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The Landmark Series: Intrahepatic Cholangiocarcinoma

Abstract

Introduction

Intrahepatic cholangiocarcinoma (ICC) is an aggressive biliary tract cancer (BTC) with distinct anatomic, molecular, and clinical characteristics that distinguishes it from other BTCs.

Methods

In this landmark series review, we highlight the critical studies that have defined the surgical management of ICC, as well as several randomized controlled trials that have investigated adjuvant therapy strategies.

Results

Surgical resection is the mainstay of treatment and should involve margin-negative resection with regional lymphadenectomy. Several recently completed and ongoing randomized controlled trials are defining the indications for adjuvant therapy among patients with resected ICC.

Conclusions

In the near future, improved understanding of the molecular features of ICC should lead to newer targeted therapies as well as a more personalized approach to systemic therapy.

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References

  1. 1.

    Pawlik TM, Cloyd JM, Dillhoff M, editors. Intrahepatic cholangiocarcinoma: diagnosis and management. Cham: Springer International Publishing. Epub ahead of print 2019. https://doi.org/10.1007/978-3-030-22258-1.

  2. 2.

    Bergquist A, von Seth E. Epidemiology of cholangiocarcinoma. Best Pract Res Clin Gastroenterol. 2015;29:221–32.

    PubMed  Google Scholar 

  3. 3.

    Rizvi S, Khan SA, Hallemeier CL, et al. Cholangiocarcinoma—evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15:95–111.

    CAS  PubMed  Google Scholar 

  4. 4.

    Ejaz A, Cloyd JM, Pawlik TM. Advances in the diagnosis and treatment of patients with intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2020;27:552–60.

    PubMed  Google Scholar 

  5. 5.

    Weber SM, Jarnagin WR, Klimstra D, et al. Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes. J Am Coll Surg. 2001;193:384–91.

    CAS  PubMed  Google Scholar 

  6. 6.

    Benson AB, D’Angelica MI, Abbott DE, et al. Guidelines insights: hepatobiliary cancers, Version 2.2019. J Natl Compr Cancer Netw JNCCN. 2019;17:302–10.

    Google Scholar 

  7. 7.

    Weber SM, Ribero D, O’Reilly EM, et al. Intrahepatic cholangiocarcinoma: expert consensus statement. HPB. 2015;17:669–80.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

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

    PubMed  Google Scholar 

  9. 9.

    Li M-X, Bi X-Y, Li Z-Y, et al. Impaction of surgical margin status on the survival outcome after surgical resection of intrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Surg Res. 2016;203:163–73.

    PubMed  Google Scholar 

  10. 10.

    de Jong MC, Nathan H, Sotiropoulos GC, et al. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol. 2011;29:3140–5.

    PubMed  Google Scholar 

  11. 11.

    Spolverato G, Yakoob MY, Kim Y, et al. The impact of surgical margin status on long-term outcome after resection for intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2015;22:4020–8.

    PubMed  Google Scholar 

  12. 12.

    Zhang X-F, Bagante F, Chakedis J, et al. Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy. J Gastrointest Surg. 2017;21:1841–50.

    PubMed  Google Scholar 

  13. 13.

    Si A, Li J, Yang Z, et al. Impact of anatomical versus non-anatomical liver resection on short- and long-term outcomes for patients with intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2019;26:1841–50.

    PubMed  Google Scholar 

  14. 14.

    Reames BN, Ejaz A, Koerkamp BG, et al. Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis. J Surg Oncol. 2017;116:133–9.

    PubMed  Google Scholar 

  15. 15.

    Zhang X-F, Bagante F, Chen Q, et al. Perioperative and long-term outcome of intrahepatic cholangiocarcinoma involving the hepatic hilus after curative-intent resection: comparison with peripheral intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma. Surgery. 2018;163:1114–20.

    PubMed  Google Scholar 

  16. 16.

    Shiraiwa DK, Carvalho PFDC, Maeda CT, et al. The role of minimally invasive hepatectomy for hilar and intrahepatic cholangiocarcinoma: a systematic review of the literature. J Surg Oncol. Epub ahead of print January 4, 2020. https://doi.org/10.1002/jso.25821.

  17. 17.

    Zhang X-F, Chen Q, Kimbrough CW, et al. Lymphadenectomy for intrahepatic cholangiocarcinoma: has nodal evaluation been increasingly adopted by surgeons over time? A national database analysis. J Gastrointest Surg. 2018;22:668–75.

    PubMed  Google Scholar 

  18. 18.

    Zhang X-F, Xue F, Dong D-H, et al. Number and station of lymph node metastasis after curative-intent resection of intrahepatic cholangiocarcinoma impact prognosis. Ann Surg. Epub ahead of print January 14, 2020. https://doi.org/10.1097/sla.0000000000003788.

  19. 19.

    Okami J, Dono K, Sakon M, et al. Patterns of regional lymph node involvement in intrahepatic cholangiocarcinoma of the left lobe. J Gastrointest Surg. 2003;7:850–6.

    PubMed  Google Scholar 

  20. 20.

    Horgan AM, Amir E, Walter T, et al. Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol. 2012;30:1934–40.

    PubMed  Google Scholar 

  21. 21.

    Cloyd JM, Pawlik TM. Adjuvant therapy for biliary tract cancers: new evidence to resolve old questions. J Oncol Pract. 2018;14:723–4.

    PubMed  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;362:1273–81.

