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Surgical treatment of intrahepatic cholangiocarcinoma

  • Annabel K. Gravely
    Affiliations
    Multi-Organ Transplant and HPB Surgical Oncology, Division of General Surgery, University Health Network, University of Toronto, Toronto, Canada
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  • Eric Vibert
    Affiliations
    Centre Hépato-Biliaire, Paul Brousse Hospital, Paris Saclay University, AP-HP, Villejuif, France
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  • Gonzalo Sapisochin
    Correspondence
    Corresponding author. Address: HBP & Multi Organ Transplant Program Peter Munk Building, Toronto General Hospital, University Health Network 585 University Avenue, M5G 2N2, Toronto, ON, Canada.
    Affiliations
    Multi-Organ Transplant and HPB Surgical Oncology, Division of General Surgery, University Health Network, University of Toronto, Toronto, Canada
    Search for articles by this author
      Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy of the intrahepatic bile ducts. In recent years, the incidence of iCCA has increased but it is unknown to what extent this increase can be attributed to improved classification or true escalation. From a surgical perspective, though major hepatic resection has been the most appropriate treatment option for those eligible, liver transplant has recently emerged as a second surgical option for unresectable patients. However, in order for these surgical treatments to be most effective, progress is needed at all points on the patient timeline: diagnosis, selection, neoadjuvant therapy, surgery, and adjuvant therapy. This snapshot will summarize current knowledge and future research priorities regarding surgery for iCCA.
      While the prognosis of hepatocellular carcinoma (HCC) has improved with the increasing availability of surgical treatment, iCCA is still associated with much worse outcomes. iCCA is rarely diagnosed at an early stage and systemic treatment is the only mainstay at more advanced stages. As effective surgical treatment depends on early and accurate diagnoses, biopsy and molecular sequencing of iCCA are crucial, and will also be important for the development of personalized treatment plans based on molecular alterations (e.g. IDH1, FGFR2).
      • Mazzaferro V.
      • Gorgen A.
      • Roayaie S.
      • dit Busset M.D.
      • Sapisochin G.
      Liver transplantation and resection for intrahepatic cholangiocarcinoma.
      Continued understanding of iCCA genetic profiles and associated tumor response could eventually inform selection for surgical treatment. Major liver resection (LR) is the only curative treatment for iCCA, though only 12-40% of patients referred are resectable.
      • Wu L.
      • Tsilimigras D.I.
      • Paredes A.Z.
      • Mehta R.
      • Hyer J.M.
      • Merath K.
      • et al.
      Trends in the incidence, treatment and outcomes of patients with intrahepatic cholangiocarcinoma in the USA: facility type is associated with margin status, use of lymphadenectomy and overall survival.
      • de Jong M.C.
      • Nathan H.
      • Sotiropoulos G.C.
      • Paul A.
      • Alexandrescu S.
      • Marques H.
      • et al.
      Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment.
      • Tan J.C.
      • Coburn N.G.
      • Baxter N.N.
      • Kiss A.
      • Law C.H.
      Surgical management of intrahepatic cholangiocarcinoma–a population-based study.
      Considering a patient for LR includes consideration of the location and spread of local tumors, the presence of peritoneal and distant metastases, the quality of the liver (presence of cirrhosis or disease), the presence of portal hypertension, the extent of lymph node involvement, and more. All are considered with respect to the difficult goal of balancing complete R0 resection with preservation of a sufficient future liver remnant (FLR).
      • Mazzaferro V.
      • Gorgen A.
      • Roayaie S.
      • dit Busset M.D.
      • Sapisochin G.
      Liver transplantation and resection for intrahepatic cholangiocarcinoma.
      Liver transplant has only been an acceptable option for iCCA since 2014 and it is limited to patients with early stage (single tumor ≤2 cm) unresectable tumors, such as those with cirrhosis.
      • Sapisochin G.
      • Facciuto M.
      • Rubbia-Brandt L.
      • Marti J.
      • Mehta N.
      • Yao F.Y.
      • et al.
      Liver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment.
      Though tumor extension outside of the liver precludes transplant, some very preliminary case studies have reported transplant for locally advanced iCCA.
      Neoadjuvant therapy aims to address low resectability by downstaging unresectable cases. These techniques include hepatic artery infusion chemotherapy, combined systemic and intra-arterial chemotherapy, selective internal radiation therapy, and external beam radiation.
      • Mazzaferro V.
      • Gorgen A.
      • Roayaie S.
      • dit Busset M.D.
      • Sapisochin G.
      Liver transplantation and resection for intrahepatic cholangiocarcinoma.
