Pancreatic Cancer pp 1187-1202 | Cite as

Neoadjuvant Chemotherapy in Pancreatic Cancer

  • Theodoros Michelakos
  • Cristina R. Ferrone
Reference work entry


More than 30% of pancreatic ductal adenocarcinoma (PDAC) patients present with borderline resectable (BR) or locally advanced (LA) disease. Historically, this patient population had a poor prognosis, with the majority not being offered an operation. Following the promising results of modern combination regimens such as FOLFIRINOX (5-FU, oxaliplatin and irinotecan) and gemcitabine plus nab-paclitaxel for patients with metastatic PDAC, these regimens have been utilized in patients with BR or LA disease to render them resectable. Indeed, neoadjuvant FOLFIRINOX increases resectability of LA PDAC up to 44%, with margin-negative resection rates and overall survival rates comparable to upfront resectable patients. Neoadjuvant chemotherapy also aids in obviating adjuvant therapy, which is frequently not initiated or completed due to the morbidity associated with pancreatic operations. Based on the encouraging results in locally advanced and borderline patients, neoadjuvant chemotherapy may also be of use in patients presenting with resectable disease. Neoadjuvant therapy may aid in screening patients with aggressive disease who progress on neoadjuvant therapy, and therefore may not benefit from an operation. Clinical trials currently underway will provide further information on the efficacy of modern neoadjuvant therapies for PDAC patients.


Pancreatic ductal adenocarcinoma Neoadjuvant chemotherapy FOLFIRINOX Gemcitabine and nab-paclitaxel Locally advanced pancreatic adenocarcinoma Borderline resectable pancreatic adenocarcinoma 


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.CrossRefGoogle Scholar
  2. 2.
    Stathis A, Moore MJ. Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol. 2010;7(3):163–72.CrossRefGoogle Scholar
  3. 3.
    Ferrone CR, Marchegiani G, Hong TS, Ryan DP, Deshpande V, McDonnell EI, et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. Ann Surg. 2015;261(1):12–7.CrossRefGoogle Scholar
  4. 4.
    Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362(17):1605–17.CrossRefGoogle Scholar
  5. 5.
    Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7(4):e1000267.CrossRefGoogle Scholar
  6. 6.
    Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, et al. Effect of Chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without Erlotinib: the LAP07 randomized clinical trial. JAMA. 2016;315(17):1844–53.CrossRefGoogle Scholar
  7. 7.
    Andriulli A, Festa V, Botteri E, Valvano MR, Koch M, Bassi C, et al. Neoadjuvant/preoperative gemcitabine for patients with localized pancreatic cancer: a meta-analysis of prospective studies. Ann Surg Oncol. 2012;19(5):1644–62.CrossRefGoogle Scholar
  8. 8.
    Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.CrossRefGoogle Scholar
  9. 9.
    Faris JE, Blaszkowsky LS, McDermott S, Guimaraes AR, Szymonifka J, Huynh MA, et al. FOLFIRINOX in locally advanced pancreatic cancer: the Massachusetts General Hospital cancer center experience. Oncologist. 2013;18(5):543–8.CrossRefGoogle Scholar
  10. 10.
    Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, et al. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer. 2012;12:199.CrossRefGoogle Scholar
  11. 11.
    Mellon EA, Hoffe SE, Springett GM, Frakes JM, Strom TJ, Hodul PJ, et al. Long-term outcomes of induction chemotherapy and neoadjuvant stereotactic body radiotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma. Acta Oncol. 2015;54(7):979–85.CrossRefGoogle Scholar
  12. 12.
    Sadot E, Doussot A, O’Reilly EM, Lowery MA, Goodman KA, Do RK, et al. FOLFIRINOX induction therapy for stage 3 pancreatic adenocarcinoma. Ann Surg Oncol. 2015;22(11):3512–21.CrossRefGoogle Scholar
  13. 13.
    Suker M, Beumer BR, Sadot E, Marthey L, Faris JE, Mellon EA, et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol. 2016;17(6):801–10.CrossRefGoogle Scholar
  14. 14.
    Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.CrossRefGoogle Scholar
  15. 15.
    Motoi F, Ishida K, Fujishima F, Ottomo S, Oikawa M, Okada T, et al. Neoadjuvant chemotherapy with gemcitabine and S-1 for resectable and borderline pancreatic ductal adenocarcinoma: results from a prospective multi-institutional phase 2 trial. Ann Surg Oncol. 2013;20(12):3794–801.CrossRefGoogle Scholar
  16. 16.
    Sahora K, Kuehrer I, Eisenhut A, Akan B, Koellblinger C, Goetzinger P, et al. NeoGemOx: gemcitabine and oxaliplatin as neoadjuvant treatment for locally advanced, nonmetastasized pancreatic cancer. Surgery. 2011;149(3):311–20.CrossRefGoogle Scholar
  17. 17.
    Callery MP, Chang KJ, Fishman EK, Talamonti MS, William Traverso L, Linehan DC. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol. 2009;16(7):1727–33.CrossRefGoogle Scholar
  18. 18.
    Konstantinidis IT, Warshaw AL, Allen JN, Blaszkowsky LS, Castillo CF, Deshpande V, et al. Pancreatic ductal adenocarcinoma: is there a survival difference for R1 resections versus locally advanced unresectable tumors? What is a “true” R0 resection? Ann Surg. 2013;257(4):731–6.CrossRefGoogle Scholar
  19. 19.
    Fernandez-del Castillo C, Morales-Oyarvide V, McGrath D, Wargo JA, Ferrone CR, Thayer SP, et al. Evolution of the Whipple procedure at the Massachusetts General Hospital. Surgery. 2012;152(3 Suppl 1):S56–63.CrossRefGoogle Scholar
  20. 20.
    Cameron JL, Riall TS, Coleman J, Belcher KA. One thousand consecutive pancreaticoduodenectomies. Ann Surg. 2006;244(1):10–5.CrossRefGoogle Scholar
  21. 21.
    Ho CK, Kleeff J, Friess H, Buchler MW. Complications of pancreatic surgery. HPB (Oxford). 2005;7(2):99–108.CrossRefGoogle Scholar
  22. 22.
    Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297(3):267–77.CrossRefGoogle Scholar
  23. 23.
    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.CrossRefGoogle Scholar
  24. 24.
    Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 1982;5(6):649–55.CrossRefGoogle Scholar
  25. 25.
    Conroy T, Paillot B, Francois E, Bugat R, Jacob JH, Stein U, et al. Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer – a Groupe Tumeurs digestives of the federation Nationale des Centres de Lutte Contre le cancer study. J Clin Oncol. 2005;23(6):1228–36.CrossRefGoogle Scholar
  26. 26.
    Gunturu KS, Yao X, Cong X, Thumar JR, Hochster HS, Stein SM, et al. FOLFIRINOX for locally advanced and metastatic pancreatic cancer: single institution retrospective review of efficacy and toxicity. Med Oncol. 2013;30(1):361.CrossRefGoogle Scholar
  27. 27.
    Hohla F, Hopfinger G, Romeder F, Rinnerthaler G, Bezan A, Stattner S, et al. Female gender may predict response to FOLFIRINOX in patients with unresectable pancreatic cancer: a single institution retrospective review. Int J Oncol. 2014;44(1):319–26.CrossRefGoogle Scholar
  28. 28.
    Kraemer PC, Schmidt HH, Ladekarl M. Danish experiences with FOLFIRINOX as first-line therapy in patients with inoperable pancreatic cancer. Dan Med J. 2014;61(4):A4819.PubMedGoogle Scholar
  29. 29.
    Blazer M, Wu C, Goldberg RM, Phillips G, Schmidt C, Muscarella P, et al. Neoadjuvant modified (m) FOLFIRINOX for locally advanced unresectable (LAPC) and borderline resectable (BRPC) adenocarcinoma of the pancreas. Ann Surg Oncol. 2015;22(4):1153–9.CrossRefGoogle Scholar
  30. 30.
