Identifying Indications for Neoadjuvant Therapy in Cholangiocarcinoma

OncologyONCOLOGY Vol 38, Issue 4
Volume 38
Issue 4
Pages: 160-162

The recent Hot Topics section focuses on survival rates for patients with cholangiocarcinoma.

The recent Hot Topics section focuses on survival rates for patients with cholangiocarcinoma.

The recent Hot Topics section focuses on survival rates for patients with cholangiocarcinoma.

The incidence of cholangiocarcinoma (CCA) is rising, and survival rates remain low. Recent randomized, controlled trials (RCTs) demonstrated improved survival with adjuvant chemotherapy and immunotherapy in the metastatic and postoperative settings. Neoadjuvant therapy is increasingly used for other cancers to achieve R0 resection and as an indicator of treatment response. Although there has not been an RCT for neoadjuvant therapy in CCA, there are multiple supportive retrospective studies. Data from the recent phase 2 NEO-GAP (NCT03579771) prospective trial for neoadjuvant chemotherapy in patients with resectable high-risk intrahepatic CCA demonstrated safety and the increased likelihood of R0 resection with a neoadjuvant approach.

CCA is biliary tract cancer classified by location: intrahepatic (iCCA) or extrahepatic (eCCA; perihilar and distal). The rising incidence of CCA is attributed to advancements in imaging, molecular testing, and pathologic diagnosis of iCCA.1,2 The 5-year relative survival rate for all stages of iCCA is 9%, and 11% for extrahepatic CCA.3 Surgical R0 resection remains the best chance for cure. However, only approximately 40% of patients are amenable to surgical resection, with only 30% to 35% of resections truly curative due to the high rate of recurrence.4-10 Randomized, controlled trial results demonstrated a survival benefit in patients with resectable CCA after adjuvant capecitabine (phase 3 BILCAP [NCT00363584]),11 in patients with locally advanced disease after gemcitabine/cisplatin with durvalumab (Imfinzi; phase 3 TOPAZ-1 [NCT03875235])12, and in patients with metastatic disease after pembrolizumab (Keytruda; phase
3 KEYNOTE-966 [NCT04003636]).13 Neoadjuvant therapy in CCA offers a strategy to reduce tumor size, promote resectability by increasing the likelihood of an R0 resection, treat occult metastatic disease, and assess tumor biology as a prognostic indicator of treatment response.6


Much of the evidence supporting neoadjuvant chemotherapy (NAC) in iCCA is retrospective. Accepted definitions of high-risk or locally advanced disease, data on patients likely to benefit from NAC, or any defined parameters regarding the adequacy of response are lacking. One study demonstrated improved overall survival (OS) without improved recurrence-free survival in resectable iCCA after NAC.14 The authors argue that NAC may identify patients with stable or responsive disease as having favorable tumor biology, being less likely to have a recurrence, and being more likely to benefit from surgical resection.14 Another retrospective study using the National Cancer Database (NCDB) found that patients with resectable stage II to III iCCA trend toward improved survival with NAC,15 which is statistically significant after propensity score matching compared with up-front resection.16 Utuama et al argue for NAC in patients with resectable but more advanced disease: stage II to III with high-risk features such as larger tumor size, vascular invasion, or lymph node (LN) involvement.16 These findings are similar to the results of a multi-institutional international, retrospective study that found a nonsignificant improvement with outcomes in resectable iCCA after NAC upon propensity matching.17

In a retrospective analysis of a prospectively maintained database, patients who were high-risk with stage III resectable iCCA who underwent NAC exhibited extended OS; however, survival was not associated with pathologic response to NAC.18 High-risk features were defined as including regional lymphadenopathy, multifocal disease, satellite lesions, and vascular involvement with either tumor embolus or arterial encasement.18 The NEO-GAP trial determined the feasibility of NAC with gemcitabine, cisplatin, and nab-paclitaxel (Abraxane) for patients with resectable, high-risk iCCA.7 Patients were considered high risk if their tumor size was greater than 5 cm or if they had multiple tumors, major vascular invasion, or LN involvement.7 Investigators reported an R0 resection rate of 73%, comparable to the 62% R0 resection rate in the BILCAP trial.6,7,11 Overall, there may be a benefit for NAC in resectable iCCA, especially in locally advanced disease and resectable disease with high-risk features.

