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Pancreatic Cancer

October 19, 2022 - read ≈ 50 min



Lily V. Saadat, MD


Joshua S. Jolissaint, MD

Thomas E. Clancy, MD



There will be approximately 57,600 new pancreatic cancer diagnoses in the United States in 2020. While the incidence has been stable over the last decade in the United States at a rate of 12.3-12.8 cases per 100,000 persons,[1] worldwide, the incidence of pancreatic cancer has risen 2.3-fold since 1990, resulting in 400,000 deaths in 2017 alone. The incidence of pancreatic cancer varies considerably between countries, with the highest incidence and mortality rates found in high-income countries.[2]

Although pancreatic cancer will only contribute to 3.2% of new cancer diagnoses in 2020, it is estimated to become the 3rd leading cause of cancer-related mortality, surpassing breast cancer by over 47,000 deaths. Based on data from the 2013-2017 Surveillance, Epidemiology, and End Results (SEER) Program, men are more likely to be diagnosed with pancreatic cancer than women (14.9 versus 11.6 cases per 100,000 person, age-adjusted mortality rates) and African Americans have the highest incidence and death rate for both genders, as well as lower overall survival compared to White patients.[1] While African Americans have a higher prevalence of multiple risk factors traditionally associated with pancreatic cancer, including smoking, diabetes, and chronic pancreatitis, previous studies have also revealed lower rates of surgical evaluation, resection, and chemotherapy utilization that may be in part related to socioeconomic disparities and access to care.[3]

The current 5-year estimated survival is 10.0% for all individuals, although survival varies considerably by the extent of disease and resectability. For patients with pancreatic cancer localized to the pancreatic parenchyma, 5-year survival is 39.4%, however survival decreases to 13.3% when cancer has spread to locoregional lymph nodes, and <3% in the presence of distant metastases.[1]

The pancreas is composed of both exocrine and endocrine components: the exocrine pancreas produces digestive enzymes, whereas the endocrine pancreas produces hormones such as insulin, glucagon, somatostatin, pancreatic polypeptide, and vasoactive intestinal peptide. Cancer of the exocrine pancreas accounts for approximately 90% of pancreatic cancer, with the most common histological subtype being pancreatic ductal adenocarcinoma (PDAC). Mucinous cystadenocarcinomas are a second, albeit much rarer, subtype of exocrine pancreatic cancer with a better prognosis compared to PDAC, and are more common in women compared to men.[4] Additional rare subtypes include acinar cell carcinoma, adenosquamous carcinoma, and colloid carcinoma. Cancers of the endocrine pancreas, also called pancreatic neuroendocrine tumors (PNETs), arise from a- and b-cells and account for <5% of pancreatic cancers. However, PNETs have a significantly better prognosis compared to other histological subtypes with a 5-year survival of >90%. For the purposes of this chapter, we will describe factors as they relate to the most prominent subtype, PDAC.

Multiple risk factors for pancreatic cancer have been described, however due to the low prevalence of disease, the relative importance of each risk factor is unknown or with variable effects reported in the literature. In terms of modifiable risk factors, smoking has the strongest association, followed by obesity, diabetes mellitus (DM), and alcohol (although this association is controversial and may be more related to chronic pancreatitis).{5] Non-modifiable risk factors include age, with a median diagnosis of 70 years, male gender, African American race, and Type A blood.[1,5]

Multiple genetic mutations/syndromes have an associated increased risk of PDAC, including mutations in the BRCA1/2 (hereditary breast and ovarian cancer), STK11 (Peutz-Jeghers syndrome), PRSS1 (hereditary pancreatitis), CDKN2A (familial atypical multiple mole melanoma), PALB2, and ATM genes, and those genes involved in hereditary non-polyposis colorectal cancer (HNPCC) (MLH1, MSH2, MSH6, and PMS2); however these genetic syndromes and mutations only explain approximately 10% of familial PDAC.[6]


Patients with PDAC often have vague and non-specific complaints, which may be intermittent prior to diagnosis, leading to a false reassurance of their etiology.[5] The most common presenting symptom for patients with PDAC is painless jaundice due to conjugated hyperbilirubinemia as a sequelae of biliary tract obstruction, seen more commonly in patients with cancer of the pancreatic head. Additional symptoms include malaise, fatigue, weight loss, steatorrhea, dyspepsia, and abdominal pain radiating to the back. A new diagnosis of DM, particularly in patients older than 50-years, or African American and Hispanic patients, may also be reflective of underlying, yet undiagnosed PDAC.[7]


The United States Preventive Services Task Force (USPTF) has issued a Grade D rating and advises against routine screening of asymptomatic adults at normal risk of pancreatic cancer. In part, due to the low prevalence and lifetime risk of PDAC, the USPTF has found no evidence that imaging-based screening tests (including computed tomography [CT], magnetic resonance imaging [MRI] or endoscopic ultrasonography [EUS]), abdominal palpation, or serological markers have any benefit in improving disease-specific morbidity, mortality, or all-cause mortality. Moreover, with a Grade D recommendation, there is evidence that these diagnostic methods may result in harm that outweighs any benefit rendered.

