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Pancreatic cancer treatment: better, but a long way to go

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Abstract

Remarkable progress has been made in treating pancreatic cancer over the past century, including refinement of our surgical techniques and improvements in adjuvant and neoadjuvant therapies. Despite these advances, the incidence of pancreatic cancer is rising globally, and it remains a deadly disease. In this review, we highlight the historical perspectives of pancreatic cancer treatment and outline the areas of future advancement that will assist progression towards better outcomes. Areas of future advancement include improving prevention strategies and early detection, refining our molecular understanding of pancreatic cancer, identifying more effective systemic therapies, and improving quality of life and surgical outcomes. Furthermore, systems need to be put in place to ensure all patients with pancreatic cancer receive high quality care and are given the appropriate options and sequence of therapy. This is best achieved through multidisciplinary care.

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References

  1. De Morgagni GB. sedibus, et causis morborum per anatomen indagatis libri quinque. Venice: Remondini:; 1761.

    Google Scholar 

  2. Costa JMD. On the morbid anatomy and symptoms of cancer of the pancreas. Philadelphia: J.B. Lippincott & Co.; 1858.

    Google Scholar 

  3. Pourshams A, Sepanlou SG, Ikuta KS, Bisignano C, Safiri S, Roshandel G, et al. The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol. 2019;4(12):934–47.

    Google Scholar 

  4. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    PubMed  Google Scholar 

  5. Siegel RL, Miller KD, Jemal A. Cancer statistics 2020. CA A Cancer J Clin. 2020;70(1):7–30.

    Google Scholar 

  6. Witzel O. Aus der Klinik des Herrn Prof. Trendelenburg Beiträge zur Chirurgie der Bauchorgane. Deutsche Zeitschrift für Chirurgie. 1886;24(3):326–54.

    Google Scholar 

  7. Griffin JF, Poruk KE, Wolfgang CL. Pancreatic cancer surgery: past, present, and future. Chin J Cancer Res. 2015;27(4):332–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Schnelldorfer T, Sarr MG. Alessandro codivilla and the first pancreatoduodenectomy. JAMA Surgery. 2009;144(12):1179–84.

    Google Scholar 

  9. Halsted WS. Contributions to the Surgery of the Bile Passages, Especially of the Common Bile-Duct. The Boston Medical and Surgical Journal. 1899;141(26):645–54.

    Google Scholar 

  10. Kausch W. Das Carcinom der Papilla duodeni und seine radikale Entfernung. Beitr Klin Chir. 1912;78:439–86.

    Google Scholar 

  11. Whipple AO, Parsons WB, Mullins CR. Treatment of carcinoma of the ampulla of vater. Ann Surg. 1935;102(4):763–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Whipple AO. Present-day surgery of the pancreas. N Engl J Med. 1942;226(13):515–26.

    Google Scholar 

  13. Whipple AO. Observations on radical surgery for lesions of the pancreas. Surg Gynecol Obstet. 1946;82:623–31.

    CAS  PubMed  Google Scholar 

  14. Whipple AO. A reminiscence: pancreaticduodenectomy. Rev Surg. 1963;20:221–5.

    CAS  PubMed  Google Scholar 

  15. Glenn F, Thorbjarnarson B. Carcinoma of the pancreas. Ann Surg. 1964;159(6):945–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Gallitano A, Fransen H, Martin RG. Carcinoma of the pancreas. Results of treatment Cancer. 1968;22(5):939–44.

    CAS  PubMed  Google Scholar 

  17. Crist DW, Sitzmann JV, Cameron JL. Improved hospital morbidity, mortality, and survival after the Whipple procedure. Ann Surg. 1987;206(3):358–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Birkmeyer JD, Finlayson SR, Tosteson AN, Sharp SM, Warshaw AL, Fisher ES. Effect of hospital volume on in-hospital mortality with pancreaticoduodenectomy. Surgery. 1999;125(3):250–6.

    CAS  PubMed  Google Scholar 

  19. Yoshioka R, Yasunaga H, Hasegawa K, Horiguchi H, Fushimi K, Aoki T, et al. Impact of hospital volume on hospital mortality, length of stay and total costs after pancreaticoduodenectomy. BJS. 2014;101(5):523–9.

    CAS  Google Scholar 

  20. Torphy RJ, Friedman C, Halpern A, Chapman BC, Ahrendt SS, McCarter MM, et al. Comparing short-term and oncologic outcomes of minimally invasive versus open pancreaticoduodenectomy across low and high volume centers. Ann Surg. 2019;270(6):1147–55.

    PubMed  Google Scholar 

  21. Hata T, Motoi F, Ishida M, Naitoh T, Katayose Y, Egawa S, et al. Effect of hospital volume on surgical outcomes after pancreaticoduodenectomy: a systematic review and meta-analysis. Ann Surg. 2016;263(4):664–72.

    PubMed  Google Scholar 

  22. Kalser MH, Ellenberg SS. Pancreatic cancer Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985;120(8):899–903.

    CAS  PubMed  Google Scholar 

  23. Khorana AA, McKernin SE, Berlin J, Hong TS, Maitra A, Moravek C, et al. Potentially curable pancreatic adenocarcinoma: ASCO clinical practice guideline update. J Clin Oncol. 2019;37(23):2082–8.

