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Surgical resection for intrahepatic cholangiocarcinoma – can we really improve survival by resecting more lymph nodes?

  • Bas Groot Koerkamp
    Affiliations
    Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
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  • Pierre-Alain Clavien
    Affiliations
    Department of Surgery and Transplantation, University Hospital of Zurich, Switzerland
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  • Wojciech G. Polak
    Correspondence
    Corresponding author. Address: Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
    Affiliations
    Department of Surgery, Division of Hepatopancreatobiliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
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Published:December 23, 2022DOI:https://doi.org/10.1016/j.jhep.2022.12.003

      Keywords

      Linked Article

      See Article, pages 356–363
      Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary hepatic tumor after hepatocellular carcinoma and its worldwide incidence has increased over the last decades.
      • Javle M.
      • Lee S.
      • Azad N.S.
      • Borad M.J.
      • Kate Kelley R.
      • Sivaraman S.
      • et al.
      Temporal changes in Cholangiocarcinoma incidence and mortality in the United States from 2001 to 2017.
      ,
      • Bertuccio P.
      • Malvezzi M.
      • Carioli G.
      • Hashim D.
      • Boffetta P.
      • El-Serag H.B.
      • et al.
      Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma.
      The chance of cure after resection of iCCA is only 10%.
      • Spolverato G.
      • Vitale A.
      • Cucchetti A.
      • Popescu I.
      • Marques H.P.
      • Aldrighetti L.
      • et al.
      Can hepatic resection provide a long-term cure for patients with intrahepatic cholangiocarcinoma?.
      Even when treated in the world’s expert centers, most patients with resected iCCA will eventually die from recurrent disease. In this issue of Journal of Hepatology, Sposito and colleagues investigated whether the removal of at least six lymph nodes can improve survival after resection of iCCA.
      • Sposito C.
      • Ratti F.
      • Cucchetti A.
      • Ardito F.
      • Ruzzenente A.
      • Di Sandro S.
      • et al.
      Survival benefit of adequate lymphadenectomy in patients undergoing liver resection for clinically node-negative intrahepatic cholangiocarcinoma.
      Previous studies identified several poor prognostic factors for patients with iCCA; tumor size, number of liver tumors, poor tumor differentiation, invasion of adjacent structures, and lymph node metastases (LNM).
      • Lamarca A.
      • Santos-Laso A.
      • Utpatel K.
      • La Casta A.
      • Stock S.
      • Forner A.
      • et al.
      Liver metastases of intrahepatic cholangiocarcinoma: implications for an updated staging system.
      • 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.
      • Choi W.J.
      • Williams P.J.
      • Claasen M.P.A.W.
      • Ivanics T.
      • Englesakis M.
      • Gallinger S.
      • et al.
      Systematic review and meta-analysis of prognostic factors for early recurrence in intrahepatic cholangiocarcinoma after curative-intent resection.
      The 8th edition of the AJCC/UICC Cancer Staging Manual brings these factors together in the TNM classification.

      TNM Classification of Malignant Tumors, 8th Edition.

      The presence of nodal metastasis, one of the strongest predictors of poor prognosis, is associated with a median survival of less than 20 months and a 5-year overall survival rate of only 15%.
      • 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.
      Recovery of at least six lymph nodes (LNs) is recommended for adequate staging in the 8th edition of the AJCC/UICC Cancer Staging Manual.

      TNM Classification of Malignant Tumors, 8th Edition.

