Pancreatic Cancer

Pancreatic cancers can arise from the exocrine or endocrine portions of the pancreas, but the vast majority develop in the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. Of all pancreatic malignancies, 90% are adenocarcinomas of the ductal epithelium (pancreatic ductal adenocarcinoma [PDAC]).[2] Less common histologic variants of PDAC, which usually present in a similar fashion, include acinar cell adenocarcinoma (AAC), adenosquamous carcinoma (ASCP) , and cystadenocarcinoma (serous and mucinous types). Rare pancreatic malignancies include the following[2]

• Giant cell carcinoma
• Invasive adenocarcinoma associated with cystic mucinous neoplasm or intraductal papillary mucinous neoplasm
• Mixed type (ductal or acinar endocrine)
• Mucinous carcinoma
• Pancreatoblastoma
• Papillary-cystic neoplasm (Frantz tumor); this tumor has lower malignant potential and may be curable with surgery alone
• Papillary mucinous carcinoma
• Signet ring carcinoma
• Small cell carcinoma
• Undifferentiated carcinoma

Pancreatic neoplsams with borderline malignancy include the following[2] :

• Intraductal papillary mucinous tumor with dysplasia
• Mucinous cystic tumor with dysplasia
• Pseudopapillary solid tumor

AAC is a rare variant of pancreatic adenocarcinoma.[9] It is more common in young adults and adolescents. While it usually presents at an advanced and unresectable stage, it does portend a somewhat better prognosis than PDAC; 5-year survival is around 45%, much higher than 7-10% for PDAC.[10]

Unlike PDAC, ACCs often harbor potentially targetable genetic abnormalities such as in BRCA1/2 (somatic and germline up to 22%), PALB2, BAP1, ATM, JAK1, BRAF and ID3.[11, 12] The molecular and genomic signature of ACC is characterized by relative rarity of mutations in KRAS (2%), TP53 (15%), CDKN2 (14%), and SMAD (16%). mutations.[13] At the clinicopathologic level, these malignancies are characterized by a relative lack of desmoplastic reaction and stroma.[9]

ASCP represents another rare and distinct variant.[14] All ASCPs exhibit mutations in KRAS. Other characteristic features include a high frequency of mutations in TP53 (50%) and SMAD4 (25%), high TOPO2A expression, and low ERCC1 and TS expression (suggestive of sensitivity to platinum, TOPO2 inhibitors, and fluoropyrimidines).[15] Histologically, ASCP is distinguished by a characteristic mixed pathology with glandular and squamous epithelium.

Surveillance, Epidemiology, and End Results (SEER) data suggest that patients with ASCP have poorer outcomes than similarly staged patients with PDAC.Patients usually present with advanced-stage disease, elevated levels of CEA (in addition to CA 19.9), a high degree of lymph node involvement, and hypercalcemia.[16]

Metastasis

Typically, pancreatic cancer first metastasizes to regional lymph nodes, then to the liver and, less commonly, to the lungs. It can also directly invade surrounding visceral organs such as the duodenum, stomach, and colon, or it can metastasize to any surface in the abdominal cavity via peritoneal spread. Ascites may result, and this has an ominous prognosis. Pancreatic cancer may spread to the skin as painful nodular metastases. Metastasis to bone is uncommon.

Pancreatic cancer rarely spreads to the brain, but it can produce meningeal carcinomatosis.

Tobacco smoking is the most common recognized risk factor for pancreatic cancer.[17] Other factors include the following[18] :

• Obesity
• Diabetes mellitus
• Chronic pancreatitis
• Family history of pancreatic cancer
• Hereditary syndromes ^[18]
• Lifestyle factors ^[19]

Less than 5% of all pancreatic cancers are related to underlying chronic pancreatitis.[20] Alcohol consumption does not appear to be an independent risk factor for pancreatic cancer unless it is associated with chronic pancreatitis.

Smoking

Smoking is the most common environmental risk factor for pancreatic carcinoma. Estimates indicate that smoking accounts for up to 30% of cases of pancreatic cancer.[17]

People who smoke have at least a 2-fold greater risk for pancreatic cancer than do nonsmokers. Current smokers with over a 40 pack-year history of smoking may have up to a 5-fold risk greater risk for the disease. Smokeless tobacco also increases the risk of pancreatic cancer.

Obesity and dietary factors

In a number of studies, obesity, especially central, has been associated with a higher incidence of pancreatic cancer. For example, Li et al found that being overweight or obese during early adulthood was associated with a greater risk of pancreatic cancer and a younger age of disease onset, while obesity at an older age was associated with lower overall survival.[21] Several other studies have supported a link between early obesity and the risk of pancreatic cancer.[22, 23]

The incidence of pancreatic cancer is lower in persons with a diet rich in fresh fruits and vegetables. Fruits and vegetables rich in folate and lycopenes (such as tomatoes) may be especially good at reducing the risk of pancreatic cancer.[24, 25]

Consumption of red meat, especially of the processed kinds, is associated with a higher risk of pancreatic cancer. Poultry and dairy product consumption does not increase the risk of this disease.[26]

Despite early reports to the contrary, coffee consumption is not associated with an increased risk of pancreatic cancer.[27]

Diabetes mellitus

In patients recently diagnosed with diabetes mellitus, risk for pancreatic cancer i is 5.4 fold above average. It has been suggested that diabetes may be at least in part a consequence or an early manifestation of pancreatic cancer.[28] However, the International Pancreatic Cancer Case-Control Consortium reported that a 30% excess risk for pancreatic cancer persists for more than 2 decades after diabetes diagnosis, which supports the hypothesis that the relation between diabetes and pancreatic cancer is bidirectional.[29]

A systematic review of 30 studies concluded that patients with diabetes mellitus of at least 5-years' duration have a 2-fold increased risk of developing pancreatic carcinoma. Pancreatic cancer may follow 18-36 months after a diagnosis of diabetes mellitus in elderly patients with no family history of diabetes mellitus.

The National Comprehensive Cancer Network (NCCN) acknowledges long-standing diabetes mellitus as a risk factor for pancreatic cancer. The NCCN also notes an association between sudden onset of type 2 diabetes mellitus in an adult older than 50 years and a new diagnosis of pancreatic cancer, although in those cases the diabetes is thought to be caused by the cancer.[30]

Chronic pancreatitis

Long-standing, chronic pancreatitis is a substantial risk factor for the development of pancreatic cancer. A multicenter study of more than 2000 patients with chronic pancreatitis showed a 26-fold increase in the risk of developing pancreatic cancer. This risk increased linearly with time, with 4% of patients who had chronic pancreatitis for 20 years' duration developing pancreatic cancer.[31]

The risk of pancreatic cancer is even higher in patients with hereditary pancreatitis. The mean age of development of pancreatic cancer in these patients is approximately 57 years. The relative risk of pancreatic cancer in hereditary pancreatitis is increased more than 50-fold, and the cumulative risk rate of pancreatic cancer by age 70 years is 40%.

This cumulative risk increases to 75% in persons whose family has a paternal inheritance pattern.[32]

Chronic pancreatitis from alcohol consumption is also associated a much higher incidence and an earlier age of onset of pancreatic carcinoma.[33]

Genetic factors

Approximately 5-10% of patients with pancreatic carcinoma have some genetic predisposition to developing the disease.[34]

Certain precursor lesions have been associated with pancreatic tumors arising from the ductal epithelium of the pancreas. The main morphologic form associated with ductal adenocarcinoma of the pancreas is pancreatic intraepithelial neoplasia (PIN). These lesions arise from specific genetic mutations and cellular alterations that contribute to the development of invasive ductal adenocarcinoma.[35]

The initial alterations appear to be related to KRAS2 gene mutations and telomere shortening. Thereafter, p16/CDKN2A is inactivated. Finally, the inactivation of TP53 and MAD4/DPC4 occur. These mutations have been correlated with increasing development of dysplasia and thus with the development of ductal carcinoma of the exocrine pancreas.

Based on more recent data from sequencing of human tumors, pancreatic cancer is a genetically complex and heterogeneous disease.[36] This is confounded by considerable variability in terms of the genetic malformations and pathways involved between individual tumors. In addition, the long time from early to clinically manifested disease (21.2 y on average) allows for an accumulation of complex genetic changes, which probably explains the fact that it is often resistant to chemotherapy and radiation therapy.[37, 38]

The inherited disorders that increase the risk of pancreatic cancer include the following:

• Hereditary pancreatitis
• Multiple endocrine neoplasia ( MEN)
• Hereditary nonpolyposis rectal cancer ( HNPCC)
• Familial adenomatous polyposis ( FAP) and Gardner syndrome
• Familial atypical multiple mole melanoma ( FAMMM) syndrome
• von Hippel-Lindau syndrome ( VHL)
• Germline mutations in the BRCA1 and BRCA2 genes

Hereditary pancreatitis has been associated with a 40% cumulative risk of developing pancreatic cancer at 40%.[32] MEN-1 and VHL are other genetic syndromes associated with pancreatic endocrine tumor development.

Patients with MEN-1 develop symptomatic pancreatic endocrine tumors about 50% of the time, and these pancreatic tumors are noted to be the leading cause of disease-specific mortality.[39] In patients with VHL, 17% of masses found in the pancreas have proved to be malignant.[40]

Syndromes associated with an increased risk of the development of colon cancer, such as HNPCC and FAP (and Gardner syndrome), have also shown an increased correlation with pancreatic cancer, but the statistics have not been impressive.

In a cohort study of 1391 patients with FAP, only 4 developed pancreatic adenocarcinoma. No statistics are available to show the incidence of pancreatic cancer in patients with HNPCC.[41]

FAMMM has been shown to increase relative risk of developing pancreatic cancer by 13- to 22-fold and the incidence in sporadic cases to be 98%.[42]

The above disorders have specific genetic abnormalities associated with the noted increased risk of pancreatic cancer. Pancreatic cancer in hereditary pancreatitis is associated with a mutation in the PRSS1 gene. Pancreatic cancer appearing in FAP and HNPCC has been associated with a mutation in the APC gene and MSH2 and MLH1 genes respectively. FAMMM and pancreatic cancer has been associated with a mutation in CDKN2A. Endocrine tumors of the pancreas associated with VHL are thought to develop by way of the inactivation of the VHL tumor suppressor gene.[34]

Germline mutations in BRCA1 and BRCA2 have been shown to moderately increase the risk of developing pancreatic cancer by 2.3- to 3.6-fold, but BRCA2 has been associated more commonly with pancreatic cancer, at an incidence of 7%.[34]

The NCCN recommends genetic evaluation and germline testing in every patient diagnosed with exocrine pancreatic cancer, as well as their first-degree relatives, and in patients diagnosed with neuroendocrine pancreatic tumors.[43] This is important because pancreatic cancer is thought to have a hereditary component in about 10% of cases, and family history is often poorly predictive.

Race-related factors

Black men in the United States have the highest incidence rate of pancreatic cancer.[44]  (See Epidemiology.) The reasons for this are unclear. Certainly, differences in risk factors for pancreatic cancer, such as dietary habits, obesity, and the frequency of cigarette smoking, are recognized among different population groups and may contribute to the higher incidence of this disease among Blacks.

However, Arnold et al found that excess pancreatic cancer in Blacks cannot be attributed to currently known risk factors, suggesting that as-yet undetermined factors play a role in the disease process.[45] One possibility is a difference in the underlying frequency of predisposing genetic mutations for pancreatic cancer.

