Pancreatic Cancer pp 1105-1130 | Cite as

Treatment of Recurrent Pancreatic Cancer After Surgery

  • Oliver Strobel
  • Willem Niesen
  • Markus W. Büchler
Reference work entry


The majority of patients with pancreatic cancer eventually develop and die from recurrence even after successful surgical resection and adjuvant therapy. Pancreatic cancer recurrence and its treatment are, therefore, very relevant clinical concerns. For several reasons there is a striking lack of knowledge and evidence with respect to the incidence and pattern, the detection, and the management of pancreatic cancer recurrence. This chapter summarizes available data on the incidence, timing, and pattern of recurrence, discusses the need for and the potential of structured surveillance programs, and provides an overview of treatment options for pancreatic cancer recurrence. While most patients will eventually die from systemic recurrences, a relevant subgroup of 20–30% of patients at first present with isolated local recurrence. For systemic recurrences chemotherapy is the only treatment option. However, data from observational cohort studies suggest that treatment strategies that include local approaches may be associated with prolonged survival patients with isolated local recurrences. In order to improve the treatment of both local and systemic recurrence of pancreatic cancer and to enable clinical trials, it will be important to establish surveillance programs after resection and to address treatment options for recurrence in future guidelines.


Pancreatic cancer Resection Surveillance Recurrence Isolated local recurrence Systemic recurrence Re-resection Outcome Survival 