      The presence of at least one positive LN constitutes N1 and consequently stage IIIB disease. The presence of at least one positive extraregional LN (e.g., aortocaval or truncal) constitutes M1 disease. Nevertheless, the impact of an adequate lymphadenectomy (i.e., harvesting at least six LNs) on survival is still uncertain.
      • Sposito C.
      • Droz Dit Busset M.
      • Virdis M.
      • Citterio D.
      • Flores M.
      • Bongini M.
      • et al.
      The role of lymphadenectomy in the surgical treatment of intrahepatic cholangiocarcinoma: a review.
      Using data from five expert centers in Italy, the authors investigated whether adequate lymphadenectomy is associated with superior survival. They included 706 patients with clinically node-negative (N0) disease at radiological staging. Of these patients, 59.1% underwent adequate lymphadenectomy, which increased over time. Patients with and without adequate lymphadenectomy differed in baseline patient and tumor characteristics. Therefore, they performed a propensity score analysis with an inverse probability of treatment weights model. The yield of an adequate lymphadenectomy was on average ten LNs vs. only three LNs for an inadequate lymphadenectomy. The authors then confirmed the importance of adequate lymphadenectomy for staging. With adequate lymphadenectomy the chance of N1 disease was 40.0% compared to 17.8% with inadequate lymphadenectomy. Moreover, the extension of lymphadenectomy beyond the hepatoduodenal ligament (station 13 for right-sided iCCA and station 7 for left-sided iCCA) increased the detection of positive LNs from 28.1% to 42.2%.
      Unfortunately, the authors could not demonstrate that an adequate lymphadenectomy was associated with superior survival (hazard ratio [HR] 1.20, 95% CI 0.69–2.09, p = 0.41). This is not proof that such survival benefit does not exist, but simply that it could not be detected in the present study with more than 700 patients.
      • Altman D.G.
      • Bland J.M.
      Absence of evidence is not evidence of absence.
      In a subgroup analysis of patients with N0 disease, the authors found that an adequate lymphadenectomy was associated with superior survival (HR 1.81; 95% CI 1.41–2.33, p = 0.003). This apparent survival benefit, however, is explained by misclassification bias; the group of patients with N0 disease after inadequate lymphadenectomy included many patients with “occult” N1 disease. We can estimate the extent of misclassification bias, assuming that the propensity score model resulted in comparable groups for adequate and inadequate lymphadenectomy. The actual proportion of N1 disease (including both detected and occult positive LN) in the inadequate lymphadenectomy group should be the same as in the adequate lymphadenectomy group (i.e., 40.0%). That means that 22 out of 100 patients (40.0-17.8 = 22.2) classified as N0 with inadequate lymphadenectomy, in fact had occult N1 disease. The inferior survival of patients with inadequate lymphadenectomy in the N0 group is most likely explained by these patients (22 out of 100) with occult N1 disease.
      An adequate lymphadenectomy was also associated with superior survival in patients with N1 disease (HR 1.82; 95% CI 1.14–2.90; p = 0.023). Therefore, the authors concluded that adequate lymphadenectomy improved survival in patients with N1 disease. This difference in survival, however, could also be explained by a difference in the extent of nodal disease (i.e., the number of positive LNs). The adequate lymphadenectomy group included all patients with nodal disease with a median of ten harvested LNs. The inadequate lymphadenectomy group included only those patients with nodal disease detected by harvesting only three LNs on average. It is likely that N1 patients who were identified by sampling only three LNs on average, had more advanced disease (i.e., more positive LNs) than those with adequate lymphadenectomy, and therefore worse survival. Inadequate lymphadenectomy results in misclassification of N1 patients with only one or two positive LNs as N0; the patients with the best prognosis in the N1 group are transferred to the N0 group. The result of this misclassification is a decrease in survival in both the N0 and the N1 subgroups of the inadequate lymphadenectomy population. This is a common source of bias in staging and could entirely explain the apparent superior survival of patients with N1 disease who underwent an adequate lymphadenectomy.
      Moreover, the N1 disease group is a subgroup analysis of patients with clinically N0 disease, which cannot be identified at the time of diagnosis. Therefore, no clinical decision (such as adequate lymphadenectomy) can be made for this subgroup. Finally, the appropriate statistical analysis for heterogeneity of treatment effects in subgroups is an interaction test.
      • Matthews J.N.
      • Altman D.G.
      Statistics notes. Interaction 2: compare effect sizes not P values.
