pancreatic cancer
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Etiology
- ductal adenocarcinoma 90%
- endocrine neoplasms
- connective tissue neoplasm
- acinar cell neoplasm
- epidermoid neoplasm
- mixed cell tumors
- risk factors:
- diabetes mellitus type 2
- 10 mg/dL increase in fasting blood glucose associated with 14% increase in risk of pancreatic cancer[15]
- chronic pancreatitis*
- hereditary pancreatitis
- carcinogens
- benzidine
- cigarette smoking
- alcohol
- high-fat diet
- early adult obesity or excess weight[6]
- age >=50 years
- intraductal papillary mucinous neoplasms[3]
- intestinal infection with Malassezia[25]
- diabetes mellitus type 2
* regular aspirin use associated with reduced risk (RR=0.52)[14]; each year of low-dose aspirin associated with reduced risk (RR=0.94); speculation that effect of aspirin may be due to inhibition of COX2[14]
* dihydropyridine calcium channel blockers do not increase risk of pancreatic cancer[33]
Epidemiology
- more common in men than women
- generally presents between ages 60-80
- 4th leading cause of cancer death in USA[5]; 3rd leading cause of cancer death[29]
Pathology
- 80-90% of all pancreatic cancers are adenocarcinomas
- only 2% of exocrine pancreatic tumors are benign
- COX2 is upregulated in pancreatic cancer precursor lesions[14]
- effects of invasive pancreatic cancer on celiac plexus can cause intractable pain[38]
- Malassezia (especially, M globosa) travel from the gut through the sphincter of Oddi to the pancreas
- in pancreatic cancer, M globosa is present in concentrations 3000 X its concentrations in normal or benignly inflamed pancreatic tissue[25]
- Malassezia triggered tumor growth involves inflammation via activation of complement C3[25]
- pancreatic cancers produce relatively few neoantigens (antigens unique to the cancer) that are recognized by the immune system[34]
- see Notes: & Clinical trials: below
Genetics
- chromosomal inversion(s) found in nearly all metastatic pancreatic cancer[7]
- telomeres are dysfunctional, control of cell cycle is lost
- initiation of pancreatic cancer begin 15 years prior & metastasis 5 years prior to clinical presentation[7]
- defects in SMAD4 are a cause of pancreatic carcinoma
- overexpression of: TM4SF5, LSM1
- implicated genes MLL4, WDR45, ANKRD37, IGF2BP3, MGAT4A, MGAT4B, AMIGO2, SULF1, HES2, ANLN, WIPI2, HCC1, TBRG1, ARID4B, LRRC26, OLFM4, PALLD, MTUS1, BCL9L, ARHGAP27, S100PBP, PTPRH, MUC17, NT5DC3, PEG10, ZNF146, CCKBR, CD97, PLXNB1, GNG7, RAB20, S100P, TSPAN8, BIRC5
Clinical manifestations
- generally presents late in the course of the disease
- presenting signs & symptoms
- frequent
- prodrome of malaise, anorexia & weight loss
- upper abdominal pain, lumbar back pain
- obstructive jaundice (lesion of head of pancreas)
- infrequent
- may present as depression
- frequent
- non-bacterial (thrombotic) 'marantic' endocarditis
- hepatomegaly, ascites, abdominal mass
- left supraclavicular adenopathy
Laboratory
- non-specific elevations in serum transaminases, serum alkaline phosphatase, serum amylase may be present
- complete blood count: anemia is variable
- serum CA 19-9 > 800 ug/mL indicates a poor prognosis (tumor markers not used for diagnosis)[3]
- germline testing for BRCA mutations & mismatch repair deficiency in all patients[3]
- serum IgG4
- investigational
- a signature for pancreatic cancer based on microRNAs identified in the exomes shed from pancreatic cancers & cell-free DNA in blood
- 90% accurate for stage I/II pancreatic cancer[39]
- addition of serum CA 19-9 increases accuracy to 97%[39]
- performance the same whether the tumor was in the head or tail of the pancreas[39]
- licensed to Pharus Diagnostics for commercial development[39]
- a signature for pancreatic cancer based on microRNAs identified in the exomes shed from pancreatic cancers & cell-free DNA in blood
- see ARUP consult[9]
Diagnostic procedures
- endoscopic retrograde cholangiopancreatography (ERCP)