CA 19-9

Carbohydrate antigen 19-9


Computed tomography


Pancreatic ductal adenocarcinoma


Positron emission tomography


Randomized controlled trial


  1. 1.
    Hartwig W, Werner J, Jäger D, Debus J, Büchler MW. Improvement of surgical results for pancreatic cancer. Lancet Oncol. 2013;14(11):e476–85.CrossRefGoogle Scholar
  2. 2.
    Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, et al. Pancreatic cancer. Nat Rev Dis Prim. 2016;2:16022.CrossRefGoogle Scholar
  3. 3.
    Esposito I, Kleeff J, Bergmann F, Reiser C, Herpel E, Friess H, et al. Most pancreatic cancer resections are R1 resections. Ann Surg Oncol. 2008;15(6):1651–60.CrossRefGoogle Scholar
  4. 4.
    Verbeke CS, Leitch D, Menon KV, McMahon MJ, Guillou PJ, Anthoney A. Redefining the R1 resection in pancreatic cancer. Br J Surg. 2006;93(10):1232–7.CrossRefGoogle Scholar
  5. 5.
    Chandrasegaram MD, Goldstein D, Simes J, Gebski V, Kench JG, Gill AJ, et al. Meta-analysis of radical resection rates and margin assessment in pancreatic cancer. Br J Surg. 2015;102(12):1459–72.CrossRefGoogle Scholar
  6. 6.
    Strobel O, Hank T, Hinz U, Bergmann F, Schneider L, Springfeld C, et al. Pancreatic cancer surgery: the new r-status counts. Ann Surg. 2017;265(3):565–573.CrossRefGoogle Scholar
  7. 7.
    Fernández-Cruz L, Johnson C, Dervenis C. Locoregional dissemination and extended lymphadenectomy in pancreatic cancer. Dig Surg. 1999;16(4):313–9.CrossRefGoogle Scholar
  8. 8.
    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.CrossRefGoogle Scholar
  9. 9.
    Smeenk HG, van Eijck CHJ, Hop WC, Erdmann J, Tran KCK, Debois M, et al. Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: long-term results of EORTC trial 40891. Ann Surg. 2007;246(5):734–40.CrossRefGoogle Scholar
  10. 10.
    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
  11. 11.
    Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299(9):1019–26.CrossRefGoogle Scholar
  12. 12.
    Ueno H, Kosuge T, Matsuyama Y, Yamamoto J, Nakao A, Egawa S, et al. A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. Br J Cancer. 2009;101(6):908–15.CrossRefGoogle Scholar
  13. 13.
    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
  14. 14.
    Van Laethem J-L, Hammel P, Mornex F, Azria D, Van Tienhoven G, Vergauwe P, et al. Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC-40013-22012/FFCD-9203/GERCOR phase II study. J Clin Oncol. 2010;28(29):4450–6.CrossRefGoogle Scholar
  15. 15.
    Schmidt J, Abel U, Debus J, Harig S, Hoffmann K, Herrmann T, et al. Open-label, multicenter, randomized phase III trial of adjuvant chemoradiation plus interferon Alfa-2b versus fluorouracil and folinic acid for patients with resected pancreatic adenocarcinoma. J Clin Oncol. 2012;30(33):4077–83.CrossRefGoogle Scholar
  16. 16.
    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.CrossRefGoogle Scholar
  17. 17.
    Strobel O, Büchler MW. Management of cancer recurrence. In: Beger HG, Warshaw AL, Büchler MW, Kozarek RA, Lerch MM, Neoptolemos JP, et al., editors. The pancreas. Oxford, UK: Wiley. in press.Google Scholar
  18. 18.
    Hartwig W, Hackert T, Hinz U, Gluth A, Bergmann F, Strobel O, et al. Pancreatic cancer surgery in the new millennium. Ann Surg. 2011;254(2):311–9.CrossRefGoogle Scholar
  19. 19.
    Lewis R, Drebin JA, Callery MP, Fraker D, Kent TS, Gates J, et al. A contemporary analysis of survival for resected pancreatic ductal adenocarcinoma. HPB (Oxford). 2013;15(1):49–60.CrossRefGoogle Scholar
  20. 20.
    Strobel O, Hinz U, Gluth A, Hank T, Hackert T, Bergmann F, et al. Pancreatic adenocarcinoma: number of positive nodes allows to distinguish several N categories. Ann Surg. 2015;261(5):961–9.CrossRefGoogle Scholar
  21. 21.
    NCCN Guideline. Pancreatic Adenocarcinoma Version 2.2016, 08/16/16 © National Comprehensive Cancer Network, Inc. 2016. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Accessed 29 Sept 2016.