    CAS  PubMed  Google Scholar 

  24. NCCN Clinical Practice Guidelines in oncology: Pancreatic adenocarcinoma. (Version 1.2020). https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed 1 Jan 2020.

  25. Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, et al. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016;388(10041):248–57.

    CAS  PubMed  Google Scholar 

  26. Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med. 2018;379(25):2395–406.

    CAS  PubMed  Google Scholar 

  27. Antwi SO, Oberg AL, Shivappa N, Bamlet WR, Chaffee KG, Steck SE, et al. Pancreatic cancer: associations of inflammatory potential of diet, cigarette smoking and long-standing diabetes. Carcinogenesis. 2016;37(5):481–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Raimondi S, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol. 2009;6(12):699–708.

    PubMed  Google Scholar 

  29. Hruban RH, Canto MI, Goggins M, Schulick R, Klein AP. Update on familial pancreatic cancer. Adv Surg. 2010;44:293–311.

    PubMed  PubMed Central  Google Scholar 

  30. Torphy RJ, Schulick RD. Screening of patients at risk for familial pancreatic cancer: what is beneficial? Surg Clin North Am. 2018;98(1):25–35.

    PubMed  Google Scholar 

  31. Basturk O, Hong SM, Wood LD, Adsay NV, Albores-Saavedra J, Biankin AV, et al. A revised classification system and recommendations from the baltimore consensus meeting for neoplastic precursor lesions in the pancreas. Am J Surg Pathol. 2015;39(12):1730–41.

    PubMed  PubMed Central  Google Scholar 

  32. Goggins M, Overbeek KA, Brand R, Syngal S, Del Chiaro M, Bartsch DK, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020;69(1):7–17.

    CAS  PubMed  Google Scholar 

  33. Vasen H, Ibrahim I, Ponce CG, Slater EP, Matthai E, Carrato A, et al. Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three european expert centers. J Clin Oncol. 2016;34(17):2010–9.

    CAS  PubMed  Google Scholar 

  34. Canto MI, Almario JA, Schulick RD, Yeo CJ, Klein A, Blackford A, et al. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology. 2018;155(3):740–751.e742.

    PubMed  Google Scholar 

  35. Tanaka M, Fernandez-Del Castillo C, Kamisawa T, Jang JY, Levy P, Ohtsuka T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology. 2017;17(5):738–53.

    PubMed  Google Scholar 

  36. Del Chiaro M, Besselink MG, Scholten L, Bruno MJ, Cahen DL, Gress TM, et al. European study group on cystic tumours of the pancreas. European evidence-based guidelines on pancreatic cystic neoplasms. Gut. 2018;67(5):789–804.

    Google Scholar 

  37. Malesci A, Tommasini MA, Bonato C, Bocchia P, Bersani M, Zerbi A, et al. Determination of CA 19–9 antigen in serum and pancreatic juice for differential diagnosis of pancreatic adenocarcinoma from chronic pancreatitis. Gastroenterology. 1987;92(1):60–7.

    CAS  PubMed  Google Scholar 

  38. Engle DD, Tiriac H, Rivera KD, Pommier A, Whalen S, Oni TE, et al. The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice. Science. 2019;364(6446):1156–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA 19–9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal. J Gastrointest Oncol. 2012;3(2):105–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kim J, Bamlet WR, Oberg AL, Chaffee KG, Donahue G, Cao XJ, et al. Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19–9 blood markers. Sci Transl Med. 2017;9(398):eaah5583.

    PubMed  PubMed Central  Google Scholar 

  41. Francis JL, Francis DA, Gunathilagan GJ. Assessment of hypercoagulability in patients with cancer using the Sonoclot Analyzer and thromboelastography. Thromb Res. 1994;74(4):335–46.

    CAS  PubMed  Google Scholar 

  42. Moore HB, Paniccia A, Lawson PJ, Torphy RJ, Nydam TL, Moore EE, et al. Utility of viscoelastic assays beyond coagulation: can preoperative thrombelastography indices predict tumor histology, nodal disease, and resectability in patients undergoing pancreatectomy? J Am Coll Surgeons. 2018;227(1):55–62.

    Google Scholar 

  43. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321(5897):1801–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Collisson EA, Bailey P, Chang DK, Biankin AV. Molecular subtypes of pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2019;16(4):207–20.

    PubMed  Google Scholar 

  45. Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011;17(4):500–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52.

    CAS  PubMed  Google Scholar 

  47. Moffitt RA, Marayati R, Flate EL, Volmar KE, Loeza SG, Hoadley KA, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet. 2015;47(10):1168–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Aung KL, Fischer SE, Denroche RE, Jang GH, Dodd A, Creighton S, et al. Genomics-driven precision medicine for advanced pancreatic cancer: early results from the COMPASS trial. Clin Cancer Res. 2018;24(6):1344–54.