Incidence in the United States

The American Cancer Society estimates that in the United States in 2022, about 62,210 new cases of pancreatic cancer (32,970 in men and 29,240 in women) will be diagnosed.[1] Over 2010-2019, age-adjusted rates for new pancreatic cancer cases rose on average 0.5% each year.[44]

International incidence

Worldwide, pancreatic cancer ranks 11th in incidence but 7th as a cause of cancer death.[46] The age-standardized rate (ASR) incidence ranges widely, from 7.7 per 100,000 population in Europe to 2.2 per 100,000 population in Africa. Among individual countries, ASRs range from 0.81 per 100,000 in males in India to 15.3 per 100,000 in males in Latvia and the Republic of Moldova.[46]

Race predilection

From 2015 to 2019, the highest incidence rate of pancreatic cancer in the United States was 17.7 cases per 100,000 persons per year, in Black men. The incidences in men in other racial/ethnic groups were as follows[44] :

• White: 15.7
• Hispanic: 12.8
• American Indian/Alaska Native: 16.5
• Asian/Pacific Islander: 11.0

The incidences in US women during that period were as follows[44] :

• Black: 14.9
• White: 11.7
• Hispanic: 11.2
• American Indian/Alaska Native: 10.0
• Asian/Pacific Islander: 9.2

Age predilection

In the absence of predisposing conditions, such as familial pancreatic cancer and chronic pancreatitis, pancreatic cancer is unusual in persons younger than 45 years. After age 50 years, the frequency of pancreatic cancer increases linearly.

The median age at diagnosis is 69 years in Whites and 65 years in Blacks; some single-institution data reported from large cancer centers suggest that the median age at diagnosis in both sexes has fallen to 63 years of age.

Mortality

Although pancreatic cancer constitutes only about 3% of all cancers in the United States, it is the fourth leading cause of cancer deaths in both men and women, being responsible for 8% of all cancer-related deaths.The American Cancer Society estimates that in the United States in 2020, about 47,050 people (24,640 men and 22,410 women) will die of pancreatic cancer. During 2008 to 2017, the death rate for pancreatic cancer increased slightly (by 0.4% per year) in Whites and decreased slightly (by 0.5% per year) in Blacks.[47]

Pancreatic carcinoma is unfortunately usually a fatal disease. The relative 1-year survival rate for patients with pancreatic cancer is only 28%, and the overall 5-year survival rate is 9%, having increased from 3% between 1975 and 1977.[44]

By stage, 5-year relative survival is 34.3% for localized disease, 11.5% for regional disease, and 2.7% for distant disease.[44] At the time of diagnosis, 52% of patients have distant disease.[47] (However, patients with neuroendocrine and cystic neoplasms of the pancreas, such as mucinous cystadenocarcinomas or intraductal papillary mucinous neoplasms [IPMN], have much better survival rates than do patients with pancreatic adenocarcinoma).

The occasional patient with metastatic disease or locally advanced disease who survives beyond 2-3 years may die of complications of local spread, such as bleeding esophageal varices.

In patients able to undergo a successful curative resection (about 20% of patients), median survival time ranges from 12-19 months, and the 5-year survival rate is 15-20%.

Tingle et al reported that in patients with unresectable pancreatic ductal adenocarcinoma, the combination of the neutrophil-albumin ratio (NAR) and the Ca19-9 level allows stratification into three groups with significantly different overall survival, as follows[48] :

• NAR ≤ 0.13 and Ca19-9 ≤ 770 U/mL - Median survival 20.5 months
• NAR > 0.13 or Ca19-9 >770 - Median survival 9.7 months
• NAR > 0.13 and Ca19-9 > 770 - Median survival 4.1 months

Smoking is the most significant reversible risk factor for pancreatic cancer. To help lower the risk of pancreatic cancer, the American Cancer Society recommends not smoking, as well as following a healthy eating pattern, getting regular physical activity, limiting alcohol consumption, and limiting exposure to certain chemicals in the workplace.[49]

Alcohol consumption does not increase the risk of pancreatic cancer unless it leads to chronic pancreatitis. A multicenter study of more than 2000 patients with chronic pancreatitis showed a 26-fold increase in the risk of developing pancreatic cancer.[31]

For patient education information, see Pancreatic Cancer.

The initial symptoms of pancreatic cancer are often quite nonspecific and subtle. Consequently, these symptoms can be easily attributed to other processes unless the physician has a high index of suspicion for the possibility of underlying pancreatic carcinoma.

Patients typically report nonspecific symptoms such as vague digestive discomfort, bloating, anorexia, nausea, fatigue, mid-epigastric or back pain, and weight loss. Mid-epigastric pain may radiate to the mid- or lower back. Radiation of the pain to the back is worrisome, as it indicates retroperitoneal invasion of the splanchnic nerve plexus by the tumor. The pain may be worse when the patient is lying flat.

Weight loss may be related to cancer-associated anorexia and/or subclinical malabsorption from pancreatic exocrine insufficiency caused by pancreatic duct obstruction by the cancer. Patients with malabsorption usually complain about diarrhea and malodorous, greasy stools. Nausea and early satiety from delayed gastric emptying due to gastric outlet obstruction from the tumor may also contribute to weight loss.

The most characteristic sign of pancreatic carcinoma of the head of the pancreas is painless obstructive jaundice. Patients with this sign may come to medical attention before their tumor grows large enough to cause abdominal pain. These patients usually notice a darkening of their urine and lightening of their stools before they or their families notice the change in skin pigmentation. Pruritus may accompany and often precedes clinical obstructive jaundice. Pruritus can often be the patient's most distressing symptom.

Physicians can usually recognize clinical jaundice when the total bilirubin reaches 2.5-3 mg/dL. Patients and their families do not usually notice clinical jaundice until the total bilirubin reaches 6-8 mg/dL. 

Depression is reported to be more common in patients with pancreatic cancer than in patients with other abdominal malignancies. In some patients, depression may be the most prominent presenting symptom, or its onset may precede that of somatic symptoms.[50] Researchers have proposed that the depression associated with pancreatic cancer is a paraneoplastic syndrome caused by the dysregulation of inflammatory cytokines.[51] 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. Men with pancreatic adenocarcinoma have a risk of suicide that is almost 11 times higher than the remainder of the population.[52]

Migratory thrombophlebitis (ie, Trousseau sign) and venous thrombosis also occur with higher frequency in patients with pancreatic cancer and may be the first presentation.[53] Marantic endocarditis may develop in pancreatic cancer, occasionally being confused with subacute bacterial endocarditis.

Pain is the most common presenting symptom in patients with pancreatic cancer. About two thirds of patients with pancreatic cancer present with pain; the pain is mild to moderate in one third of patients and severe in one third. All patients experience pain at some point in their clinical course.

As noted in History, the pain typically takes the form of mild to moderate midepigastric tenderness. In some cases, the pain radiates to the midback or lower back; this is worrisome, as it indicates retroperitoneal invasion of the celiac plexus by the tumor.

Clinical jaundice may be present. Patients with clinical jaundice may also have a palpable gallbladder (ie, Courvoisier sign) and may have skin excoriations from pruritus.

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 (referred to as a Sister Mary Joseph nodule or nodules) in the paraumbilical area signify advanced disease. A metastatic node may be palpable behind the medial end of the left clavicle (Virchow node).

The laboratory findings in patients with pancreatic cancer are usually nonspecific. However, a number of continually evolving imaging modalities are available to help diagnose pancreatic carcinoma in patients in whom the disease is suggested clinically. These include the following:

• Computed tomography (CT)
• Transcutaneous ultrasonography (TUS)
• Endoscopic ultrasonography (EUS)
• Magnetic resonance imaging (MRI)
• Endoscopic retrograde cholangiopancreatography (ERCP)
• Positron emission tomography (PET)

Which of these modalities is used at a particular institution may depend largely on the local availability of and expertise with the procedure, as well as local cancer protocols. Additional considerations in the choice of diagnostic modality include the following:

• Accuracy for providing staging information
• Allowance for simultaneous collection of tissue samples for cytologic or histologic confirmation of the diagnosis
• Capacity to facilitate therapeutic procedures, such as biliary stent placement or celiac neurolysis

The diagnosis of pancreatic carcinoma is most difficult in patients with underlying chronic pancreatitis. In such cases, all of the above imaging studies may show abnormalities that may not help to differentiate between pancreatic carcinoma and chronic pancreatitis. Even tumor markers can be elevated in patients with chronic pancreatitis. In these patients, one must often combine multiple imaging modalities, close clinical follow-up, serial imaging studies, and, occasionally, empiric resection, to diagnose an underlying pancreatic carcinoma.

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

The laboratory findings in patients with pancreatic cancer are usually nonspecific. As with many chronic diseases, a mild normochromic anemia may be present.

Patients presenting with obstructive jaundice show significant elevations in bilirubin (conjugated and total), alkaline phosphatase, gamma-glutamyl transpeptidase, and to a lesser extent, aspartate aminotransferase and alanine aminotransferase.

Serum amylase and/or lipase levels are elevated in less than half of patients with resectable pancreatic cancers and are elevated in only one quarter of patients with unresectable tumors. However, about 5% of patients with pancreatic cancer present initially with acute pancreatitis, in which case amylase and lipase would be uniformly elevated. Thus, pancreatic cancer should be in the differential diagnosis of an elderly patient presenting for the first time with acute pancreatitis without any known precipitating factors.

Liver metastases alone are not associated with clinical jaundice but may result in relatively low-grade elevations of serum alkaline phosphatase and transaminase levels.

Patients with advanced pancreatic cancers and weight loss will also have general laboratory evidence of malnutrition (eg, low serum albumin or cholesterol level).

Carbohydrate antigen 19-9

Carbohydrate antigen 19-9 (CA 19-9) is a sialylated oligosaccharide that is most commonly found on circulating mucins in cancer patients.[54] It is also normally present within the cells of the biliary tract and can be elevated in acute or chronic biliary disease. Some 5-10% of patients lack the enzyme necessary to produce CA 19-9; in these patients with low or absent titer of CA 19-9, monitoring disease with this tumor marker will not be possible.

The reference range of CA 19-9 is less than 33-37 U/mL in most laboratories. Of patients with pancreatic carcinoma, 75-85% have elevated CA 19-9 levels. In the absence of biliary obstruction, intrinsic liver disease, or benign pancreatic disease, a CA 19-9 value of greater than 100 U/mL is highly specific for malignancy, usually pancreatic.

Evaluation of CA 19-9 levels has been used as an adjunct to imaging studies for helping to determine the resectability potential of pancreatic carcinoma. Fewer than 4% of patients with a CA 19-9 level of more than 300 U/mL have been found to have resectable tumors.

Unfortunately, CA 19-9 is least sensitive for small, early-stage pancreatic carcinomas and thus has not proven to be effective for the early detection of pancreatic cancer or as a screening tool.[54]

An elevated CA 19-9 level is found in 0.2% of an asymptomatic population older than 40 years. Of these elevations, 80% are false-positive results. If only symptomatic patients are studied, 4.3% have elevated CA 19-9 levels. Two thirds of these results are false positive.

Although no standardized role has been set for CA 19-9 in the diagnosis of pancreatic carcinoma, it has growing importance in the staging and follow-up of patients with this disease. Patients presenting with low levels of CA 19-9 (< 100 IU) are unlikely to have occult metastatic disease and therefore may not need a staging laparoscopy prior to resection if other imaging shows no advanced disease.

Additionally, during surgical, chemotherapeutic, and/or radiotherapeutic treatment for pancreatic cancer, a falling CA 19-9 seems to be a useful surrogate finding for clinical response to the therapy. If biliary obstruction is not present, a rising CA 19-9 suggests progressive disease.

Preoperative CA 19-9 levels may be of prognostic value, with high levels indicating poorer outcome and less chance of resectability.[55, 56] Preoperative values above 50 U/mL have been shown to be associated with higher chances of recurrence. In contrast, a decrease in CA 19.9 levels during neoadjuvant therapy in locally advanced or borderline advanced pancreatic cancer is strong predictor of resectability and improved survival.[57]

Carcinoembryonic antigen

Carcinoembryonic antigen (CEA) is a high–molecular weight glycoprotein found normally in fetal tissues. The reference range is 2.5 mg/mL or less. CEA has commonly been used as a tumor marker in other gastrointestinal malignancies, but only 40-45% of patients with pancreatic carcinoma have elevated CEA levels. In addition, benign and malignant conditions other than pancreatic cancer can lead to elevated CEA levels. Thus, CEA is not a sensitive or specific marker for pancreatic cancer.

Research

Many other tumor markers have been studied in pancreatic cancer, but none has yet been shown to have general clinical utility in this disorder. As with all cancers, there is growing interest in molecular diagnosis using powerful techniques, such as gene expression microarrays and proteomics. These novel tests are adding to the understanding of the basic defects causing pancreatic neoplasms and pathobiology. However, these are still research tools at present.