      A survival benefit of adequate lymphadenectomy should have been supported by a difference in recurrence pattern. Unfortunately, the authors found no difference in recurrence pattern. In theory, a nodal recurrence in the liver hilum could be the one and only site of recurrent disease. This solitary nodal recurrence could subsequently cause local havoc with obstruction of the biliary confluence or portal vein or become the source of distant metastatic disease. Such a recurrence pattern, however, was not found during follow-up in the present study of more than 700 patients. Moreover, in another large study, the cause of death in 70% of patients with iCCA was intrahepatic disease progression with subsequent liver failure, not nodal disease progression or recurrence.
      • Yamashita S.
      • Koay E.J.
      • Passot G.
      • Shroff R.
      • Raghav K.P.
      • Conrad C.
      • et al.
      Local therapy reduces the risk of liver failure and improves survival in patients with intrahepatic cholangiocarcinoma: a comprehensive analysis of 362 consecutive patients.
      Since the dawn of surgical oncology, experts have discussed the benefit of (extended) lymphadenectomy.
      • Cady B.
      Basic principles in surgical oncology.
      The initial Halstedian understanding was that lymph nodes are a stepping stone from the primary tumor to distant metastatic disease. Therefore, the assumption was that resection of positive LNs could avoid the development of metastatic disease. However, for several decades, cancer scientists have considered draining lymph nodes as dead ends for metastatic spread.
      • Chaffer C.L.
      • Weinberg R.A.
      A perspective on cancer cell metastasis.
      Many studies have indeed found that more radical lymphadenectomy in patients with resectable cancer has no impact on survival and even increases morbidity. In pancreatic cancer, five randomized controlled trials (RCTs) found no benefit of extended lymphadenectomy, but only increased morbidity.
      • Orci L.A.
      • Meyer J.
      • Combescure C.
      • Bühler L.
      • Berney T.
      • Morel P.
      • et al.
      A meta-analysis of extended versus standard lymphadenectomy in patients undergoing pancreatoduodenectomy for pancreatic adenocarcinoma.
      The authors of the present study also confirmed that adequate lymphadenectomy was associated with an increase in major complications from 8.9% to 15.2% (p = 0.027).
      Sposito et al. have confirmed in this study that adequate lymphadenectomy improves staging.
      • Sposito C.
      • Ratti F.
      • Cucchetti A.
      • Ardito F.
      • Ruzzenente A.
      • Di Sandro S.
      • et al.
      Survival benefit of adequate lymphadenectomy in patients undergoing liver resection for clinically node-negative intrahepatic cholangiocarcinoma.
      They could not demonstrate that harvesting more than six LNs is associated with superior survival, while it does substantially increase major complications. Similar results were obtained in a recent systematic review and meta-analysis.
      • Zhou R.
      • Lu D.
      • Li W.
      • Tan W.
      • Zhu S.
      • Chen X.
      • et al.
      Is lymph node dissection necessary for resectable intrahepatic cholangiocarcinoma? A systematic review and meta-analysis.
      The results of 13 studies were pooled and superior survival in patients who did and did not undergo adequate lymphadenectomy could not be demonstrated (HR 1.13; 95% CI 0.94–1.36; p = 0.20). At the same time, lymphadenectomy was associated with significantly higher morbidity (odds ratio 2.67; 95% CI 1.74–4.10; p <0.001). The results of another large multicenter study showed that patients with cirrhosis were at particular risk of developing complications after lymphadenectomy.
      • Bagante F.
      • Spolverato G.
      • Weiss M.
      • Alexandrescu S.
      • Marques H.P.
      • Aldrighetti L.
      • et al.
      Surgical management of intrahepatic cholangiocarcinoma in patients with cirrhosis: impact of lymphadenectomy on peri-operative outcomes.
      This supports the recommendation from the current study that a lymphadenectomy in patients with underlying liver disease is not justified, considering the risk of the procedure.
      Surgical treatment of iCCA is evolving. Lymphadenectomy of at least 6 LNs has become an established procedure for proper staging of patients with resected iCCA. However, its impact on survival remains uncertain. Only a large RCT can properly investigate whether adequate lymphadenectomy in patients with resected iCCA confers superior survival. Such an RCT, however, is unlikely to find a survival benefit, considering current paradigms in surgical oncology and level 1 evidence for other cancers.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      The authors declare no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      BGK WP: editorial concept; BGK WP drafting of the manuscript; PAC critical revision of the manuscript for important intellectual content.

      Supplementary data

      The following are the supplementary data to this article:

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