During 2024 in the United States, an estimated 64,440 people will be diagnosed with pancreatic cancer, which represents 3.3% of all new cancer cases and the 11th most common new cancer diagnosis. The median age at diagnosis is 70 years [18].

There is some evidence that higher consumption of red/processed meat is associated with elevation in pancreatic cancer risk, but other studies have failed to identify dietary risk factors for PDAC [11]. Pancreatic cancer incidence may be lower in persons with higher intake of fresh fruits and vegetables rich in folate and lycopenes (e.g., tomatoes) [30].

A link between vitamin D and risk for pancreatic cancer is inconsistent, but some data suggest low plasma 25-hydroxyvitamin D levels may increase the risk for pancreatic cancer, especially in those with low retinol/vitamin A intake [31]. Coffee and tea consumption are not associated with pancreatic cancer risk, despite early reports to the contrary [24].

Numerous clinical series have identified new-onset diabetes, weight loss, and soft tissue changes in patients with PDAC at diagnosis, but their inter-relationship and connection to PDAC remained unaddressed. From 2000 through 2015, temporal changes in the five years preceding PDAC diagnosis of 219 patients diagnosed with PDAC were compared to 657 controls [46]. From 60 to 30 months before PDAC diagnosis, patients did not significantly differ from controls. However, starting at 30 months prediagnosis, PDAC showed three distinct metabolic phases, each marked by onset and significant progressive worsening of one or more metabolic abnormalities [46]:

Through pathways and somatic mutations that differ modestly in each lesion, PDAC develops from precancerous precursor lesions: pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasms (MCNs). The most common are PanINs (approximately 90%), and the least common are MCNs (<15%). However, all precursor lesions have key similarities [4,48,50]:

With the low population incidence of PDAC (lifetime risk: 1.3%), absence of biomarker screening targets, and high cost of sensitive imaging methods, the U.S. Preventive Services Task Force recommended against screening for pancreatic cancer in asymptomatic adults in 2019, reaffirming its previous conclusion in 2004 [74]. As population screening to achieve earlier detection and intervention of PDAC is not currently feasible, other approaches for this objective have been identified.

In Australia, public awareness campaigns have highlighted the often-vague symptoms of PDAC and encouraged individuals to seek medical attention early. Underscoring this point, one study found that many people who were ultimately diagnosed with PDAC were falsely reassured by the subtle, intermittent nature of their symptoms over the preceding months [75,76].

As a relatively rare cancer, many primary care providers will only see a PDAC case every few years, making it imperative to elevate awareness of early PDAC signs and symptoms among these professionals. A retrospective case-control study in primary care found that patients sought medical attention 18 times on average in the period preceding their pancreatic cancer diagnosis. PDAC was associated with 11 alarm symptoms; back pain, lethargy, and new-onset diabetes were unique features of PDAC [75,77].

All patients with pancreatic cancer should have germline testing and gene profiling offered as quickly as possible after diagnosis; the implications for first-line therapy and beyond are significant [79,80]. The 2020–2021 ASCO and NCCN recommendations are for all patients with PDAC to receive germline genomic testing using comprehensive gene panels for hereditary cancer syndromes, and targeted (somatic) profiling of tumor tissue using next-generation sequencing [10,11]. Patients with locally advanced or metastatic PDAC should have available tumor tissue tested for DNA mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) status. It is also recommended that these patients undergo testing for actionable somatic mutations, including fusions (ALK, NRG1, NTRK, ROS1), mutations (BRAF, BRCA1/2, HER2, KRAS, PALB2), and mismatch repair deficiency (dMMR).

Most pancreatic cancers (approximately 70%) originate in the head of the pancreas and present with biliary obstruction leading to dark urine (49%), jaundice (49%), loss of appetite (48%), weight loss (55%), and pancreatic insufficiency (25%) [134]. Symptoms of pancreatic cancer arising in the body and tail of the pancreas are more nonspecific, such as abdominal pain, back pain, weight loss and fatigue. Pancreatic cancers typically metastasize to regional lymph nodes first, then to the liver. PDAC can also directly invade surrounding visceral organs (e.g., duodenum, stomach, colon); metastasize to any surface in the abdominal cavity via peritoneal spread where development of ascites carries an ominous prognosis; or spread to the skin as painful nodular metastases. By the time of diagnosis, 85% to 90% of patients have locally advanced tumors that have involved retroperitoneal structures, spread to regional lymph nodes, or metastasized to the liver or lung [2,13,24,81].