Because CCA is highly heterogenous and often possesses targetable mutations (eg, KRAS, BRAF, EGFR, PI3k, FGFR, IDH1/IDH2, HER2/neu), tumor molecular profiling can be useful for neoadjuvant treatment. Additional strategies include locoregional therapies such as transarterial radioembolization,19-21 transarterial chemoembolization,22 and hepatic arterial infusion.23 Although there are fewer studies evaluating locoregional therapies, they demonstrate downstaging with the potential for surgical cure. Upcoming trials, including the use of neoadjuvant doublet immunotherapy (durvalumab/tremelimumab [Imjudo]) for resectable and high-risk iCCA, should provide more insight into the optimal neoadjuvant regimen.24-28


A retrospective study using the NCDB compared NAC with adjuvant chemotherapy in resectable stage I to III CCA (including both intrahepatic and extrahepatic), finding NAC associated with improved OS.29 Similarly, when grouping all patients with CCA, receiving either neoadjuvant or adjuvant chemotherapy improved OS, even in patients with margin-negative and node-negative disease. However, there was no difference in survival between those receiving neoadjuvant or adjuvant chemotherapy.30 These studies’ results suggest a potential benefit for NAC in perihilar CCA.

Specifically for perihilar CCA, results of a single-institutional study demonstrated improved OS with NAC in patients with advanced disease, including disease that was resectable with LN metastasis, borderline resectable, or unresectable/locally advanced.31 Investigators in a phase 2 trial in Japan treated patients with borderline resectable perihilar CCA with a combination of neoadjuvant gemcitabine and oral fluoropyrimidine derivative S-1, finding the regimen safe and feasible with an 81% R0 resection rate.32 They defined borderline resectable hilar CCA as regional LN metastasis and pathologically confirmed vascular invasion, due to the significantly reduced survival rates.33 For hilar CCA, there may be a role for NAC in patients who have borderline resectable disease, but additional prospective studies are needed.

NAC or chemoradiation for extrahepatic CCA also has been evaluated retrospectively in patients who are high risk. In distal CCA, Cloyd et al reported no difference in 5-year OS between up-front resection and NAC or chemoradiation.34 However, receipt of either neoadjuvant or adjuvant therapy was associated with improved OS.34 Further, LN positivity portended a poor prognosis, suggesting that there may be a role for neoadjuvant therapy in cases with high-risk features, such as LN involvement.34 Similarly, advanced extrahepatic CCA was associated with improved OS and cancer-specific survival after NAC or chemoradiation. However, the majority of this retrospective Surveillance, Epidemiology, and End Results Program cohort was patients with gallbladder cancers.35 Another study evaluating extrahepatic CCA, but excluding distal CCA, found that compared with up-front surgery, neoadjuvant chemoradiation was associated with improved postoperative outcomes, higher likelihood of an R0 resection, and improved median survival.36 


The treatment of patients with CCA must be multidisciplinary and individualized. Surgeons should strive to standardize high-risk stratification. Although propensity-matching cohorts can improve comparisons, randomized clinical trials will best elucidate the ideal regimens and neoadjuvant/adjuvant strategies for both chemotherapy and immunotherapy. Tumor molecular profiling may add additional therapies targeting genetic mutations. Designing, developing, and enrolling clinical trials should be encouraged to optimize future patient care.

Corresponding Author

Ronald F. Wolf, MD

1 Hoag Dr Building 41

Newport Beach, CA 92663

Phone: 949-764-6665

Fax: 949-764-5607

Hilary R. Keller, MD; Laura Fluke, DO
Providence Saint John’s
Cancer Institute, Santa Monica, CA

Jared A. Forrester, MD; Ronald F. Wolf, MD
Hoag Family Cancer
Institute, Newport Beach, CA


