**6. Conclusions**

Pancreatic cancer is one of the most lethal malignancies among solid tumors and unfortunately most of the times it is diagnosed as a metastatic or unresectable disease with null chances of cure.

First systemic treatments for advanced pancreatic carcinoma were controversial in results and poor outcomes were historically reported.

In the 90's decade gemcitabine became the standard of care for advanced disease, with a mild improve in survival and in response rates. Looking to improve survival, response rate and quality of life several gemcitabine-based chemotherapy combinations were assessed in clinical trials but most of them failed in their primary end points. Despite, gemcitabine- erlotinib combination resulted in a positive trial in statistical terms when compared with gemcitabine alone, allowing to get FDA approval, the clinical significance was poor and currently it is not a recommended treatment as a first option.

No relevant advances were reported until 2011 when a phase 3 French clinical trial in advanced PC showed that FOLFIRINOX when compared with gemcitabine improved OS and response rate in advanced PC but with higher toxicity. 2 years later, in 2013, the publication of another phase clinical trial showed that gemcitabine plus nab-paclitaxel combination was superior than gemcitabine in terms of survival and responses, including patients older than 75 years and with worse performance status (0–2) than the French trial (0–1). Nevertheless, no phase 3 clinical trials have been conducted in order to answer which treatment is better than the other. Meta-analysis that have included both treatments show that apparently both regimens are similar in efficacy.

A recent publication showed that among BRCA-mutated advanced-PC adding olaparib as a maintenance treatment, in patients without disease progression after FOLFIRINOX, improves progression free survival but until now no benefit in overall survival has been reported.

Second-line therapy will depend on previous therapy and current performance status. Options for patients treated with gemcitabine-based regimens are 5-fluorouracil plus leucovorin plus either nanoliposomal irinotecan, irinotecan or oxaliplatin. Patients that were treated with first line FOLFIRINOX may benefit from a

gemcitabine-based chemotherapy, but evidence from randomized trials is lacking. Other options like immunotherapy and targeted therapies yield benefit only in very selected cases, and it is still an area of research.