Because of its ubiquitous availability and its ability to image the whole abdomen and pelvis, abdominal CT scanning continues to be the mainstay of initial diagnostic modalities used for assessing patients suspected to have pancreatic carcinoma. (See the images below.)

Pancreatic cancer. Computerized tomographic scan showing a pancreatic adenocarcinoma of the pancreatic head. The gallbladder (gb) is distended because of biliary obstruction. The superior mesenteric artery (sma) is surrounded by tumor, making this an unresectable T4 lesion.

Pancreatic cancer. Abdominal CT scan of a small, vaguely seen, 2-cm pancreatic adenocarcinoma (mass) causing obstruction of both the common bile duct (cbd) and pancreatic duct (pd).

The quality of CT scanners has been rapidly evolving. The speed of image acquisition, 3D imaging, and slices as thin as 2-3 mm have revolutionized the technology.

Newer scanner models, using spiral (ie, helical) CT scanning with multiple detectors and dual or triple-phase contrast enhancement, have significantly improved the sensitivity and specificity of abdominal CT-scan findings in patients with pancreatic carcinoma.

Multidetector CT scanning (MDCT) using a pancreas protocol is at least as accurate as EUS in the overall determination of the resectability of pancreatic carcinoma. In fact, CT scanning may be more accurate than EUS in predicting involvement of the superior mesenteric artery.[58]

National Comprehensive Cancer Network (NCCN) guidelines recommend MDCT angiography as the preferred imaging tool for dedicated pancreatic imaging. Thin (preferably sub-millimeter) axial sections should be acquired using a dual-phase pancreatic protocol, with images obtained in the pancreatic and portal venous phase of contrast enhancement. Coverage may be extended to cover the chest and pelvis for complete staging, depending on institutional preferences.[30]

Other features of CT imaging include the following:

• Because of a higher rate of enhancement by the normal pancreas, malignant tumors appear as lower-density lesions ^[59] ; these are often associated with obstruction of the pancreatic duct
• When lesions are visible, CT scanning can also be used to direct fine-needle aspiration of pancreatic masses
• Small tumors can still be missed even with the most advanced CT-scanning techniques.

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

Even though it is less expensive and generally more readily available than CT scanning, TUS has less utility in pancreatic carcinoma than CT scanning, because the pancreas is often obscured by overlying gas from the stomach, duodenum, and colon.

Additionally, the depth of the pancreas from the abdominal wall limits transcutaneous ultrasonic imaging to lower frequency (2-5 MHz), and thus, a lower-resolution ultrasonogram is obtained. Therefore, TUS can help to detect only 60-70% of pancreatic carcinomas, and similar to CT scanning, more than 40% of the lesions smaller than 3 cm are missed.

However, TUS is very useful as an initial screening test in evaluating patients who present with possible obstructive jaundice. By helping to detect intrahepatic or extrahepatic bile duct dilation, abdominal ultrasonography can rapidly and accurately assess whether or not a patient has biliary obstruction. However, other studies, such as abdominal CT scanning, EUS, ERCP, or magnetic resonance cholangiopancreatography (MRCP), usually should then be performed to definitively diagnose the source of biliary obstruction.

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

EUS obviates the physical limitations of TUS by placing a high-frequency, ultrasonographic transducer on an endoscope (see the first image below), which is then positioned in the stomach or duodenum endoscopically to help visualize the head, body, and tail of the pancreas. Unlike CT, the patient requires conscious sedation for this procedure. (Adenocarcinoma of the pancreatic head is seen in the second image below.)

Pancreatic cancer. Tip of linear array echoendoscope (Pentax FG 36UX) with 22-gauge aspiration needle exiting from biopsy channel. Insert shows magnification of aspiration needle tip. Note that the needle exits from the biopsy channel such that it appears continuously in the view of the ultrasonic transducer on the tip of the echoendoscope.

Pancreatic cancer. Endoscopic ultrasound of a 2.2-cm pancreatic adenocarcinoma of the head of the pancreas obstructing the common bile duct (CBD) but not invading the portal vein (PV) or superior mesenteric vein (SMV). Findings from endoscopic ultrasound–guided fine-needle aspiration revealed a moderately to poorly differentiated adenocarcinoma. Abdominal CT findings did not show this mass, and an attempt at endoscopic retrograde cholangiopancreatography at another institution was unsuccessful.

Additionally, because of the proximity of the pancreas to the EUS transducer, high-frequency ultrasonography (7.5-12 MHz) can be used to produce very high-resolution (submillimeter) images. Where expert EUS is available, it has proven to be the most sensitive and specific diagnostic test for pancreatic cancer. A negative endoscopic ultrasonogram is nearly 100% specific at ruling out the presence of a pancreatic neoplasm.

In numerous series, EUS has been found to have detection rates of 99-100% for all pancreatic carcinomas, including those smaller than 3 cm. EUS is as accurate as ERCP or MRCP for assessing the etiology of obstructive jaundice.

An additional significant diagnostic advantage is EUS-guided fine-needle aspiration, which allows for the simultaneous cytologic confirmation of pancreatic carcinoma at the time of EUS diagnosis.

EUS appears to be equivalent to dual-phase, spiral CT scanning for assessing tumor-resectability potential. It is probably superior to CT scanning as a means of assessing the T stage of the tumor, especially when the clinician is looking for portal vein involvement in pancreatic head lesions.

EUS is probably inferior to CT scanning in assessing arterial involvement and distant metastases.[58] EUS and CT scanning are poor at detecting occult nodal involvement.

On the whole, the NCCN guidelines recommend EUS as complementary to CT. However, if no mass is evident in the pancreas on CT protocol imaging, the NCCN recommends EUS before other evaluation options. EUS is also valuable if there is possible involvement of blood vessels or lymph nodes.[30]

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

ERCP is a highly sensitive means of detecting pancreatic and/or biliary ductal abnormalities in pancreatic carcinoma. Among patients with pancreatic adenocarcinoma, 90-95% have abnormalities on ERCP findings. However, the changes observed on ERCP are not always highly specific for pancreatic carcinoma and can be difficult to differentiate from changes observed in patients with chronic pancreatitis.

ERCP is more invasive than the other diagnostic imaging modalities available for pancreatic carcinoma. ERCP also carries a 5-10% risk of significant complications. Because of this morbidity, it is usually reserved as a therapeutic procedure for biliary obstruction or for the diagnosis of unusual pancreatic neoplasms, such as intraductal pancreatic mucinous neoplasms (IPMN).

Brush cytology and forceps biopsy at the time of ERCP have been used to diagnose pancreatic carcinoma histologically; in most series, however, the yield of a cytologic diagnosis with these procedures has been less than 50%.

ERCP findings provide only limited staging information, but ERCP does have the advantage of allowing for therapeutic palliation of obstructive jaundice with either a plastic or metal biliary stent.

Interest in using MRI for abdominal imaging continues to grow. The role of MRI in pancreatic cancer has been less well studied than has the role of CT scanning, although the modality does not appear to be superior to spiral CT scanning. Dynamic, gadolinium-enhanced, 3D, gradient-echo MRI may offer enhanced sensitivity in the detection of small pancreatic lesions. However, in patients with jaundice, MRCP can be used as a noninvasive method for imaging the biliary tree and pancreatic duct.

Whether MRCP is as sensitive and specific for pancreaticobiliary pathology as other procedures is still being investigated.

Because of the difficulty of working within intense magnetic fields, MRI is limited in performing MRI-directed needle aspirations; however, this technology is undergoing rapid change.

The NCCN notes that MRI is most often used as a problem-solving tool, particularly for characterization of liver lesions that are indeterminate on CT; when pancreatic tumors are suspected, but are not visible on CT; or when contrast-enhanced CT cannot be obtained (eg, because of severe allergy to iodinated intravenous contrast material).[30]

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

PET scanning uses 18F-fluorodeoxyglucose (FDG) to image the primary tumor and metastatic disease.

PET scanning appears to be especially useful in detecting occult metastatic disease. Its role in pancreatic cancer evaluation management is still under investigation. False-positive PET scans have been reported in pancreatitis.

By itself, PET scanning does not seem to offer additional benefits to high-quality CT scanning. However, studies in which PET scanning was combined with simultaneous CT scanning (PET-CT) suggested that PET-CT scanning is more sensitive than conventional imaging for the detection of pancreatic cancer and that PET-CT–scan findings sometimes change clinical management.[60, 61]

The NCCN guidelines consider PET-CT an evolving technology; its role in the diagnosis of pancreatic cancer is not yet established.[30]

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

The necessity of obtaining a cytologic or tissue diagnosis of pancreatic cancer prior to surgery remains controversial and is highly dependent on the institution.[62]

Arguments in favor of preoperative biopsy include its ability to provide proof of pathology prior to surgery, exclude unusual pathology, and provide evidence of disease before the initiation of multidisciplinary treatment, such as neoadjuvant chemotherapy.

Arguments against preoperative biopsy of pancreatic lesions are that the biopsy results will not alter therapy, that biopsy may result in seeding and interfere with definitive surgery, and that the procedure increases the cost of care.

Studies of the risk of peritoneal contamination with CT-guided biopsy have suggested that this risk is actually very low. EUS-guided fine-needle aspiration provides the additional advantage of aspiration through tissue that would ultimately be included in the operative field should the patient undergo resection.

EUS-guided fine-needle aspiration has proven to be the most effective means for making a definitive cytologic diagnosis of pancreatic carcinoma.

Using EUS-guided fine-needle aspirations, a cytologic diagnosis can be made in 85-95% of patients. For example, a retrospective study by Turner et al found that EUS-guided fine needle aspiration was 80% accurate for the detection of pancreatic carcinoma and was 94% accurate when atypical and suspicious samples are considered positive.[63]

A study by Micames et al suggested that percutaneous aspiration may be associated with a higher risk of peritoneal tumor spread than is aspiration with EUS.[64]

Thus, for potentially resectable tumors, EUS-guided fine-needle aspiration is the preferred biopsy technique, if it is available and if a biopsy needs to be obtained. Cost-benefit analyses have also confirmed that it is the most cost-effective mode of tissue acquisition in suspected pancreatic cancer.

In a presentation delivered at the 2013 annual meeting of the American Society for Clinical Pathology, Huffman et al described a new risk-stratification system for EUS–guided fine-needle aspiration cytology results that can help determine when pancreatic lesions are malignant.[65] The researchers identified the following 3 morphologic characteristics as being significantly associated with pancreatic malignancy:

• Anisonucleosis
• Single atypical epithelial cells
• Mucinous metaplasia

The risk of malignancy was low when none of these 3 criteria are met, moderate when 1 was met, and high when 2 or 3 were met.[65]

The yield of CT-guided fine-needle aspiration or biopsy findings is approximately 50-85% in the lesions that are visible on CT scanning.

As previously mentioned, of all pancreatic cancers, 80% are adenocarcinomas of the ductal epithelium. Only 2% of tumors of the exocrine pancreas are benign. Less common histologic appearances of exocrine pancreatic cancers include giant cell carcinoma, adenosquamous carcinoma, microglandular adenocarcinoma, mucinous carcinoma, cystadenocarcinoma, papillary cystic carcinoma, acinar cystadenocarcinoma, and acinar cell cystadenocarcinoma. Very rarely, primary connective tissue cancers of the pancreas can occur. The most common of these is primary pancreatic lymphoma. (See the images below.)

Pancreatic cancer. Hematoxylin and eosin stain of a pancreatic carcinoma. Note the intense desmoplastic response around the neoplastic cells. The large amount of fibrotic reaction in these tumors can make obtaining adequate tissue by fine-needle aspiration difficult.

Pancreatic cancer. Cytologic samples from fine-needle aspirations (rapid Papanicolaou stain) of pancreatic adenocarcinomas. (A) Well differentiated, (B) moderately differentiated, (C) moderate to poorly differentiated, (D) poorly differentiated tumor.