    CAS  PubMed  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;15:819–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Lee J, Park SH, Chang H-M, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2012;13:181–8.

    CAS  PubMed  Google Scholar 

  25. 25.

    Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352:2696–704.

    CAS  Google Scholar 

  26. 26.

    Neoptolemos JP, Palmer DH, Ghaneh P, 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;389:1011–24.

    CAS  PubMed  Google Scholar 

  27. 27.

    Ebata T, Hirano S, Konishi M, et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018;105:192–202.

    CAS  PubMed  Google Scholar 

  28. 28.

    Nakachi K, Konishi M, Ikeda M, et al. A randomized phase III trial of adjuvant S-1 therapy vs. observation alone in resected biliary tract cancer: Japan Clinical Oncology Group Study (JCOG1202, ASCOT). Jpn J Clin Oncol. 2018;48:392–5.

    PubMed  Google Scholar 

  29. 29.

    Stein A, Arnold D, Bridgewater J, et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial)—a randomized, multidisciplinary, multinational phase III trial. BMC Cancer. 2015;15:564.

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Shinohara ET, Mitra N, Guo M, et al. Radiation therapy is associated with improved survival in the adjuvant and definitive treatment of intrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 2008;72:1495–501.

    PubMed  Google Scholar 

  31. 31.

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

    PubMed  Google Scholar 

  32. 32.

    Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG S0809: A phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol. 2015;33:2617–22.

    CAS  PubMed  Google Scholar 

  33. 33.

    Yang L, Shan J, Shan L, et al. Trans-arterial embolisation therapies for unresectable intrahepatic cholangiocarcinoma: a systematic review. J Gastrointest Oncol. 2015;6:570–88.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Hyder O, Marsh JW, Salem R, et al. Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol. 2013;20:3779–86.

    PubMed  Google Scholar 

  35. 35.

    Squires MH, Cloyd JM, Dillhoff M, et al. Challenges of surgical management of intrahepatic cholangiocarcinoma. Expert Rev Gastroenterol Hepatol. 2018;12:671–81.

    CAS  PubMed  Google Scholar 

  36. 36.

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

    PubMed  Google Scholar 

  37. 37.

    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. Epub ahead of print October 31, 2019. https://doi.org/10.1001/jamaoncol.2019.3702.

  38. 38.

    Ali SM, Clark CJ, Zaydfudim VM, et al. Role of major vascular resection in patients with intrahepatic cholangiocarcinoma. Ann Surg Oncol. 2013;20:2023–8.

    PubMed  Google Scholar 

  39. 39.

    Ciria R, Cherqui D, Geller DA, et al. Comparative short-term benefits of laparoscopic liver resection: 9000 cases and climbing. Ann Surg. 2016;263:761–77.

    PubMed  Google Scholar 

  40. 40.

    Cloyd JM, Mizuno T, Kawaguchi Y, et al. Comprehensive complication index validates improved outcomes over time despite increased complexity in 3707 consecutive hepatectomies. Ann Surg. Epub ahead of print October 17, 2018. https://doi.org/10.1097/sla.0000000000003043.

  41. 41.

    Merath K, Chen Q, Bagante F, et al. A multi-institutional international analysis of textbook outcomes among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma. JAMA Surg. 2019;154:e190571.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Shroff RT, Kennedy EB, Bachini M, et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J Clin Oncol. 2019;37:1015–27.

    PubMed  Google Scholar 

  43. 43.

    Labib PL, Goodchild G, Pereira SP. Molecular pathogenesis of cholangiocarcinoma. BMC Cancer. 2019;19:185.

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47:1003–10.

    CAS  PubMed  Google Scholar 

  45. 45.

    Zhu AX, Borger DR, Kim Y, et al. Genomic profiling of intrahepatic cholangiocarcinoma: refining prognosis and identifying therapeutic targets. Ann Surg Oncol. 2014;21:3827–34.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Cloyd JM, Chun YS, Ikoma N, et al. Clinical and genetic implications of DNA mismatch repair deficiency in biliary tract cancers associated with Lynch syndrome. J Gastrointest Cancer. 2018;49:93–6.

    CAS  PubMed  Google Scholar 

  47. 47.

    Massard C, Michiels S, Ferté C, et al. High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial. Cancer Discov. 2017;7:586–95.

    CAS  PubMed  Google Scholar 

  48. 48.

    Han K, Ko HK, Kim KW, et al. Radiofrequency ablation in the treatment of unresectable intrahepatic cholangiocarcinoma: systematic review and meta-analysis. J Vasc Interv Radiol JVIR. 2015;26:943–8.

    PubMed  Google Scholar 

  49. 49.

    Ray CE, Edwards A, Smith MT, et al. Metaanalysis of survival, complications, and imaging response following chemotherapy-based transarterial therapy in patients with unresectable intrahepatic cholangiocarcinoma. J Vasc Interv Radiol JVIR. 2013;24:1218–26.

    PubMed  Google Scholar 

  50. 50.

    Al-Adra DP, Gill RS, Axford SJ, et al. Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis. Eur J Surg Oncol. 2015;41:120–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Hong TS, Wo JY, Yeap BY, et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2016;34:460–8.

    CAS  PubMed  Google Scholar 

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Correspondence to Timothy M. Pawlik MD, MPH, MTS, PhD.

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Cloyd, J.M., Ejaz, A. & Pawlik, T.M. The Landmark Series: Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 27, 2859–2865 (2020). https://doi.org/10.1245/s10434-020-08621-4

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