For higher risk patients, predominantly those who would be described as at-risk for “familial pancreatic cancer”, the International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer agreed that the following cohort were appropriate candidates for screening: first degree relatives (FDRs) of someone with familial pancreatic cancer (with at least two FDRs affected), patients with Peutz-Jeghers syndrome, and patients with mutations in the p16, BRCA2, and HNPCC genes with 1 FDR affected.[6]

The initial age of screening has not been agreed upon, however 51% of the consortium agree that screening should start at age 50 with EUS or MRI as first-line screening modalities. Although not formally recommended, the authors acknowledge that screening of patients with PRSS1 mutations and chronic pancreatitis is being performed at established centers (due to the relationship between duration of chronic pancreatitis and PDAC risk); however, screening for asymptomatic patients with a PRSS1 mutation remains controversial.


If a diagnosis of PDAC is suspected, the initial diagnostic evaluation should include a contrast enhanced, dual-phase, pancreatic-protocol CT scan or MRI with sub-millimeter axial sections; this should be performed even if non-enhanced CT imaging suggests a high likelihood of PDAC, as the contrast enhanced imaging allows for characterization of the primary tumor in relation to the adjacent vasculature.[8]

Multidetector CT (MDCT) is more widely available and allows for better visualization of the tumor in relation to adjacent vasculature, local invasion, and subsequent assessment of surgical resectability. The role and utility of MRI is evolving, however this modality may provide better visualization for very small lesions, and lesions not well-visualized on CT.[9]

Laboratory studies should include a serum carbohydrate antigen (CA) 19-9, as well as serum aminotransferases to assess for underlying liver disease, and serum alkaline phosphatase, bilirubin, and lipase to assess for biliary obstruction and/or concurrent pancreatitis. Once a confirmed or highly suspected diagnosis is made, patients should be referred to a center that specializes in treating pancreatic cancer and provides robust multidisciplinary management. To complete staging, CT or MRI with intravenous contrast, or positron emission tomography-CT (PET-CT) of the chest, abdomen, and pelvis should be performed to assess for extra-pancreatic metastases.

For resectable patients, a tissue diagnosis should be pursued either with staging laparoscopy (see Treatment), percutaneous biopsy, or with EUS-guided fine needle aspiration (FNA). While tissue biopsies may be selectively omitted in patients undergoing upfront resection with high clinical suspicion for PDAC, tissue is needed for patients if neoadjuvant therapy is planned. For patients with suspected extra-pancreatic disease, tissue confirmation of a metastatic site either with EUS-guided FNA or radiographically-guided biopsy is recommended.

For patients with biliary tract obstruction, endoscopic intervention with endoscopic retrograde cholangiopancreatography (ERCP) may be therapeutic by allowing placement of a stent for biliary decompression (see Treatment) and diagnostic by simultaneously obtaining a tissue biopsy. For all patients with confirmed PDAC, the National Comprehensive Cancer Network (NCCN) Pancreatic Cancer Guidelines Version 1.2020 recommend germline genetic testing to evaluate for hereditary syndromes, as well as tumor/somatic genomic profiling for patients with locally advanced or metastatic disease to identify options for targeted therapies.


The 8th Edition of the American Joint Committee on Cancer (AJCC) TNM staging system was put into practice in 2018 and stages PDAC based on tumor size, lymph node involvement, and distant metastases (Table 1).

Table 1. Tumor size and nodal status based on the AJCC 8th Edition TNM staging system

T1Tumor diameter 2 cm in greatest dimension
T2Tumor diameter > 2 cm and £ 4 cm in greatest dimension
T3Tumor diameter > 4 cm in greatest dimension
T4Tumor involves the celiac axis, superior mesenteric artery, or common hepatic artery, regardless of size
N0No regional nodal involvement
N1Metastasis in 1-3 regional lymph nodes
N2Metastasis in 4 regional lymph nodes
M0No distant metastases
M1Distant metastasis
AJCC: American Joint Committee on Cancer

This staging system was validated by an international multicenter collaborative effort and reported comparable survival statistics to the more general stratifications used by SEER (Table 2).[10]

Table 2. Definition of cancer stage and survival based on TNM status

StageTNM5-year survival
van Roessel S, Kasumova GG, Verheij J, et al. International Validation of the Eighth Edition of the American Joint Committee on Cancer (AJCC) TNM Staging System in Patients With Resected Pancreatic Cancer. JAMA Surg. 2018;153(12):e183617. doi:10.1001/jamasurg.2018.3617

Notably, after resection, patients with localized disease (Stage I-IIA) have a 27-39% 5-year survival, depending on the T-stage of the primary tumor (T1-T3). With the involvement of locoregional lymph nodes (Stage IIB and higher) or with locally advanced disease encroaching on the celiac axis, superior mesenteric artery, or common hepatic artery (T4), survival drops precipitously.

There are several criteria that aim to classify and guide whether pancreatic tumors are technically resectable, including the NCCN criteria[8], the American Hepatopancreatobiliary Association (AHPBA)/Society for Surgical Oncology (SSO)/Society for Surgery of the Alimentary Tract (SSAT) Consensus criteria[11], the Alliance  for Clinical Trials in Oncology criteria[12], and the MD Anderson criteria[13]. The NCCN criteria for resectability is the most widely used and is differentiated by the degree of arterial or venous involvement seen on contrast-enhanced CT imaging (Table 3).

