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margin status. The one associated with the best outcomes is a R0 resection which means a total gross excision
and negative histological margins; R1 resection is a total gross excision however with positive histological
margins; and, R2 is a resection with residual gross tumor and patients that undergo R2 resection have similar
prognosis of the unresectable patients treated with non-operative therapy, on account of that, surgeries that
will result in R2 margins should not be consider as resectable [23,29] .

To improve survival for locally advanced patients neoadjuvant therapy has been evaluated aiming to shrink
tumor, enhance resectability and also to increase rates of microscopic complete tumor resection .
[30]

CHEMOTHERAPY GEMZAR - GEMCITABINE
Gemcitabine is a deoxycytidine (dCTP) analogue, which is converted by nucleoside kinases into two metabolites
diphosphate (dFdCDP) and triphosphate (dFdCTP). Each of these metabolites have a specific mechanism of action:
(1) the diphosphate metabolite (dFdCDP) inhibits ribonuclease reductase, an enzyme known for catalyzing the
reaction that generates ribonucleotides necessary for DNA synthesis; (2) the triphosphate metabolite (dFdCTP)
competes with the natural dCTP for its incorporation into DNA newly synthetized strands. Once dFdCTP
is incorporated, only one additional nucleotide is added to the growing DNA strands, which stops the DNA
synthesis and eventually results in activation of apoptosis pathway leading the cells to death .
[31]
Gemcitabine, as single-agent, became the first line treatment (1996) for advanced pancreatic cancer since a
randomized trial showing that 23.8% of patients had experienced a clinical benefit response compared with
4.8% of patients treated with fluorouracil (5-FU). Gemcitabine also confers a modest improvement in overall
survival than those observed in patients group treated with 5-FU. The patients’ overall survival rates at 12
months were 18% for gemcitabine and 2% for patients treated with 5-FU .
[32]
In the following decade, gemcitabine has become the backbone of combination regimen for new experimental
approaches with either other cytotoxic molecules or novel chemotherapy agents . Many phase II trials have
[33]
demonstrated the efficacy of gemcitabine-based combinations, which comprise other cytotoxic molecules
such as capecitabine, 5-FU, cisplatin, irinotecan [34-37] or the targeted agents sorafenib and cetuximab [38-40] .
However, in some randomized phase III trials of gemcitabine based chemotherapy combinations, these
combinations failed to show statistically significant improvement in patient’s overall survival when compared
to gemcitabine used as a single-agent [41-46] .

Nowadays, gemcitabine is used in combination with taxol, a paclitaxel albumin-stabilized nanoparticle
formulation (nab-paclitaxel) that is commercially known as abraxane. Taxol is a microtubule dynamics
inhibitor that promotes the stabilization of microtubules by preventing the catastrophe process, which
induces cell cycle arrest at the G2/M phase resulting in cell death . In preclinical studies, nab-paclitaxel
[14]
improved the intratumoral concentration of gemcitabine. The FDA approval for this approach was
obtained after a phase III study that demonstrated the efficacy and safety of this combination compared to
monotherapy with gemcitabine in patients with metastatic pancreatic cancer. Von Hoff et al. , randomized
[47]
assigned 861 patients: 431 received nab-paclitaxel plus gemcitabine and 430 gemcitabine alone. The median
overall survival was 1.8 months superior in the combination group, and the survival rate was 35% in the
nab-paclitaxel-gemcitabine group compared to 22% in the gemcitabine group in 1 year. Moreover, this
combination approach increased the median progression-free survival in 1.8 months. However, despite those
benefits rates, peripheral neuropathy and myelosuppression were increased in the group that received nab-
paclitaxel-gemcitabine combination . De vita et al. also confirmed the effectiveness in overall survival
[48]
[47]
and progression free survival from patients treated with the combination of gemcitabine plus nabpaclitaxel.
Although not yet approved by the FDA as a treatment approach for pancreatic cancer, the ESPAC-4 study
developed a phase III randomized trial that could establish the gemcitabine plus capecitabine combination