Cystic neoplasms of the pancreas account for fewer than 5% of all pancreatic tumors. These consist of benign serous cystadenomas, premalignant mucinous cystadenomas, and cystadenocarcinomas. Intraductal, mucinous pancreatic neoplasms can be benign or malignant and usually manifest as a cystic dilation of the pancreatic ductal system.

Patients can also develop tumors of the islet cells of the pancreas. These can be functionally inactive islet cell carcinomas or benign or malignant functioning tumors, such as insulinomas, glucagonomas, and gastrinomas. An estimated 40% of pancreatic endocrine tumors are nonfunctional; of these, up to 90% are malignant.[66]

Islet cell tumors in patients with inherited syndromes such as multiple endocrine neoplasia are less likely to occur singly than in patients without these syndromes, and in the case of multiple endocrine neoplasia type 1, are more frequently gastrinomas than insulinomas. These variations of tumor function affect diagnosis and treatment strategies.[66]

Pancreatic cancer is associated with numerous hereditary syndromes and the results of germline testing can help guide treatment selection. Whole-exome sequencing has been shown to find genomic lesions that are theoretically actionable in almost 50% of tumors and to result in a change in clinical management in up to 30% of cases. Although the main driver mutation is KRAS, molecular profiling can identify numerous other potentially actionable mutations.[67]

National Comprehensive Cancer Network (NCCN) guidelines recommend considering germline testing in any patient diagnosed with pancreatic cancer and considering molecular analysis of tumors in those with metastatic disease. The NCCN panel has also strongly recommended molecular profiling of tumor tissue for actionable somatic mutations in patients with locally advanced or metastatic disease who are candidates for anticancer therapy, including (but not limited to) ALK, NRG1, NTRK, and ROS1 fusions; and BRAF, BRCA 1/2, HER2, KRAS, and PALB2 mutations.[30]

Molecular profiling can detect mismatch repair deficiency (dMMR) and microsatellite instability–high (MSI-H) status. Across tumor types, patients with this phenotype may respond to pembrolizumab, which is now approved for patients with metastatic cancer of any type and dMMR/MSI-H status. Although dMMR/MSI-H is present in only 1% of patients with pancreatic cancer, in the pivotal trial of pembrolizumab, 83% of patients with dMMR pancreatic cancer showed a response.[7]

jAmerican Society of Clinical Oncology (ASCO) guidelines recommend early testing for actionable genomic alterations (both germline and tumor) for patients who are likely to be potential candidates for additional treatment after first-line therapy.[6] This includes testing for the following;

• MSI/dMMR/
• BRCA mutations (excluding variants of unknown significance)
• NTRK gene fusions

Once an imaging modality has helped to establish a probable diagnosis of pancreatic cancer, the next issue is whether the lesion is amenable to surgical resection. Pancreatic masses are characterized as resectable, unresectable, or borderline resectable, on the basis of CT and/or EUS criteria.[68] The designation of a mass as borderline resectable is usually based on the experience and technical skill of the surgeon involved in treatment, as well as on the overall health of the patient and on his or her wishes.

Only 20% of all patients presenting with pancreatic cancer are ultimately found to have easily resectable tumors with no evidence of local advancement. Noncurative resections for pancreatic carcinoma provide no survival benefit. Thus, to avoid operating on patients who cannot benefit from the operation, accurate preoperative staging is very important.

TNM classification

Cancer of the exocrine pancreas is classified by the tumor, node, metastasis (TNM) staging system. The staging for pancreatic cancer was modified by the American Joint Committee on Cancer (AJCC) in 2002.

Go to Radiologic Diagnosis and Staging of Pancreatic Carcinoma for complete information on this topic.

AJCC staging of pancreatic tumors is shown below.[69]

Tumor (T):

• TX - Primary tumor cannot be assessed
• T0 - No evidence of primary tumor
• Tis - Carcinoma in situ
• T1 - Tumor limited to the pancreas, 2 cm or smaller in greatest dimension
• T2 - Tumor limited to the pancreas, larger than 2 cm in greatest dimension
• T3 - Tumor extension beyond the pancreas (eg, duodenum, bile duct, portal or superior mesenteric vein) but not involving the celiac axis or superior mesenteric artery
• T4 - Tumor involves the celiac axis or superior mesenteric arteries

Regional lymph nodes (N):

• NX - Regional lymph nodes cannot be assessed
• N0 - No regional lymph node metastasis
• N1 - Regional lymph node metastasis

Distant metastasis (M):

• MX - Distant metastasis cannot be assessed
• M0 - No distant metastasis
• M1 - Distant metastasis

Stage grouping for pancreatic cancer is as follows:

• Stage 0 - Tis, N0, M0
• Stage IA - T1, N0, M0
• Stage IB - T2, N0, M0
• Stage IIA - T3, N0, M0
• Stage IIB - T1-3, N1, M0
• Stage III - T4, Any N, M0
• Stage IV - Any T, Any N, M1

At initial presentation, only 12% of patients present with stage I disease; 30% present with locally advanced disease and 52% present with disease metastatic to nodes or distant sites.[44]

The image below visually demonstrates the stages of pancreatic cancer.

Pancreatic cancer. T staging for pancreatic carcinoma. T1 and T2 stages are confined to the pancreatic parenchyma. T3 lesions invade local structures such as the duodenum, bile duct, and/or major peripancreatic veins, and T4 lesions invade surrounding organs (eg, stomach, colon, liver) or invade major arteries such as the superior mesenteric or celiac arteries.

Imaging studies for staging

To date, studies show that EUS is approximately 70-80% accurate for correctly staging pancreatic carcinoma. EUS appears to better assess involvement of the portal vein/superior mesenteric vein.

NCCN guidelines recommend multi-detector computed tomography (MDCT) angiography, using a dual-phase pancreatic protocol, as the preferred modality for dedicated pancreatic imaging.[30] This technique is especially good for assessing major arterial involvement or distant metastases.

EUS is better than CT scanning for detection of abnormal lymph nodes around the pancreas and celiac axis. Furthermore, with the addition of EUS-guided fine-needle aspiration, EUS can help cytologically document metastatic disease in suggestive lymph nodes.

Clinical staging

Although the TNM staging is important, it has limited practical use for non-metastatic pancreatic cancer. The clinical staging system (Evans et al), which is often used to determine resectability, relies on radiographic evidence of abutment or encasement of vascular structures, and the degree of narrowing of the superior mesenteric vein and/or portal vein, to categorize localized pancreatic cancer as resectable or borderline resectable, and also to define locally advanced unresectable pancreatic cancer. Those authors note that the majority of localized and borderline resectable cases proceed to surgery, but few cases of locally advanced pancreatic cancer become resectable after neoadjuvant therapy.[70]

Preoperative staging laparoscopy

Some centers advocate performing a staging laparoscopy before proceeding to attempted resection. The purpose of the laparoscopic staging is to avoid subjecting patients with liver or peritoneal metastases to unnecessary surgery.

Some surgeons advocate the use of routine staging laparoscopy in all patients with pancreatic cancer. Their argument is that up to 20% of attempted pancreatic resections can be prevented because of the laparoscopic findings.

Others, including the NCCN panel, advise more a selective approach to staging laparoscopy, recommending its use in patients with any of the following indications[71, 72, 73, 30] :

• CA 19-9 level >150 U/mL
• Low volume ascites
• Tumors in the body of the pancreas
• Borderline resectable tumors,
• Tumor size > 3 cm
• Common bile duct lymphadenopathy

Another argument for selective versus routine staging laparoscopy is the fact that in many cases where the tumor is deemed unresectable, laparoscopy would not have shown the vascular invasion or retroperitoneal invasion that ultimately leads to unresectability of tumor.

Most patients suspected of having pancreatic carcinoma are initially studied with transcutaneous abdominal ultrasonography and/or spiral CT scanning (best done with dual-phase contrast, thin-cut pancreatic protocols). Patient management thereafter can vary from institution to institution, depending on local expertise, interest, and protocols. (See the image below.)

Algorithm for evaluation of a patient with suspected pancreatic cancer. CT scanning for definitive diagnosis and staging must be with thin-cut, multidetector, spiral CT scanning using dual-phase contrast imaging to allow for maximal information. This schema varies among institutions depending on local expertise, research interest, and therapeutic protocols for pancreatic carcinoma.

If patients have obvious hepatic metastatic disease based on initial TUS or CT findings, they undergo a CT- or TUS-guided biopsy of one of the liver metastases and then proceed to palliative therapy.

Patients with a suggested or definite pancreatic mass observed on abdominal CT scanning or TUS or those who are still considered to have pancreatic cancer but do not have an obvious pancreatic mass need to have more definitive imaging studies. This can be done using high-quality, thin-cut, multidetector CT scanning with dual-phase contrast and/or by using other procedures, such as EUS.

In the author's institution, where high-quality EUS and EUS-guided fine-needle aspiration are readily available, EUS plays a central role in the definitive diagnosis and staging of patients with pancreatic carcinoma.

If a pancreatic mass is observed on EUS images, EUS-guided fine-needle aspiration is performed to confirm the disease cytologically. At the same time, the condition is staged using EUS to determine resectability potential. Patients thought to have resectable tumors based on EUS findings proceed directly to operative intervention.

If tumors are deemed unresectable based on EUS findings and if patients have obstructive jaundice, they proceed directly to therapeutic stent placement with ERCP while under the same endoscopic sedation. Most patients then undergo dedicated pancreas protocol multidetector CT scanning to complete preoperative staging if the initial CT scan was not of the highest quality.

MRI, MRCP, and PET scanning are rarely used in the authors' evaluation algorithm unless other procedures are still nondiagnostic in a patient with a high suspicion of pancreatic cancer or if altered gastric anatomy precludes endoscopic ultrasonographic examination.

Patients with unresectable disease are offered chemotherapy for their disease. In institutions without EUS and EUS-guided fine-needle aspiration capabilities, spiral CT scanning with CT-guided pancreatic fine-needle aspiration or biopsy plays the central role in evaluation.

Abdominal TUS can also be used as an initial diagnostic study, especially in the jaundiced patient. However, this approach rarely obviates eventually performing abdominal CT scanning or EUS in patients in whom disease is a strong possibility.

ERCP is also used frequently for evaluating patients with jaundice or patients with possible pancreatic masses based on findings from imaging modalities if EUS is not available.

There is consensus that surgery is the primary mode of treatment for pancreatic cancer. However, an important role exists for chemotherapy and/or radiation therapy in an adjuvant or neoadjuvant setting, and in the treatment of patients with unresectable disease.

Typically, extrapancreatic disease precludes curative resection, and surgical treatment may be palliative at best.

Historically, vascular involvement has been considered a contraindication to resective cure. However, tumor invasion of the superior mesenteric or portal vein is no longer an absolute contraindication.[74] These veins can be resected partially with as much as 50% narrowing of the lumen. In addition, complete reconstruction is possible, especially using native veins as replacement (ie, internal jugular, greater saphenous, or splenic).

Nonetheless, invasion of the superior mesenteric, celiac, and hepatic arteries still presents a barrier to resection. No evidence indicates that a vascular reconstruction, which permits an attempt at surgical resection, improves or contributes to survival.

After a thorough preoperative workup, the surgical approach can be tailored to the location, size, and locally invasive characteristics of the tumor. Curative resection options include pancreaticoduodenectomy, with or without sparing of the pylorus; total pancreatectomy; and distal pancreatectomy. Each procedure is associated with its own set of perioperative complications and risks, and these points should be taken into consideration by the surgical team and discussed with the patient when considering the goal of resection. In qualified high-volume centers, pancreatic surgery (especially distal pancreatectomy, but including pancreaticoduodenectomy) can often be performed laparoscopically.[75]

Guidelines from the National Comprehensive Cancer Network (NCCN) recommend that decisions about resectability involve input from a multidisciplinary group of specialists at a high-volume center. The NCCN panel also agreed that selecting patients for surgery should be based on the probability of cure as determined by resection margins. Other factors include comorbidities, overall performance, and age.[30]

The use of chemotherapy and/or radiation therapy in the neoadjuvant setting has been a source of controversy. The rationale for using neoadjuvant therapy includes the following assertions:

1. Pancreatic cancer is a systemic disease and should be treated systemically from the start.
2. Patients will be able to tolerate the toxic effects of chemotherapy more readily before undergoing major pancreatic resection than after.
3. The tumor will shrink with neoadjuvant therapy so resection will be less cumbersome, leading to improved overall survival.

Trials of preoperative chemoradiotherapy conducted at M.D. Anderson Cancer Center have shown median survival as high as 25 months.[76, 77] However, no form of neoadjuvant therapy in pancreatic carcinoma should be regarded as a standard form of therapy; this remains an area for clinical trial study.

The NCCN finds there is limited evidence to recommend specific neoadjuvant regimens off-study for patients with resectable or borderline resectable tumor, and practices vary with regard to the use of chemotherapy and radiation. The guidelines prefer consultation at a high-volume center when considering neoadjuvant therapy. If recommended, treatment should be at or coordinated through a high-volume center when possible. Participation in a clinical trial is encouraged.[30]

Possible neoadjuvant regimens include the following[30] :

• FOLFIRINOX (folinic acid [leucovorin], 5-fluorouracil, irinotecan, oxaliplatin)/modified FOLFIRINOX, with or without subsequent chemoradiation
• Gemcitabine + albumin-bound paclitaxel, with or without subsequent chemoradiation
• Gemcitabine + cisplatin (≥2–6 cycles) followed by chemoradiation (only for known  BRCA1/2 or PALB2 mutations)

A study by Dhir et al in 193 patients with resectable or borderline resectable pancreatic ductal carcinoma concluded that FOLFIRINOX and gemcitabine plus albumin-bound paclitaxel are viable options for neoadjuvant treatment. After adusting for covariates, however, overall survival was found to be 4.9 months longer with FOLFIRINOX than with gemcitabine-paclitaxel.[78]

In a retrospective study of 49 stage III locally advanced/borderline resectable patients who were initially unresectable, were downstaged through chemotherapy, and subsequently underwent surgical resection, prolonged preoperative chemotherapy was associated with excellent overall survival and high rates of lymph node–negative disease.[79, 80] A study by Loeherer et al found an improvement in overall survival from 9.2 months to 11.4 months with the addition of concurrent external beam radiation therapy to gemcitabine alone.[81]

A phase 2 randomized clinical trial of preoperative and postoperative chemotherapy with modified FOLFIRINOX or gemcitabine/albumin-bound paclitaxel in patients with resectable pancreatic cancer found that 2-year overall survival was not significantly improved with either regimen, compared with historical data from trials of adjuvant therapy in resectable pancreatic cancer.[82]

Patients who will most likely benefit from this procedure have a tumor located in the head of the pancreas or the periampullary region. The Whipple procedure is not strictly the surgical approach for pancreatic head tumors. Pancreatic ductal tumors, cholangiocarcinoma (bile duct cancer), and duodenal masses will all require this resection. The operation traditionally 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 accomplished 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.

Pancreaticoduodenectomy has been shown to have an overall mortality rate of 6.6%.[83] Many forms of morbidity are associated with the operation. One of these is delayed gastric emptying. This occurs in approximately 25% of patients. This condition may require nasogastric decompression and will lead to a longer hospital stay.[84] Other morbidities include pancreatic anastomotic leak. This can be treated with adequate drainage. Postoperative abscesses are not uncommon.

Although preoperative biliary drainage was introduced to improve the postoperative outcome in patients with obstructive jaundice caused by tumors of the pancreatic head, van der Gaag et al found that routine use of this maneuver increases the rate of complications. In a multicenter, randomized trial, 202 patients with obstructive jaundice and a bilirubin level of 40–250 mmol/L (2.3-4.6 mg/dL) were assigned to undergo either preoperative biliary drainage for 4-6 weeks, followed by surgery, or surgery alone within 1 week after diagnosis. The rate of serious complications was higher in the biliary drainage group than in the early surgery group (74% vs 39%, respectively). No significant difference was noted in mortality or length of hospital stay between the 2 groups.[85]

Similarly, Limongelli et al found that preoperative biliary drainage predisposes patients to a positive intraoperative biliary culture, which in turn is associated with an increased risk of postoperative infectious complications and wound infection.[86]

The standard Whipple operation may be altered in order to include a pylorus-sparing procedure. This modification was previously incorporated to increase nutritional strength in these patients, because the increased gastric emptying associated with antrectomy caused nutritional deficiencies. Although many believe that delayed gastric emptying is worsened by this modification, studies have proven both resections to be equivalent in that regard.

Another source of controversy is the extent of lymphadenectomy that is necessary in a Whipple operation. In an elegant study, Pawlik et al found that the ratio of positive nodes to total nodes removed was an important prognostic factor.[87] This was even more significant than margin positivity.[88]

This procedure possesses a lower mortality rate than the standard Whipple procedure does, at 3.5%, but its use in curative resection remains limited.[83] Essentially, a distal pancreatectomy may be an effective procedure for tumors located in the body and tail of the pancreas. Unfortunately, masses located in this area present later than the periampullary tumors and hence have a higher unresectability rate.

The procedure involves isolation of the distal portion of the pancreas containing the tumor, followed by resection of that segment, with oversewing of the distal pancreatic duct. The main complications for distal pancreatectomy involve pancreatic stump leak, hemorrhage, and endocrine insufficiency.[89] Once again, the best treatment for pancreatic leak is adequate drainage.

Although this procedure is the least commonly performed and has the highest associated mortality rate (8.3%), it may still be a valuable instrument in the surgical cure of pancreatic cancer.[83]

The indication for the use of total pancreatectomy is in cases in which the tumor involves the neck of the pancreas. This can either be a situation in which the tumor originates from the neck or is growing into the neck. These patients obviously get insulin-dependent diabetes. In some cases, the diabetes can be hard to control. Despite this, the morbidity of a total pancreatectomy is comparable to that of a Whipple procedure.[90]

Several studies suggested the possibility that postoperative chemotherapy, with or without radiation therapy, would significantly improve median survivals following surgical resection of operable disease. These included the Gastrointestinal Tumor Study Group (GITSG), European Study Group for Pancreatic Cancer (ESPAC), and Charité Onkologie (CONKO) trials.[91, 92, 93, 94, 95]

The first well-powered study to establish the role of adjuvant chemotherapy in pancreatic cancer, conducted by Neuhaus et al in 368 patients with resected pancreatic cancer, found that adjuvant gemcitabine prolongs survival when compared with surgery alone. The 3-year survival rates were 36.5% and 19.5% for the gemcitabine and surgery-only arms of the study, respectively. The 5-year survival rates were 21% and 9% for the gemcitabine and surgery-only arms, respectively.[95]

Based on encouraging efficacy shown in the metastatic setting, the PRODIGE Group tested FOLFIRINOX in the adjuvant setting, in 493 patients who had undergone curative resection of the pancreas. Median overall survival was 54.4 months in the FOLFIRINOX arm, compared with 35 months in patients randomized to gemcitabine (the control arm).[96] This study established modified FOLFIRINOX as a main choice for adjuvant chemotherapy in patients with resected pancreatic cancer.  

Another landmark trial, conducted by ESPAC, compared adjuvant therapy with gemcitabine only and gemcitabine plus capecitabine (GemCap) in 732 patients who had undergone R0 or R1 resection for pancreatic ductal adenocarcinoma (PDAC). Median overall survival was  28 months in the gemcitabine plus capecitabine arm versus 25.5 months for gemcitabine arm, suggesting a benefit from adding capecitabine to gemcitabine in the postoperative setting.[97]

Although GemCap has never been compared with modified FOLFIRINOX in a randomized trial, GemCap can be still considered as an option for patients too old or too frail to receive FOLFIRINOX (see Chemotherapy for Unresectable and Metastatic Pancreatic Cancer).[98, 30]

Combining gemcitabine with nab-paclitaxel for adjuvant therapy was explored in the phase 3 APACT trial, which included 8666 patients who had undergone complete resection of pancreatic cancer. While there was a suggestion of benefit from gemcitabine plus nab-paclitaxel compared with gemcitabine alone, the study did not meet its primary endpoint of longer disease-free survival or its secondary endpoint of improved overall survival.[99] Consequently, this combination cannot be currently recommended in the adjuvant setting.

Current European Society for Medical Oncology (ESMO) guidelines include the following recommendations for adjuvant therapy[100] :

• mFOLFIRINOX should be the first adjuvant therapeutic option after resection of pancreatic cancer in selected and fit patients, in view of survival outcomes and associated toxicity profile.
• In more frail patients (age > 70, Eastern Cooperative Oncology Group performance status 2, or patients who have any contraindication to the drugs used in FOLFIRINOX), GemCap could be an option.
• Gemcitabine alone should be used only in frail patients.

A systematic review and meta-analysis by Wan et al found that adjuvant therapy with metformin signficantly reduced the risk of death in Asian patients with pancreatic cancer, but not in Whites. Mortality risk was reduced in Asian patients with stage I-II disease treated with metformin (hazard ratio [HR]=0.76, 95% CI=0.68-0.86) as well as in those with stage I-IV disease (HR=0.88, 95% CI=0.79-0.99), but not in those with stage III-IV disease.[101]

Acinar cell adenocarcinoma

The existing literature on treatment of acinar cell adenocarcinoma (ACC) consists largely of retrospective cohorts and case reviews; there are almost no prospective randomized trials to provide high-level evidence to treat ACC differently than PDAC. As first-line therapy in fit patients, there appears to be a slight preference for using fluoropyrimidine-based combinations (FOLFIRINOX or FOLFOX) versus gemcitabine plus nab-paclitaxel. Regardless of regimen, the disease control rate in ACC seems to be higher than is seen in PDAC. Also based on some small studies, ACC appears to be more radiosensitive than PDAC, thus warranting consideration of radiotherapy or stereotactic brachytherapy in the neoadjuvant or palliative setting. Overall, the stage-based treatment paradigm is similar to the one for PDAC.

Adenosquamous carcinoma of the pancreas

Due to the rarity of adenosquamous carcinoma of the pancreas (ASCP), no randomized trials have addressed treatment strategy for it. Based on small case cohorts and the molecular profile of ASCP,  there is a sense that ASCP may have sensitivity to regimens comprising a fluoropyrimidine plus platinum (eg, FOLFIRINOX, XELOX). As expected for a squamous variant, ASCPs tend to be radiosensitive. Although ASCP tends to have higher expression of PDL-1 than PDAC, the efficacy of immune checkpoint inhibitors in these patients has not been studied.