Table 3. NCCN criteria defining resectability

Resectability StatusArterialVenous
ResectableNo arterial tumor contact with the celiac artery (CA), common hepatic artery (CHA), or superior mesenteric artery (SMA)No tumor contact with the superior mesenteric vein (SMV) or portal vein (PV) or 180° contact without vein contour irregularity
Borderline ResectablePancreatic head/uncinate process
• Solid tumor contact with the CHA without extension to the CA or HA
• Solid tumor contact with the SMA of 180°
• Solid tumor contact with variant arterial anatomy
Pancreatic body/tail
• Solid tumor contact with the CA of 180°
• Solid tumor contact with the CA of > 180° without involvement of the aorta or gastroduodenal artery
Solid tumor contact with the SMV or PV of > 180°

Solid tumor contact with the SMV or PV of 180° with contour irregularity or thrombosis but allowing for complete resection or reconstruction
Locally AdvancedPancreatic head/uncinate process
• Solid tumor contact with the SMA > 180°
• Solid tumor contact with the CA > 180°
Pancreatic body/tail
• Solid tumor contact of > 180° with the SMA or CA
• Solid tumor contact with the CA and aortic involvement
Unreconstructible SMV/PV due to tumor involvement or occlusion
Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic Adenocarcinoma V.1.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved.  The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the guideline, go online to NCCN.org. The NCCN guidelines are a work in progress that may be refined as often as new significant data becomes available.

Generally, ≤ 180° of solid tumor arterial contact (abutment) with the celiac artery (CA), superior mesenteric artery (SMA), or common hepatic artery (CHA), or > 180° of contact (encasement) of the superior mesenteric vein (SMV) or portal vein (PV) allowing for complete resection and reconstruction is considered borderline resectable (BR). Tumors with > 180° solid tumor contact with the CA, SMA, CHA, or unreconstructible SMV/PV involvement are deemed locally advanced (LA). Between each of these criteria and within the NCCN criteria itself, there are nuanced differences and exceptions to these generalizations.[14] Notably, the MD Anderson Criteria also incorporate additional “high risk” criteria, including a CA 19-9 of > 500 U/mL with a normal bilirubin and reversible/optimizable comorbidities as factors in the decision-making for resectable PDAC.

Current guidelines recommend induction chemotherapy prior to attempted resection for patients with BR or LA PDAC (see Treatment); however <50% of these patients will ultimately undergo resection.[15-18] Unfortunately, after chemotherapy radiographic imaging criteria as previously described may be unreliable and not predictive of intraoperative resectability.[19]


Surgery is the only potentially curative therapy for patients with PDAC; however, it is estimated that approximately 80% of patients will present with metastatic or locally unresectable disease due to vascular involvement. In addition to a thorough evaluation of preoperative imaging, physical performance status also helps determine candidacy for resection. For those patients who are not eligible for resection, treatment with chemotherapy, radiation, and/or pharmacologic and non-pharmacologic supportive care may be considered. All patients with PDAC may also benefit from a social work evaluation and nutritionist consultation.

Resectable Disease

Candidates for upfront resection must have evidence of resectable disease on imaging, as defined in Table 3, and an adequate performance status, as measured by either the Karnofsky or Eastern Cooperative Oncology Group (ECOG) performance status measures (Table 4). Contraindications to resection include metastatic disease, encasement or occlusion of the SMA, unreconstructable SMV or SMV-PV confluence occlusion, or direct involvement of the IVC, aorta, or celiac axis.

Table 4. Karnofsky and Eastern Cooperative Oncology Group performance status measures

While historically, vessel involvement was a contraindication to surgical intervention, some centers have demonstrated the feasibility of venous reconstruction for patients with focal tumor involvement of the SMV or PV.[20-22]

Data on this technique and associated outcomes remain heterogenous. Single center retrospective series have demonstrated similar morbidity and mortality in highly selected patients treated at high-volume institutions; conversely, Castleberry et al analyzed data from the American College of Surgeons National Surgical Quality Improvement Program database and observed higher rates of morbidity and mortality in patients who underwent vascular resection during pancreatectomy.[23,24]

Borderline or Locally Advanced Disease

For patients with BR or LA PDAC, the current NCCN guidelines recommend neoadjuvant chemotherapy with consideration of resection, dependent on disease progression or response.[8] The rationale for neoadjuvant therapy in this population includes the treatment of micro-metastatic disease, increased rates of margin-negative resection, more appropriate selection of patients who will ultimately benefit from resection, and an increased likelihood of chemotherapy receipt and compliance when given prior to surgery.

Metastatic Disease

For patients with metastatic disease at time of presentation, efforts should be focused on symptom palliation. These include palliative systemic chemotherapy, celiac plexus neurolysis and radiation therapy for pain management, stent placement for palliation of jaundice, and enteral stenting or surgical bypass for management of gastric outlet obstruction (see Palliative Surgery). Patients with metastatic disease may also benefit from intermittent paracentesis for management of ascites due to peritoneal metastases.

Preoperative Considerations

Despite advancements in imaging techniques, small-volume metastatic disease may be missed by conventional CT, MRI, or PET scans.[25] Initially missed metastatic disease, subsequently discovered on surgical exploration, has been reported in up to 8% of cases.[26]

Identification of occult metastases, defined as lesions < 1 cm in diameter not visualized on imaging, is critical for treatment planning as well as prognostication. Staging laparoscopy for the identification of occult metastases has been proposed in the following clinical scenarios: advanced vascular involvement, primary tumor > 3.0 cm, body or tail lesions without jaundice, CA 19-9 level > 1000 U/mL, or radiographic evidence of occult metastatic disease.