- ultrasound-guided biopsy with histopathology or cytology
- endoscopic ultrasonography with fine-needle aspiration of pancreas for diagnostic confirmation if no metastases on abdominal CT[3]
- recommended in patients with imaging characteristic of resectable pancreatic cancer[3]
- surgical resection formerly recommended prior to histopathology for diagnosis[3]
- percutaneous transhepatic cholangiopancreatography
Radiology
- contrast-enhanced computed tomography (CT) imaging modality of choice[3]
- evaluation of pancreatic & bile ducts
- pancreatic mass, calcifications
- useful for staging
- 90% sensitivity for detecting pancreatic cancer[3]
- magnetic resonance cholangiopancreatography if CT imaging negative
- most sensitive test for small lesions
- abdominal ultrasound, evaluation of pancreatic & bile ducts
- 'double-duct' sign:
- obstruction of both the pancreatic duct & bile duct
- PET scan does not add value in staging or treatment survelliance[3]
Complications
Differential diagnosis
- autoimmune pancreatitis - elevated IgG4
Management
- geriatric assessment prior to palliative care consult in elderly[35][36][37]
- palliative care consult for patients with newly diagnosed advanced cancer
- neoadjuvant chemotherapy with or without radiation typically used for locally advanced pancreatic cancer
- neoadjuvant FOLFIRINOX, losartan, followed by chemoradiotherapy for locally advanced pancreatic adenocarcinoma[24][30]
- also see pancreatic adenocarcinoma
- surgical resection affords the only hope of cure
- most lesions are non-resectable
- criteria for resection
- tumor < 2 cm
- absence of lymph node invasion
- absence of mesenteric vasculature involvement
- absence of metastases
- surgical procedures:
- Whipple procedure
- total pancreatectomy
- survival is the same
- neoadjuvant chemoradiation
- may improve survival[21]
- does improve survival in borderline-resectable pancreatic cancer vs chemotherapy alone[27]
- palliative surgery
- intraoperative chemical splanchnicectomy
- endoscopic biliary stent placement for obstructive jaundice
- expandable stent of gastrojejunostomy for relief of bowel obstruction
- celiac nerve block (celiac plexus neurolysis) when systemic analgesics are not effective
- radiation therapy may have some role, but survival is unchanged
- hypofractionated ablative radiation therapy following standard chemotherapy may be associated survival benefit in locally advanced, inoperable pancreatic cancer[28]
- adjuvant chemotherapy seems to have some benefit
- gemcitabine plus daily oral erlotinib[5] for metastases
- gemcitabine for 6 months after surgical resection of pancreatic cancer improves 10 year disease-free survival from 6% to 14%[12]
- gemcitabine + capecitabine better than gemcitabine alone[3]
- nab-paclitaxel 125 mg/m2 followed by gemcitabine 1000 mg/m2 on days 1, 8, & 15 every 4 weeks[13] increases survival
- induction therapy with nab-paclitaxel + gemcitabine may confer survival advantage 8.8 vs 6. months in locally-advanced pancreatic cancer[20]
- protocols include:
- FOLFIRINOX for metastatic disease[16] & for adjuvant chemotherapy after surgical resection[3][22]
- alternative gemcitabine + capecitabine (Xeloda)
- gemcitabine +/- nab-paclitaxel (GEM+NPTX) after surgical resection was the standard of care[12][13]
- FOLFIRINOX & GEM+NPTX with regimens with the best outcomes in Japan
- 5-fluorouracil
- 5-fluorouracil or gemcitabine with radiation therapy[3]
- immunotherapy in pancreatic cancer works by recruiting & activating T cells that recognize tumor-specific antigens (still investigational)[10]
- targeted therapies with receptor tyrosine kinase inhibitors plus immunotherapy may work synergistically[10]
- metastatic recurrence in patients with good performance status treated with FOLFIRINOX[3][16]
- pancrealipase for pancreatic insufficiency (see chronic diarrhea)
- prognosis:
- 5 year survival < 6%; 10%[29]
- may be up to 20% if localized disease[3]
- gemcitabine may improve overall survival to 14%[12]
