Elsevier

The Lancet

Volume 378, Issue 9791, 13–19 August 2011, Pages 607-620
The Lancet

Seminar
Pancreatic cancer

https://doi.org/10.1016/S0140-6736(10)62307-0Get rights and content

Summary

Substantial progress has been made in our understanding of the biology of pancreatic cancer, and advances in patients' management have also taken place. Evidence is beginning to show that screening first-degree relatives of individuals with several family members affected by pancreatic cancer can identify non-invasive precursors of this malignant disease. The incidence of and number of deaths caused by pancreatic tumours have been gradually rising, even as incidence and mortality of other common cancers have been declining. Despite developments in detection and management of pancreatic cancer, only about 4% of patients will live 5 years after diagnosis. Survival is better for those with malignant disease localised to the pancreas, because surgical resection at present offers the only chance of cure. Unfortunately, 80–85% of patients present with advanced unresectable disease. Furthermore, pancreatic cancer responds poorly to most chemotherapeutic agents. Hence, we need to understand the biological mechanisms that contribute to development and progression of pancreatic tumours. In this Seminar we will discuss the most common and deadly form of pancreatic cancer, pancreatic ductal adenocarcinoma.

Section snippets

Epidemiology

Pancreatic cancer is the fourth leading cause of cancer death in the USA and leads to an estimated 227 000 deaths per year worldwide.1 Risk factors for this malignant disease include smoking, family history2 of chronic pancreatitis, advancing age, male sex, diabetes mellitus, obesity, non-O blood group,3, 4 occupational exposures (eg, to chlorinated hydrocarbon solvents and nickel),5 African-American ethnic origin, a high-fat diet, diets high in meat and low in vegetables and folate, and

Pathophysiology

Pancreatic ductal adenocarcinomas evolve through non-invasive precursor lesions, most typically pancreatic intraepithelial neoplasias (figure 1, panel 2), acquiring clonally selected genetic and epigenetic alterations along the way (figure 2). Pancreatic cancers can also evolve from intraductal papillary mucinous neoplasms (figure 3) or mucinous cystic neoplasms (panel 2).

The exomes of 24 pancreatic ductal adenocarcinomas were sequenced to characterise more fully the genes mutated in pancreatic

Screening to detect curable precursor lesions

The deadly nature of invasive pancreatic cancer, and recognition that most patients present with advanced stage disease,73 has led to efforts to screen individuals with an inherited predisposition for early curable disease—such as pancreatic intraepithelial neoplasias, and non-invasive intraductal papillary mucinous neoplasms and mucinous cystic neoplasms. Family history has been used as a quantitative predictor of pancreatic cancer risk.2, 10, 30, 31, 32, 74 Indeed, screening has identified

Clinical presentation

Early-stage pancreatic cancer is usually clinically silent, and disease only becomes apparent after the tumour invades surrounding tissues or metastasises to distant organs. Most people who present with symptoms attributable to pancreatic cancer have advanced disease.81 Pancreatic cancer patients who have undergone abdominal CT scans for other reasons before their diagnosis are usually noted in retrospect to have had subtle abnormalities suspicious for pancreatic cancer up to 1 year before

Diagnosis and staging

Tri-phasic pancreatic-protocol CT is the best initial diagnostic test for pancreatic cancer. It is also best for disease staging, and optimum CT scans—including 3-dimensional reconstruction—provide about 80% accuracy for prediction of resectability. The quality of CT varies, and imaging technology continues to improve. The ability of high-quality pancreatic-protocol CT scans to detect locally advanced and metastatic disease reliably has greatly reduced the number of unnecessary laparotomies and

Principles of management

Patients with pancreatic cancer are best managed by a multidisciplinary team that includes oncologists, surgeons, radiologists, gastroenterologists, radiation oncologists, pathologists, pain management experts, social workers, dietitians, and (when appropriate) palliative care experts.92 Pancreatic cancer is a heterogeneous disease at the molecular, pathological, and clinical level. A patient's response to treatment and outcome depends on many factors, including the biology of their cancer,

Surgery

Operative mortality from pancreatic resection is low at most expert centres.93 Findings of several studies show that mortality from pancreaticoduodenectomy is considerably lower in high-volume compared with low-volume centres. For this reason, consensus panels recommend that pancreaticoduodenectomy should be undertaken at institutions doing at least 15–20 of these operations a year. Furthermore, many candidates for curative resection do not undergo surgical resection.94, 95 Postoperative