Another consideration prior to operative intervention is the utility and necessity of preoperative biliary drainage in patients with jaundice. The combination of PDAC and jaundice may theoretically predispose patients to coagulopathy and malabsorption, and by correcting jaundice, biliary drainage has been hypothesized to improve perioperative morbidity. However, the evidence for routine biliary drainage in the preoperative setting is discordant. Recent meta-analyses incorporating data from multiple randomized clinical trials, concluded that overall postoperative morbidity was higher in patients with preoperative drainage compared to patients without.[27,28]

As such, use of routine biliary drainage in clinical practice remains controversial. Many surgeons reserve biliary decompression for patients whose serum bilirubin exceeds 12 mg/dL, however, stents are often placed by gastroenterologists at time of initial endoscopy, prior to determination of resectability. Placement of a stent at this time may be preferred to minimize the need for a second endoscopic procedure for stenting if patients are deemed BR or LA with plans to receive induction chemotherapy. 


For patients with pancreatic head or uncinate tumors, the standard operation is pancreaticoduodenectomy, or Whipple’s procedure. For patients with pancreatic tail or body tumors, the standard approach is distal pancreatectomy with or without splenectomy. More central or extensive tumors may require a central pancreatectomy or total pancreatectomy, respectively. Enucleation may be used for small benign lesions of the pancreatic head, however, should not be used for malignant lesions or lesions > 2 cm.

The conventional Whipple’s procedure involves excision of the pancreatic head, common bile duct, duodenum, first 15 cm of jejunum, and gallbladder, with a partial gastrectomy. A pylorus-preserving Whipple’s procedure is an alternate approach, sparing the gastric antrum, pylorus and proximal 3-4 cm of the duodenum. The purported benefit of pylorus preservation is reduction in postoperative dumping and bile reflux gastritis, however studies comparing the two surgical approaches have had conflicting results.[29,30]A recent Cochrane review, including eight randomized controlled trials assessing pylorus-preserving versus classic pancreaticoduodenectomy, concluded that there were no major differences in morbidity, mortality and survival between the two cohorts.[31,32]

Lymphadenectomy is typically performed at the time of tumor resection. For patients with head or neck tumors, the key regional lymph node basins include those along the common bile duct, CHA, SMV, PV, and the pyloric, posterior and anterior pancreaticoduodenal arcades. Evaluation of at least 15 lymph nodes is recommended for adequate staging.[33] This recommendation is based on data from the SEER program from 1988-2002 which determined that 15 examined lymph nodes provided the optimal discrimination in survival between pN0 and pN1a; moreover, 90% of patients who would be considered pN1a were identified by examining 15 nodes.[33] The number of positive nodes is now included in staging, as part of the 8th edition of the AJCC cancer staging manual; N1 disease is defined as metastasis to 1-3 regional lymph nodes and N2 disease is defined as metastases to 4 nodes (Table 1).  

Postoperative management focuses on pain control, nutritional support, return of bowel function, and drain management. Studies evaluating oral feeding versus enteral feeding after a Whipple’s procedure have suggested that oral feeding is preferred when possible. Oral feeding has been associated with shorter hospitalization without increasing the risk or grade of postoperative pancreatic fistulas.[34]

Postoperative Morbidity and Mortality

Operative mortality after pancreatectomy has substantially improved over time.[35-37] While initially prohibitively high, with rates between 30-50%, advances in surgical technique and perioperative care have led to significant improvements.[38-41] Data from the National Cancer Database on 21,482 patients from 970 different hospitals between 2007-2010 reported a 30- and 90-day mortality rate of 3.7% and 7.4%, respectively.[37] Other contemporary single-institution series have reported 30-day mortality rates ranging from 1-5%.[42-44]

In addition to improved operative technique and perioperative care, improvements in mortality have also been attributed to regionalization of care over the last several decades. A volume-outcome relationship has been well-established for pancreatic surgery, with numerous studies observing improved outcomes in patients admitted to higher volume hospitals.[35,45-51] In one study using national Medicare claims data combined with the Nationwide Inpatient Sample, mortality rates after pancreatectomy at high volume hospitals was 3.8% compared to 17.6% in very low volume hospitals.[52] Mortality rates after pancreaticoduodenectomy have been reported as low as 1% in highly specialized centers with high-volume surgical expertise.[53]  While the definition of a high volume center is variable in the literature, it has been suggested that high-volume hepatobiliary surgeons perform at least 15 pancreaticoduodenectomies per year.[53]

While thirty-day surgical mortality has substantially improved over time, morbidity after pancreatectomy remains substantial and relatively unchanged, estimated to range between 30-50%.[54-58] The primary postoperative complications include delayed gastric emptying (DGE), postoperative pancreatic fistula (POPF), hemorrhage, and bile leak. The International Study Group for Pancreatic Surgery (ISGPS) has proposed several definitions to standardize reporting and improve classification of these complications.

