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.
SeminarPancreatic cancer
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
References (150)
- et al.
Antidiabetic therapies affect risk of pancreatic cancer
Gastroenterology
(2009) - et al.
Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer
Gastroenterology
(2009) - et al.
Physician assessment of family cancer history and referral for genetic evaluation in colorectal cancer patients
Clin Gastroenterol Hepatol
(2004) - et al.
Screening for pancreatic neoplasia in high risk individuals
Clin Gastroenterol Hepatol
(2004) - et al.
Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study
Clin Gastroenterol Hepatol
(2006) - et al.
High prevalence of pancreatic cysts detected by screening magnetic resonance imaging examinations
Clin Gastroenterol Hepatol
(2010) - et al.
International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas
Pancreatology
(2006) - et al.
Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia
Am J Pathol
(2002) - et al.
Trp53(R172H) and KraS(G12D) cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice
Cancer Cell
(2005) - et al.
CpG island methylation profile of pancreatic intraepithelial neoplasia
Mod Pathol
(2008)
Differential and epigenetic gene expression profiling identifies frequent disruption of the RELN pathway in pancreatic cancers
Gastroenterology
DNA methylation alterations in endoscopic retrograde cholangiopancreatography brush samples of patients with suspected pancreaticobiliary disease
Clin Gastroenterol Hepatol
Use of tumour-responsive T cells as cancer treatment
Lancet
Finding and killing the CRABs of pancreatic cancer
Gastroenterology
Pain as a predictor of outcome in patients with operable pancreatic carcinoma
Surgery
Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus
Gastroenterology
Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer
Gastroenterology
Probability of pancreatic cancer following diabetes: a population-based study
Gastroenterology
New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer
Lancet Oncol
Current utility of staging laparoscopy for pancreatic and peripancreatic neoplasms
J Am Coll Surg
Endosonography-guided fine needle aspiration biopsy in the evaluation of pancreatic masses
Am J Gastroenterol
Preoperative endoscopic tattooing of pancreatic body and tail lesions decreases operative time for laparoscopic distal pancreatectomy
Surgery
Epidemiology of pancreatic cancer: an overview
Nat Rev Gastroenterol Hepatol
Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds
Cancer Res
Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer
Nat Genet
ABO blood group and the risk of pancreatic cancer
J Natl Cancer Inst
Occupational exposures and pancreatic cancer: a meta-analysis
Occup Environ Med
Genetic mutations associated with cigarette smoking in pancreatic cancer
Cancer Res
Pancreatic cancer genetic epidemiology consortium
Cancer Epidemiol Biomarkers Prev
Importance of age of onset in pancreatic cancer kindreds
J Natl Cancer Inst
Increased prevalence of precursor lesions in familial pancreatic cancer patients
Clin Cancer Res
Elevated cancer mortality in the relatives of patients with pancreatic cancer
Cancer Epidemiol Biomarkers Prev
Familial pancreatic cancer
Arch Pathol Lab Med
Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%
Cancer Res
BRCA2 germline mutations in familial pancreatic carcinoma
J Natl Cancer Inst
The prevalence of BRCA2 mutations in familial pancreatic cancer
Cancer Epidemiol Biomarkers Prev
Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas
Cancer Res
Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene
Science
PALB2 mutations in European familial pancreatic cancer families
Clin Genet
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Nature
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Nature
In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor
Clin Cancer Res
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
Risk of pancreatic cancer in families with Lynch syndrome
JAMA
A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33
Nat Genet
PancPRO: risk assessment for individuals with a family history of pancreatic cancer
J Clin Oncol
Progression model for pancreatic cancer
Clin Cancer Res
Update on pancreatic intraepithelial neoplasia
Int J Clin Exp Pathol
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
DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease
Cancer Res
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