  22. 22.
    Seufferlein T, Porzner M, Becker T, Budach V, Ceyhan G, Esposito I, et al. S3-guideline exocrine pancreatic cancer. Z Gastroenterol. 2013;51:1395–440.CrossRefGoogle Scholar
  23. 23.
    Khorana AA, Mangu PB, Berlin J, Engebretson A, Hong TS, Maitra A, et al. Potentially curable pancreatic cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2016;34(21):JCO675553–2556.CrossRefGoogle Scholar
  24. 24.
    Seufferlein T, Bachet JB, Van Cutsem E, Rougier P. ESMO Guidelines Working Group. Pancreatic adenocarcinoma: ESMO-ESDO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(Suppl 7):vii33–40.CrossRefGoogle Scholar
  25. 25.
    PDQ Adult Treatment Editorial Board. Pancreatic Cancer Treatment (PDQ®): Health Professional Version. Bethesda: National Cancer Institute (US); 2016. Accessed 28 Sept 2016. [PMID: 26389394].
  26. 26.
    Takaori K, Bassi C, Biankin A, Brunner TB, Cataldo I, Campbell F, et al. International Association of Pancreatology (IAP)/European Pancreatic Club (EPC) consensus review of guidelines for the treatment of pancreatic cancer. Pancreatology. 2016;16(1):14–27.CrossRefGoogle Scholar
  27. 27.
    Parikh AA, Maiga A, Bentrem D, Squires MH, Kooby DA, Maithel SK, et al. Adjuvant therapy in pancreas cancer: does it influence patterns of recurrence? J Am Coll Surg. 2016;222(4):448–56.CrossRefGoogle Scholar
  28. 28.
    Hishinuma S, Ogata Y, Tomikawa M, Ozawa I, Hirabayashi K, Igarashi S. Patterns of recurrence after curative resection of pancreatic cancer, based on autopsy findings. J Gastrointest Surg. 2006;10(4):511–8.CrossRefGoogle Scholar
  29. 29.
    Iacobuzio-Donahue CA, Fu B, Yachida S, Luo M, Abe H, Henderson CM, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27(11):1806–13.CrossRefGoogle Scholar
  30. 30.
    Tanaka H, Takamori H, Kanemitsu K, Chikamoto A, Beppu T, Baba H. An autopsy study to clarify characteristics of local recurrence after extended pancreatectomy with intraoperative radiation therapy in patients with pancreatic cancer. Langenbeck’s Arch Surg. 2012;397(6):927–32.CrossRefGoogle Scholar
  31. 31.
    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
  32. 32.
    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):1–463.CrossRefGoogle Scholar
  33. 33.
    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
  34. 34.
    Tzeng C-WD, Abbott DE, Cantor SB, Fleming JB, Lee JE, Pisters PWT, et al. Frequency and intensity of postoperative surveillance after curative treatment of pancreatic cancer: a cost-effectiveness analysis. Ann Surg Oncol. 2013;20(7):2197–203.CrossRefGoogle Scholar
  35. 35.
    Tjaden C, Michalski CW, Strobel O, Giese N, Hennche A-K, Büchler MW, et al. Clinical impact of structured follow-up after pancreatic surgery. Pancreas. 2016;45(6):895–9.CrossRefGoogle Scholar
  36. 36.
    Heye T, Zausig N, Klauss M, Singer R, Werner J, Richter GM, et al. CT diagnosis of recurrence after pancreatic cancer: is there a pattern? WJG. 2011;17(9):1126–34.CrossRefGoogle Scholar
  37. 37.
    Balaj C, Ayav A, Oliver A, Jausset F, Sellal C, Claudon M, et al. CT imaging of early local recurrence of pancreatic adenocarcinoma following pancreaticoduodenectomy. Abdom Radiol (NY). 2016;41(2):273–82.CrossRefGoogle Scholar
  38. 38.
    Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015;523(7559):177–82.CrossRefGoogle Scholar
  39. 39.
    Zill OA, Greene C, Sebisanovic D, Siew LM, Leng J, Vu M, et al. Cell-Free DNA next-generation sequencing in pancreatobiliary carcinomas. Cancer Discov. 2015;5(10):1040–8.CrossRefGoogle Scholar
  40. 40.
    Crippa S, Bittoni A, Sebastiani E, Partelli S, Zanon S, Lanese A, et al. Is there a role for surgical resection in patients with pancreatic cancer with liver metastases responding to chemotherapy? Eur J Surg Oncol. 2016;42(10):1533–9.CrossRefGoogle Scholar