Venous thromboembolism (VTE) is a common and sometimes fatal complication in patients with pancreatic cancer.[53] Primary prophylaxis with low molecular weight heparin (LMWH) or direct oral anticoagulants (DOAC) has been shown to significantly reduce the rate of VTE, without increasing the risk of major bleeding. Consequently, most clinical practice guidelines recommend thromboprophylaxis for ambulatory cancer patients at high risk of VTE, in the absence of contraindications.[102]

Risk for VTE can be determined by calculating the Khorana score (see the Khorana risk score calculator). However, the Khorana score assigns +2 points for pancreatic cancer and so classifies all patients with pancreatic cancer at at least intermediate risk of VTE; thus, some guidelines recommend considering primary VTE prophylaxis in all patients with pancreatic cancer who are undergoing chemotherapy.[102]

In the phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), the addition of nanoparticle albumin–bound (nab)-paclitaxel to gemcitabine significantly improved overall survival in treatment-naive patients with metastatic pancreatic cancer compared with gemcitabine alone. Overall survival was approximately 2 months longer in patients treated with combination therapy (8.5 vs 6.7 months). One-year and 2-year survival rates were also higher in the combination therapy group (35% vs 22% and 9% vs 4%, respectively).[3]

FOLFIRINOX demonstrated a survival advantage compared with gemcitabine, but increased toxicity, in the European phase III ACCORD/PRODIGE trial, conducted in 342 patients with metastatic pancreatic cancer. Median survival in the FOLFIRINOX arm was 11.1 months, versus 6.8 months on the gemcitabine arm, but the incidence of adverse events and febrile neutropenia was significantly higher on the FOLFIRINOX arm, despite the fact that only patients with ECOG performance status of 0-1 were included in this trial.[103]

The NCCN currently recommends FOLFIRINOX or modified FOLFIRINOX as a preferred first-line treatment for patients with metastatic or locally advanced unresectable disease who have good performance status. The alternative first-line option is gemcitabine plus nab-paclitaxel. For patients with poor performance status, the NCCN recommends gemcitabine monotherapy.[30] Capecitabine alone may provide second-line therapy benefit in patients whose cancer is refractory to gemcitabine.[104]

Another recommended second-line regimen in patients with metastatic pancreatic cancer that has failed to respond to gemcitabine-based therapy is liposomal irinotecan (Onivyde) in combination with fluorouracil and leucovorin. US Food and Drug Administration (FDA) approval for this was based on a 3-arm, randomized, open-label study (NAPOLI-1 trial) in which median overall survival with liposomal irinotecan/fluorouracil/leucovorin was 6.1 months, compared with 4.2 months for patients treated with fluorouracil/leucovorin or liposomal irinotecan alone. Improvement in progression-free survival was also observed, to a median of 3.1 months with irinotecan liposomal plus fluorouracil/leucovorin compared with 1.5 months for fluorouracil/leucovorin alone.[105]

In the 5-9% of pancreatic cancer patients with BRCA1/2 or PALB2 germline mutations, or those rare patients with somatic (tumor) BRCA mutations, platinum-based chemotherapy combinations such as FOLFIRINOX or gemcitabine plus cisplatin should be considered as first-line options for  unresectable or metastatic disease.[106, 107] For patients with borderline performance status, carboplatin can be considered as an alternative to cisplatin. Mitomycin C is another DNA intercalating agent that has shown activity in BRCA2-associated pancreatic cancer.[108]

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, is indicated for first-line maintenance treatment of adults with deleterious or suspected deleterious germline BRCA1/2 mutations whose metastatic pancreatic adenocarcinoma has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. FDA approval for this indication was based on the POLO trial, in which patients on olaparib maintenance arm had superior progression-free survival (7.4 months, vs 3.8 months in the placebo arm).[8]

Rucaparib, another selective PARP inhibitor, also demonstrated efficacy in a phase 2 trial, with overall response rate of 25% and disease control rate of 32%.[109] Unfortunately, adding the PARP inhibitor veliparib to gemcitabine plus cisplatin chemotherapy, or to modified FOLFIRI, did not demonstrate additive benefit.[110, 111]

Pain

Patients not undergoing resection for pancreatic cancer should have therapy focused on palliating their major symptoms. Pain relief is crucial in these patients. Narcotic analgesics should be used early and in adequate dosages. Combining narcotic analgesics with tricyclic antidepressants or antiemetics can sometimes potentiate their analgesic effects. In some patients, narcotics are insufficient and other approaches must be considered.

Neurolysis of the celiac ganglia may provide significant, long-term pain relief in patients with refractory abdominal pain. This can be performed transthoracically or transabdominally by invasive radiology or anesthesiology, transgastrically using EUS-guided fine-needle injection, or intraoperatively when assessing the patient's potential for resection.

Radiation therapy for pancreatic cancer can palliate pain but does not affect the patient's survival.

Some patients may experience pain from the obstruction of the pancreatic or biliary ducts, especially if the pain significantly worsens after eating. These patients may benefit from endoscopic decompression with stents.

Jaundice

Obstructive jaundice warrants palliation if the patient has pruritus or right upper quadrant pain or has developed cholangitis. Some patients’ anorexia also seems to improve after relief of biliary obstruction.

Biliary obstruction from pancreatic cancer is usually best palliated by the endoscopic placement of plastic or metal stents. The more expensive and permanent metallic stents appear to have a longer period of patency and are preferable in patients with an estimated lifespan of more than 3 months. Plastic stents usually need to be replaced every 3-4 months.

Patients can also undergo operative biliary decompression, either by choledochojejunostomy or cholecystojejunostomy, at the time of an operation for resectability assessment.

Duodenal obstruction

Approximately 5% of patients develop duodenal obstruction secondary to pancreatic carcinoma. These patients can be palliated operatively with a gastrojejunostomy or an endoscopic procedure.

Endoscopic stenting of duodenal obstruction is usually reserved for patients who are poor operative candidates. Some surgeons empirically palliate patients with a gastrojejunostomy at the time of an unsuccessful attempt at pancreatic resection in an effort to prevent the later need for this operation.

As with most patients with advanced cancer, patients with pancreatic carcinoma are often anorexic. Pharmacologic stimulation of appetite is usually unsuccessful, but it may be tried.

Patients may have some degree of malabsorption secondary to exocrine pancreatic insufficiency caused by the cancer obstructing the pancreatic duct. Patients with malabsorption diarrhea and weight loss may benefit from pancreatic enzyme supplementation. Their diarrhea may also be improved by avoidance of high-fat or high-protein diets.

The management of pancreatic carcinoma is a multidisciplinary process. Typically, the management of pancreatic cancer entails consultations with a gastroenterologist, medical oncologist, general surgeon or surgical oncologist, and, possibly, a radiation oncologist.

A gastroenterologist is usually involved either for evaluation of the cause of the patient's presenting symptoms (eg, abdominal pain, nausea, weight loss, diarrhea) or for a definitive diagnosis of the cause of jaundice by EUS and/or ERCP. Consultation with a gastroenterologist is also needed if an endoscopically placed stent is needed for palliation of obstructive jaundice.

Consultation with a medical oncologist is often needed to select and administer neoadjuvant, adjuvant, or primary chemotherapy for the disease. Consultation with a medical oncologist is also useful for the management of other common cancer symptoms, such as pain and nausea.

Consultation with a surgeon is needed when the patient's imaging studies suggest that operative resection may be feasible. The surgeon may perform diagnostic laparoscopy or even laparoscopic ultrasonography prior to an attempt at definitive resection.

If curative resection is not possible, consultation with a surgeon may still be useful to consider operative palliation of biliary and/or duodenal obstruction. Consult with a surgeon or surgical oncologist who is very experienced in performing pancreaticoduodenectomies.

Consultation with a radiologist may be needed for special issues, such as obstructive jaundice that is difficult to manage where percutaneous transhepatic cholangiography may be needed.

Consultation with a radiation oncologist is usually considered at the discretion of a medical oncologist when combined chemoradiation may be beneficial. This approach is only indicated when this combination therapy is the subject of a clinical trial.

Guidelines Contributor: Lewis J Rose, MD Clinical Associate Professor of Medical Oncology, Division of Regional Cancer Care, Kimmel Cancer Center, Thomas Jefferson University Hospital; Consulting Staff, LRCRZ Associates

Screening

Guidelines on pancreatic cancer screening have been issued by the following organizations:

• U.S. Preventive Services Task Force (USPSTF)
• American Academy of Family Physicians (AAFP)
• International Cancer of the Pancreas Screening (CAPS) Consortium
• American Gastroenterological Association (AGA)

USPSTF recommendations

The USPSTF found no evidence that screening for pancreatic cancer is effective in reducing mortality and recommends against routine screening in asymptomatic adults using abdominal palpation, ultrasonography, or serologic markers.[112]  The AAFP guidelines concur with the USPSTF recommendation.[113]

The USPSTF did not review the effectiveness of screening individuals at high risk for pancreatic cancer.

International CAPS Consortium recommendations

The International CAPS Consortium, a panel of 49 multidisciplinary experts, released consensus guidelines for pancreatic cancer screening in 2012 and updated them in 2020.[114, 115] The consortium recommends screening for stage I pancreatic cancer and pancreatic cancer precursor lesions with high-grade dysplasia in the following high-risk groups[115] :

• All patients with Peutz-Jeghers syndrome (carriers of a germline LKB1/STK11 gene mutation)
• All carriers of a germline CDKN2A mutation
•  Carriers of a germline BRCA2, BRCA1, PALB2, ATM, MLH1, MSH2, or MSH6 gene mutation with at least one affected first-degree blood relative
• Individuals who have at least one first-degree relative with pancreatic cancer who in turn also has a first-degree relative with pancreatic cancer (familial pancreatic cancer kindred)

The recommended age at which to start surveillance varied by gene mutation status and family history, as follows[115] :

• Familial pancreatic cancer kindred (without a known germline mutation) -  Start at age 50 or 55, or 10 years younger than the youngest affected blood relative
• CDKN2A or Peutz-Jegher syndrome - Start at age 40
• BRCA2,ATM, PALB2 BRCA1, MLH1/MSH2 - Start at age 45 or 50, or 10 years younger than the youngest affected blood relative

Recommended screening techniques are as follows[115] :

• At baseline - Magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) plus endoscopic ultrasound (EUS) plus fasting blood glucose and/or HbA1c
• During followup - Alternate MRI/MRCP and EUS; routinely test fasting blood glucose and/or HbA1c
• As indicated -  Serum CA 19–9, if concerning features on imaging; EUS-FNA only for solid lesions of ≥5 mm, cystic lesions with worrisome features, or asymptomatic main pancreatic duct (MPD) strictures (with or without mass); CT only for solid lesions, regardless of size, or asymptomatic MPD strictures of unknown etiology (without mass)

The consortium recommends a screening interval of every 12 months in patients with no abnormalities, or only non-concerning abnormalities (eg, pancreatic cysts without worrisome features), and every 3 or 6 months in patients with abnormalities that are not suspicious for malignancy but are concerning; immediate surgical resection is indicated for abnormalities suspicious for malignancy.[115]

American Gastroenterological Association recommendations

In 2020, the AGA published a clinical practice guideline update containing best practice advice for identifying and screening patients at high risk for pancreatic cancer. The goal of screening is to detect resectable stage 1 pancreatic ductal adenocarcinoma, and high-risk precursor neoplasms such as intraductal papillary mucinous neoplasms (IPMNs) with high-grade dysplasia and some enlarged pancreatic intraepithelial neoplasias.[116]

The guideline recommends against screening average-risk individuals for pancreas cancer. The guideline recommends considering screening in patients determined to be at high risk, including first-degree relatives of patients with pancreas cancer with at least two affected genetically related relatives, and in patients with genetic syndromes associated with an increased risk of pancreas cancer, including all patients with the following[116] :

• Peutz-Jeghers syndrome
• Hereditary pancreatitis
• CDKN2A gene mutation
• One or more first-degree relatives with pancreas cancer with Lynch syndrome
• Mutations in BRCA1, BRCA2, PALB2, and ATM genes

Further recommendations are as follows[116] :

• Consider genetic testing and counseling for familial pancreas cancer relatives who are eligible for surveillance. A positive germline mutation is associated with an increased risk of neoplastic progression and may also lead to screening for other relevant associated cancers.
• When possible, high-risk patients undergoing pancreas cancer screening should participate in a registry or be referred to a pancreas center of excellence.
• Begin pancreas cancer screening in high-risk individuals at age 50, or 10 years younger than the initial age of familial onset. Initiate screening at age 40 in CKDN2A and PRSS1 mutation carriers with hereditary pancreatitis and at age 35 in patients with Peutz-Jeghers syndrome.
• MRI and EUS in combination are the preferred screening modalities for pancreas cancer screening.
• Screening intervals of 12 months should be considered when there are no concerning pancreas lesions, with shortened intervals and/or the performance of EUS in 6-12 months directed towards lesions determined to be low risk (by a multidisciplinary team). EUS evaluation within 3-6 months for indeterminate lesions and within 3 months for high-risk lesions, if surgical resection is not planned. New-onset diabetes in a high-risk patient should lead to additional diagnostic studies or change in surveillance interval.
• Decisions regarding therapy directed towards abnormal findings detected during screening should be made by a dedicated multi-disciplinary team together with the high risk individual and their family.
• Surgical resection should be performed at high volume centers.
• Consider discontinuing pancreas cancer screening in high-risk individuals when they are more likely to die of causes unrelated to pancreas cancer, due to co-morbidity and/or are not candidates for pancreas resection.
• The limitations and potential risks of pancreas cancer screening should be discussed with patients prior to initiating a screening program.