- median survival with metastatic disease 3-6 months
- median survival with locally unresectable disease is 1 year[3]
- poor survival mostly due to presentation & diagnosis at a late stage[29]
- 5 year survival < 6%; 10%[29]
- USPSTF recommends against screening for pancreatic cancer[23]
- risk of pancreatic cancer associated with new onset hyperglycemia varies with race/ethnicity; screening is not recommended[26]
- persons at high-risk for pancreatic cancer may benefit from early detection[29]
- inherited predisposition to pancreatic cancer
- new-onset diabetes mellitus
- mucinous pancreatic cyst
- chronic pancreatitis
Clinical trials
- a personalized mRNA neoantigen vaccine created by sequenced DNA & RNA from resected pancreatic cancer as neoadjuvant therapy in combination with an immune checkpoint inhibitor & adjuvant chemotherapy eliminated the primary tumor in 8 of 16 patients[34] (see Notes:)
Comparative biology
- C elegans exposed to urine of patients with early-stage pancreatic cancer show chemotaxis towards the urine vs controls[31]
Notes
- pancreatic cancer expresses relatively few neoantigens (antigens unique to the cancer recognized by the immune system), thus immune checkpoint inhibitors that initiate a response to neoantigens perform poorly[34]
More general terms
More specific terms
Additional terms
- cancer antigen CA 19-9 (carbohydrate antigen 19-9) in serum
- Courvoisier's sign
- Trousseau's syndrome; Trousseau's sign of malignancy; thrombophlebitis migrans
References
- ↑ Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 382-83
- ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 315
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021.
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 582
- ↑ 5.0 5.1 5.2 Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 Apr 23; [Epub ahead of print] PMID: https://www.ncbi.nlm.nih.gov/pubmed/17452677
- ↑ 6.0 6.1 Li D et al Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA 2009 Jun 24; 301:2553. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19549972
- ↑ 7.0 7.1 7.2 Campbell PJ et al The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 2010 Oct 28; 467:1109 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20981101
Yachida S et al Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010 Oct 28; 467:1114 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20981102
Luebeck EG. Genomic evolution of metastasis. Nature 2010 Oct 28; 467:1053 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20981088 - ↑ Nieto J et al Metastatic pancreatic cancer 2008: is the glass less empty? Oncologist. 2008 May;13(5):562-76. Review PMID: https://www.ncbi.nlm.nih.gov/pubmed/18515741
- ↑ 9.0 9.1 ARUP Consult: Pancreatic Cancer The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/pancreatic-cancer
- ↑ 10.0 10.1 10.2 Gunturu KS, Rossi GR, Saif MW Immunotherapy updates in pancreatic cancer: are we there yet? Ther Adv Med Oncol. 2013 Jan;5(1):81-9 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23323149
- ↑ Hidalgo M. Pancreatic cancer. N Engl J Med. 2010 Apr 29;362(17):1605-17. PMID: https://www.ncbi.nlm.nih.gov/pubmed/20427809
- ↑ 12.0 12.1 12.2 12.3 Oettle H et al Adjuvant Chemotherapy With Gemcitabine and Long-term Outcomes Among Patients With Resected Pancreatic Cancer. The CONKO-001 Randomized Trial. JAMA. 2013;310(14):1473-1481 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24104372 <Internet> http://jama.jamanetwork.com/article.aspx?articleid=1750131
- ↑ 13.0 13.1 13.2 Von Hoff DD et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24131140 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1304369
- ↑ 14.0 14.1 14.2 14.3 Streicher SA, Yu H, Lu L et al Case-Control Study of Aspirin Use and Risk of Pancreatic Cancer. Cancer Epidemiol Biomarkers Prev. Online: June 26, 2014 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24969230 <Internet> http://cebp.aacrjournals.org/content/early/2014/06/19/1055-9965.EPI-13-1284.abstract
- ↑ 15.0 15.1 Liao W-C et al. Blood glucose concentration and risk of pancreatic cancer: Systematic review and dose-response meta-analysis. BMJ 2015 Jan 3; 349:g7371 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25556126
- ↑ 16.0 16.1 16.2 Conroy T, Desseigne F, Ychou M, Bouche O et al FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21561347
- ↑ Muniraj T, Jamidar PA, Aslanian HR. Pancreatic cancer: a comprehensive review and update. Dis Mon. 2013 Nov;59(11):368-402. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24183261
- ↑ Canto MI, Harinck F, Hruban RH et al International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013 Mar;62(3):339-47 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23135763
- ↑ Kleynberg RL, Guralnik G Pancreatic Cancer: Difficult Diagnosis, Ominous Outlook. Medscape. March 24, 2016 http://reference.medscape.com/features/slideshow/pancreatic-cancer
- ↑ 20.0 20.1 Bankhead C. Combo Tx Active in Locally Advanced Pancreatic Ca - Impact on clinical practice uncertain. MedPage Today. January 21, 2018 https://www.medpagetoday.com/meetingcoverage/mgics/70651
Hammel P, et al Phase II LAPACT trial of nab-paclitaxel (nab-P) plus gemcitabine (G) for patients with locally advanced pancreatic cancer. Gastrointestinal Cancers Symposium (GICS) 2018; Abstract 204. - ↑ 21.0 21.1 Ingram I Pre-Surgical CRT May Boost Survival in Pancreatic Ca Further data needed to clarify best approach and who would benefit most. MedPage Today. June 04, 2018 https://www.medpagetoday.com/meetingcoverage/asco/73276
van Tienhoven G et al Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): A randomized, controlled, multicenter phase III trial. American Society of Clinical Oncology (ASCO) 2018; Abstract LBA4002. - ↑ 22.0 22.1 Nelson R Best Survival Ever in Resectable Pancreatic Cancer. Medscape. Jun 04, 2018. https://www.medscape.com/viewarticle/897600
- ↑ 23.0 23.1 U.S. Preventive Services Task Force (USPSTF) Screening for Pancreatic Cancer. US Preventive Services Task Force Reaffirmation Recommendation Statement JAMA. 2019;322(5):438-444. Aug 6 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31386141 https://jamanetwork.com/journals/jama/fullarticle/2740727
U.S. Preventive Services Task Force (USPSTF) Screening for Pancreatic CancerUpdated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2019;322(5):445-454. Aug 6 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31386140 https://jamanetwork.com/journals/jama/fullarticle/2740726
Lucas AL, Kastrinos F Screening for Pancreatic Cancer. JAMA. 2019;322(5):407-408. Aug 6 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31386115 https://jamanetwork.com/journals/jama/fullarticle/2740696 - ↑ 24.0 24.1 Murphy JE, Wo JY, Ryan DP et al Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer. A Phase 2 Clinical Trial. JAMA Oncol. Published online May 30, 2019 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31145418 https://jamanetwork.com/journals/jamaoncology/fullarticle/2734827
- ↑ 25.0 25.1 25.2 25.3 Aykut B et al. The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature 2019 Oct; 574:264 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31578522 https://www.nature.com/articles/s41586-019-1608-2
- ↑ 26.0 26.1 Wu BU, Butler RK, Lustigova E et al Association of Glycated Hemoglobin Levels With Risk of Pancreatic Cancer. JAMA Netw Open. 2020;3(6):e204945 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32530471 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767067
- ↑ 27.0 27.1 Bankhead C. Preop RT Flunks Test in Borderline Pancreatic Cancer - Chemotherapy alone judged efficacious but not chemoradiation MedPage Today January 20, 2021 https://www.medpagetoday.com/meetingcoverage/mgics/90793
Katz MHG, et al Alliance A021501: Preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy for borderline resectable adenocarcinoma of the pancreas. Gastrointestinal Cancers Symposium (GICS) 2021; Abstract 377. - ↑ 28.0 28.1 Ingram I et al Ablative Radiation Improves Outcomes in Inoperable Pancreatic Cancer - Median survival in patients treated at Sloan Kettering surpassed 2 years. MedPage Today March 11, 2021 https://www.medpagetoday.com/oncology/othercancers/91592
Reyngold M et al Association of ablative radiation therapy with survival among patients with inoperable pancreatic cancer JAMA Oncol 2021; March 11 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33704353 https://jamanetwork.com/journals/jamaoncology/article-abstract/2777063
Horowitz DP et al Ablative radiotherapy for patients with inoperable pancreas cancer -- Ready for prime time? JAMA Oncol 2021. March 11 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33704355 https://jamanetwork.com/journals/jamaoncology/article-abstract/2777065 - ↑ 29.0 29.1 29.2 29.3 29.4 Garg SK. Chari ST Early Detection of Pancreatic Cancer. Curr Opin Gastroenterol. 2020;36(5):456-461 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32657789 https://www.medscape.com/viewarticle/935443
- ↑ 30.0 30.1 Mavros MN, Moris D, Karanicolas PJ et al Clinical Trials of Systemic Chemotherapy for Resectable Pancreatic Cancer. A Review. JAMA Surg. Published online March 31, 2021. PMID: https://www.ncbi.nlm.nih.gov/pubmed/33787841 https://jamanetwork.com/journals/jamasurgery/fullarticle/2777910
- ↑ 31.0 31.1 Coffey D Tiny Worms Sniff Out Early-Stage Pancreatic Cancer. Medscape. October 22, 2021 https://www.medscape.com/viewarticle/961423
Asai A, Konno M, Ozaki M et al Scent test using Caenorhabditis elegans to screen for early-stage pancreatic cancer. Oncotarget 2021 12:1687-1696 https://www.oncotarget.com/article/28035/text/ - ↑ Takumoto Y, Sasahara Y, Narimatsu H et al Comparative Outcomes of First-Line Chemotherapy for Metastatic Pancreatic Cancer Among the Regimens Used in Japan. A Systematic Review and Network Meta-analysis. JAMA Netw Open. 2022;5(1):e2145515 PMID: https://www.ncbi.nlm.nih.gov/pubmed/35099549 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2788498
- ↑ 33.0 33.1 Rouette J, McDonald EG, Schuster T et al Dihydropyridine Calcium Channel Blockers and Risk of Pancreatic Cancer: A Population-Based Cohort Study. J Am Heart Assoc (JAHA). 2022. Dec 14 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36515246 Free article https://www.ahajournals.org/doi/full/10.1161/JAHA.122.026789
- ↑ 34.0 34.1 34.2 34.3 34.4 Rojas LA et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 2023 May 10; [e-pub]. https://www.nature.com/articles/s41586-023-06063-y
Huff AL, ] Zaidi N. Vaccine boosts T cells that target pancreatic tumours. Nature 2023 May 10; [e-pub]. https://www.nature.com/articles/d41586-023-01526-8 - ↑ 35.0 35.1 Higuera O, Ghanem I, Nasimi R, Prieto I, Koren L, Feliu J. Management of pancreatic cancer in the elderly. World J Gastroenterol. 2016 Jan 14;22(2):764-75. PMID: https://www.ncbi.nlm.nih.gov/pubmed/26811623 PMCID: PMC4716075 Free PMC article. Review.
- ↑ 36.0 36.1 Hurria A, Togawa K, Mohile SG et al Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011 Sep 1;29(25):3457-65 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21810685
- ↑ 37.0 37.1 Parmar AD, Vargas GM, Tamirisa NP et al Trajectory of care and use of multimodality therapy in older patients with pancreatic adenocarcinoma. Surgery. 2014 Aug;156(2):280-9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24851723 PMCID: PMC4099282 Free PMC article.
- ↑ 38.0 38.1 NEJM Knowledge+
- ↑ 39.0 39.1 39.2 39.3 39.4 Otto MA Liquid Biopsy Has Near-Perfect Accuracy for Early Pancreatic Cancer. Medscape. April 10, 2024 https://www.medscape.com/viewarticle/liquid-biopsy-has-near-perfect-accuracy-early-pancreatic-2024a10006ut
- ↑ National Cancer Institute Pancreatic Cancer - Health Professional version https://www.cancer.gov/types/pancreatic/hp
- ↑ National Cancer Institute Pancreatic Cancer Treatment (Adult) (PDQ) - Health Professional version https://www.cancer.gov/types/pancreatic/hp/pancreatic-treatment-pdq
Patient information
pancreatic cancer patient information