Consensus Conference on Intrahepatic Cholangiocarcinoma Ghassan K. Abou-Alfa1,2, Jean-Franc ß ois Geschwind3, Michael Choti4 & Michael I. d’Angelica1,2 1 Memorial Sloan Kettering Cancer Center, New York, NY, USA, 2Weill Cornell Medical College, New York, NY, USA, 3Yale Medical Center, New Haven, CT, USA, and 4UT-Southwestern, Dallas, TX, USA

Correspondence Ghassan K. Abou-Alfa, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY 10065, USA. Tel.: +16468884184. Fax: +16468884255. E-mail: [email protected]

Intrahepatic cholangiocarcinoma (ICC) is rising in incidence owing to improved recognition and a truly increased rate of the disease. Therefore, understanding the disease, its natural history and the impact of resection is critical for surgeons. The authors have succinctly reviewed the role of surgical intervention and acknowledged the controversies and significant remaining questions1. Resection is indicated for a single tumour without nodal metastases or other sites of extrahepatic disease. This is based on long-term survival figures and, most importantly, the potential for a cure. There is no controversy on this point. Furthermore, there is no controversy about the conclusion that surgery is not indicated in patients with distant extrahepatic metastatic disease. Surgery does not appear to impact the short survival seen in such patients and could only be considered palliative and non-curative. The review dedicates a significant amount of space to the discussion of multi-focal liver disease and satellitosis. While these two entities are difficult to distinguish from each other and remain poorly defined, they are both poor prognostic signs. Although well-established definitions are lacking, and most studies do not distinguish between the two, the presence of satellite tumours and distant multi-focal hepatic disease are likely a spectrum of the same biologic phenomenon – metastatic disease. It is possible that multi-focal tumours could be representative of simultaneous primary tumours but, to our knowledge, this has never been demonstrated in ICC. While rare long-term survival is seen after resection of multi-focal disease, one must always be cognizant of the rare long-term survival that can be seen with almost any advanced malignancy associated with almost any therapy. It is likely that these longterm survivors are patients with indolent cancer who are not cured. Survival statistics demonstrate that nearly all patients with multi-focal disease will succumb to their disease, and








Consensus Conference on the Multidisciplinary Management of Bile Duct Cancer.

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most will die quickly. Large case series have demonstrated that multi-focal disease and satellitosis (usually grouped together) are signs of advanced disease, and surgery is rarely associated with durable long-term disease-free survival2–4. Surgery for patients with multi-focal disease should only be considered in unusual situations, and preferably within a study protocol. Whether there is a difference between satellites and multi-focal disease remains to be determined. The same can be said of regional nodal metastases. Most series analysing outcome after a resection in the setting of nodal metastases demonstrate a similar poor long-term survival. These series are likely reporting on gross nodal disease as a routine lymphadenectomy is not uniformly practiced. While long-term survival with resection for nodal disease is reported, it is uncommon, and the majority of patients perform poorly and die quickly after surgery. It is likely that the reported long-term survivors are patients with occult microscopic nodal disease (as mentioned in the review) although this issue is typically not addressed in studies. Patients who present with radiologically gross nodal disease, even if localized to the porta hepatis, have a poor prognosis and upfront resection probably should be avoided. Given the very high risk of early recurrence after resection, re-assessment after a course of neoadjuvant systemic chemotherapy is a strategy to consider. A routine lymphadenectomy is strongly recommended by the authors as this confers better staging. We find it interesting that the prognostic value of lymph node metastases in patients with resected ICC has been known for a long time but only recently has the issue of routine staging lymphadenectomy been raised. The reader should consider why this is suddenly such an important issue for ICC. In an opposite trend, the value of a lymphadenectomy in patients with melanoma and breast cancer is now being questioned. Despite decades of research, a standard lymphadenectomy for solid tumours has not been shown to improve survival and probably should only be used for staging information – preferably with specific treatment strategies based on the results. Further, in a very similar clinical situation (yield of positive nodes and prognostic value) of resectable

