The investigation of the survival time after recurrence in patients with pancreatic ductal adenocarcinoma for individualization of adjuvant chemotherapy

  • Daisaku Yamada
  • Hidetoshi Eguchi
  • Yoshifumi Iwagami
  • Tadafumi Asaoka
  • Takehiro Noda
  • Koichi Kawamoto
  • Kunihito Gotoh
  • Shogo Kobayashi
  • Masaki Mori
  • Yuichiro Doki
Original Article
  • 12 Downloads

Abstract

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease; however, the frequency of recurrence can be reduced if curative surgery following adjuvant chemotherapy is applied. At present, adjuvant chemotherapy is uniformly performed in all patients, as it is unclear which tumor types are controlled best or worst. We investigated patients with recurrence to establish the optimum treatment strategy.

Methods

Of 138 patients who underwent curative surgery for PDAC, 85 developed recurrence. Comprehensive clinicopathological factors were investigated for their association with the survival time after recurrence (SAR).

Results

The median SAR was 12.6 months. Treatments for recurrence included best supportive care, GEM-based therapy and S-1. The performance status [hazard ratio (HR) 0.12, P < 0.001], histological invasion of lymph vessels (HR 0.27, P < 0.001), kind of treatment for recurrence (HR 5.0, P < 0.001) and initial recurrence site (HR 2.9, P < 0.001) were independent significant risk factors for the SAR. The initial recurrence sites were the liver (n = 21, median SAR 8.8 months), lung (n = 10, 14.9 months), peritoneum (n = 6, 1.7 months), lymph nodes (n = 6, 14.7 months), local site (n = 17, 13.9 months) and multiple sites (n = 25, 10.1 months). A shorter recurrence-free survival (< 1 year) and higher postoperative CA19-9 level were significantly associated with critical recurrence (peritoneal/liver).

Conclusions

Several risk factors for SAR were detected in this study. Further investigations are needed to individualize the adjuvant chemotherapy for each patient with PDAC.

Keywords

Pancreatic ductal adenocarcinoma Recurrence Adjuvant chemotherapy 

Notes

Acknowledgements

We thank Dr. Paul Kretchmer and all of the other editors at San Francisco Edit for helping in editing the English language content of our paper.

Funding

We have nothing to disclose. This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Supplementary material

595_2018_1674_MOESM1_ESM.docx (31 kb)
Supplementary material 1 (DOCX 30 KB)

References

  1. 1.
    Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378(9791):607–20.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Mikamori M, Yamada D, Eguchi H, Hasegawa S, Kishimoto T, Tomimaru Y, et al. MicroRNA-155 controls exosome synthesis and promotes gemcitabine resistance in pancreatic ductal adenocarcinoma. Sci Rep. 2017;7:42339.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Mizuguchi T, Torigoe T, Satomi F, Shima H, Kutomi G, Ota S, et al. Trials of vaccines for pancreatic ductal adenocarcinoma: Is there any hope of an improved prognosis? Surg Today. 2016;46(2):139–48.CrossRefPubMedGoogle Scholar
  4. 4.
    Asari S, Matsumoto I, Toyama H, Shinzeki M, Goto T, Ishida J, et al. Preoperative independent prognostic factors in patients with borderline resectable pancreatic ductal adenocarcinoma following curative resection: the neutrophil-lymphocyte and platelet-lymphocyte ratios. Surg Today. 2016;46(5):583–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Komo T, Murakami Y, Kondo N, Uemura K, Hashimoto Y, Nakagawa N, et al. Prognostic impact of para-aortic lymph node micrometastasis in pancreatic ductal adenocarcinoma. Ann Surg Oncol. 2016;23(6):2019–27.CrossRefPubMedGoogle Scholar
  6. 6.
    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.CrossRefPubMedGoogle Scholar
  7. 7.
    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.CrossRefPubMedGoogle Scholar
  8. 8.
    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
  9. 9.
    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.CrossRefPubMedGoogle Scholar
  10. 10.
    DeWitt J, Yu M, Al-Haddad MA, Sherman S, McHenry L, Leblanc JK. Survival in patients with pancreatic cancer after the diagnosis of malignant ascites or liver metastases by EUS-FNA. Gastrointest Endosc. 2010;71(2):260–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Thomas RM, Truty MJ, Nogueras-Gonzalez GM, Fleming JB, Vauthey JN, Pisters PW, et al. Selective reoperation for locally recurrent or metastatic pancreatic ductal adenocarcinoma following primary pancreatic resection. J Gastrointest Surg. 2012;16(9):1696–704.CrossRefPubMedGoogle Scholar
  12. 12.
    Eguchi H, Nagano H, Tanemura M, Takeda Y, Marubashi S, Kobayashi S, et al. Preoperative chemoradiotherapy, surgery and adjuvant therapy for resectable pancreatic cancer. Hepatogastroenterology. 2013;60(124):904–11.PubMedGoogle Scholar
  13. 13.
    Eguchi H, Nagano H, Kobayashi S, Kawamoto K, Wada H, Hama N, et al. A phase I trial of combination therapy using gemcitabine and S-1 concurrent with full-dose radiation for resectable pancreatic cancer. Cancer Chemother Pharmacol. 2014;73(2):309–15.CrossRefPubMedGoogle Scholar
  14. 14.
    Takeda Y, Nakamori S, Eguchi H, Kobayashi S, Marubashi S, Tanemura M, et al. Neoadjuvant gemcitabine-based accelerated hyperfractionation chemoradiotherapy for patients with borderline resectable pancreatic adenocarcinoma. Jpn J Clin Oncol. 2014;44(12):1172–80.CrossRefPubMedGoogle Scholar
  15. 15.
    Tomihara H, Eguchi H, Yamada D, Gotoh K, Kawamoto K, Wada H, et al. Preoperative chemoradiotherapy does not compromise the feasibility of adjuvant chemotherapy for patients with pancreatic ductal adenocarcinoma. Surg Today. 2017;47(2):218–26.CrossRefPubMedGoogle Scholar
  16. 16.
    Yamada D, Eguchi H, Asaoka T, Tomihara H, Noda T, Wada H, et al. The basal nutritional state of PDAC patients is the dominant factor for completing adjuvant chemotherapy. Surg Today. 2017;47(11):1361–71.CrossRefPubMedGoogle Scholar
  17. 17.
    Yamada D, Eguchi H, Iwagami Y, Mukai Y, Hashimoto Y, Asaoka T, et al. Patients treated with preoperative chemoradiation for pancreatic ductal adenocarcinoma have impaired bone density, a predictor of distant metastasis. Ann Surg Oncol. 2017;24(12):3715–24.CrossRefPubMedGoogle Scholar
  18. 18.
    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.CrossRefPubMedGoogle Scholar
  19. 19.
    Iwagami Y, Eguchi H, Wada H, Tomimaru Y, Hama N, Kawamoto K, et al. Implications of peritoneal lavage cytology in resectable left-sided pancreatic cancer. Surg Today. 2015;45(4):444–50.CrossRefPubMedGoogle Scholar
  20. 20.
    Kleger A, Perkhofer L, Seufferlein T. Smarter drugs emerging in pancreatic cancer therapy. Ann Oncol. 2014;25(7):1260–70.CrossRefPubMedGoogle Scholar
  21. 21.
    Geng Y, Qi Q, Sun M, Chen H, Wang P, Chen Z. Prognostic nutritional index predicts survival and correlates with systemic inflammatory response in advanced pancreatic cancer. Eur J Surg Oncol. 2015;41(11):1508–14.CrossRefPubMedGoogle Scholar
  22. 22.
    Kanda M, Fujii T, Kodera Y, Nagai S, Takeda S, Nakao A. Nutritional predictors of postoperative outcome in pancreatic cancer. Br J Surg. 2011;98(2):268–74.CrossRefPubMedGoogle Scholar
  23. 23.
    Watanabe J, Otani S, Sakamoto T, Arai Y, Hanaki T, Amisaki M, et al. Prognostic indicators based on inflammatory and nutritional factors after pancreaticoduodenectomy for pancreatic cancer. Surg Today. 2016;46(11):1258–67.CrossRefGoogle Scholar
  24. 24.
    Smith RA, Ghaneh P, Sutton R, Raraty M, Campbell F, Neoptolemos JP. Prognosis of resected ampullary adenocarcinoma by preoperative serum CA19-9 levels and platelet-lymphocyte ratio. J Gastrointest Surg. 2008;12(8):1422–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Evans DB, Rich TA, Byrd DR, Cleary KR, Connelly JH, Levin B, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg. 1992;127(11):1335–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, Izbicki J, et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery. 2005;138(1):8–13.CrossRefPubMedGoogle Scholar
  27. 27.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    von Burstin J, Eser S, Paul MC, Seidler B, Brandl M, Messer M, et al. E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology. 2009;137(1):361–71 (371 e1–5).CrossRefGoogle Scholar
  29. 29.
    Forssell H, Wester M, Akesson K, Johansson S. A proposed model for prediction of survival based on a follow-up study in unresectable pancreatic cancer. BMJ Open. 2013;3(12):e004064.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329–35.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17(6):816–26.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Thomassen I, Lemmens VE, Nienhuijs SW, Luyer MD, Klaver YL, de Hingh IH. Incidence, prognosis, and possible treatment strategies of peritoneal carcinomatosis of pancreatic origin: a population-based study. Pancreas. 2013;42(1):72–5.CrossRefPubMedGoogle Scholar
  33. 33.
    Koizumi M, Sata N, Kasahara N, Morishima K, Sasanuma H, Sakuma Y, et al. Remnant pancreatectomy for recurrent or metachronous pancreatic carcinoma detected by FDG-PET: two case reports. JOP. 2010;11(1):36–40.PubMedGoogle Scholar
  34. 34.
    Dalla Valle R, Mancini C, Crafa P, Passalacqua R. Pancreatic carcinoma recurrence in the remnant pancreas after a pancreaticoduodenectomy. JOP. 2006;7(5):473–7.PubMedGoogle Scholar
  35. 35.
    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.CrossRefPubMedGoogle Scholar
  36. 36.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Bockhorn J, Prat A, Chang YF, Liu X, Huang S, Shang M, et al. Differentiation and loss of malignant character of spontaneous pulmonary metastases in patient-derived breast cancer models. Cancer Res. 2014;74(24):7406–17.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Motoi F, Rikiyama T, Katayose Y, Egawa S, Unno M. Retrospective evaluation of the influence of postoperative tumor marker status on survival and patterns of recurrence after surgery for pancreatic cancer based on RECIST guidelines. Ann Surg Oncol. 2011;18(2):371–9.CrossRefPubMedGoogle Scholar
  39. 39.
    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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Daisaku Yamada
    • 1
  • Hidetoshi Eguchi
    • 1
  • Yoshifumi Iwagami
    • 1
  • Tadafumi Asaoka
    • 1
  • Takehiro Noda
    • 1
  • Koichi Kawamoto
    • 1
  • Kunihito Gotoh
    • 1
  • Shogo Kobayashi
    • 1
  • Masaki Mori
    • 1
  • Yuichiro Doki
    • 1
  1. 1.Department of Gastroenterological surgery, Graduate School of MedicineOsaka UniversitySuitaJapan

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