Cholangiocarcinoma (CCA)


Cholangiocarcinoma (CCA) is a rare adenocarcinoma that develops in the biliary tree.1 CCA represents around 15% to 20% of the overall hepatobiliary malignancies and 3% of all gastrointestinal cancers.2,3 Tumors are classified according to their anatomical location as intrahepatic (iCCA) and extrahepatic (eCCA). The eCCA type can be further subdivided into 2 subtypes, perihilar (pCCA) and distal (dCCA).2,3 eCCA is the most common subtype of cancer outside East Asian countries.4 pCCA accounts for 60% to 70% of CCA cases, while dCCA is responsible for 20% to 30% of the tumors. iCCA corresponds to up to 10% of the cases.5

A diagnosis of CCA in many cases is made when the tumor is in an advanced stage.6 Typically, no risk factors are identified for most of the patients, even though many factors are known to contribute for tumor development.1,7 The prognosis is poor and suggests a reduced long-term survival.1,8 The clinical presentation for these tumors is also in many cases nonspecific with symptoms such as weight loss and malaise requiring a thorough investigation and a differential diagnosis.3 

CCA treatment combines different approaches, specifically surgical resection, systemic therapy and other therapies such as radiation.1 An aggressive treatment is often carried out, combining surgery with adjuvant or neoadjuvant therapies. This strategy offers the highest hypothesis of cure for patients.1

A multidisciplinary team including gastroenterologists, surgeons and medical and radiation oncology specialists is required for diagnosing, treating and monitoring CCA.9 

CCA Medical Care

Locoregional therapies can be used in patients that have advanced iCCA. When the tumor is unresectable, transarterial chemoembolization (TACE) can help improve survival as much as  15 months.10,11,12 External beam radiation therapy (EBRT) may also be an option when treating localized unresectable iCCA.13 Advanced EBRT techniques include three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) that can selectively target malignant tissues.13 In few patients with resected CCA, postoperative EBRT combined with systemic therapy may be beneficial.16 The role of radiation therapy, however, needs to be further clarified in cases of localized and unresectable eCCA.13

Neoadjuvant and adjuvant chemotherapy also play an important role in CCA. Gemcitabine combined with cisplatin is the first-line chemotherapy treatment available for patients that have advanced disease untreatable with surgery or locoregional therapies.13 The role of neoadjuvant therapy combined with surgery, however, is not clear.6 Adjuvant chemotherapy in turn can help increase survival in patients that present a higher risk of recurrence in iCCA diagnosis.14 Capecitabine showed efficacy in CCA patients that have gone through surgical procedures with an increase in median overall survival of 51 months.15

Other medical procedures, such as biliary bypass or a stent placement, can be performed to alleviate bile duct blockage and drain bile.16,17 In addition, photodynamic therapy (PDT) can be combined with stenting procedures.16

CCA Surgical Care

Many CCA patients are asymptomatic and present unresectable tumors at the time they are diagnosed.18 However, whenever surgical resection is possible, it is the first line of treatment.6 Not all patients will be candidates for surgery. The tumor should be located in the liver and bile duct only so it can be completely resected with tumor-free margins.3,6 Recurrence rates are surpassed and typically intrahepatic.19,20 Patients that present distant metastases or comorbidities that may increase operative risks, are not candidates for a surgical intervention.21 In pCCA, a simultaneous diagnosis of primary sclerosing cholangitis (PSC) is a contraindication for surgery. Regional lymphadenopathy is linked to the worst outcomes after surgery.13

A successful and curative surgery requires not only a R0 resection but also the preservation of remnant and functional liver.6,14 The surgical approach may involve an extended hepatectomy and an extrahepatic bile duct resection in iCCA or a pancreaticoduodenectomy (Whippple procedure) in dCCA patients.13,22 A preoperative workup to increase resectability and reduce morbidity and mortality post-resection may be performed and it includes biliary drainage and portal vein embolization.6 Postoperative complications include leaks of the bile ducts and intra abdominal abscesses.19

Liver transplantation after surgical resection and neoadjuvant chemoradiation can provide cure in pCCA.13 Patients need to meet several criteria for transplant eligibility, including a tumor radial diameter less than 3 cm and no metastatic disease.23

CCA Prevention

There is no known way of preventing CCA development. There are, however, few behaviors that can help decrease the risk of developing a malignant disease. These include keeping a healthy weight and diet, avoiding smoking, excluding or limiting alcohol consumption, as well as maintaining physical activity. Preventing infections from hepatitis B and C virus or treating these infections when a diagnosis is already made, can help prevent cirrhosis and potentially reduce the risk of CCA.24

References

1. Doherty B, Nambudiri VE, Palmer WC. Update on the diagnosis and treatment of cholangiocarcinoma. Curr Gastroenterol Rep. 2017 Jan;19(1):2. doi:10.1007/s11894-017-0542-4

