric cancer [ 37 ]. In clinical practice, the prevalence
of prescription is still varying widely in different geographical
regions, infusional 5FU being used more commonly used in the
West while oral fluoropyrimidines are more popular in the East.
Combination Chemotherapy: Cisplatin vs. Oxaliplatin: Cisplatin
is a referenced standard in the combination therapy against
advanced metastatic esophageal or esophagogastric carcinoma but
its tolerability is a concern in the palliative setting. Oxaliplatin,
docetaxel, and irinotecan have been evaluated in a number of stud-
ies with encouraging results. Oxaliplatin has lower incidence of
nausea and vomiting, renal toxicity and ototoxicity but more
neurotoxicity when compared with cisplatin. In the REAL-2 study
that has been discussed above, a noninferiority of oxaliplatin and
cisplatin was shown in the primary analysis while the EOX regimen
Chemotherapy