It has remained in clinical use, often in combination with albumin-bound (Nab) Paclitaxel, which improved survival time compared to Gemcitabine monotherapy ( 10). While several chemotherapy regimens have been approved for metastatic PDAC, the most widely used and best-studied agent is Gemcitabine, a drug was first approved by the FDA for metastatic PDAC in 1996, after showing marginal efficacy in clinical trials ( 7– 9). Further, a significant number of patients experience grade 3-4 adverse effects ( 6). While chemotherapy provides a survival benefit in both resectable and non-resectable forms of the disease, these benefits are modest as almost all patients harbor some degree of drug resistance ( 6). As such, nearly all are offered conventional chemotherapy. While surgical resection offers a clear survival benefit and increases 5-year survival to 25%, the majority of patients present with disseminated and/or locally advanced disease, precluding them from undergoing resection. Based on recent trends in PDAC incidence and survival and the improvements in survival in cancers of the lung and breast, it has been proposed that PDAC will become the second leading cause of cancer-related death by 2030 ( 5). Currently, the overall 5-year survival rate is approximately 10% ( 4). There has been a slow but progressive increase in PDAC incidence in the US, but the overall survival rate has also increased. Risk factors for PDAC include tobacco smoking, germline mutations in such genes as breast cancer gene 1 ( BRCA1) and BRCA2, chronic pancreatitis, obesity, long-standing type 2 diabetes (T2DM), and prolonged and excessive alcohol consumption ( 1– 3). Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer death in the US. Combined, this review highlights an unmet clinical need to improve our understanding of the mechanisms underlying the poor therapeutic responses seen in patients with PDAC, in hopes of increasing drug efficacy, extending patient survival, and improving quality of life. Here we discuss the current state of pancreatic cancer therapy, both surgical and medical, and emerging factors limiting the efficacy of both. In cases of inoperable disease, cytotoxic therapies are less efficacious but still carry the same risk of serious adverse effects, and clinical outcomes remain particularly poor. However, chemotherapy is all too often associated with toxicity, and many patients elect for palliative care. Despite the high prevalence of drug-resistant phenotypes, nearly all patients are offered chemotherapy leading to modest improvements in postoperative survival. Clinically, these poor outcomes are attributed to several factors, including late stage at the time of diagnosis impeding resectability, as well as multi-drug resistance. Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a median survival time of 10-12 months.
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