    Boone BA, Steve J, Krasinskas AM, Zureikat AH, Lembersky BC, Gibson MK, et al. Outcomes with FOLFIRINOX for borderline resectable and locally unresectable pancreatic cancer. J Surg Oncol. 2013;108(4):236–41.CrossRefGoogle Scholar
  31. 31.
    Marthey L, Sa-Cunha A, Blanc JF, Gauthier M, Cueff A, Francois E, et al. FOLFIRINOX for locally advanced pancreatic adenocarcinoma: results of an AGEO multicenter prospective observational cohort. Ann Surg Oncol. 2015;22(1):295–301.CrossRefGoogle Scholar
  32. 32.
    Moorcraft SY, Khan K, Peckitt C, Watkins D, Rao S, Cunningham D, et al. FOLFIRINOX for locally advanced or metastatic pancreatic ductal adenocarcinoma: the Royal Marsden experience. Clin Colorectal Cancer. 2014;13(4):232–8.CrossRefGoogle Scholar
  33. 33.
    Peddi PF, Lubner S, McWilliams R, Tan BR, Picus J, Sorscher SM, et al. Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma. JOP. 2012;13(5):497–501.PubMedGoogle Scholar
  34. 34.
    Mahaseth H, Brutcher E, Kauh J, Hawk N, Kim S, Chen Z, et al. Modified FOLFIRINOX regimen with improved safety and maintained efficacy in pancreatic adenocarcinoma. Pancreas. 2013;42(8):1311–5.CrossRefGoogle Scholar
  35. 35.
    Pietrasz D, Marthey L, Wagner M, Blanc JF, Laurent C, Turrini O, et al. Pathologic major response after FOLFIRINOX is prognostic for patients secondary resected for borderline or locally advanced pancreatic adenocarcinoma: an AGEO-FRENCH, prospective, multicentric cohort. Ann Surg Oncol. 2015;22(Suppl 3):S1196–205.CrossRefGoogle Scholar
  36. 36.
    Hackert T, Sachsenmaier M, Hinz U, Schneider L, Michalski CW, Springfeld C, et al. Locally advanced pancreatic cancer: neoadjuvant therapy with Folfirinox results in Resectability in 60% of the patients. Ann Surg. 2016;264(3):457–63.CrossRefGoogle Scholar
  37. 37.
    Rombouts SJ, Walma MS, Vogel JA, van Rijssen LB, Wilmink JW, Mohammad NH, et al. Systematic review of resection rates and clinical outcomes after FOLFIRINOX-based treatment in patients with locally advanced pancreatic cancer. Ann Surg Oncol. 2016;23(13):4352–60.CrossRefGoogle Scholar
  38. 38.
    Dias-Santos D, Ferrone CR, Zheng H, Lillemoe KD, Fernandez-Del CC. The Charlson age comorbidity index predicts early mortality after surgery for pancreatic cancer. Surgery. 2015;157(5):881–7.CrossRefGoogle Scholar
  39. 39.
    Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(21):3496–502.CrossRefGoogle Scholar
  40. 40.
    Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouche O, Guimbaud R, et al. Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013;31(1):23–9.CrossRefGoogle Scholar
  41. 41.
    Stokes JB, Nolan NJ, Stelow EB, Walters DM, Weiss GR, de Lange EE, et al. Preoperative capecitabine and concurrent radiation for borderline resectable pancreatic cancer. Ann Surg Oncol. 2011;18(3):619–27.CrossRefGoogle Scholar
  42. 42.
    Chun YS, Milestone BN, Watson JC, Cohen SJ, Burtness B, Engstrom PF, et al. Defining venous involvement in borderline resectable pancreatic cancer. Ann Surg Oncol. 2010;17(11):2832–8.CrossRefGoogle Scholar
  43. 43.
    Kang CM, Chung YE, Park JY, Sung JS, Hwang HK, Choi HJ, et al. Potential contribution of preoperative neoadjuvant concurrent chemoradiation therapy on margin-negative resection in borderline resectable pancreatic cancer. J Gastrointest Surg. 2012;16(3):509–17.CrossRefGoogle Scholar
  44. 44.