Delayed Gastric Emptying

DGE after pancreatectomy is broadly defined as a functional gastroparesis, occurring in 14-61% of cases.[59-61] The wide range in incidence of DGE is in part due to variable definitions used in the literature. To address this heterogeneity, the ISGPS introduced a consensus definition and grading of DGE after pancreatic surgery. This definition divides DGE into grade A, B, and C, according to clinical features including nasogastric tube requirement, days of oral intolerance, vomiting, gastric distension and use of prokinetics (Table 5).[57]

Table 5. ISGPS Consensus Definition and Grading of Delayed Gastric Emptying after Pancreatic Surgery

GradeNGT RequirementDays of PO IntoleranceVomiting/Gastric DistensionUse of Prokinetics
A4-7 days or reinsertion > POD 37+/-+/-
B8-14 days or reinsertion > POD 714++
C>14 days or reinsertion > POD 1421++
Wente MN, Bassi C, Dervenis C, et al. Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery. 2007;142(5):761-768.

An upper gastrointestinal contrast series or endoscopy can be used to rule out mechanical obstruction in symptomatic patients. A history of prior abdominal surgery and preoperative diabetes mellitus are risk factors for development of DGE postoperatively, however the etiology in most patients remains unknown.[62]

A Cochrane review comparing the effectiveness of antecolic and retrocolic reconstruction after partial pancreaticoduodenectomy found no significant differences in rates of DGE (OR 0.60; 95% CI 0.31 to 1.18; P = 0.14).[32] Management of DGE is supportive and includes nasogastric decompression and use of prokinetic agents to improve symptoms. Parenteral nutrition or enteral nutrition through an existing jejunostomy tube can be considered after 7-10 days of oral intolerance.

Pancreatic Fistula

POPF occur in 3-45% of pancreatic resections.[63-67] Similar to DGE after pancreatectomy, the heterogeneity in published rates of POPF may be due to the variable definitions used in the literature. A consensus definition introduced in 2005 by the International Study Group of Pancreatic Fistula [ISGPF], characterized POPF as drain output of any measurable volume of fluid on or after postoperative day 3 with an amylase content greater than 3 times the serum amylase activity.[68]

The complication was graded A-C based on clinical severity, taking into consideration imaging results, supportive treatments, persistent drainage, sepsis, reoperation, readmission rates, and death. This definition was updated in 2016 to the following: “a drain output of any measurable volume of fluid with an amylase level >3 times the upper limit of institutional normal serum amylase activity, associated with a clinically relevant development/condition related directly to the postoperative pancreatic fistula” (Table 6).[67]

Table 6. Revised 2016 ISGPS Classification and Grading of Postoperative Pancreatic Fistula after Pancreatic Surgery: Checklist for Clinical Use

EventBL (No POPF)Grade B POPFGrade C POPF
Increased amylase activity > 3 times upper limit institutional normalYESYESYES
Persisting peripancreatic drainage > 3 weeksNOYESYES
Clinically relevant change in management of POPFNOYESYES
POPF percutaneous or endoscopic specific interventionsNOYESYES
Angiographic procedures for POPF related bleedingNOYESYES
Reoperation for POPFNONOYES
Signs of infection related to POPFNOYES, without organ failureYES, with organ failure
POPF related organ failureNONOYES
POPF related deathNONOYES
Bassi C, Marchegiani G, Dervenis C, et al. The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 Years After. Surgery. 2017;161(3):584-591.

Grade A POPF are now referred to as biochemical leaks; grade B POPF require a change in postoperative management; and grade C POPF require reoperation or lead to organ failure and/or death. Risk factors for development of POPF include higher patient body mass index, soft pancreas, small pancreatic duct, high operative blood loss, and prolonged operative time.[69]

Management of uncomplicated, low-volume fistulas includes percutaneous drainage of intra-abdominal collections, nutritional support, and restriction of oral intake. Patients with clinical instability or signs of sepsis and/or organ failure may require reoperation.


Post-pancreatectomy hemorrhage occurs after approximately 1-8% of resections.[54,70,71] A consensus definition of hemorrhage was introduced by the ISGPS in 2006.[70] Early hemorrhage is classified as bleeding within 24 hours of surgery and late hemorrhage occurs any time after 24 hours. Bleeding is further characterized by location and severity. The proposed grading scale includes grade A (early, mild bleeding), B (early, severe bleeding or late mild bleeding), and C (late, severe bleeding) (Table 7).

Table 7. ISGPS Proposed Classification of Post-Pancreatectomy Hemorrhage

GradeTime of onset, location, severity and clinical impact of bleedingClinical conditionDiagnostic consequenceTherapeutic consequence
AEarly, intra- or extraluminal, mildWellObservation, blood count, ultrasonography and, if necessary, computed tomographyNo
BEarly, intra- or extraluminal, severeLate, intra- or extraluminal, mildOften well/ intermediate, very rarely life-threateningObservation, blood count, ultrasonography, computed tomography, angiography, endoscopy†Transfusion of fluid/blood, intermediate care unit (or ICU), therapeutic endoscopy, embolization, relaparotomy for early PPH
CLate, intra- or extraluminal, severeSeverely impaired, life-threateningAngiography, computed tomography, endoscopyLocalization of bleeding, angiography and embolization, (endoscopyor relaparotomy, ICU
Wente MN, Veit JA, Bassi C, et al. Postpancreatectomy hemorrhage (PPH): an International Study Group of Pancreatic Surgery (ISGPS) definition. Surgery. 2007;142(1):20-25.

The etiology of hemorrhage is variable. Early hemorrhage is often due to inadequate intraoperative hemostasis, whereas late hemorrhage may be secondary to the development of arterial pseudoaneurysms, most commonly at the gastroduodenal artery stump. Localization of bleeding with angiography and embolization is recommended when possible.

Bile Leaks

Bile leaks after pancreatectomy are rare, occurring in less than 4% of patients at high-volume institutions.[72] Risk factors for bile leaks include small common bile duct diameter, poor nutritional status, POPF, and DGE. Three different classification systems have been reported in the literature to characterize degree of bile leakage after pancreatectomy.[73-75]

The International Study Group of Liver Surgery defined bile leakage in 2011 as a drain bilirubin concentration of at least 3 times the serum bilirubin concentration on or after postoperative day 3. Patients who require intervention for management of biliary collections or bile peritonitis may also be deemed to have a postoperative bile leak. Similar to POPF, the grading system for bile leaks is as follows: Grade A causes no change in a patient’s clinical management; Grade B requires therapeutic intervention and Grade C bile leaks require laparotomy. These complications are primarily managed conservatively with continued drainage.


Neoadjuvant Chemotherapy

The role of neoadjuvant chemotherapy in patients with upfront resectable disease is evolving, although no clear consensus currently exists. The rationale for using neoadjuvant therapy is to improve rates of margin-negative (R0) resections, improve long term survival, and maximize delivery and receipt of chemotherapy, as prolonged operative recovery often prevents eligibility for adjuvant therapy. While updated NCCN guidelines suggest that patients with high-risk tumors (defined as those with concerning imaging findings, elevated CA19-9 levels, and/or large tumors or regional lymph nodes) may benefit from neoadjuvant therapy, ASCO guidelines suggest that patients with resectable disease should not be offered neoadjuvant treatment, in the absence of mesenteric vessel involvement.[77]

The feasibility and efficacy of neoadjuvant therapy for patients with resectable PDAC has been investigated in multiple single-center series. In one small European study of 28 patients with resectable PDAC, an R0 resection was obtained in 80% of patients who received neoadjuvant gemcitabine and cisplatin.[78] A more recent meta-analysis, evaluating 38 studies and including resectable and BR PDAC, found that neoadjuvant treatment may improve overall survival despite lower resection rates.[79]

For patients with BR disease, use of neoadjuvant therapy has been popularized as a method to downstage tumors and control micro-metastatic disease, with the ultimate goal of resection when possible. FOLFIRINOX-based regimens have been demonstrated to be well-tolerated in patients with BR PDAC. In a pilot study of 23 patients with BR PDAC, patients received modified FOLFIRINOX followed by external-beam radiation with capecitabine prior to pancreatectomy. A total of 68% of patients underwent pancreatectomy, of which 93% had negative margins and 13% had pathologic complete response, and the median overall survival was 21.7 months.[80]

Subsequently, a phase II clinical trial by Murphy et al in 2018 evaluated neoadjuvant FOLFIRINOX followed by individualized chemoradiotherapy for BR PDAC, with an R0 resection rate of 97% in patients who underwent resection and a median survival of 37.7 months.[81] The recently published PREOPANC-1 randomized phase III trial evaluated preoperative gemcitabine-based chemoradiotherapy versus immediate surgery for resectable and BR PDAC. While this trial found no significant benefit in overall survival for patients treated with preoperative chemoradiotherapy (16.0 months with preoperative chemoradiotherapy vs. 14.3 months with immediate surgery; HR, 0.78; 95% CI, 0.58-1.05; p=0.096), secondary endpoints, including R0 resection rate, recurrence-free survival, and locoregional failure-free interval favored the receipt of neoadjuvant treatment. On subgroup analysis, patients with BR PDAC in the neoadjuvant arm had a higher negative margin rate (R0, 79% vs. 13%; p<0.001) and better median overall survival (17.6 vs. 13.2 months; p=0.029).[82] Trials are ongoing to assess the role of neoadjuvant therapy in this setting, however these preliminary results are promising.

Similar to those with BR disease, patients with LA PDAC have also been shown to benefit from the use of neoadjuvant therapy. A retrospective study from Memorial Sloan Kettering Cancer Center evaluating patients with LA PDAC who received induction FOLFIRINOX observed that 23% of patients developed distant metastases, 15% underwent resection, and 63% proceeded to chemoradiation at the time of initial restaging.[83] Of those who underwent chemoradiation, 16% of patients underwent resection, while 5% had progression to metastatic disease. The median overall survival for patients who progressed on FOLFIRINOX was 11 months, compared to 26 months in patients without progression. A subsequent single-arm phase II clinical trial evaluating patients with LA PDAC receiving FOLFIRINOX and losartan for 8 cycles followed by short-course chemoradiotherapy with capecitabine or long-course chemoradiotherapy with 5-FU or capecitabine reported an R0 resection rate of 61%, overall median progression-free survival of 17.5 months, and median survival of 31.4 months.[84]

Currently, the standard neoadjuvant chemotherapeutic regimens include FOLFIRINOX-based regimens or gemcitabine-based regimens. FOLFIRINOX is administered in 14-day cycles of 85 mg/m2 oxaliplatin, 400 mg/m2 leucovorin, 180 mg/m2 irinotecan and a 400 mg/m2 5-fluorouracil bolus followed by 2,400 mg/m2 infusion over 46 hours. Modified FOLFIRINOX offers a similar regimen without the 5-fluorouracil bolus. Gemcitabine (1,000 mg/m2) and N-albumin-bound (nab) paclitaxel (125 mg/m2) is administered biweekly for 4 weeks. While the optimal duration of treatment prior to surgery has not been established, 3 months of therapy is often offered prior to interval re-staging.