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metastatic colorectal cancer to the liver, a lymphadenectomy is not routinely recommended as it does not impact upon treatment paradigms. Although the authors address specific lymph node basins to be resected as ‘first-echelon’ nodes, it must also be acknowledged that the lymph node drainage of the liver is quite variable. While certainly reasonable to perform a lymphadenectomy, surgeons should understand that this procedure only provides prognostic information that is not necessarily actionable as there is no proven adjuvant therapy. The authors appropriately point out the high rates of recurrence after a resection and the fact that the majority of recurrences involve the liver. This is an important point as we consider and study adjuvant strategies as well as the treatment of recurrent liver disease. In the well-selected patient, a repeat resection is reasonable to consider although unlikely to be curative. We believe the future of adjuvant therapy for ICC, as well as the treatment of recurrent liver disease, should involve hepatic regional therapies. Intra-arterial therapies for ICC are safe and can lead to stable disease or a partial response in up to three-quarters of well-selected patients. Although the existing evidence is limited by the lack of prospective randomized data, observational studies suggest an associated prolonged overall survival. The most commonly used intra-arterial therapies include transarterial chemoembolization (around 65% of all intra-arterial therapies) and radioembolization with yttrium 90. Additionally, hepatic artery infusional chemotherapy (HAIC) has been studied in patients with unresectable disease. Single-arm studies of HAIC have demonstrated response rates of approximately 50% and the potential for long-term survival.5 Given the promising response rates and survival associated with these therapies, further prospective evaluation within clinical trials is warranted. Lastly, the role of staging laparoscopy is reviewed and recommended; at least selectively. Nobody would argue with the value of avoiding a laparotomy in a patient with radiologically occult unresectable disease. Although imaging is improving and the yield of staging laparoscopy is likely decreasing, the selective use of staging laparoscopy is well justified and should be considered in high-risk cases and certainly in cases where the pre-operative imaging raises specific concerns of metastatic disease. We have much work to do to define better the extent and role of surgery in the treatment of ICC. These carefully worded consensus statements outline the issues well, and any investigator should be able to take away many issues for study. The definition of resectability needs further refinement and the role of surgery in patients with multifocal disease, or gross nodal disease needs better definition. Distinguishing between satellitosis and multi-focal metastatic disease and whether these two entities are prognostically different requires further evaluation. A routine lymphadenectomy has been recommended, but the goals of this procedure require examination. The controversy regarding the treatment of locally advanced or metastatic cholangiocarcinoma has been put to rest with the

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advent of gemcitabine plus cisplatin chemotherapy doublet as a standard of care.6 This recent study showed an improved overall survival for the combination compared with gemcitabine alone (11.7 versus 8.1 months, hazard ratio, 0.64, P < 0.001), and thus the combination is now the standard of care. This benefit held true in all subsets of different biliary duct cancers including intrahepatic cholangiocarcinoma. One of the unanswered controversies is the duration of therapy that was limited to 24 weeks, or 8 cycles, in the ABC-02 study,6 while in practice oncologists may treat until progression or intolerance occurs. The difference in outcome from that perspective has not been measured. If anything, there is greater enthusiasm for developing therapy triads by adding biologics of interest to the chemotherapy doublet. Despite solid scientific rationales, such approaches have already failed when sorafenib alone was added,7 with a similar fate for sorafenib combined with erlotinib.8 Current studies evaluating other targets are underway – with two focusing on MEK inhibition in combination with gemcitabine/cisplatin (http://www.clinicaltrials.gov NCT01828034) and as a single agent (http://www.clinicaltrials. gov NCT02042443). Genomic analyses of biliary cancers has been reported by several groups; however, there is no clarity yet regarding any specific patterns or clustering of genetic changes. Nonetheless, mutation-driven studies are underway despite the fact that their impact will be limited owing to the low number of tumours expressing these genetic changes. (http://www.clinicaltrials.gov NCT02073994, and NCT02150967). There is significant controversy in the application of adjuvant therapy for intrahepatic cholangiocarcinoma, and there still lacks randomized phase III trials to help provide definitive recommendations. The best argument for the use of adjuvant chemotherapy emanates from a meta-analysis of over 6000 patients in 20 studies, most of which were retrospective.9 There was a trend for adjuvant therapy over observation. However, this lacked statistical significance (odds ratio 0.75, CI 0.55–1.01, P = 0.06). Added to the studies reported in the meta-analysis, a recently completed single-arm phase II study of gemcitabine plus capecitabine followed by capecitabine-based external-beam radiotherapy showed promising safety and efficacy outcomes.10 The limitation of these studies, however, is the low number of intrahepatic cholangiocarcinoma cases that were included. Thus, there remains a strong need for future studies. In addition, there is eager anticipation from three ongoing/recently-completed studies: The BILCAP study evaluating capecitabine compared to observation (http://www.clinicaltrials.gov NCT00363584), The UNICANCER study of gemcitabine/oxaliplatin compared to observation (http://www.clinicaltrials.gov NCT01313377) and the BCAP study of gemcitabine compared to observation (http://www.clinicaltrials.gov NCT000000820). Unfortunately, these studies may have some of the same limitations of the others – namely, low accrual of intrahepatic cholangiocarcinoma. The rare situation of combined hepatocellular–cholangiocarcinoma (cHCC-CC) is well reviewed and discussed.

