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Page 6 of 14 Pereira et al. J Cancer Metastasis Treat 2018;4:30 I http://dx.doi.org/10.20517/2394-4722.2018.13

possible in patients who respond to this treatment? They found that FOLFIRINOX regimen have substantial
activity in locally advanced pancreatic cancer patients and also, that the use of FOLFIRINOX regimen could
induce cancer conversion to resectability in more than 20% of patients. From those patients that could
resect the cancer, 3 from 5 had recurrence and 1/3 of patients had experienced significant toxicity signals
that required visits to emergency department or hospitalization. The most prevalent effects were anemia
grade 1 or 2, thrombocytopenia (mostly grade 1), neutropenia, diarrhea/dehydration. Due to high toxicity
of FOLFIRINOX regimen, further studies were suggested to reach an optimized treatment to patients with
locally advanced pancreatic cancer.

In the other hand, FOLFIRINOX has been studied as neoadjuvant option for locally advanced and borderline
resectable patients [63-65] . The neoadjuvant therapy can benefit by converting a few locally advanced tumors
into resectable ones and increase R0 resectability in borderline tumors [66,67] . The FOLFIRINOX combination
regime was associated with an increase in R0 resection rates when administered with or without radiotherapy
before surgery in borderline resectable and locally advanced patients. The most important result is the down
staging of the disease in locally advanced, thus making it possible for patients to undergo surgery and
increasing the median progression free survival [19,68,69] . However, phase III studies should be prompted to
confirm whether preoperative neoadjuvant vs. postoperative adjuvant treatment relates to better survival for
those patients that can undergo surgery .
[70]

ONYVIDE - NANOLIPOSOMAL IRINOTECAN, 5-FU AND FOLINIC ACID
Nanoliposomal irinotecan has potential antineoplastic activity; its liposome encapsulation promotes better
delivery of drugs into the cytosol from the endosome compartment of the cell. This encapsulation platform
of drug delivery reduces the premature systemic drug release but maintains its intra tumoral release,
enhancing antitumor activity .
[71]
On October 22, 2015, the U.S. FDA has approved the onivyde (irinotecan liposome injection) in combination
with 5-FU and leucovorin to treat patients with advanced metastatic pancreatic cancer who have been
previously treated with gemcitabine-based chemotherapy. The approval was due to a phase III study,
conducted after preceding trials showing promising activity of the nanoliposomal irinotecan in patients
with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine .
[72]
In the phase III trial, nanoliposomal irinotecan was tested alone or in combination with 5-FU and folinic
acid, compared with a common control (5-FU and folinic acid) in patients with metastatic pancreatic cancer
progression after a regimen of gemcitabine. It was a global, randomized, open-label trial in 14 countries.
Their results showed that nanoliposomal irinotecan plus 5-FU and folinic acid significantly improved the
overall survival. Also, the results related with progression-free survival, objective tumor response, time
to treatment failure and CA19-9 tumor marker response for those patients were significantly improved
in contrast to the 5-FU and folinic acid control group. Neutropenia, fatigue, diarrhea and regurgitating
were the main side effects observed in patients group (14.5%, 13.7%, 12.8%, 11.1% respectively) submitted to
treatment with the combination of nanoliposomal irinotecan with 5-FU and folinic acid. With a manageable
safety profile, this approach represents a new treatment option for many patients with metastatic pancreatic
cancer that previously received an unsuccessful gemcitabine therapy .
[73]
There is an ongoing trial, randomized, open-label, phase II study of onivyde vs. nab-paclitaxel + gemcitabine
[74]
in patients with metastatic pancreatic adenocarcinoma (NCT02551991) .

IMMUNOTHERAPY
Despite all chemotherapy combinations and new trials with targeted therapies, overall survival of advanced
pancreatic cancer patients remains poor. The establishments of new therapies that provide long-term