    Christians KK, Tsai S, Mahmoud A, Ritch P, Thomas JP, Wiebe L, et al. Neoadjuvant FOLFIRINOX for borderline resectable pancreas cancer: a new treatment paradigm? Oncologist. 2014;19(3):266–74.CrossRefGoogle Scholar
  45. 45.
    Takahashi H, Ohigashi H, Gotoh K, Marubashi S, Yamada T, Murata M, et al. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013;258(6):1040–50.CrossRefGoogle Scholar
  46. 46.
    Kim SS, Nakakura EK, Wang ZJ, Kim GE, Corvera CU, Harris HW, et al. Preoperative FOLFIRINOX for borderline resectable pancreatic cancer: is radiation necessary in the modern era of chemotherapy? J Surg Oncol. 2016;114(5):587–96.CrossRefGoogle Scholar
  47. 47.
    Katz MH, Shi Q, Ahmad SA, Herman JM, Marsh Rde W, Collisson E, et al. Preoperative modified FOLFIRINOX treatment followed by Capecitabine-based chemoradiation for borderline resectable pancreatic cancer: alliance for clinical trials in oncology trial A021101. JAMA Surg. 2016;151(8):e161137.CrossRefGoogle Scholar
  48. 48.
    Okada K, Kawai M, Hirono S, Satoi S, Yanagimoto H, Ioka T, et al. Impact of treatment duration of neoadjuvant FIRINOX in patients with borderline resectable pancreatic cancer: a pilot trial. Cancer Chemother Pharmacol. 2016;78(4):719–26.CrossRefGoogle Scholar
  49. 49.
    Paniccia A, Edil BH, Schulick RD, Byers JT, Meguid C, Gajdos C, et al. Neoadjuvant FOLFIRINOX application in borderline resectable pancreatic adenocarcinoma: a retrospective cohort study. Medicine (Baltimore). 2014;93(27):e198.CrossRefGoogle Scholar
  50. 50.
    Shaib WL, Hawk N, Cassidy RJ, Chen Z, Zhang C, Brutcher E, et al. A phase 1 study of stereotactic body radiation therapy dose escalation for borderline resectable pancreatic cancer after modified FOLFIRINOX (NCT01446458). Int J Radiat Oncol Biol Phys. 2016;96(2):296–303.CrossRefGoogle Scholar
  51. 51.
    Katz MH, Pisters PW, Evans DB, Sun CC, Lee JE, Fleming JB, et al. Borderline resectable pancreatic cancer: the importance of this emerging stage of disease. J Am Coll Surg. 2008;206(5):833–46. discussion 46–8CrossRefGoogle Scholar
  52. 52.
    Buettner S, Peters N, Suker M, Beumer B, Wang-Gillam A, Hosein P, et al. Preoperative folfirinox in patients with borderline resectable pancreatic cancer: A systematic review and patient-level meta-analysis. In: 51st annual pancreas club meeting. Chicago; 2017.Google Scholar
  53. 53.
    Ferrone CR, Pieretti-Vanmarcke R, Bloom JP, Zheng H, Szymonifka J, Wargo JA, et al. Pancreatic ductal adenocarcinoma: long-term survival does not equal cure. Surgery. 2012;152(3 Suppl 1):S43–9.CrossRefGoogle Scholar
  54. 54.
    Assifi MM, Lu X, Eibl G, Reber HA, Li G, Hines OJ. Neoadjuvant therapy in pancreatic adenocarcinoma: a meta-analysis of phase II trials. Surgery. 2011;150(3):466–73.CrossRefGoogle Scholar
  55. 55.
    Mokdad AA, Minter RM, Zhu H, Augustine MM, Porembka MR, Wang SC, et al. Neoadjuvant therapy followed by resection versus upfront resection for resectable pancreatic cancer: a propensity score matched analysis. J Clin Oncol. 2017;35(5):515–522.CrossRefGoogle Scholar
  56. 56.