Use of Tumor Markers in Pancreatic Cancer

In its 2006 update, the American Society of Clinical Oncology (ASCO) expanded the scope of the guidelines for use of tumor markers in gastrointestinal cancer to include CA 19-9 as a marker for pancreatic cancer. The recommendations for evaluation of CA 19-9 levels are as follows[54] :

• CA 19-9 is least sensitive for small, early-stage pancreatic carcinomas and thus is not effective for the early detection of pancreatic cancer or as a screening tool

• Use of CA 19-9 levels alone is not recommended for use in determining operability

• Rising levels of CA 19-9 postoperatively may predict recurrent disease, but confirmation with imaging studies and/or biopsy is required.

• CA 19-9 can be measured at the start of treatment for locally advanced metastatic disease and every 1-3 months during active treatment; elevation of levels in serial determinations may be an indication of progressive disease, but confirmation with other studies is required

• 5-10% of patients lack the enzyme necessary to produce CA 19-9; in these patients with low or absent titer of CA 19-9, monitoring disease with this tumor marker will not be possible

Both the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) guidelines for diagnosis and treatment of pancreatic cancer recommend the measurement of serum CA 19-9 levels after surgery and before adjuvant therapy to guide treatment and follow up.[117, 30]

Diabetes Mellitus as Risk Factor 

The NCCN guideline for pancreatic adenocarcinoma acknowledges long-standing diabetes mellitus as a risk factor for pancreatic cancer. The guideline also notes an association between sudden onset of type 2 diabetes mellitus in an adult older than 50 years and a new diagnosis of pancreatic cancer. NCCN guidelines states that clinicians should consider pancreatic cancer in patients with diabetes who have unusual symptoms such as continuous weight loss and abdominal problems.[30]

The European Society of Medical Oncology (ESMO) recommendations for diagnosis of pancreatic cancer include the following[117] :

• Abdominal ultrasound for the initial examination

• Endoscopic ultrasound (EUS), contrast-enhanced multi-detector computed tomography (MD-CT) and MRI combined with magnetic resonance cholangiopancreatography (MRCP) for additional evaluation

• Endoscopic retrograde cholangiopancreatography (ERCP) only to relieve bile duct obstruction

• ERCP and biliary stenting should be performed only if surgery is not possible

• Positron emission tomography (PET) is not recommended for diagnosis

• Biopsy is recommended only when imaging results of a pancreatic lesion are ambiguous; EUS-guided biopsy is preferred and percutaneous sampling should be avoided

• Metastatic lesions can be biopsied percutaneously under ultrasound or CT guidance or during EUS

The NCCN guidelines recommend that diagnostic management involve multidisciplinary consultation and be done at a high-volume center with appropriate high-quality imaging that includes specialized pancreatic CT or MRI. Additional recommendations include the following[30] :

• Patients should undergo triphasic multidetector CT with thin-slice, cross-sectional imaging; the difference in contrast enhancement is highest during the second phase, so a triphasic approach enables a clear distinction between a hypodense lesion and the rest of the pancreas.

• Contrast MRI is acceptable when CT is not possible, but MRI has not been shown to be more effective or accurate in diagnosing and staging pancreatic cancer; however, MRI can be a useful adjunct in diagnosing high-risk patients.

• PET/CT is not a substitute for high-quality contrast-enhanced CT, but may be considered after CT to detect small metastatic deposits.

• If no mass is evident in the pancreas on CT protocol imaging, EUS is recommended before other evaluation options.

• EUS-guided fine-needle aspiration (FNA) offers better safety and lower risk of peritoneal seeding than CT-guided FNA

The NCCN recommends staging laparoscopy in patients who meet any of the following criteria[30] :

• CA 19-9 level >150 U/mL
• Low-volume ascites
• Tumor in the body of the pancreas
• Borderline resectable tumor
• Tumor size >3 cm
• Common bile duct lymphadenopathy

The NCCN guidelines aside, staging laparoscopy may not be absolutely necessary in a patient with a borderline resectable tumor, if the treatment team plans to use neoadjuvant chemotherapy to shrink the tumor before resection.

The NCCN guidelines recommend that clinicians consider germline testing in any patient diagnosed with pancreatic cancer and consider a molecular analysis of tumors in those with metastatic disease. The NCCN panel has also strongly recommended somatic profiling of tumor tissue.[30]

In patients diagnosed with metastatic pancreatic cancer, American Society of Clinical Oncology (ASCO) guidelines recommend the following as part of the initial assessment[6] :

• Perform a multiphase CT scan of the chest, abdomen, and pelvis to assess the extent of disease. Perform other staging studies only as dictated by symptoms.
• Evaluate the patient’s baseline performance status (PS), symptom burden, and comorbidity profile.
• Discuss the goals of care (including an advance directive), patient preferences, and support systems.

Multidisciplinary collaboration to formulate treatment and care plans and disease management should be the standard of care.

Early testing for actionable genomic alterations is recommended to guide treatment decisions for patients who are likely to be potential candidates for additional treatment after first-line therapy. Both germline and somatic testing for the following are recommended:

• Microsatellite instability (MSI)/mismatch repair deficiency (dMMR)
• BRCA mutations with known significance
• NTRK gene fusions

Defining Resectability Status

The National Comprehensive Cancer Network (NCCN) has adopted criteria for defining resectability status, which the European Society of Medical Oncology (ESMO) also recommends. For tumors to be considered localized and clearly resectable, they must demonstrate the following[30] :

• No distant metastases
• No evidence of superior mesenteric vein (SMV) or portal vein (PV) distortion
• Clear fat planes around the celiac axis, hepatic artery and superior mesenteric artery (SMA)

Borderline resectable tumors include the following:

• No distant metastases Involvement of the SMV or PV with distortion or narrowing or occlusion of the vein with vessel proximal and distal, allowing for resection and replacement
• Gastroduodenal artery encasement up to the hepatic artery, without extension to the celiac axis.
• Tumor abutment to the SMA < 180° of the circumference of the vessel wall.

The American Society of Clinical Oncology (ASCO) recommends primary surgical resection of the primary tumor and regional lymph nodes for all patients meeting the following criteria[118] :

• No clinical evidence for metastatic disease
• Performance status and comorbidity profile that can withstand major abdominal surgery
• No radiographic interface between primary tumor and mesenteric vasculature
• CA 19-9 level suggestive of localized disease

Treatment

American Society of Clinical Oncology guidelines for the treatment of potentially curable pancreatic cancer include the following key recommendations[118] :

• After histopathologic confirmation of the diagnosis, a multiphase CT scan of the abdomen and pelvis using a pancreatic protocol or MRI  should be performed to gauge the anatomic relations of the tumor to other internal structures and to evaluate patients for the presence of intra-abdominal metastases.
• Supplemental studies may include endoscopic ultrasound, diagnostic laparoscopy, or both.
• Performance status, symptom burden, and comorbidity profile should be carefully evaluated at baseline, and the goals of care should be shaped by patient preferences before arriving at a multidisciplinary treatment plan.
• Patients should be informed about any relevant clinical trials for experimental or palliative care.

Preoperative therapy is recommended for patients who meet any of the following criteria[118] :

• Radiographic findings are suspicious but not diagnostic for extrapancreatic disease
• Poor performance status or comorbidities not conducive to major abdominal surgery if it is thought that their status might be reversed after treatment
• A radiographic interface between the primary tumor and mesenteric vasculaturea radiographic interface that does not meet appropriate criteria for primary resection
• CA 19-9 level (in absence of jaundice) suggestive of disseminated disease

After preoperative treatment, patients should be restaged before making plans for surgery.

Postoperative recommendations include the following[119, 118] :

• In the absence of medical or surgical contraindications, patients who did not receive preoperative therapy should be offered 6 months of adjuvant chemotherapy with modified FOLFIRINOX (folinic acid [leucovorin], 5-fluorouracil [5-FU], irinotecan, oxaliplatin), if there are no concerns for toxicity or tolerance; alternatively, gemcitabine and capecitabine, gemcitabine alone, or 5-FU fluorouracil plus leucovorin can be offered. Adjuvant therapy should be initiated within 8 weeks of surgical resection.
• Patients who have not received preoperative therapy and who have microscopically positive margins or node-positive disease after 4 to 6 months of adjuvant chemotherapy should be offered adjuvant chemoradiation.
• For patients who underwent preoperative therapy, although evidence supporting the duration of post-operative therapy is weak, the panel recommends that patients receive a total of 6 months of adjuvant therapy, including time spent on the preoperative regimen.
• Patients  should receive ongoing supportive care for symptom burden that may result from the operation and (preoperative and/or adjuvant) chemotherapy
• Patients who have completed treatment and have no evidence of disease should be monitored for recovery of treatment-related toxicities and recurrence. Visits may be offered at 3- to 6-month intervals but the role of serial cross-sectional imaging, the extent to which surveillance intervals should be prolonged over time, and the duration of recommended surveillance are all undefined 

The European Society of Medical Oncology (ESMO) recommendations for treatment of pancreatic cancer include the following[117] :

• Radical surgery is the only curative treatment and is mainly suitable for patients with stage I and some patients with stage II

• In elderly patients (>75 years old), comorbidity can be a reason to abstain from resection; the risk of perioperative mortality in patients undergoing pancreatic resection can be estimated using a surgical outcomes analysis and research (SOAR) pancreatectomy score

ESMO recommendations for treatment of resectable disease are as follows[117] :

• Pancreatoduodenectomy (Whipple procedure) is the treatment of choice for tumors of the pancreatic head

• For tumors in the body or tail of the pancreas, distal pancreatectomy, including the resection of the body and the tail of the pancreas and the spleen, is usually performed

• No evidence exists that extended lymphadenectomy is beneficial; standard lymphadenectomy should involve the removal of ≥15 lymph nodes to allow adequate pathologic staging

• Postoperative gemcitabine or 5-FU chemotherapy is recommended

• No chemoradiation should be given to patients after surgery except in clinical trials

For patients with borderline resectable lesions, ESMO recommends participation in clinical trials wherever possible. Otherwise, preoperativechemotherapy (gemcitabine or FOLFIRINOX) followed by chemoradiation and then surgery appears to be the best option.

NCCN treatment guidelines concur that resection is the only potentially curative treatment for pancreatic cancer, but note that 80% of patients present with incurably advanced disease. Key recommendations for treatment of localized disease include the following[30] :

• Decisions about treatment and resectability should involve input from a multidisciplinary group of specialists.

• Selection of patients for surgery should be based on the probability of cure, as determined by resection margins; other factors include comorbidities, overall performance status, and age.

• Postoperative adjuvant therapy improves outcomes but no definite standard has been set. Options for patients who did not receive preoperative neoadjuvant therapy include clinical trials (preferred), chemotherapy, or chemoradiation. When chemotherapy alone is chosen, gemcitabine is preferred over 5-FU/leucovorin; capecitabine should only be considered when other options are contraindicated.

• For patients who received neoadjuvant therapy, post-operative therapy options are dependant on response to neoadjuvant therapy and other clinical considerations. 

Like ESMO, NCCN recommends considering preoperative neoadjuvant therapy for patients with resectable or borderline resectable tumors, but notes that "there is limited evidence to recommend specific neoadjuvant regimens off-study, and practices vary with regard to the use of chemotherapy and radiation." NCCN recommendations on neoadjuvant therapy in pancreatic carcinoma are as follows[30] :

• Consult with a high-volume center when neoadjuvant therapy is being considered\.
• If neoadjuvant therapy is recommended, treat at or coordinate through a high-volume center, when feasible. 
• Participation in a clinical trial is encouraged.
•  Subsequent chemoradiation is sometimes included.