Early-stage pancreatic cancer is notoriously difficult to diagnose. The most common symptoms in a series of patients diagnosed with PDAC were fatigue (86%), weight loss (85%), anorexia (83%), abdominal pain (79%), epigastric pain (71%), jaundice (56%), nausea (51%), diarrhea (44%), pruritus (32%), and steatorrhea (25%) [82].

Development of abdominal pain, jaundice, or weight loss in the context of newly diagnosed diabetes, family history of PDAC, or history of pancreatitis should trigger inclusion of PDAC in the differential diagnosis [2]. Furthermore, past three-year onset of diabetes or ongoing hyperglycemia with significant weight loss and decreasing serum lipids should be considered a potential PDAC, even if abdominal pain or jaundice are absent, with urgent referral a priority.

A peculiar herald sign of occult pancreatic cancer is the insidious onset of an enigmatic depression, absent abdominal pain and often accompanied by anorexia and weight loss. In some patients, depression may be the most prominent presenting symptom, possibly secondary to delayed diagnosis. In addition, although patients may not communicate it to their families, they are often aware that a serious illness of some kind is occurring in them [24]. The risk of suicide among male patients with PDAC is almost 11 times higher than the general male population. Patients who underwent resection are more likely to commit suicide, specifically in the early postoperative period [83].

Referral for genetic counseling should be considered for patients diagnosed with pancreatic cancer, especially those with a family history of cancer or who are young, those of Ashkenazi Jewish ancestry, or for whom a hereditary cancer syndrome is suspect. A free pancreatic cancer risk prediction tool, PancPRO, is available and may help determine risk [11].

Abdominal pain is the most common symptom, usually insidious in onset and often present for one to two months at the time of presentation, the pain is often severe, and unrelenting in nature. The typical gnawing, visceral quality of pain is generally epigastric, radiating to the sides and/or straight through to the back; some patients may describe the pain as originating in the back. Nighttime pain is often the predominant complaint. Some patients note increased pain after eating and worsened pain when lying flat [24,81]. Rarely, acute pain develops when an episode of acute pancreatitis results in tumor occlusion of the main pancreatic duct [84].

Pancreatic cancer cachexia is a multifactorial paraneoplastic syndrome characterized by a loss of skeletal muscle mass, commonly associated with adipose tissue wasting and anorexia, fatigue, and reduced exercise tolerance. Cachexia develops in approximately 80% of patients with PDAC, in whom the syndrome is typically present at diagnosis and responds poorly to therapeutic interventions [47,86].

Metastatic disease most commonly affects the liver, peritoneum, lungs, and less frequently, bone [24,84]. Patients presenting with or developing advanced intra-abdominal disease may have ascites, a palpable abdominal mass, hepatomegaly from liver metastases, or splenomegaly from portal vein obstruction. Subcutaneous metastases (termed Sister Mary Joseph nodules) in the paraumbilical area signify advanced disease; pancreatic cancer is the origin of a cutaneous metastasis to the umbilicus in 7% to 9% of cases [24,84]. A metastatic mass in the rectal pouch may be palpable on rectal examination (Blumer shelf). As a metastatic node, left supraclavicular lymphadenopathy may be palpable, while other nodes in the cervical area may also be involved.

Routine laboratory tests are often abnormal but nonspecific for PDAC. Common abnormalities include an elevated serum bilirubin and alkaline phosphatase levels, and presence of mild anemia [84].

Multidetector computed tomography (MDCT) angiography with intravenous (IV) contrast is the preferred imaging for initial evaluation of suspected PDAC. The Pancreatic CT Protocol standardizes its use, making MDCT highly accurate for assessing tumor extent, vascular invasion, and distant metastases [11,16,88,89]. The degree of contact between the tumor and local blood vessels (i.e., uninvolved, abutted, or encased) is used to define the most optimal initial treatment [134]. The NCCN recommends that MDCT angiography should also cover the chest and pelvis for complete staging [11].

