Skip to main content

Advertisement

SpringerLink
Log in

Pancreatic Cancer: a Challenge to Cure

  • Original Article
  • Published:
Indian Journal of Surgery Aims and scope Submit manuscript

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a challenging disease, as overall survival has not improved over the last several decades. The disease is characterized by late diagnosis, difficult major surgery in resectable patients, and a biologically chemoresistant tumor. Intense research in the field is ongoing to develop biomarkers for early detection and prognostication. Surgery is presently the crux of the management of PDA and has been standardized over the years with high-volume centers reporting <5 % operative mortality. The biggest problem is to overcome the inherent chemoresistance of the tumor that is densely fibrotic and hypoxic and has a tendency to invade surrounding neuronal plexuses. This review attempts to summarize in brief the reasons why PDA is difficult to treat, and provides a glimpse of the ongoing research in the field.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hidalgo M (2010) Pancreatic cancer. N Engl J Med 362:1605–1617

    Article  PubMed  CAS  Google Scholar 

  2. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M (2011) Pancreatic cancer. Lancet 378:607–620

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kawai M, Yamaue H (2010) Analysis of clinical trials evaluating complications after pancreaticoduodenectomy: a new era of pancreatic surgery. Surg Today 40:1011–1017

    Article  PubMed  Google Scholar 

  4. Winter JW, Cameron JL, Campbell KA, Arnold MA, Chang DC, Coleman J et al (2006) 1423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest Surg 10:1199–1211

    Article  PubMed  Google Scholar 

  5. Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK et al (2013) Recent progress in pancreatic cancer. CA Cancer J Clin 63:318–348

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hruban RH, Adsay NV, Albores-Saavedra J et al (2001) Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 25:579–586

    Article  PubMed  CAS  Google Scholar 

  7. Clores MJ, Thosani A, Buscaglia JM (2014) Multidisciplinary diagnostic and therapeutic approaches to pancreatic cystic lesions. J Multidiscip Healthc 7:81–91

    PubMed  PubMed Central  Google Scholar 

  8. Yachida S, Jones S, Bozic I, Antal T et al (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467(7319):1114–1117

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Rhim A, Mirek E, Aiello N et al (2012) EMT and dissemination precede pancreatic tumor formation. Cell 148:349–361

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Shi C, Hruban RH, Klein AP (2009) Familial pancreatic cancer. Arch Pathol Lab Med 133:365–374

    PubMed  Google Scholar 

  11. Klein AP, Brune KA, Petersen GM et al (2004) Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 64:2634–2638

    Article  PubMed  CAS  Google Scholar 

  12. van der Heijden MS, Brody JR, Dezentje DA et al (2005) In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. Clin Cancer Res 11:7508–7515

    Article  PubMed  Google Scholar 

  13. Winder JM, Yeo CJ, Broody JR (2013) Diagnostic, prognostic, and predictive biomarkers in pancreatic cancer. J Surg Oncol 107:15–22

    Article  Google Scholar 

  14. Tempero MA, Uchida E, Takasaki H et al (1987) Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer. Cancer Res 47:5501–5503

    PubMed  CAS  Google Scholar 

  15. Marrelli D, Caruso S, Pedrazzani C et al (2009) CA19-9 serum levels in obstructive jaundice: clinical value in benign and malignant conditions. Am J Surg 198:333–339

    Article  PubMed  CAS  Google Scholar 

  16. Ballehaninna UK, Chamberlain RS (2012) The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal. J Gastrointest Oncol 3:105–119

    PubMed  CAS  PubMed Central  Google Scholar 

  17. Parikh DA, Durbin-Johnson B, Urayama S (2014) Utility of serum CA19-9 levels in the diagnosis of pancreatic ductal adenocarcinoma in an endoscopic ultrasound referral population. J Gastrointest Cancer 45(1):74–79

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. O’Brien DP, Sandanayake NS, Jenkinson C et al (2015) Serum CA19-9 is significantly up-regulated up to 2 years prior to diagnosis with pancreatic cancer: implications for early disease detection. Clin Cancer Res 21(3):622–631

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hwang TL, Liang Y, Chien KY et al (2006) Overexpression and elevated serum levels of phosphoglycerate kinase 1 in pancreatic ductal adenocarcinoma. Proteomics 6:2259–2272

    Article  PubMed  CAS  Google Scholar 

  20. Patwa TH, Li C, Poisson LM et al (2009) The identification of phosphoglycerate kinase-1 and histone H4 autoantibodies in pancreatic cancer patient serum using a natural protein microarray. Electrophoresis 30:2215–2226

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Guo J, Wang W, Liao P et al (2009) Identification of serum biomarkers for pancreatic adenocarcinoma by proteomic analysis. Cancer Sci 100:2292–2301

    Article  PubMed  CAS  Google Scholar 

  22. Rong Y, Jin D, Hou C et al (2010) Proteomics analysis of serum protein profiling in pancreatic cancer patients by DIGE: up-regulation of mannose-binding lectin 2 and myosin light chain kinase 2. BMC Gastroenterol 10:68

    Article  PubMed  PubMed Central  Google Scholar 

  23. Xue A, Scarlett CJ, Chung L et al (2010) Discovery of serum biomarkers for pancreatic adenocarcinoma using proteomic analysis. Br J Cancer 103:391–400

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. OuYang D, Xu J, Huang H, Chen Z (2011) Metabolomic profiling of serum from human pancreatic cancer patients using 1H NMR spectroscopy and principal component analysis. Appl Biochem Biotechnol 165(1):148–154

    Article  PubMed  Google Scholar 

  25. Napoli C, Sperandio N, Lawlor RT et al (2012) Urine metabolic signature of pancreatic ductal adenocarcinoma by (1)h nuclear magnetic resonance: identification, mapping, and evolution. J Proteome Res 11(2):1274–1283

    Article  PubMed  CAS  Google Scholar 

  26. Davis VW, Schiller DE, Eurich D, Bathe OF, Sawyer MB (2013) Pancreatic ductal adenocarcinoma is associated with a distinct urinary metabolomic signature. Ann Surg Oncol 20(Suppl 3):S415–S423

    Article  PubMed  Google Scholar 

  27. Gowda GA (2010) Human bile as a rich source of biomarkers for hepatopancreatobiliary cancers. Biomark Med 4(2):299–314

    Article  PubMed  CAS  Google Scholar 

  28. Schultz NA, Dehlendorff C, Jensen BV et al (2014) MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA 311(4):392–404

    Article  PubMed  CAS  Google Scholar 

  29. Jones S, Zhang X, Parsons DW et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Chiorean EG, Coveler AL (2015) Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies. Drug Des Devel Ther 9:3529–3545

    Article  PubMed  PubMed Central  Google Scholar 

  31. Shi C, Fukushima N, Abe T et al (2008) Sensitive and quantitative detection of KRAS2 gene mutations in pancreatic duct juice differentiates patients with pancreatic cancer from chronic pancreatitis, potential for early detection. Cancer Biol Ther 7:353–360

    Article  PubMed  CAS  Google Scholar 

  32. Winter JM, Tang LH, Klimstra DS et al (2012) A novel survival- based tissue microarray of pancreatic cancer identifies clinical useful candidate biomarkers. PLoS One 7(7), e40157. doi:10.1371/journal.pone.0040157

  33. Koops A, Wojciechowski B, Broering DC, Adam G, Krupski- Berdien G (2004) Anatomic variations of the hepatic arteries in 604 selective celiac and superior mesenteric angiographies. Surg Radiol Anat 26:239–244

    Article  PubMed  CAS  Google Scholar 

  34. Balachandran A, Darden DL, Tamm EP, Faria SC, Evans DB, Charnsangavej C (2008) Arterial variants in pancreatic adenocarcinoma. Abdom Imaging 33(2):214–221

    Article  PubMed  Google Scholar 

  35. Perwaiz A, Singh A, Singh T, Chaudhary A (2010) Incidence and management of arterial anomalies in patients undergoing pancreaticoduodenectomy. JOP 11(1):25–30 (Online)

    PubMed  Google Scholar 

  36. Kimura W, Watanabe T (2011) Anatomy of the pancreatic nerve plexuses and significance of their dissection. Nihon Geka Gakkai Zasshi 112(3):170–176

    PubMed  Google Scholar 

  37. Ceyhan GO, Demir IE, Altintas B et al (2008) Neural invasion in pancreatic cancer: a mutual tropism between neurons and cancer cells. Biochem Biophys Res Commun 374:442–447

    Article  PubMed  CAS  Google Scholar 

  38. Kayahara M, Nakagawara H, Kitagawa H, Ohta T (2007) The nature of neural invasion by pancreatic cancer. Pancreas 35:218–223

    Article  PubMed  Google Scholar 

  39. Ceyhan GO, Giese NA, Erkan M et al (2006) The neurotrophic factor artemin promotes pancreatic cancer invasion. Ann Surg 244:274–281

    Article  PubMed  PubMed Central  Google Scholar 

  40. Takahashi T, Ishikura H, Motohara T et al (1997) Perineural invasion by ductal adenocarcinoma of the pancreas. J Surg Oncol 65:164–170

    Article  PubMed  CAS  Google Scholar 

  41. Gulbinas A, Barauskas G, Pundzius J (2004) Pancreaticojejunal anastomosis: the “Achilles heel” of pancreaticoduodenectomy. Medicina (Kaunas) 40:927–934

    Google Scholar 

  42. Tewari M, Hazrah P, Kumar V, Shukla HS (2010) Options of restorative pancreaticoenteric anastomosis following pancreaticoduodenectomy: a review. Surg Oncol 19(1):17–26

    Article  PubMed  Google Scholar 

  43. Birkmeyer JD, Siewers JE, Finlayson EVA et al (2002) Hospital volume and hospital mortality in the United States. N Engl J Med 346:1128–1137

    Article  PubMed  Google Scholar 

  44. Wang Z, Li Y, Ahmad A et al (2011) Pancreatic cancer: understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol 8:27–33

    Article  PubMed  CAS  Google Scholar 

  45. Zalatnai A, Molnar J (2007) Review. Molecular background of chemoresistance in pancreatic cancer. In Vivo 21:339–347

    PubMed  CAS  Google Scholar 

  46. Erkan M, Hausmann S, Michalski CW et al (2012) The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 9(8):454–467

    Article  PubMed  CAS  Google Scholar 

  47. Neesse A, Michl P, Frese KK et al (2011) Stromal biology and therapy in pancreatic cancer. Gut 60(6):861–868

    Article  PubMed  Google Scholar 

  48. Wormann SM, Diakopoulos KN, Lesina M, Algul H (2014) The immune network in pancreatic cancer development and progression. Oncogene 33(23):2956–2967

    Article  PubMed  CAS  Google Scholar 

  49. Erkan M, Adler G, Apte MV et al (2012) StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut 61:172–178

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Demir IE, Ceyhan GO, Rauch U et al (2010) The microenvironment in chronic pancreatitis and pancreatic cancer induces neuronal plasticity. Neurogastroenterol Motil 22(480–490):e112–e483

    Google Scholar 

  51. Michl P, Gress TM (2012) Improving drug delivery to pancreatic cancer: breaching the stromal fortress by targeting hyaluronic acid. Gut 61(10):1377–1379

    Article  PubMed  CAS  Google Scholar 

  52. Koong AC, Mehta VK, Le QT, Fisher GA et al (2000) Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 48(4):919–922

    Article  PubMed  CAS  Google Scholar 

  53. Komar G, Kauhanen S, Liukko K et al (2009) Decreased blood flow with increased metabolic activity: a novel sign of pancreatic tumor aggressiveness. Clin Cancer Res 15(17):5511–5517

    Article  PubMed  CAS  Google Scholar 

  54. Olive KP, Jacobetz MA, Davidson CJ et al (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324(5933):1457–1461

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  55. Stephenson J, Wolpin BM, Becerra C et al (2011) The safety of IPI-926, a novel hedgehog pathway inhibitor, in combination with gemcitabine in patients (pts) with metastatic pancreatic cancer. J Clin Oncol 29(Suppl):4114

    Google Scholar 

  56. Von Hoff DD, Ervin T, Arena FP et al (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691–1703

    Article  Google Scholar 

  57. Goldstein D, El-Maraghi RH, Hammel P et al (2014) Analyses of updated overall survival (OS) and prognostic effect of neutrophil-to-lymphocyte ratio (NLR) and CA 19-9 from the phase III MPACT study of nab-paclitaxel (nab-P) plus gemcitabine (Gem) versus Gem for patients (pts) with metastatic pancreatic cancer (PC) [abstract]. ASCO Meet Abstr 32:4027

    Google Scholar 

  58. Von Hoff DD, Ramanathan RK, Borad MJ et al (2011) Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 29(34):4548–4554

    Article  Google Scholar 

  59. Neesse A, Frese KK, Chan DS et al (2014) SPARC independent drug delivery and antitumour effects of nab-paclitaxel in genetically engineered mice. Gut 63(6):974–983

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. Frese K, Neesse A, Cook N et al (2012) nab-paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov 2:260–269

    Article  PubMed  CAS  Google Scholar 

  61. Fattahi R, Balci N, Perman W et al (2009) Pancreatic diffusion-weighted imaging (DWI): comparison between mass-forming focal pancreatitis (FP), pancreatic cancer (PC), and normal pancreas. J Magn Reson Imaging 29:350–356

    Article  PubMed  Google Scholar 

  62. Yao X, Zeng M, Wang H et al (2012) Evaluation of pancreatic cancer by multiple breath-hold dynamic contrast-enhanced magnetic resonance imaging at 3.0T. Eur J Radiol 81:e917–e922

    Article  PubMed  Google Scholar 

  63. D’Onofrio M, Zamboni G, Malago R et al (2009) Resectable pancreatic adenocarcinoma: is the enhancement pattern at contrast-enhanced ultrasonography a pre-operative prognostic factor? Ultrasound Med Biol 35:1929–1937

    Article  PubMed  Google Scholar 

  64. Opačić D, Rustemović N, Kalauz M et al (2015) Endoscopic ultrasound elastography strain histograms in the evaluation of patients with pancreatic masses. World J Gastroenterol 21(13):4014–4019

    Article  PubMed  PubMed Central  Google Scholar 

  65. Bausch D, Thomas S, Mino-Kenudson M et al (2011) Plectin-1 as a novel biomarker for pancreatic cancer. Clin Cancer Res 17(2):302–309

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. Patel M, Gomes A, Ruderman S et al (2014) Polarization gating spectroscopy of normal-appearing duodenal mucosa to detect pancreatic cancer. Gastrointest Endosc 80(5):786–93.e1-2

    Article  PubMed  PubMed Central  Google Scholar 

  67. Le DT, Wang-Gillam A, Picozzi V et al (2015) Safety and survival with GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol 33(12):1325–1333

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

I am very grateful to Dr. William Jarnagin, MD, FACS, Chief, Hepatopancreatobiliary Service; Benno C. Schmidt Chair in Surgical Oncology, Memorial Sloan Kettering Cancer Centre, New York, for going through this manuscript and for his guidance while I was in his unit as a UICC fellow.

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India

    M. Tewari

Authors
  1. M. Tewari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Tewari.

Ethics declarations

Conflict of Interest

The author declares that she has no competing interests.

Additional information

Dr. Mallika Tewari, M.S., M.Ch. (Surgical Oncology), MRCS.Ed

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tewari, M. Pancreatic Cancer: a Challenge to Cure. Indian J Surg 77, 350–357 (2015). https://doi.org/10.1007/s12262-015-1369-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12262-015-1369-6

Keywords

Search

Navigation