Neoadjuvant regimen options include the following[30] :

• FOLFIRINOX/modified FOLFIRINOX, with or without subsequent chemoradiation
• Gemcitabine + albumin-bound paclitaxel, with or without subsequent chemoradiation
• Gemcitabine + cisplatin (≥2–6 cycles) followed by chemoradiation (only for known BRCA1/2 mutations)

The ASCO guidelines include the following recommendations for treatment of locally advanced, unresectable disease[120] :

• Multiphase CT scans to assess disease extent in the chest, abdomen, and pelvis. Other staging studies should be performed only as dictated by symptoms 
• Patients should also be assessed for baseline performance status, symptom burden, and comorbidities, and clinicians again need to discuss the goals of treatment in collaboration with a multidisciplinary team shaped by patient preferences.
• Patients should  be informed about any relevant clinical trials for which they might be eligible.
• Initial treatment should include some form of combination regimen for individuals who have a performance status of 0 or 1, who have a favorable comorbidity profile, and who want to and are able to undergo an aggressive medical regimen.
• There is no clear evidence to support one regimen over another and therapy may be offered on the basis of extrapolation from data derived from studies in the metastatic setting.
• Chemoradiotherapy (CRT) or stereotactic body radiotherapy (SBRT) may be offered to patients with local progression but no metastases, provided they have a performance status of 2 or less and a favorable comorbidity profile.
• CRT or SBRT may be offered to patients who have responded to an initial 6 months of chemotherapy or have stable disease, have developed unacceptable chemotherapy-related toxicities, or have a decline in performance status as a consequences of chemotherapy toxicity
• If patients respond or their disease has at least stabilized after 6 months of induction chemotherapy, CRT or SBRT may be offered as an alternative to continuing chemotherapy alone
• SBRT may be offered even though evidence supporting SBRT is not robust.

On completion of treatment, patients whose disease has stabilized or who have no disease progression should have a follow-up visit every 2 to 3 months in which they undergo liver and renal function tests. They should also be tested for CA 19-9 levels and undergo CT scans at least every 3 months in the first 2 years after completion of treatment, and every 6 months if disease remains stable.[120]

Patients who do not benefit from first-line treatment recommendations and who progress despite clinicians' best efforts should be treated according to the ASCO guidelines for the treatment of metastatic pancreatic cancer (see Metastatic Disease and Palliative Care, below).[120]

NCCN treatment guidelines include the following recommendations[30] :

• FOLFIRINOX/modified FOLFIRINOX or gemcitabine plus nab-paclitaxel is a first-line treatment for patients who have good performance status

• Gemcitabine monotherapy, or palliative therapy and best supportive care, is recommended for locally advanced unresectable disease in symptomatic patients with poor performance status

American Society of Clinical Oncology recommendations

For first-line treatment of metastatic pancreatic cancer, ASCO guidelines recommend FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) for patients who meet all of the following criteria[121, 6] :

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Favorable comorbidity profile
• Patient preference and a support system for aggressive medical therapy
• Access to chemotherapy port and infusion pump management services

Gemcitabine plus nab-paclitaxel is recommended for patients who meet all of the following criteria:

• ECOG performance status  0-1
• Relatively favorable comorbidity profile
• Patient preference and a support system for relatively aggressive medical therapy 

Gemcitabine alone is recommended for patients who have either an ECOG performance status of 2 or a comorbidity profile that precludes more aggressive regimens and for patients who wish to pursue cancer-directed therapy. The addition of nab-paclitaxel or capecitabine or erlotinib to gemcitabine may be offered, with proactive dose and schedule adjustments to minimize toxicities.

In patients with an ECOG performance status of 3 or with poorly controlled comorbid conditions despite ongoing active medical care, cancer-directed therapy should be offered only on a case-by-case basis. Major emphasis should be on optimizing supportive care measures. 

Treatment options after first-line therapy:

• In patients with tumors harboring NTRK fusions, treatment with larotrectinib or entrectinib is recommended.
• The programmed death–1 immune checkpoint inhibitor pembrolizumab is recommended as second-line therapy for patients who have tested positive for mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) tumors.
• In patients who have a germline BRCA1 or BRCA2 mutation and who have received first-line platinum-based chemotherapy without disease progression for at least 16 weeks, options for continued treatment include chemotherapy or the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib.

Gemcitabine plus nab-paclitaxel may be offered as second-line therapy to patients who meet all of the following criteria:

• First-line treatment with FOLFIRINOX
• ECOG performance status 0-1
• Relatively favorable comorbidity profile
• Patient preference and a support system for aggressive medical therapy

Fluorouracil plus nanoliposomal irinotecan, or fluorouracil plus irinotecan when the former combination is unavailable, is preferred as a second-line therapy for patients who meet all of the following criteria:

• First-line treatment with a gemcitabine-based regimen
• ECOG performance status 0-1
• Relatively favorable comorbidity profile
• Patient preference and a support system for aggressive medical therapy
• Access to chemotherapy port and infusion pump management services

Fluorouracil plus oxaliplatin may be considered as second-line therapy for patients who meet all of the following criteria:

• First-line treatment with gemcitabine plus nab-paclitaxel
• ECOG performance status 0-1
• Relatively favorable comorbidity profile
• Patient preference and a support system for aggressive medical therapy
• Access to chemotherapy port and infusion pump management services

Gemcitabine or fluorouracil can be considered as second-line therapy for patients who have either an ECOG performance status of 2 or a comorbidity profile that precludes more aggressive regimens and who wish to pursue cancer-directed therapy (the addition of nab-paclitaxel to gemcitabine or nanoliposomal irinotecan to fluorouracil may be offered, with proactive dose and schedule adjustments to minimize toxicities).

No data are available to recommend third-line or further therapy with a cytotoxic agent. Clinical trial participation is encouraged.

Follow-up and surveillance

For patients on active cancer-directed therapy outside of a clinical trial, imaging to assess first response should be offered at 2 to 3 months from the initiation of therapy. Computed tomography scans with contrast are the preferred modality. Thereafter, clinical assessment, conducted frequently during visits for cancer-directed therapy, should supplant imaging assessment. Routine use of positron emission tomography scans is not recommended. CA19-9 is not considered an optimal substitute for imaging for the assessment of treatment response.

No data exist on the duration of cancer-directed therapy. An ongoing discussion of the goals of care and assessment of treatment response and tolerability should guide decisions to continue or to hold or terminate cancer-directed therapy.

European Society for Medical Oncology recommendations

For patients with advanced/metastatic disease, ESMO recommendations are as follows[117] :

• For biliary stenting, the endoscopic method is safer than percutaneous insertion and is as successful as surgical hepatojejunostomy

• Pain control is mandatory and frequently requires consultation with a pain specialist

• In patients with ECOG performance status 3/4, with significant morbidities and a very short life expectancy, only symptomatic treatment can be considered

• In very selected patients with performance status 2 due to heavy tumor load, gemcitabine and nab-paclitaxel can be considered for best chance of response

• In patients with performance status 2 and/or bilirubin level higher than 1.5 times the upper limit of normal, monotherapy with gemcitabine should be considered

• In patients with performance status 0 or 1 and bilirubin level less than 1.5 times the upper limit of normal, combination chemotherapy with either FOLFIRINOX or the combination of gemcitabine and nab-paclitaxel should be considered

• For fit patients, nanoliposomal irinotecan combined with 5-fluorouracil and leucovorin may constitute an active and tolerable second-line treatment option[122]

• The efficacy of treatment has to be evaluated every 2 months with a comparative CT scan

National Comprehensive Cancer Network recommendations

NCCN treatment guidelines include the following recommendations[30] :

• Decisions about treatment and resectability should involve input from a multidisciplinary group of specialists

• Selection of patients for surgery should be based on the probability of cure, as determined by resection margins; other factors include comorbidities, overall performance status, and age

• FOLFIRINOX/modified FOLFIRINOX or gemcitabine plus nab-paclitaxel is recommended as a first-line treatment for patients with metastatic or locally advanced unresectable disease who have good performance status

• Gemcitabine monotherapy, or palliative therapy and best supportive care, is recommended for metastatic or locally advanced unresectable disease in symptomatic patients with poor performance status

Palliative Care

The NCCN guidelines for palliative care include the following[30] :

• Endoscopic biliary metal stent is preferred for biliary obstruction
• Enteral stent for gastric outlet obstruction
• Consider radiation therapy with or without chemotherapy to palliate pain
• Pancreatic enzyme replacement for pancreatic insufficiency
• Low-molecular-weight heparin is preferred over warfarin for management of thromboembolic disease

The ESMO guidelines for palliative care recommend morphine as the drug of choice for pain management. Parenteral or transdermal administration may be considered for patients with swallowing impairment or gastrointestinal obstructions. For patients with poor tolerance for opioids, percutaneous celiacoplexus blockade is suggested.[117]

The American Cancer Society (ACS) has issued guidelines for cancer prevention that focus on recommendations for individual choices regarding diet and physical activity patterns. Because individual choices are impacted by community measures that can either facilitate or create barriers to healthy behaviors, recommendations for community action are also included.

The ACS guidelines include recommendations for maintaining a healthy weight, adopting a physically active lifestyle, consuming a healthy diet, and limiting alcohol consumption.

The guidelines are consistent with guidelines from the American Heart Association and the American Diabetes Association for the prevention of coronary heart disease and diabetes, as well as for general health promotion.

The ACS guidelines include the following specific dietary recommendations for patients with pancreatic cancer[123] :

• Supplementation with omega-3 fatty acids

• Pancreatic enzyme replacement therapy, along with diet modification, to manage disease symptoms and treatment side effects

• Consultation and close follow-up with a registered dietitian for an individualized dietary prescription

The most active agents for pancreatic cancer have been 5-fluorouracil (5-FU) and gemcitabine. Gemcitabine appears to be slightly more active than 5-FU. Both of those agents are commonly used in combination regimens—for example, 5-FU plus folinic acid [leucovorin], irinotecan, and oxaliplatin (FOLFIRINOX); and gemcitabine plus capecitabine (GemCap). Objective responses, meaning actual regression of tumor, have been 20% or less.

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, is used for maintenance therapy in pancreatic adenocarcinoma. Olaparib has US Food and Drug Administration (FDA) approval for adults with germline BRCA-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.[8]

Class Summary

These agents inhibit cell growth and proliferation. They are used for chemotherapy.

Gemcitabine (Gemzar)

A frequently quoted trial showed a small, but statistically significant, improvement in overall survival with gemcitabine versus 5-FU (5.7 vs 4.4 mo). Additionally, gemcitabine improved the quality of life in approximately 25% of patients. It is a pyrimidine antimetabolite that nhibits DNA polymerase and ribonucleotide reductase, which in turn inhibit DNA synthesis.

Fluorouracil (Adrucil)

This is a fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and also interferes with ribonucleic acid (RNA) synthesis and function. Fluorouracil has some effect on DNA and is useful in symptom palliation for patients with progressive disease. It is commonly used in patients with gastrointestinal malignancies. Response rates are typically less than 20% in pancreatic cancer.

Erlotinib (Tarceva)

This agent is pharmacologically classified as a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. EGFR is expressed on the cell surface of normal cells and cancer cells. Erlotinib has been approved by the FDA for use, in combination with gemcitabine, as a first-line treatment for locally advanced, unresectable, or metastatic pancreatic cancer.

Capecitabine (Xeloda)

Capecitabine is a prodrug of fluorouracil that undergoes hydrolysis in liver and tissues to form the active moiety (fluorouracil), inhibiting thymidylate synthetase, which in turn blocks methylation of deoxyuridylic acid to thymidylic acid. This step interferes with DNA, and to a lesser degree with RNA synthesis.

Paclitaxel protein bound (Abraxane)

Paclitaxel protein bound is a microtubular inhibitor (albumin-conjugated formulation) and a natural taxane that prevents depolymerization of cellular microtubules, which results in DNA, RNA, and protein synthesis inhibition. It is indicated for metastatic adenocarcinoma of the pancreas as first-line treatment in combination with gemcitabine.

Irinotecan liposomal (Onivyde)

Irinotecan sucrosofate salt in a pegylated liposomal formulation. Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase-1 DNA complex and prevent re-ligation of the single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death. Irinotecan liposomal is used in combination with fluorouracil and leucovorin for metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.

Olaparib (Lynparza)

Olaparib is a poly (DP-ribose) polymerase (PARP) inhibitor. PARP enzymes are involved in normal cellular function (eg, DNA transcription and repair). It is indicated for maintenance treatment of adults with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.

Oxaliplatin (Eloxatin)

Platinum coordination compound that inhibits DNA synthesis; cross-links and denatures strands of DNA; disrupts DNA function by covalently binding to DNA bases.