  1. Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-year trends in cholangiocarcinoma incidence in the U.S.: intrahepatic disease on the rise. Oncologist. 2016;21(5):594-599. doi:10.1634/theoncologist.2015-0446
  2. Mukkamalla SKR, Naseri HM, Kim BM, Katz SC, Armenio VA. Trends in incidence and factors affecting survival of patients with cholangiocarcinoma in the United States. J Natl Compr Canc Netw. 2018;16(4):370-376. doi:10.6004/jnccn.2017.7056
  3. Survival rates for bile duct cancer. American Cancer Society. Updated March 1, 2023. Accessed February 17, 2024.
  4. Zhang XF, Beal E, Bagante F, et al. Early versus late recurrence of intrahepatic cholangiocarcinoma after resection with curative intent. Br J Surg. 2018;105(7):848-856. doi:10.1002/bjs.10676
  5. Langella S, Russolillo N, Ossola P, et al. Recurrence after curative resection for intrahepatic cholangiocarcinoma: how to predict the chance of repeat hepatectomy? J Clin Med. 2021;10(13):2820. doi:10.3390/jcm10132820
  6. Tran Cao HS, Ferrone C, Maithel SK, Rocha FG. Great debates: neoadjuvant therapy should be routinely given for high-risk cholangiocarcinoma. Ann Surg Oncol. 2023;30(13):7960-7965. doi:10.1245/s10434-023-14254-0
  7. Maithel SK, Keilson JM, Cao HST, et al. NEO-GAP: a single-arm, phase II feasibility trial of neoadjuvant gemcitabine, cisplatin, and nab-paclitaxel for resectable, high-risk intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2023;30(11):6558-6566. doi:10.1245/s10434-023-13809-5
  8. Weber SM, Ribero D, O’Reilly EM, Kokudo N, Miyazaki M, Pawlik TM. Intrahepatic cholangiocarcinoma: expert consensus statement. HPB (Oxford). 2015;17(8):669-680. doi:10.1111/hpb.12441
  9. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17(9):557-588. doi:10.1038/s41575-020-0310-z
  10. Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma—evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15(2):95-111. doi:10.1038/nrclinonc.2017.157
  11. Primrose JN, Fox RP, Palmer DH, et al; BILCAP study group. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20(5):663-673. doi:10.1016/S1470-2045(18)30915-X
  12. Oh DY, He AR, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. J Clin Oncol. 2022;40(suppl 4):378. doi.10.1200/JCO.2022.40.4_suppl.378
  13. Kelley RK, Ueno M, Yoo C, et al; KEYNOTE-966 Investigators. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401(10391):1853-1865. doi:10.1016/S0140-6736(23)00727-4
  14. Sutton TL, Billingsley KG, Walker BS, et al. Neoadjuvant chemotherapy is associated with improved survival in patients undergoing hepatic resection for intrahepatic cholangiocarcinoma. Am J Surg. 2021;221(6):1182-1187. doi:10.1016/j.amjsurg.2021.02.029
  15. Marcus R, Christopher W, Keller J, et al. Systemic therapy is associated with improved oncologic outcomes in resectable stage II/III intrahepatic cholangiocarcinoma: an examination of the national cancer database over the past decade. Cancers (Basel). 2022;14(17):4320. doi:10.3390/cancers14174320
  16. Utuama O, Permuth JB, Dagne G, et al. Neoadjuvant chemotherapy for intrahepatic cholangiocarcinoma: a propensity score survival analysis supporting use in patients with high-risk disease. Ann Surg Oncol. 2021;28(4):1939-1949. doi:10.1245/s10434-020-09478-3
  17. Buettner S, Koerkamp BG, Ejaz A, et al. The effect of preoperative chemotherapy treatment in surgically treated intrahepatic cholangiocarcinoma patients-a multi‐institutional analysis. J Surg Oncol. 2017;115(3):312-318. doi:10.1002/jso.24524
  18. Ayabe RI, Paez-Arango N, Estrella JS, et al. Neoadjuvant chemotherapy for high-risk intrahepatic cholangiocarcinoma - does pathologic response mean better outcomes? HPB (Oxford). 2023;25(4):472-480. doi:10.1016/j.hpb.2023.01.011
  19. Buettner S, Braat AJAT, Margonis GA, et al. Yttrium-90 radioembolization in intrahepatic cholangiocarcinoma: a multicenter retrospective analysis. J Vasc Interv Radiol. 2020;31(7):1035-1043. e2. doi:10.1016/j.jvir.2020.02.008
  20. Rayar M, Sulpice L, Edeline J, et al. Intra-arterial yttrium-90 radioembolization combined with systemic chemotherapy is a promising method for downstaging unresectable huge intrahepatic cholangiocarcinoma to surgical treatment. Ann Surg Oncol. 2015;22(9):3102-3108. doi:10.1245/s10434-014-4365-3
  21. Edeline J, Touchefeu Y, Guiu B, et al. Radioembolization plus chemotherapy for first-line treatment of locally advanced intrahepatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2020;6(1):51-59. doi:10.1001/jamaoncol.2019.3702
  22. Burger I, Hong K, Schulick R, et al. Transcatheter arterial chemoembolization in unresectable cholangiocarcinoma: initial experience in a single institution. J Vasc Interv Radiol. 2005;16(3):353-361. doi:10.1097/01.RVI.0000143768.60751.78
  23. Cercek A, Boerner T, Tan BR, et al. Assessment of hepatic arterial infusion of floxuridine in combination with systemic gemcitabine and oxaliplatin in patients with unresectable intrahepatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2020;6(1):60-67. doi:10.1001/jamaoncol.2019.3718
  24. Durvalumab and tremelimumab with platinum-based chemotherapy in intrahepatic cholangiocarcinoma (ICCA). Updated January 3, 2024. Accessed February 17. 2024.
  25. Neoadjuvant mFOLFOXIRI for potentially resectable cholangiocarcinoma. Updated September 1, 2021. Accessed February 20, 2024.
  26. PD1 antibody (toripalimab), GEMOX and lenvatinib neoadjuvant treatment for resectable intrahepatic cholangiocarcinoma with high-risk recurrence factors. Updated August 10, 2020. Accessed February 20, 2024.
  27. Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone with or without adjuvant chemotherapy in incidentally detected gallbladder carcinoma after simple cholecystectomy or in front of radical resection of BTC (GAIN). Updated March 6, 2024. Accessed February 20, 2024.
  28. Neoadjuvant gemcitabine plus cisplatin with or without durvalumab in resectable biliary tract cancer (DEBATE). Updated January 17, 2024. Accessed February 20, 2024.
  29. Yadav S, Xie H, Bin-Riaz I, et al. Neoadjuvant vs. adjuvant chemotherapy for cholangiocarcinoma: a propensity score matched analysis. Eur J Surg Oncol. 2019;45(8):1432-1438. doi:10.1016/j.ejso.2019.03.023
  30. Parente A, Kamarajah SK, Baia M, et al. Neoadjuvant chemotherapy for intrahepatic, perihilar, and distal cholangiocarcinoma: a national population-based comparative cohort study. J Gastrointest Surg. 2023;27(4):741-749. doi:10.1007/s11605-023-05606-y
  31. Gyoten K, Kuriyama N, Maeda K, et al. The safety and efficacy of neoadjuvant chemotherapy based on our resectability criteria for locally advanced perihilar cholangiocarcinoma. Langenbecks Arch Surg. 2023;408(1):261. doi.10.1007/s00423-023-03000-5
  32. Matsuyama R, Mori R, Ota Y, et al. Impact of gemcitabine plus S1 neoadjuvant chemotherapy on borderline resectable perihilar cholangiocarcinoma. Ann Surg Oncol. 2022;29(4):2393-2405. doi:10.1245/s10434-021-11206-4
  33. Matsuyama R, Morioka D, Mori R, et al. Our rationale of initiating neoadjuvant chemotherapy for hilar cholangiocarcinoma: a proposal of criteria for “borderline resectable” in the field of surgery for hilar cholangiocarcinoma. World J Surg. 2019;43(4):1094-1104. doi:10.1007/s00268-018-04883-y
  34. Cloyd JM, Prakash L, Vauthey JN, et al. The role of preoperative therapy prior to pancreatoduodenectomy for distal cholangiocarcinoma. Am J Surg. 2019;218(1):145-150. doi:10.1016/j.amjsurg.2018.08.024
  35. Toyoda J, Sahara K, Takahashi T, et al. Neoadjuvant therapy for extrahepatic biliary tract cancer: a propensity score-matched survival analysis. J Clin Med. 2023;12(7):2654. doi:10.3390/jcm12072654
  36. Silver CM, Joung RH, Logan CD, et al. Neoadjuvant therapy use and association with postoperative outcomes and overall survival in patients with extrahepatic cholangiocarcinoma. J Surg Oncol. 2023;127(1):90-98. doi:10.1002/jso.27112

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