Adjuvant Chemotherapy

The use of adjuvant chemotherapy has been demonstrated to improve survival for patients with resectable PDAC. The benefit of adjuvant chemotherapy was first demonstrated in the ESPAC-1 trial, which included 541 patients who were randomized to postoperative treatment in one of three parallel studies: adjuvant chemoradiotherapy versus no chemoradiotherapy, adjuvant chemotherapy versus no chemotherapy, and a two-by-two factorial design trial with four groups. This demonstrated a significant survival benefit for adjuvant chemotherapy alone but no survival benefit for adjuvant chemoradiotherapy.[85]

The subsequent CONKO-001 trial observed a survival benefit for adjuvant gemcitabine monotherapy in patients with R0 or R1 resections.[86] A recent randomized clinical trial, assessing modified FOLFIRINOX versus gemcitabine as adjuvant therapy for patients with resected PDAC, concluded that modified FOLFIRINOX led to a significantly longer survival than gemcitabine, although with higher toxic side effects.[87] In light of these results, currently, for patients with good functional and performance status, adjuvant modified FOLFIRINOX (85 mg/m2 oxaliplatin, 400 mg/m2 leucovorin, 150 mg/m2 irinotecan, and 2400 mg/m2 5-fluorouracil infusion over 46 hours, every 14 days for 12 cycles) may be preferable. Alternatively, gemcitabine plus capecitabine (1,660 mg/m2/day on days 1-21 every 4 weeks), gemcitabine plus nab-paclitaxel, gemcitabine monotherapy, or 5-fluorouracil and leucovorin may be offered for patients who do not tolerate other regimens due to side effects.

Systemic Chemotherapy for Metastatic Disease

Patients who present with metastatic disease should be considered for clinical trial enrollment or palliative systemic chemotherapy. Selection of chemotherapeutic agents for metastatic disease have evolved with novel data regarding efficacy, survival, and toxicity. Results from the ACCORD 11 trial established FOLFIRINOX as the treatment standard over gemcitabine monotherapy for patients with good performance status, no cardiac ischemia and normal bilirubin levels. In this trial, 342 patients with metastatic PDAC were assigned to receive gemcitabine or FOLFIRINOX. Response rate (32% versus 9%), median progression-free survival (6.4 versus 3.3 months) and overall survival (11.1 versus 6.8 months) were all significantly higher with FOLFIRINOX.[88]

For patients who cannot tolerate FOLFIRINOX, gemcitabine monotherapy has been compared to gemcitabine combination therapy, including nab-paclitaxel, 5-FU, cisplatin, oxaliplatin, irinotecan, and docetaxel. Despite multiple randomized trials evaluating these gemcitabine-based treatment combinations, combined therapy with nab-paclitaxel is the only regimen associated with a significant survival benefit.[89]

Currently, for patients with metastatic disease, good performance status, and serum total bilirubin level less than 1.5 times the upper limit of normal, FOLFIRINOX therapy is preferred. Gemcitabine plus nab-paclitaxel is an acceptable alternative for patients who do not tolerate FOLFIRINOX or experience progression of disease despite FOLFIRINOX. For patients with ECOG performance status 2, monotherapy with gemcitabine alone is preferred. For patients with elevated serum bilirubin despite stent placement, other regimens, such as FOLFOX, may be advisable, given toxicity of gemcitabine in patients with impaired hepatic clearance. After at least 4-6 months of systemic chemotherapy, patients without evidence of disease progression may be considered for maintenance therapy. For patients with germline BRCA1/2 mutations, olaparib was recently approved by the Food and Drug Administration (FDA) for maintenance treatment, based on results from the POLO trial which established improved progression-free survival in patients on maintenance olaparib versus placebo.[90]

For patients with metastatic PDAC, genomic testing and tissue profiling is now routinely recommended. Understanding the genomic landscape of these tumors is critical for treatment planning and selection. Information regarding BRCA mutations, deficient mismatch repair (dMMR) or microsatellite instability (MSI-H) may help guide treatment selection for patients with metastatic PDAC. For example, the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab has been approved as second-line therapy in patients with dMMR or MSI-H.

Radiation Therapy

The role of radiation therapy (RT) for management of PDAC remains unclear. The goal of delivering RT is to improve the likelihood of a margin-negative resection, sterilize vessel margins in the context of an R1 resection, and improve locoregional disease control both postoperatively, and in the case of unresectable disease. RT has also been suggested as a palliative treatment option for the management of pain or bleeding in patients with progressive disease.

