28
reduce the risk of death by 20% in the comparison against ECF
(HR 0.80, 95% CI 0.66–0.97; p = 0.02) [ 29 ]. Oxaliplatin was
associated with lower incidence of grade 3 or 4 neutropenia, alope-
cia, renal toxicity, and thromboembolism but slightly higher inci-
dence of grade 3 or 4 diarrhea and neuropathy. A phase III study
by the German Study Group also showed similar messages in terms
of toxicity profile and efficacy. There was a trend toward improved
median progression-free survival with FLO (5FU, leucovorin, and
oxaliplatin) over FLP (5FU, leucovorin, cisplatin) (5.8 months vs.
3.9 months; p = 0.077) but no difference in overall survival.
Interestingly, patients older than 65 years enjoyed better outcomes
with FLO [ 38 ]. Another Japanese study that evaluated the combi-
nation of S-1 plus oxaliplatin (SOX) in a phase III randomized
setting. SOX was noninferior to cisplatin plus S-1 (CS). The haz-
ard ratios for overall survival and progression-free survival were
close to unity. A more favorable toxicity profile was again demon-
strated with SOX [ 39 ]. In short, oxaliplatin is a feasible substitute
for cisplatin due to its improved safety profile and comparable effi-
cacy. However, cumulative neurotoxicity is a concern and may
impair tolerability to second-line treatment.
Platinum-Free Regimens: Taxanes and Irinotecan: Taxanes
including docetaxel and paclitaxel are commonly used alone or in
combination for advanced metastatic disease. Docetaxel was first
evaluated in the V325 study to evaluate its safety and efficacy in
addition to cisplatin and 5FU [ 40 ]. Despite a small clinical benefit
in the response rate, time-to-progression, and overall survival, the
triplet regimen had an alarming rate of grade 3 or 4 neutropenia
(82%) and complicated neutropenia (29%). To alleviate the toxicity
of the triplet regimen, various modifications have been studied in
the phase II setting [ 41 – 43 ]. Due to the high incidence of hema-
tologic toxicity of triplet containing regimen, docetaxel-containing
doublet regimen is more commonly used in practice. The phase III
START study [ 44 ] randomized patients to S-1 with or without
docetaxel has reported its result that mostly replicates that of the
SPIRITS study [ 34 ]. Combination of docetaxel and S-1 achieved
a significantly improved median progression-free survival of
5.3 months and overall survival of 12.5 months. Of note, survival
outcomes of the S-1 monotherapy arm were also highly consistent
with the previously reported studies [ 33 , 34 ]. Irinotecan was often
evaluated in combination with fluoropyrimidine as platinum-free
regimen. Dunk et al. reported a phase III randomized study of
irinotecan, folinic acid, and 5FU (IF) versus cisplatin and 5FU in
333 patients [ 46 ]. Although superiority of IF was not demon-
strated for overall survival, a significantly improved time-to-
treatment failure and a more favorable toxicity profile was shown
with IF. In another phase III randomized study that compared
ECX with FOLFIRI, median time-to-treatment failure was signifi-
cantly prolonged with FOLFIRI (5.1 months vs. 4.2 months;Ka-On Lam and Dora L. W. Kwong