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Unfortunately, there is little to comment on as the disease is rare and, therefore, difficult to study. There are limited data on imaging, pathology and outcomes after resection of cHCC– CC making significant conclusions impossible. For the patient with a single resectable tumour, pre-operative diagnosis is probably not important as the treatment is resection regardless of final histology. For the patient with advanced disease, the issue becomes more relevant. For the ICC component, there is effective systemic chemotherapy6 and, for the HCC component, there is effective regional therapy with intra-arterial embolic therapies. Currently, we have imaging and tumour markers to try to make the diagnosis and offer clues regarding how therapy should proceed in patients who have cHCC–CC. Needle biopsies are problematic as there is a significant chance of a sampling error, as only a tiny percentage of the tumour is sampled. Of course, whether HCC or ICC strategies are most effective for advanced cHCC–CC is completely unknown. Whether it is an atypical pattern of abnormal tumour markers, imaging or biopsy that suggests cHCC–ICC, the best we have to offer patients with this rare disease is an attempt at CC or HCC treatment strategies – with the final decision probably best discussed at a multi-disciplinary tumour board. The most relevant issue for the practitioner is to be aware of the diagnosis and the potential treatment strategies available.


3. de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H et al. (2011) Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol 29:3140–3145. 4. Uenishi T, Ariizumi S, Aoki T, Ebata T, Ohtsuka M, Tanaka E et al. (2014) Proposal of a new staging system for mass-forming intrahepatic cholangiocarcinoma: a multicenter analysis by the Study Group for Hepatic Surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepatobiliary Pancreat Sci 21:499–508. 5. Konstantinidis IT, Do RK, Gultekin DH, Gonen M, Schwartz LH, Fong Y et al. (2014) Regional chemotherapy for unresectable intrahepatic cholangiocarcinoma: a potential role for dynamic magnetic resonance imaging as an imaging biomarker and a survival update from two prospective clinical trials. Ann Surg Oncol 21:2675–2683. 6. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A et al. (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273–1281. 7. Lee JK, Capanu M, O’Reilly EM, Ma J, Chou JF, Shia J et al. (2013) A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas. Br J Cancer 109:915–919. 8. El-Khoueiry AB, Rankin C, Siegel AB, Iqbal S, Gong IY, Micetich KC et al. (2014) S0941: a phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma. Br J Cancer 110:882–887. 9. Horgan AM, Amir E, Walter T, Knox JJ. (2012) Adjuvant therapy in the treatment of biliary tract cancer: a systematic review and meta-analysis. J Clin Oncol 30:1934–1940.

References 1. Weber SM, Ribero D, O’Reilly EM, Kokudo N, Miyazaki M, Pawlik TM. (2015) Intrahepatic Cholangiocarcinoma: expert consensus statement. HPB 17:669–681. 2. Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D et al. (2008) Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 248:84–96.

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10. Ben-Josef EGK, El-Khoueiry A, Corless C, Zalupski M, Lowy A, Thomas C et al. (2014) SWOG S0809: A phase II trial of adjuvant capecitabine (cap)/gemcitabine (gem) followed by concurrent capecitabine and radiotherapy in extrahepatic cholangiocarcinoma (EHCC) and gallbladder carcinoma (GBCA). American Society of Clinical Oncology Annual Meeting. 2014:abstr 4030. PubMed PMID: J Clin Oncol 32:5s, 2014 (suppl; abstr 4030).

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Consensus conference on intrahepatic cholangiocarcinoma.

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