While chemoradiotherapy has been demonstrated to improve R0 resection rates in patients with BR disease, a survival benefit from chemoradiotherapy versus chemotherapy alone has been difficult to demonstrate.[91,92,93] Furthermore, concerns regarding toxicity have limited wide adoption of RT for management of PDAC.[94] The American Society for Radiation Oncology published guidelines for RT in the management of PDAC in 2019[95], which conditionally recommend adjuvant fractionated RT with chemotherapy in high risk patients, including those with positive lymph nodes and margins. For patients with BR or LA PDAC, neoadjuvant systemic chemotherapy followed by conventionally fractionated RT is conditionally recommended based on moderate quality evidence. While data regarding the type and dosing of RT are currently limited by low quality evidence, trials assessing the role of RT for patients with PDAC are ongoing.

Use of intraoperative radiation therapy (IORT) has also been considered for patients with BR PDAC, although the indications remain unclear. IORT theoretically allows for the delivery of high-dose treatment without the toxicity of irradiating adjacent normal tissue. Data from over 30 years at Massachusetts General Hospital observed that in well-selected patients with LA PDAC, small tumors, and low Charlson-Deyo comorbidity indices, IORT can improve long-term outcomes.[96] Despite these data, a systematic review concluded that IORT was not more effective than other therapies for management of LA PDAC.[97]

Palliative Surgery

For patients with gastric outlet obstruction from advanced PDAC, surgical bypass or enteral stenting may be considered. Duodenal stent placement may be preferred for patients with advanced disease and short anticipated life expectancy. The surgical alternative, gastrojejunostomy, provides more long-term relief of obstruction and may be considered in appropriate surgical candidates.


Most patients with PDAC will die of cancer-related causes. For all patients, tumor stage appears to be the most important prognostic factor. For those who undergo resection, the most important prognostic factor is nodal status. Patients with node-positive disease have been found to have a 10% five-year survival following pancreaticoduodenectomy, compared to 30% for patients with node-negative disease.[98,99] Other factors that may modulate prognosis include surgical margin status for resected patients, lymphovascular invasion on pathology specimen, preoperative and postoperative CA 19-9, and lifestyle factors such as smoking.


The primary goal of surveillance after curative therapy is to detect recurrence. A standardized clinical and radiographic surveillance strategy has been demonstrated to capture 55% of recurrent PDAC prior to onset of symptoms.[100] While recommendations for post-treatment surveillance differ based on the guidelines in question, the consensus-based NCCN guidelines recommend history and physical examination, laboratory evaluation including CA 19-9 and follow up CT scans every 3-6 months for two years and then every 6-12 months. While elevation in the CA 19-9 prompts CT imaging, as an elevated post-treatment CA 19-9 level may be associated with recurrence, it must be noted that mild elevations of CA 19-9 may be due to expected biliary tract dysfunction after resection.

After surgical treatment, the majority of recurrences occur within 2 years and may be present at local or distant sites. In a retrospective analysis of 145 consecutive resections for PDAC, the majority of recurrences were found to be extra-pancreatic and in the abdominal cavity. In this study, the type of cancer recurrence did not significantly influence overall survival, however status of resection margins was identified as a negative prognostic factor.[101] 


The feasibility of resection is partially dependent on preoperative resectability criteria, which take into consideration the primary tumor and involvement of local vessels. These criteria have evolved over time, owing to advances in surgery and neoadjuvant therapy. Multiple guidelines for classification currently exist to assist clinicians in determining resectability (see Staging). As these definitions are variable, there is often ambiguity in patient classification, particularly for patients with BR or LA disease. Recent data further suggest that the BR and LA distinction may not significantly affect survival.[102]

There appears to be a continuum between resectable and LA unresectable disease, making clinical adherence to classification schemes difficult. As accurate staging is critical for treatment planning as well as research and clinical trial enrollment, treatment decisions are often based on multidisciplinary discussion.

Summary and Recommendations

Despite improvements in chemotherapy and novel therapeutic options, pancreatic cancer remains a highly lethal disease process with dismal prognosis for most patients. While curative, surgery is limited to patients with resectable disease. Ongoing efforts to improve early cancer detection and improve cancer-related mortality are indicated for patients with PDAC.


  • AHPBA: American Hepatopancreatobiliary Association
  • AJCC: American Joint Committee on Cancer
  • BR: borderline resectable
  • CA 19-9: carbohydrate antigen 19-9
  • CAPS: Cancer of the Pancreas Screening Consortium
  • CA: celiac artery
  • CHA: common hepatic artery
  • CT: computed tomography
  • DGE: delayed gastric emptying
  • DM: diabetes mellitus
  • EUS: endoscopic ultrasound
  • ERCP: endoscopic retrograde cholangiopancreatography
  • FDR: first degree relative
  • FNA: fine needle aspiration
  • HNPCC: hereditary non-polyposis colorectal cancer
  • IORT: intraoperative radiation therapy
  • ISGPS: International Study Group of Pancreatic Surgery
  • LA: locally advanced
  • MRI: magnetic resonance imaging
  • NCCN: National Comprehensive Cancer Network
  • PDAC: pancreatic ductal adenocarcinoma
  • PET: positron emission tomography
  • PNET: pancreatic neuroendocrine tumor
  • PV: portal vein
  • RT: radiation therapy
  • SEER: Surveillance, Epidemiology, and End Results
  • SMA: superior mesenteric artery
  • SMV: superior mesenteric vein
  • SSAT: Society for Surgery of the Alimentary Tract
  • SSO: Society for Surgical Oncology
  • USPTF: United States Preventive Services Task Force


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