  41. 41.
    Tachezy M, Gebauer F, Janot M, Uhl W, Zerbi A, Montorsi M, et al. Synchronous resections of hepatic oligometastatic pancreatic cancer: disputing a principle in a time of safe pancreatic operations in a retrospective multicenter analysis. Surgery. 2016;160(1):136–44.CrossRefGoogle Scholar
  42. 42.
    Robinson LA, Tanvetyanon T, Springett G, Fontaine J, Toloza E, Hodul P, et al. Pulmonary metastasectomy for suspected pancreaticobiliary cancer. J Thorac Cardiovasc Surg. 2016;152(1):75–82.CrossRefGoogle Scholar
  43. 43.
    Kruger S, Haas M, Burger PJ, Ormanns S, Modest DP, Westphalen CB, et al. Isolated pulmonary metastases define a favorable subgroup in metastatic pancreatic cancer. Pancreatology. 2016;16(4):593–8.CrossRefGoogle Scholar
  44. 44.
    Arnaoutakis GJ, Rangachari D, Laheru DA, Iacobuzio-Donahue CA, Hruban RH, Herman JM, et al. Pulmonary resection for isolated pancreatic adenocarcinoma metastasis: an analysis of outcomes and survival. J Gastrointest Surg. 2011;15(9):1611–7.CrossRefGoogle Scholar
  45. 45.
    Yamashita K, Miyamoto A, Hama N, Asaoka T, Maeda S, Omiya H, et al. Survival impact of pulmonary metastasis as recurrence of pancreatic ductal adenocarcinoma. Dig Surg. 2015;32(6):464–71.CrossRefGoogle Scholar
  46. 46.
    Thomas RM, Truty MJ, Nogueras-Gonzalez GM, Fleming JB, Vauthey J-N, Pisters PWT, et al. Selective reoperation for locally recurrent or metastatic pancreatic ductal adenocarcinoma following primary pancreatic resection. J Gastrointest Surg. 2012;16(9):1696–704.CrossRefGoogle Scholar
  47. 47.
    Nakajima M, Ueno T, Suzuki N, Matsui H, Shindo Y, Sakamoto K, et al. Novel indications for surgical resection of metachronous lung metastases from pancreatic cancer after curative resection. J Clin Gastroenterol. 2016 May 31. [Epub ahead of print], [PMID:27253466].Google Scholar
  48. 48.
    Wangjam T, Zhang Z, Zhou XC, Lyer L, Faisal F, Soares KC, et al. Resected pancreatic ductal adenocarcinomas with recurrence limited in lung have a significantly better prognosis than those with other recurrence patterns. Oncotarget. 2015;6(34):36903–10.CrossRefGoogle Scholar
  49. 49.
    Zhong Y, Macgregor-Das AM, Saunders T, Whittle M, Makohon-Moore A, Kohutek Z, et al. Mutant p53 together with TGFβ signaling influence organ-specific hematogenous colonization patterns of pancreatic cancer. Clin Cancer Res. 2016 Sep 16. doi:10.1158/1078-0432.CCR-15-1615. [Epub ahead of print].CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Wilkowski R, Thoma M, Bruns C, Dühmke E, Heinemann V. Combined chemoradiotherapy for isolated local recurrence after primary resection of pancreatic cancer. JOP. 2006;7(1):34–40.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Wild AT, Hiniker SM, Chang DT, Tran PT, Khashab MA, Limaye MR, et al. Re-irradiation with stereotactic body radiation therapy as a novel treatment option for isolated local recurrence of pancreatic cancer after multimodality therapy: experience from two institutions. J Gastrointest Oncol. 2013;4(4):343–51.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Habermehl D, Brecht IC, Bergmann F, Welzel T, Rieken S, Werner J, et al. Chemoradiation in patients with isolated recurrent pancreatic cancer – therapeutical efficacy and probability of re-resection. Radiat Oncol Biomed Cent. 2013;8(1):27.CrossRefGoogle Scholar
  53. 53.
    Nakamura A, Itasaka S, Takaori K, Kawaguchi Y, Shibuya K, Yoshimura M, et al. Radiotherapy for patients with isolated local recurrence of primary resected pancreatic cancer. Prolonged disease-free interval associated with favorable prognosis. Strahlenther Onkol. 2014;190(5):485–90.CrossRefGoogle Scholar
  54. 54.
    Zeng X-L, Wang H-H, Meng M-B, Wu Z-Q, Song Y-C, Zhuang H-Q, et al. Stereotactic body radiation therapy for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph nodes or postoperative stump including pancreatic stump and other stump. Onco Targets Ther. 2016;9:3985–92.CrossRefGoogle Scholar
  55. 55.
    Kleeff J, Reiser C, Hinz U, Bachmann J, Debus J, Jaeger D, et al. Surgery for recurrent pancreatic ductal adenocarcinoma. Ann Surg. 2007;245(4):566–72.CrossRefGoogle Scholar
  56. 56.
    Lavu H, Nowcid LJ, Klinge MJ, Mahendraraj K, Grenda DR, Sauter PK, et al. Reoperative completion pancreatectomy for suspected malignant disease of the pancreas. J Surg Res. 2011;170(1):89–95.CrossRefGoogle Scholar
  57. 57.
    Strobel O, Hartwig W, Hackert T, Hinz U, Berens V, Grenacher L, et al. Re-resection for isolated local recurrence of pancreatic cancer is feasible, safe, and associated with encouraging survival. Ann Surg Oncol. 2013;20(3):964–72.CrossRefGoogle Scholar
  58. 58.
    Boone BA, Zeh HJ, Mock BK, Johnson PJ, Dvorchik I, Lee K, et al. Resection of isolated local and metastatic recurrence in periampullary adenocarcinoma. HPB (Oxford). 2014;16(3):197–203.CrossRefGoogle Scholar
  59. 59.
    Miyazaki M, Yoshitomi H, Shimizu H, Ohtsuka M, Yoshidome H, Furukawa K, et al. Repeat pancreatectomy for pancreatic ductal cancer recurrence in the remnant pancreas after initial pancreatectomy: is it worthwhile? Surgery. 2014;155(1):58–66.CrossRefGoogle Scholar
  60. 60.
    Shima Y, Okabayashi T, Kozuki A, Sumiyoshi T, Tokumaru T, Saisaka Y, et al. Completion pancreatectomy for recurrent pancreatic cancer in the remnant pancreas: report of six cases and a review of the literature. Langenbeck’s Arch Surg. 2015;400(8):973–8.CrossRefGoogle Scholar
  61. 61.
    Chang S-C, Hsu C-P, Tsai C-Y, Liu Y-Y, Liu K-H, Hsu J-T, et al. Selective reoperation after primary resection as a feasible and safe treatment strategy for recurrent pancreatic cancer. Medicine (Baltimore). 2016;95(30):e4191.CrossRefGoogle Scholar
  62. 62.
    Hartwig W, Hackert T, Hinz U, Hassenpflug M, Strobel O, Büchler MW, et al. Multivisceral resection for pancreatic malignancies: risk-analysis and long-term outcome. Ann Surg. 2009;250(1):81–7.CrossRefGoogle Scholar
  63. 63.
    Sperti C, Pasquali C, Piccoli A, Pedrazzoli S. Recurrence after resection for ductal adenocarcinoma of the pancreas. World J Surg. 1997;21(2):195–200.CrossRefGoogle Scholar
  64. 64.
    Jung W, Jang J-Y, Kang MJ, Chang YR, Shin YC, Chang J, et al. The clinical usefulness of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) in follow-up of curatively resected pancreatic cancer patients. HPB (Oxford). 2016;18(1):57–64.CrossRefGoogle Scholar
  65. 65.
    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;17:500–3. 1–5CrossRefGoogle Scholar
  66. 66.
    Waddell N, Pajic M, Patch A-M, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495–501.CrossRefGoogle Scholar
  67. 67.
    Noll EM, Eisen C, Stenzinger A, Espinet E, Muckenhuber A, Klein C, et al. CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma. Nat Med. 2016;22(3):278–87.CrossRefGoogle Scholar
  68. 68.
    Bailey P, Chang DK, Nones K, Johns AL, Patch A-M, Gingras M-C, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47–52.CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Oliver Strobel
    • 1
  • Willem Niesen
    • 1
  • Markus W. Büchler
    • 1
  1. 1.Department of General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany

Section editors and affiliations

  • James L. Abbruzzese
    • 1
  • Raul A. Urrutia
    • 2
  • John Neoptolemos
    • 3
  • Markus W. Büchler
    • 4
  1. 1.Duke University Medical CenterDurhamUSA
  2. 2.Mayo Clinic Cancer CenterMayo ClinicRochesterUSA
  3. 3.Division of Surgery and OncologyUniversity of LiverpoolLiverpoolUK
  4. 4.Department of General, Visceral and Transplantation SurgeryUniversity of HeidelbergHeidelbergGermany

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