2. Patel T. Cholangiocarcinoma–controversies and challenges. Nat Rev Gastroenterol Hepatol. 2011 Apr;8(4):189-200. doi:10.1038/nrgastro.2011.20

3.Blechacz B. Cholangiocarcinoma: current knowledge and new developments. Gut Liver. 2017 Jan 15;11(1):13-26. doi:10.5009/gnl15568

4. Shin HR, Oh JK, Masuyer E, Curado MP, Bouvard V, Fang Y et al. Comparison of incidence of intrahepatic and extrahepatic cholangiocarcinoma–focus on east and south-eastern asia. Asian Pac J Cancer Prev. 2010;11(5):1159-66. PMID: 21198257

5. Petrowsky H, Hong JC. Current surgical management of hilar and intrahepatic cholangiocarcinoma: the role of resection and orthotopic liver transplantation. Transplant Proc. 2009 Dec;41(10):4023-35. doi:10.1016/j.transproceed.2009.11.001

6. Sapisochin G, Ivanics T, Subramanian V, Doyle M, Heimbach JK, Hong JC. Multidisciplinary treatment for hilar and intrahepatic cholangiocarcinoma: a review of the general principles. Int J Surg. 2020 Oct;82S:77-81. doi:10.1016/j.ijsu.2020.04.067

7.Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588. doi:10.1038/s41575-020-0310-z

8. Morise Z, Sugioka A, Tokoro T, Tanahashi Y, Okabe Y, Kagawa T et a. Surgery and chemotherapy for intrahepatic cholangiocarcinoma. World J Hepatol. 2010 Feb 27;2(2):58-64. doi:10.4254/wjh.v2.i2.58

9. Treating Bile duct cancer. cancer.org. Accessed 22 Jun 2021.

10. Kiefer MV, Albert M, McNally M, Robertson M, Sun W, Fraker D, Olthoff K, Christians K, Pappas S, Rilling W, Soulen MC. Chemoembolization of intrahepatic cholangiocarcinoma with cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol: a 2-center study. Cancer. 2011 Apr 1;117(7):1498-505. doi:10.1002/cncr.25625.

11. Park SY, Kim JH, Yoon HJ, Lee IS, Yoon HK, Kim KP. Transarterial chemoembolization versus supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma. Clin Radiol. 2011 Apr;66(4):322-8. doi:10.1016/j.crad.2010.11.002

12. Vogl TJ, Naguib NN, Nour-Eldin NE, Bechstein WO, Zeuzem S, Trojan J, Gruber-Rouh T. Transarterial chemoembolization in the treatment of patients with unresectable cholangiocarcinoma: results and prognostic factors governing treatment success. Int J Cancer. 2012 Aug 1;131(3):733-40. doi:10.1002/ijc.26407

13.Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma – evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018 Feb;15(2):95-111. doi: 10.1038/nrclinonc.2017.157.

14. Entezari P, Riaz A. Intrahepatic cholangiocarcinoma. Semin Intervent Radiol. 2020 Dec;37(5):475-483. doi:10.1055/s-0040-1719188

15. Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019 May;20(5):663-673. doi:10.1016/S1470-2045(18)30915-X. Erratum in: Lancet Oncol. 2019 Apr 2

16. Palliative therapy for bile duct cancer. cancer.org. Assessed 22 Jun 2021

17. Cholangiocarcinoma. Orpha.net. Assessed 22 Jun 2021

18. Valle JW. Advances in the treatment of metastatic or unresectable biliary tract cancer. Ann Oncol. 2010 Oct;21 Suppl 7:vii345-8. doi:10.1093/annonc/mdq420

19. Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008 Jul;248(1):84-96. doi:10.1097/SLA.0b013e318176c4d3

20. Weber SM, Jarnagin WR, Klimstra D, DeMatteo RP, Fong Y, Blumgart LH. Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes. J Am Coll Surg. 2001 Oct;193(4):384-91. doi:10.1016/s1072-7515(01)01016-x

21. Moazzami B, Majidzadeh-A K, Dooghaie-Moghadam A, Eslami P, Razavi-Khorasani N, Iravani S et al. Cholangiocarcinoma: state of the art. J Gastrointest Cancer. 2020 Sep;51(3):774-781. doi:10.1007/s12029-020-00390-3

22. Buettner S, van Vugt JL, IJzermans JN, Groot Koerkamp B. Intrahepatic cholangiocarcinoma: current perspectives. Onco Targets Ther. 2017 Feb 22;10:1131-1142. doi:10.2147/OTT.S93629

23. Rosen CB, Heimbach JK, Gores GJ. Liver transplantation for cholangiocarcinoma. Transpl Int. 2010 Jul;23(7):692-7. doi:10.1111/j.1432-2277.2010.01108.x24. Can bile duct cancer be prevented? cancer.org. Assessed 22 Jun 2021

Reviewed by Harshi Dhingra, MD, on 7/1/2021.

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