      Fortunately, good outcomes for neoadjuvant therapy and LR have been found in several retrospective studies but are yet to be validated prospectively. Like LR, the most effective neoadjuvant therapies/combination therapies are still an active research question, along with how response to neoadjuvant therapy can influence transplant decision-making.
      • Mazzaferro V.
      • Gorgen A.
      • Roayaie S.
      • dit Busset M.D.
      • Sapisochin G.
      Liver transplantation and resection for intrahepatic cholangiocarcinoma.
      Even after consideration of these patient characteristics, 5-year overall survival after LR is only 25-40%, with 50-70% facing tumor recurrence.
      • de Jong M.C.
      • Nathan H.
      • Sotiropoulos G.C.
      • Paul A.
      • Alexandrescu S.
      • Marques H.
      • et al.
      Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment.
      ,
      • Hyder O.
      • Marques H.
      • Pulitano C.
      • Marsh J.W.
      • Alexandrescu S.
      • Bauer T.W.
      • et al.
      A nomogram to predict long-term survival after resection for intrahepatic cholangiocarcinoma: an Eastern and Western experience.
      ,
      • Patel T.
      Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States.
      This emphasizes the rationale for research beyond determining resectability, focussing on surgical approach. For instance, Si et al. determined that anatomic resection is associated with superior recurrence-free and overall survival compared to non-anatomic resection for iCCA and Spolverato et al. determined promising outcomes for repeated LR.
      • Si A.
      • Li J.
      • Yang Z.
      • Xia Y.
      • Yang T.
      • Lei Z.
      • et al.
      Impact of anatomical versus non-anatomical liver resection on short- and long-term outcomes for patients with intrahepatic cholangiocarcinoma.
      ,
      • Spolverato G.
      • Kim Y.
      • Alexandrescu S.
      • Marques H.P.
      • Lamelas J.
      • Aldrighetti L.
      • et al.
      Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma following previous curative-intent surgical resection.
      Due to frequent infiltration and vascular encasement of iCCA, vascular resection of the inferior vena cava or portal vein has also been studied with good outcomes in R0 resection. Most importantly, for this highly lymphophilic cancer, lymphadenectomy of a minimum of 6 nodes is suggested for staging, but further clarification on optimal number and location should be made.
      • Palmer W.C.
      • Patel T.
      Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma.
      Preliminary research has also brought up the use of techniques to induce hypertrophy of the FLR such as portal vein embolization (PVE) or associated liver partition and portal vein ligation (ALPPS). However, these are controversial techniques with low evidence levels. In the other direction, the study of laparoscopic LR for iCCA has been largely unfavorable due to the requirement for lymphadenectomy.
      • Mazzaferro V.
      • Gorgen A.
      • Roayaie S.
      • dit Busset M.D.
      • Sapisochin G.
      Liver transplantation and resection for intrahepatic cholangiocarcinoma.
      However, due to advances in this technique comparative studies are urgently needed.
      After LR, adjuvant therapy has been primarily explored as a treatment for patients at high risk of recurrence such as those with R1 resection or with positive lymph nodes. Recent studies include the BILCAP trial looking at capecitabine after LR, gemcitabine and oxaliplatin trials, intra-arterial chemotherapy and radiation therapy trials. Currently adjuvant therapy with capecitabine has been adopted as standard of care by ASCO.
      • Shroff R.T.
      • Kennedy E.B.
      • Bachini M.
      • Bekaii-Saab T.
      • Crane C.
      • Edeline J.
      • et al.
      Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guidelines.
      The downside of adjuvant therapies with LR for iCCA is surgical morbidity, which in many cases may preclude initiation of therapy. Though there are no studies to date on the role of adjuvant therapy after transplant for patients with iCCA, it may enable the optimization of personalized treatment in the future.
      • Mazzaferro V.
      • Gorgen A.
      • Roayaie S.
      • dit Busset M.D.
      • Sapisochin G.
      Liver transplantation and resection for intrahepatic cholangiocarcinoma.
      Surgical treatment of iCCA has evolved and become more selective, resulting in improved outcomes after resection and, more recently, transplant. However, overall prognosis is still poor due to a combination of advanced-stage diagnosis, narrow eligibility, and limited surgical approaches. In order to move forward, improvements need to be made at each step of the iCCA patient timeline. Diagnoses made early and accurately, refined selection criteria, optimizing surgical approach, and strategizing neoadjuvant and adjuvant therapies should be the focus of future studies.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      Gravely A.K – conception and design. Sapisochin G – conception, design, and critical review. Vibert E – critical review.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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