Pancreatic cancer is one of the most rapidly rising causes of mortality in the United States. In 2016, the number of deaths from pancreatic cancer exceeded those from breast cancer, making it the third leading cause of cancer-related death in the United States.1 It is projected that by 2020 pancreatic cancer will overtake colorectal malignancies to become the second most common cause of cancer death in this country.1,2 The term pancreatic cancer encompasses both exocrine and endocrine tumors. However, since 80% of pancreatic cancers are classified as pancreatic ductal adenocarcinoma (PDA), when speaking about pancreatic cancer most clinicians and scientists are referring to PDA.
Even with advances in chemotherapy and radiotherapy over the past decade, the only curative option for PDA is surgical resection. Unfortunately, only 20% of patients are appropriate surgical candidates at the time of diagnosis.3 Considering the lack of screening options and the ambiguity of symptomatology, roughly 4 out 5 patients with PDA are diagnosed as having locally advanced or metastatic disease that is initially not amenable to surgery.
Locally advanced pancreatic adenocarcinoma presents unique challenges in management and treatment. Treatment options include multi-agent chemotherapy, chemoradiation, or radiotherapy. Some patients can be successfully down-staged with these therapies and be deemed surgical candidates. Other challenges include selecting the appropriate sequence of therapies and stratifying therapies based on comorbidities. In this article, we review the epidemiology, biology, and diagnostic approach to PDA and focus on current treatment strategies for locally advanced pancreatic cancer (LAPC).
In 2012, GLOBOCAN estimated that PDA caused 331,000 deaths per year, accounting for 4% of all worldwide mortality.4,5 Despite high incidence rates internationally, PDA is a disease of Western and industrialized nations. In the Unites States, PDA is a malignancy of middle to late adulthood, with a sharp upsurge in incidence after age 50 years.6 More than one third of new cases are diagnosed in patients older than 70 years, and more than half of patients diagnosed are older than 60 years of age.2 The incidence of pancreatic cancer is fairly equal among men and women, with a slightly higher rate for the male sex. It has an incidence preference for African-Americans by 4.8 cases per 100,000 persons nationally.7
Risk factors for the development of exocrine pancreatic cancer include hereditary disposition, underlying medical conditions, and environmental factors. One of the most significant environmental risk factors for the development of PDA is smoking,8 which is associated with up to 25% of all cases.9 Smoking cessation leads to a rapid reduction in risk for pancreatic cancer, with the risk among former smokers approaching that for never smokers less than 10 years after quitting.9 Other environmental factors that contribute to the development of pancreatic cancer include increased body mass index, a high-salt and high-saturated fat diet, heavy alcohol intake, and increased utilization of nonsteroidal inflammatory drugs.10–13
There is a strong association between new-onset diabetes and increased risk for developing PDA.14,15 Data also suggest that diabetes may be a risk factor and/or a consequence of tissue destruction that arises during the development or progression of PDA.16,17 Interestingly, ABO blood grouping is another underlying medical disposition that confers an altered risk profile. Studies have shown that patients with blood group O were less likely than those with type A, B, or AB to develop pancreatic cancer.18
Genetic predisposition syndromes can elevate an individual patient’s risk for developing PDA. Genetic syndromes and gene alterations that increase the risk for PDA include BRCA1/2, Peutz-Jeghers syndrome, and Lynch syndrome risk.19–21 Up to 10% to 15% of PDA cases may be due to an inherited familial cancer.22 Having a first-degree relative with PDA increases the odds of developing PDA 1.76-fold compared to those without a family history.23 The exact biologic and molecular mechanisms of familial pancreatic cancer are unclear. It is estimated that about 10% of patients with familial pancreatic cancer (FPC) carry BRCA2 mutations.24 Individuals at risk for FPC should undergo genetic screening for the presence of the most frequently inherited pancreatic cancer susceptibility genetic defects: BRCA2, PALB2, and ATM germline mutations.25 Carriers of BRCA2, who are also at increased risk for developing breast, ovarian, and prostate cancer, should be monitored closely. Of all hereditary conditions, hereditary pancreatitis confers the highest risk for developing PDA, with an approximate risk elevation of 40% to 50%.26,27 Although several genetic predisposition syndromes have been identified, most cases of pancreatic adenocarcinoma are thought to be sporadic.