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Pereira et al. J Cancer Metastasis Treat 2018;4:30 I http://dx.doi.org/10.20517/2394-4722.2018.13 Page 5 of 14

as the treatment of choice for adjuvant setting after resection . In this study, they aimed to demonstrate
[49]
the safety and efficacy of the combination for resected pancreatic cancer since a phase III randomized
comparison between gemcitabine plus capecitabine and gemcitabine alone showed a significant improvement
in objective response rate (P = 0.03) and progression-free survival (P = 0.004) and was associated with a trend
toward improved overall survival (P = 0.08) in patients with advanced pancreatic cancer that underwent the
combination approach . The capecitabine is an oral prodrug of 5-FU, a fluoropyrimidine carbamate, that
[50]
provides prolonged fluorouracil tumor exposure at lower peak concentration. The conversion of capecitabine
in the active drug needs an enzyme named thymidine phosphorylase which is present at higher levels in
tumor cells compared to other tissues which improves tolerability and intratumor drug concentration .
[51]

FOLFIRINOX REGIMEN - FLUOROURACIL, LEUCOVORIN, IRINOTECAN AND OXALIPLATIN
5-FU is a fluoropyrimidine antimetabolite drug that exerts antitumoral effects inhibiting the enzyme
thymidylate synthase, impairing the synthesis of the pyrimidine thymine, which is required for genetic
material synthesis. The fluoronucleotides are misincorporated into RNA and DNA strands resulting in cell
death . Leucovorin is a metabolite of folinic acid, known as 5-formyltetrahydrofolic acid, which is the
[52]
5-formyl derivative of tetrahydrofolic acid . Leucovorin is indicated for use as rescue therapy to reduce
[53]
the toxicity associated of folinic acid antagonists that inhibits de novo synthesis of purines, pyrimidines and
methionine. The combination of leucovorin and 5-FU can extend the survival in the palliative treatment
of patients with advanced pancreatic cancer [54,55] . Irinotecan is a derivative of camptothecin that has a
cytotoxic action via a potent and specific inhibition of DNA topoisomerase I, preventing the DNA strand
ligation leading to double-strand DNA breakage and cell death . Oxaliplatin is a platinum-based drug
[56]
that belongs to the same family of cisplatin and carboplatin. In oxaliplatin the two amine groups were
replaced by cyclohexyldiamine, which increases its antitumor effect. The chlorine ligands were replaced by
the oxalato bidentate derived from oxalic acid that improves its water solubility [57,58] . Oxaliplatin is converted
to active derivatives via displacement of the labile oxalate ligand. Its reactive species monoaquo and diaquo
diaminocyclohexane platinum binds guanine and cytosine moieties of DNA and this association produces
cross-linking of DNA inhibiting the DNA synthesis and transcription .
[59]
A phase 1 study involving patients with advanced solid tumor was developed to determine the maximum-
tolerated dose and the recommended dose of the triple combination (oxaliplatin, irinotecan, leucovorin/5-FU). A
fair response in patients with advanced pancreatic cancer utilizing this combining regimen was observed .
[60]
Then, a phase 2 study of FOLFIRINOX regimen was conducted involving 46 advanced pancreatic cancer
patients with good performance status. FOLFIRINOX showed a high efficacy against this malignant
tumor, but it has produced severe neutropenia in half of the patients. It was prompted started the phase
2-3 trial in order to compare FOLFIRINOX regimen with gemcitabine as single antitumoral agent. In
this trial, 342 patients were randomly assigned. The median overall survival and the median progression-
free survival were significantly extended for the FOLFIRINOX regimen group (48% of patients submitted
to FOLFIRINOX regimen were alive after 1 year compared to 20% treated with gemcitabine). Due to its
high toxicity, the group treated with FOLFIRINOX showed more intense side effects such as grade 3 or
4 neutropenia, thrombocytopenia and grade 2 alopecia. However, despite the higher incidence of intense
side effects, the FOLFIRINOX treated group showed a significant increase of time period that precedes
the definitive deterioration of the quality of life compared to gemcitabine group. These results lead to the
conclusion that FOLFIRINOX is an effective therapeutic option but only suitable for patients with metastatic
pancreatic cancer that hold a good performance status .
[61]

After the effectiveness of FOLFIRINOX regimen in the palliative setting has been established, Faris et al.
[62]
had performed a retrospective study in the Massachusetts General Hospital Cancer Center to answer two
questions that remained unclear: will the benefit in response rate and overall survival in the metastatic
setting translate to patients with locally advanced pancreatic cancer? And are curative-intent resections