    Heinrich S, Pestalozzi BC, Schafer M, Weber A, Bauerfeind P, Knuth A, et al. Prospective phase II trial of neoadjuvant chemotherapy with gemcitabine and cisplatin for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(15):2526–31.CrossRefGoogle Scholar
  57. 57.
    Palmer DH, Stocken DD, Hewitt H, Markham CE, Hassan AB, Johnson PJ, et al. A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with cisplatin. Ann Surg Oncol. 2007;14(7):2088–96.CrossRefGoogle Scholar
  58. 58.
    Varadhachary GR, Wolff RA, Crane CH, Sun CC, Lee JE, Pisters PW, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(21):3487–95.CrossRefGoogle Scholar
  59. 59.
    Wagner M, Antunes C, Pietrasz D, Cassinotto C, Zappa M, Sa Cunha A, et al. CT evaluation after neoadjuvant FOLFIRINOX chemotherapy for borderline and locally advanced pancreatic adenocarcinoma. Eur Radiol. 2017;27(7):3104–3116.CrossRefGoogle Scholar
  60. 60.
    Katz MH, Fleming JB, Bhosale P, Varadhachary G, Lee JE, Wolff R, et al. Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators. Cancer. 2012;118(23):5749–56.CrossRefGoogle Scholar
  61. 61.
    Tamm EP, Loyer EM, Faria S, Raut CP, Evans DB, Wolff RA, et al. Staging of pancreatic cancer with multidetector CT in the setting of preoperative chemoradiation therapy. Abdom Imaging. 2006;31(5):568–74.CrossRefGoogle Scholar
  62. 62.
    White RR, Paulson EK, Freed KS, Keogan MT, Hurwitz HI, Lee C, et al. Staging of pancreatic cancer before and after neoadjuvant chemoradiation. J Gastrointest Surg. 2001;5(6):626–33.CrossRefGoogle Scholar
  63. 63.
    Bednar F, Zenati MS, Steve J, Winters S, Ocuin LM, Bahary N, et al. Analysis of predictors of resection and survival in locally advanced stage III pancreatic cancer: does the nature of chemotherapy regimen influence outcomes? Ann Surg Oncol. 2017;24(5):1406–13.CrossRefGoogle Scholar
  64. 64.
    Boone BA, Steve J, Zenati MS, Hogg ME, Singhi AD, Bartlett DL, et al. Serum CA 19-9 response to neoadjuvant therapy is associated with outcome in pancreatic adenocarcinoma. Ann Surg Oncol. 2014;21(13):4351–8.CrossRefGoogle Scholar
  65. 65.
    Aldakkak M, Christians KK, Krepline AN, George B, Ritch PS, Erickson BA, et al. Pre-treatment carbohydrate antigen 19-9 does not predict the response to neoadjuvant therapy in patients with localized pancreatic cancer. HPB (Oxford). 2015;17(10):942–52.CrossRefGoogle Scholar
  66. 66.
    Katz MH, Varadhachary GR, Fleming JB, Wolff RA, Lee JE, Pisters PW, et al. Serum CA 19-9 as a marker of resectability and survival in patients with potentially resectable pancreatic cancer treated with neoadjuvant chemoradiation. Ann Surg Oncol. 2010;17(7):1794–801.CrossRefGoogle Scholar
  67. 67.
    Caparello C, Meijer LL, Garajova I, Falcone A, Le Large TY, Funel N, et al. FOLFIRINOX and translational studies: towards personalized therapy in pancreatic cancer. World J Gastroenterol. 2016;22(31):6987–7005.CrossRefGoogle Scholar
  68. 68.
    Capello M, Lee M, Wang H, Babel I, Katz MH, Fleming JB, et al. Carboxylesterase 2 as a determinant of response to irinotecan and neoadjuvant FOLFIRINOX therapy in pancreatic ductal adenocarcinoma. J Natl Cancer Inst. 2015;107(8);djv132.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of SurgeryMassachusetts General Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations