Time to Rethink Upfront Surgery for Resectable Intrahepatic Cholangiocarcinoma? Implications from the Neoadjuvant Experience



While surgery is a mainstay of curative-intent treatment for patients with intrahepatic cholangiocarcinoma (IHC), the role of neoadjuvant therapy (NT) has not been well-established. We sought to describe trends in NT utilization, characterize associated factors, and evaluate association with overall survival (OS).


Retrospective cohort study of 4456 surgically resected IHC patients within National Cancer Data Base (2006–2016). NT included chemotherapy alone and/or (chemo)radiation. Descriptive statistics used to describe the cohort. Multivariable hierarchical logistic regression models were used to examine factors associated with NT administration. Analyses conducted comparing OS among upfront surgery patients and NT patients using propensity matching using nearest-neighbor methodology and adjustment using inverse probability of treatment weighting (IPTW). Association between NT and risk of death evaluated using multivariable Cox shared frailty modeling.


Utilization of NT did not significantly increase over time (11%-2006 to 16%-2016, trend test p = 0.07) but did increase among patients with clinical nodal involvement (cN+, 13% to 36%, p = 0.002). Factors associated with NT use include cN+ disease (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.31–2.15) and advanced clinical T stage: T2 (OR 1.65, 95% CI 1.33–2.06); T3 (OR 1.51, 95% CI 1.13–2.02). After propensity matching, NT associated with a 23% decreased risk of death relative to upfront surgery (hazard ratio [HR] 0.77, 95% CI 0.61–0.97). Findings were similar after IPTW (HR 0.83, 95% CI 0.78–0.88).


NT is increasingly used for the management of IHC patients with characteristics indicating aggressive tumor biology and is associated with decreased risk of death. These data suggest need for prospective studies of NT in management of patients with potentially resectable IHC.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2


  1. 1.

    Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol. 2004;40(3):472–7.

    Article  Google Scholar 

  2. 2.

    Khan SA, Thomas HC, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet. 2005;366(9493):1303–14.

    Article  Google Scholar 

  3. 3.

    Khan SA, Toledano MB, Taylor-Robinson SD. Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma. HPB (Oxford). 2008;10(2):77–82.

    CAS  Article  Google Scholar 

  4. 4.


  5. 5.

    Nathan H, Pawlik TM, Wolfgang CL, Choti MA, Cameron JL, Schulick RD. Trends in survival after surgery for cholangiocarcinoma: a 30-year population-based SEER database analysis. J Gastrointest Surg. 2007;11(11):1488–96 (discussion 1496-7).

  6. 6.

    DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg. 2007;245(5):755–62.

    Article  Google Scholar 

  7. 7.

    Bridgewater J, Galle PR, Khan SA, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014;60(6):1268–89.

    Article  Google Scholar 

  8. 8.

    Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysis. JAMA Surg. 2014;149(6):565–74.

    Article  Google Scholar 

  9. 9.

    Tsilimigras DI, Sahara K, Wu L, et al. Very early recurrence after liver resection for intrahepatic cholangiocarcinoma: considering alternative treatment approaches. JAMA Surg. 2020;155:823–831.

  10. 10.

    Miura JT, Johnston FM, Tsai S, et al. Chemotherapy for surgically resected intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2015;22(11):3716–23.

    Article  Google Scholar 

  11. 11.

    Sur MD, In H, Sharpe SM, et al. Defining the benefit of adjuvant therapy following resection for intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2015;22(7):2209–17.

    Article  Google Scholar 

  12. 12.

    van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074–84.

    Article  Google Scholar 

  13. 13.

    Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20.

    CAS  Article  Google Scholar 

  14. 14.

    Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731–40.

    CAS  Article  Google Scholar 

  15. 15.

    Motoi F, Kosuge T, Ueno H, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05). Jpn J Clin Oncol. 2019;49(2):190–4.

    Article  Google Scholar 

  16. 16.

    Kato A, Shimizu H, Ohtsuka M, et al. Surgical resection after downsizing chemotherapy for initially unresectable locally advanced biliary tract cancer: a retrospective single-center study. Ann Surg Oncol. 2013;20(1):318–24.

    Article  Google Scholar 

  17. 17.

    Le Roy B, Gelli M, Pittau G, et al. Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma. Br J Surg. 2018;105(7):839–47.

    Article  Google Scholar 

  18. 18.

    Yadav SXH, Bin-Riaz I, Sharma P, Durani U, Goyal G, Borah B, Borad MJ, Smoot RL, Roberts LR, Go RS, McWilliams RR, Mahipal A. Neoadjuvant vs. adjuvant chemotherapy for cholangiocarcinoma: a propensity score matched analysis. Eur J Surg Oncol. 2019;45(8):1432–8.

  19. 19.

    NCCN Clinical Practice Guidelines—Hepatobiliary Cancers. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed 11 Mar 2020.

  20. 20.

    Bilimoria KY, Stewart AK, Winchester DP, Ko CY. The National Cancer Data Base: a powerful initiative to improve cancer care in the United States. Ann Surg Oncol. 2008;15(3):683–90.

    Article  Google Scholar 

  21. 21.

    Winchester DP, Stewart AK, Phillips JL, Ward EE. The national cancer data base: past, present, and future. Ann Surg Oncol. 2010;17(1):4–7.

    Article  Google Scholar 

  22. 22.

    Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–81.

    CAS  Article  Google Scholar 

  23. 23.

    Malka D, Cervera P, Foulon S, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. 2014;15(8):819–28.

    CAS  Article  Google Scholar 

  24. 24.

    Ercolani G, Vetrone G, Grazi GL, et al. Intrahepatic cholangiocarcinoma: primary liver resection and aggressive multimodal treatment of recurrence significantly prolong survival. Ann Surg. 2010;252(1):107–14.

    Article  Google Scholar 

  25. 25.

    . Chun YS, Javle M. Systemic and adjuvant therapies for intrahepatic cholangiocarcinoma. Cancer Control. 2017;24(3):1073274817729241.

    Article  Google Scholar 

  26. 26.

    Primrose JN, Fox RP, Palmer DH, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20(5):663–73.

    CAS  Article  Google Scholar 

  27. 27.

    Amin MB, Edge S, Greene F, et al. American joint committee on cancer. 8th ed. Chicago: American Cancer Society; 2017.

    Google Scholar 

  28. 28.

    Datta J, Lewis RS Jr, Mamtani R, et al. Implications of inadequate lymph node staging in resectable gastric cancer: a contemporary analysis using the National Cancer Data Base. Cancer. 2014;120(18):2855–65.

    Article  Google Scholar 

  29. 29.

    Wang W, Shen Z, Shi Y, et al. Accuracy of nodal positivity in inadequate lymphadenectomy in pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: a population study using the US SEER database. Front Oncol. 2019;9:1386.

    Article  Google Scholar 

  30. 30.

    Janssen QP, Buettner S, Suker M, et al. Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer: a systematic review and patient-level meta-analysis. J Natl Cancer Inst. 2019;111(8):782–94.

    Article  Google Scholar 

  31. 31.

    Shroff RT, Javle MM, Xiao L, et al. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019;5(6):824–30.

    Article  Google Scholar 

Download references


The CoC’s NCDB and the hospitals participating in the CoC’s NCDB are the source of the deidentified data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors.


Coauthor Dr. Massarweh is supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, and the Center for Innovations in Quality, Effectiveness and Safety (CIN 13-413).

Author information




Drs. Tran Cao and Mason conceived of the study concept and design and prepared the manuscript. Ms. Chiang had access to the data and completed all statistical analyses. All authors contributed to the study’s interpretation, review, and manuscript approval.

Corresponding author

Correspondence to Hop S. Tran Cao MD.

Ethics declarations


None of the authors has any conflicts of interest to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mason, M.C., Massarweh, N.N., Tzeng, CW.D. et al. Time to Rethink Upfront Surgery for Resectable Intrahepatic Cholangiocarcinoma? Implications from the Neoadjuvant Experience. Ann Surg Oncol (2021). https://doi.org/10.1245/s10434-020-09536-w

Download citation