    CAS  PubMed  Google Scholar 

  49. Versteijne E, Suker M, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the dutch randomized phase III PREOPANC Trial. J Clin Oncol. 2020;38(16):1763–73.

    PubMed  PubMed Central  Google Scholar 

  50. O’Reilly EM, Ferrone C. Neoadjuvant or adjuvant therapy for resectable or borderline resectable pancreatic cancer: which is preferred? J Clin Oncol. 2020;38(16):1757–9.

    PubMed  PubMed Central  Google Scholar 

  51. Unno M, Motoi F, Matsuyama Y, Satoi S, Matsumoto I, Aosasa S, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP-05). J Clin Oncol. 2019;37(4_suppl):189.

    Google Scholar 

  52. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33(8):828–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Torphy RJ, Zhu Y, Schulick RD. Immunotherapy for pancreatic cancer: barriers and breakthroughs. Ann Gastroenterol Surg. 2018;2(4):274–81.

    PubMed  PubMed Central  Google Scholar 

  55. O’Reilly EM, Oh D-Y, Dhani N, Renouf DJ, Lee MA, Sun W, et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncology. 2019;5(10):1431–8.

    PubMed Central  PubMed  Google Scholar 

  56. Infante JR, Korn RL, Rosen LS, LoRusso P, Dychter SS, Zhu J, et al. Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours. Br J Cancer. 2018;118(2):e3.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Elahi-Gedwillo KY, Carlson M, Zettervall J, Provenzano PP. Antifibrotic therapy disrupts stromal barriers and modulates the immune landscape in pancreatic ductal adenocarcinoma. Cancer Res. 2019;79(2):372–86.

    CAS  PubMed  Google Scholar 

  58. Doherty GJ, Tempero M, Corrie PG. HALO-109-301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer. Future Oncol. 2018;14(1):13–22.

    CAS  PubMed  Google Scholar 

  59. Asbun HJ, Moekotte AL, Vissers FL, Kunzler F, Cipriani F, Alseidi A, et al. The miami international evidence-based guidelines on minimally invasive pancreas resection. Ann Surg. 2020;271(1):1–14.

    PubMed  Google Scholar 

  60. Braga M, Pecorelli N, Ferrari D, Balzano G, Zuliani W, Castoldi R. Results of 100 consecutive laparoscopic distal pancreatectomies: postoperative outcome, cost-benefit analysis, and quality of life assessment. Surg Endosc. 2015;29(7):1871–8.

    PubMed  Google Scholar 

  61. de Rooij T, van Hilst J, van Santvoort H, Boerma D, van den Boezem P, Daams F, et al. Minimally invasive versus open distal pancreatectomy (LEOPARD): a multicenter patient-blinded randomized controlled trial. Ann Surg. 2019;269(1):2–9.

    PubMed  Google Scholar 

  62. Nassour I, Wang SC, Christie A, Augustine MM, Porembka MR, Yopp AC, et al. Minimally invasive versus open pancreaticoduodenectomy: a propensity-matched study from a national cohort of patients. Ann Surg. 2018;268(1):151–7.

    PubMed  Google Scholar 

  63. van Hilst J, de Rooij T, Bosscha K, Brinkman DJ, van Dieren S, Dijkgraaf MG, et al. Laparoscopic versus open pancreatoduodenectomy for pancreatic or periampullary tumours (LEOPARD-2): a multicentre, patient-blinded, randomised controlled phase 2/3 trial. Lancet Gastroenterol Hepatol. 2019;4(3):199–207.

    PubMed  Google Scholar 

  64. Zureikat AH, Moser AJ, Boone BA, Bartlett DL, Zenati M, Zeh HJ 3rd. 250 robotic pancreatic resections: safety and feasibility. Ann Surg. 2013;258(4):554–62.

    PubMed  Google Scholar 

  65. Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230(6):776–82 (discussion 782-774).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200–10.

    CAS  PubMed  Google Scholar 

  67. Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, 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):1473–81.

    CAS  PubMed  Google Scholar 

  68. Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304(10):1073–81.

    CAS  PubMed  Google Scholar 

  69. Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011–24.

    CAS  PubMed  Google Scholar 

  70. Tempero MA, Reni M, Riess H, Pelzer U, O'Reilly EM, Winter JM, et al. APACT: phase III, multicenter, international, open-label, randomized trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma. J Clin Oncol. 2019;37(15_suppl):4000.

    Google Scholar 

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Acknowledgements

Robert J. Torphy is supported by the National Institute of Health/National Center for Advancing Translational Science (NIH/NCATS) Colorado CTSA Grant Number TL1 TR002533.

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  1. Department of Surgery, School of Medicine, Cancer Center, University of Colorado, Anschutz Medical Campus, 12631 E. 17th Avenue, C-305, Aurora, CO, 80045, USA

    Robert J. Torphy, Yuki Fujiwara & Richard D. Schulick

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Torphy, R.J., Fujiwara, Y. & Schulick, R.D. Pancreatic cancer treatment: better, but a long way to go. Surg Today 50, 1117–1125 (2020). https://doi.org/10.1007/s00595-020-02028-0

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