Pathological findings after surgery

Pathological assessment of the resected pancreatic tumour provides important prognostic information. The pathologist must ascertain if the surgeon has achieved a negative (R0) resection margin. An R1 margin is positive at the microscopic level but not grossly visible, and an R2 resection has grossly visible cancer at the resection margin. Standardised protocols for establishing margin status pathologically are not available, resulting in variability in assessment of margin status. One change in

Adjuvant therapy

Adjuvant treatment is recommended for individuals who undergo pancreatic resection with curative intent.104 It is generally given once patients have recovered from surgery (1–2 months). Baseline CT scans and CA19-9 concentrations should be obtained before initiation of adjuvant treatment. The benefit of this therapy has been established from findings of randomised controlled trials (GITSG,105 CONKO-001,106 and RTOG-9704)107 and retrospective studies.108, 109, 110, 111 In the GITSG trial,

Management of borderline resectable disease

Resections are attempted in many patients with borderline resectable cancer (ascertained by clinical staging) if the clinician suspects that an R0 resection can be achieved. Optimum preoperative staging can target individuals who should undergo initial chemoradiotherapy rather than surgery.92, 119 The regimens used for adjuvant and neoadjuvant chemoradiotherapy are those typically administered to patients with borderline resectable disease. In an uncontrolled study of individuals with

Management of advanced disease

Survival is significantly better for patients with locally advanced disease (median survival 9–15 months) than for those with metastatic disease (3–6 months). Chemotherapy is the mainstay of treatment for individuals with advanced disease—provided they have adequate performance status—but is not helpful for those with poor performance status. Gemcitabine is standard for patients with advanced pancreatic cancer: it induces a partial response in a few people and can alleviate symptoms in some

Measurement of tumour response

CT is the standard method for measurement of tumour burden, and clinical trials usually use RECIST (response evaluation criteria in solid tumours) criteria to gauge tumour response. However, CT-based measurements of tumour size do not always quantify treatment response accurately and are usually only established after two cycles of treatment, which is a long time for patients with low survival. Although not sufficiently accurate for diagnosis, serial CA19-9 concentrations predict treatment

Investigational treatments for advanced pancreatic cancer

The success of targeted treatments in other cancers supports the need for further research to identify new targets and better predictors of response to therapy. Several targeted agents are undergoing clinical trials for pancreatic cancer.143, 144 Ongoing studies are shown in the webappendix (p 3).

Pancreatic cancer cells with defects in the BRCA2-PALB2-Fanconi DNA repair pathway are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors.53, 54 PARP enzymes add large branched chains of poly

Supportive care

Findings show that palliative care can help patients even as they are undergoing treatment for advanced disease.147 Supportive care begins with provision of support and information from the time of diagnosis and the appropriate amount of hope for the patient's stage of disease.148

Pain management is an important component of treatment. Identification of the cause of pain can guide effective therapy. Pain from coeliac plexus infiltration can be treated effectively with endoscopic ultrasound or

Search strategy and selection criteria

We searched ISI Web of Science for articles in English from the past 6 years (since the previous Seminar about pancreatic cancer was published in The Lancet in 2004), with the keyword “pancreatic cancer” as a topic, generated a citation report, and prioritised papers on the basis of citations and clinical or biological importance. We also included important papers published before 2004. Because of space limitations, many important references could not be included.

References (150)

  • N Sato et al.

    Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers

    Gastroenterology

    (2006)
  • MA Parsi et al.

    DNA methylation alterations in endoscopic retrograde cholangiopancreatography brush samples of patients with suspected pancreaticobiliary disease

    Clin Gastroenterol Hepatol

    (2008)
  • ML Disis et al.

    Use of tumour-responsive T cells as cancer treatment

    Lancet

    (2009)
  • ME Caldwell et al.

    Finding and killing the CRABs of pancreatic cancer

    Gastroenterology

    (2009)
  • DP Kelsen et al.

    Pain as a predictor of outcome in patients with operable pancreatic carcinoma

    Surgery

    (1997)
  • R Pannala et al.

    Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus

    Gastroenterology

    (2008)
  • ST Chari et al.

    Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer

    Gastroenterology

    (2008)
  • ST Chari et al.

    Probability of pancreatic cancer following diabetes: a population-based study

    Gastroenterology

    (2005)
  • R Pannala et al.

    New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer

    Lancet Oncol

    (2009)
  • R White et al.

    Current utility of staging laparoscopy for pancreatic and peripancreatic neoplasms

    J Am Coll Surg

    (2008)
  • GC Harewood et al.

    Endosonography-guided fine needle aspiration biopsy in the evaluation of pancreatic masses

    Am J Gastroenterol

    (2002)
  • NA Newman et al.

    Preoperative endoscopic tattooing of pancreatic body and tail lesions decreases operative time for laparoscopic distal pancreatectomy

    Surgery

    (2010)
  • S Raimondi et al.

    Epidemiology of pancreatic cancer: an overview

    Nat Rev Gastroenterol Hepatol

    (2009)
  • AP Klein et al.

    Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds

    Cancer Res

    (2004)
  • L Amundadottir et al.

    Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

    Nat Genet

    (2009)
  • BM Wolpin et al.

    ABO blood group and the risk of pancreatic cancer

    J Natl Cancer Inst

    (2009)
  • IA Ojajärvi et al.

    Occupational exposures and pancreatic cancer: a meta-analysis

    Occup Environ Med

    (2000)
  • A Blackford et al.

    Genetic mutations associated with cigarette smoking in pancreatic cancer

    Cancer Res

    (2009)
  • GM Petersen et al.

    Pancreatic cancer genetic epidemiology consortium

    Cancer Epidemiol Biomarkers Prev

    (2006)
  • KA Brune et al.

    Importance of age of onset in pancreatic cancer kindreds

    J Natl Cancer Inst

    (2010)
  • C Shi et al.

    Increased prevalence of precursor lesions in familial pancreatic cancer patients

    Clin Cancer Res

    (2009)
  • L Wang et al.

    Elevated cancer mortality in the relatives of patients with pancreatic cancer

    Cancer Epidemiol Biomarkers Prev

    (2009)
  • C Shi et al.

    Familial pancreatic cancer

    Arch Pathol Lab Med

    (2009)
  • KM Murphy et al.

    Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%

    Cancer Res

    (2002)
  • SA Hahn et al.

    BRCA2 germline mutations in familial pancreatic carcinoma

    J Natl Cancer Inst

    (2003)
  • FJ Couch et al.

    The prevalence of BRCA2 mutations in familial pancreatic cancer

    Cancer Epidemiol Biomarkers Prev

    (2007)
  • M Goggins et al.

    Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas

    Cancer Res

    (1996)
  • S Jones et al.

    Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene

    Science

    (2009)
  • EP Slater et al.

    PALB2 mutations in European familial pancreatic cancer families

    Clin Genet

    (2010)
  • H Farmer et al.

    Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy

    Nature

    (2005)
  • HE Bryant et al.

    Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase

    Nature

    (2005)
  • MS van der Heijden et al.

    In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor

    Clin Cancer Res

    (2005)
  • MC Villarroel et al.

    Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer

    Mol Cancer Ther

    (2011)
  • F Kastrinos et al.

    Risk of pancreatic cancer in families with Lynch syndrome

    JAMA

    (2009)
  • GM Petersen et al.

    A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33

    Nat Genet

    (2010)
  • W Wang et al.

    PancPRO: risk assessment for individuals with a family history of pancreatic cancer

    J Clin Oncol

    (2007)
  • RH Hruban et al.

    Progression model for pancreatic cancer

    Clin Cancer Res

    (2000)
  • RH Hruban et al.

    Update on pancreatic intraepithelial neoplasia

    Int J Clin Exp Pathol

    (2008)
  • K Brune et al.

    Detailed pathologic evaluation of non-invasive precursor lesions of the pancreas in patients with a strong family history of pancreatic cancer

    Am J Surg Pathol

    (2006)
  • H Matsubayashi et al.

    DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease

    Cancer Res

    (2006)
  • Cited by (2123)

    • Natural products targeting the MAPK-signaling pathway in cancer: overview

      2025, Journal of Cancer Research and Clinical Oncology
    View all citing articles on Scopus
    View full text