Endoscopic ultrasound-guided biopsy is preferable to a CT-guided biopsy in patients with non-metastatic disease because of better diagnostic yield, safety, and lower risk of peritoneal seeding when compared with the percutaneous approach. Biopsy proof of malignancy is not required before surgical resection, and a non-diagnostic biopsy should not delay surgical resection when the clinical suspicion for pancreatic cancer is high [11]. However, when histologic confirmation of a pancreatic cancer diagnosis is required, as in certain situations, endoscopic ultrasonography-guided fine-needle core biopsy is the best modality for obtaining a tissue diagnosis.

A pathologic diagnosis is indicated to confirm PDAC in locally advanced or metastatic disease, before neoadjuvant therapy, and in atypical presentations in which differential diagnosis is needed with other pancreatic masses (e.g., pancreatitis, lymphoma, tuberculosis). If a biopsy does not confirm malignancy, it should be repeated at least once [16].

CA19-9 is a sialylated Lewis A blood group antigen, commonly expressed and shed in benign and malignant pancreatic and biliary disease. Although not sufficiently sensitive or specific for routine screening, CA19-9 is the most clinically useful biomarker in PDAC, with sensitivity (79% to 81%) and specificity (82% to 90%) in symptomatic patients. A normal serum level is 37 U/mL [90].

The NCCN guideline classes PDAC resectability into the following clinical stages [11]:

Curative surgical approaches for resectable pancreatic cancer are well-established. In contrast, the pace of new U.S. Food and Drug Administration (FDA) approvals and/or phase III evidence continue to make chemotherapy, molecular-targeted therapy, radiation, and chemoradiotherapy approaches a fluid, evolving area, requiring frequent updating and revisions in multidisciplinary clinical practice guidelines for pancreatic cancer treatment. Many potential treatment approaches lacking phase III or prospective evidence are being addressed, with publication of trial results awaited [2].

Used for tumors in the pancreatic head or periampullary region, the conventional Whipple procedure involves removal of the pancreatic head, duodenum, gallbladder, and the antrum of the stomach, with surgical drainage of the distal pancreatic duct and biliary system, usually through anastomosis to the jejunum. The primary reason for removing so much of the intra-abdominal structures is that they all share a common blood supply [24,102].

ASTRO guidelines for neoadjuvant chemoradiation specify a radiation dose of 4,500–5,040 cGy in 180–200 cGy fractions [12]. They recommend delivery of radiation therapy following two to six months of chemotherapy.

Symptomatic biliary obstruction develops in approximately 80% of patients with carcinoma of the head of the pancreas [143]. Biliary stents relieve troublesome pruritis and may be used to improve liver function sufficiently to permit safe administration of cancer treatment. Endoscopic retrograde stenting is superior to surgical or percutaneous approaches to address bile duct obstruction because of a more favorable adverse event rate. Successful biliary stent placement can be achieved in more than 90% of patients, with potential post-procedure complications of pancreatitis, bleeding, or cholangitis in 5% of cases [143]. Self-expandable metal stents are preferred over plastic stents in patients with a life expectancy of more than three months in terms of patency duration, less therapeutic failure and need for reintervention, lower cholangitis incidence, and better patient quality of life. Patency rates between covered and uncovered metal stents are not significantly different [16]. Endoscopic ultrasonography-guided biliary drainage is an alternative if endoscopic biliary stent placement is unsuccessful or technically not feasible.

Many agents have been evaluated for the treatment of CACS, but only corticosteroids (e.g., dexamethasone) and progesterone analogs (e.g., megestrol acetate) have a proven benefit in the anorexia associated with this syndrome [122]. Selection is based on life expectancy and assessment of risks versus benefits. Dexamethasone is suggested for patients for whom only weeks of therapy are anticipated, while megestrol acetate or medroxyprogesterone acetate (another progesterone analog) are suggested for patients with longer life expectancies [126].

Counselling of family members regarding what to expect with disease progression is important—it can alleviate distress that leads to well-meaning but futile attempts to pressure or coerce the patient into increased feeding. Key points to discuss with patients and their family members, related to interactions about nutrition and eating near the end of life, include the following [131]: