**1. Introduction**

Advanced exocrine pancreatic cancer (PC) is one of the most lethal malignancies among all types of solid tumors. According to data from United States of America (USA) registries, 29% of the patients will debut with locally advanced disease, and 53% will have metastases at diagnosis [1]. Even in the cases when resection is feasible, long-term survival rates are among 3.9 and 9.3%, meanwhile 5 years-overall survival for stage IV is lesser than 3% [1, 2]. The late stage at presentation and the particular microenvironment characterized by predominant desmoplastic tissue and immunosuppressive cells explain why PC poses such a challenge [3].

Historically, median overall survival (mOS) for advanced stages was around 6 months when the patient was treated with gemcitabine or gemcitabine-based

combinations but new chemotherapy regimens and better understanding of the tumor biology has led to improved, yet still poor, survival [4].

Unlike other cancers, target therapy has yielded only modest benefit in PC. There are only two targeted agents than historically have got approval for metastatic or unresectable PC: erlotinib and olaparib. Erlotinib, a tyrosine kinase inhibitor (TKi) targeting the epidermal grow factor receptor (EGFR), in combination with gemcitabine, when compared with gemcitabine alone, showed a statistically significant, but clinically modest benefit in OS [5]. Just recently, the US Food and Drug Administration (FDA) approved the PARP inhibitor olaparib for PC in patients with deleterious or suspected deleterious germline BRCA mutations [6], which are present only in approximately 5% of pancreatic cancer patients.

Immunotherapy has showed great advances in melanoma and lung cancer among others, has not yield any promising results in PC. The site agnostic FDA approval for checkpoint inhibitors for mismatch repair deficient tumors (dMMR) or tumors with high microsatellite instability (MSI-H) has modest impact in PC [7], given that those abnormalities are infrequent in pancreatic adenocarcinoma.

Current research is looking for development of new drugs with different mechanisms of action in order to overcome chemotherapy resistance wishing to improve survival and quality of life in advanced PC patients.

Considering that pancreatic cancer is mainly a systemic disease we have focused this chapter in systemic treatments addressed to unrecoverable patients and we will not refer here to local treatments such as radiation therapy or chemoradiation that can be curative in a very small amount of patients but that do not have a real impact in survival in the metastatic or micrometastatic scenario.

## **2. First steps: chemotherapy development in metastatic or unresectable pancreatic adenocarcinoma**

Earlier tested in gastric cancer by the Southwest Oncology Group the combination of 5-Fluoruracil, Adriamycin and Mitomycin C (FAM) was later assessed in advanced PC patients and published in 1980. Smith et al. reported a 37% of partial responses (PR) and 11% of stable disease (SD) among 27 patients that were treated with this regimen and had measurable disease, with a median duration of response (mDOR) of 9 months. Patients with better performance status were more likely to response (55%) and patients with Performance Status (PS)2–3 only achieved a 29% of response rate (RR) (p < 0.15). Median OS was higher in patients that responded (12 months) when compared with nonresponders (3.5 months) (p < 0.01). Myelosuppression was the most relevant toxicity reported in this trial [8].

In 1985, a multicenter phase 3 clinical trial that compared 5-Fluoruracil (5FU) alone or in combination with Adriamycin (FA) or in combination with Adriamycin plus Mitomycin C (FAM) in treating advanced pancreatic and gastric carcinoma was published. This trial that included 144 PC patients from 11 centers of the United States with advanced or metastatic adenocarcinoma of the pancreas, did not show any benefit of both combination arms when compared with 5-FU alone in terms of median OS, median time to progression (TTP), objective response rate (ORR) and parameters of palliation, however, the reported hematological and nonhematological toxicities were higher in the FA and FAM arms when compared with 5 FU alone [9]. This clinical trial led to a decreasing use of FAM regimen and for the increasing need to look for new treatments for these population of patients.

*Current Systemic Treatment Options for Metastatic and Unresectable Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.93225*
