Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma

Importance Data on outcomes following surgical management of intrahepatic cholangiocarcinoma (ICC) are limited. The incidence of ICC is increasing and it has a poor prognosis. No consensus has been reached regarding the optimal treatment modalities. Objective To systematically review and synthesize the available evidence regarding treatment and prognosis in patients with ICC. Data Sources The PubMed database was searched for relevant articles published between January 1, 2000, and April 1, 2013. Study Selection Only studies assessing predictors of survival or recurrence in patients undergoing curative-intent surgical treatment of ICC were included. Small series, studies reporting on mixed types of cholangiocarcinoma, or exclusively on hepatolithiasis-associated cholangiocarcinoma, and those published in a language other than English, French, German, Italian, or Greek, were excluded. Fifty-seven of 960 articles were therefore analyzed. Data Extraction and Synthesis Data on preoperative, intraoperative, and postoperative variables were extracted by 3 independent reviewers. Multiple studies reporting on the same population were excluded. Data were pooled using a random-effects model. Main Outcomes and Measures We hypothesized that preoperative variables and tumor characteristics affect patient survival. The outcomes of the study were overall survival and recurrence-free survival. The hypothesis was formulated before data collection. Results Fifty-seven studies (4756 patients) were included in the review. Median patient age ranged from 49 to 67 years, and 57% were male. Most patients had a solitary (69%), large (median size, 4.5-8.0 cm) tumor of the mass-forming type (86%). Approximately one-third of the patients had lymph node metastasis (34%) or vascular (38%), perineural (29%), or biliary invasion (29%). Most underwent a major hepatectomy (82%), often accompanied by lymphadenectomy (67%) and sometimes by extrahepatic bile duct resection (23%). Median and 5-year overall survival (OS) generally were approximately 28 months (range, 9-53 months) and 30% (range, 5%-56%), respectively; factors predicting shorter OS included large tumor size, multiple tumors, lymph node metastasis, and vascular invasion. Adjuvant chemotherapy or radiotherapy did not appear to be beneficial. Seven studies (2132 patients) provided data for the meta-analysis. Factors associated with shorter OS included older age (pooled hazard ratio, 1.10; 95% CI, 1.03-1.17), larger tumor size (1.09; 1.02-1.16), presence of multiple tumors (1.70; 1.43-2.02), lymph node metastasis (2.09; 1.80-2.43), vascular invasion (1.87; 1.44-2.42), and poor tumor differentiation (1.41; 1.17-1.71). Conclusions and Relevance The prognosis of ICC is dictated mainly by tumor factors. Future research could focus on the usefulness of adjuvant treatment as well as other multidisciplinary treatment modalities.

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Treatment and Prognosis for Patients With Intrahepatic Cholangiocarcinoma Systematic Review and Meta-analysis

An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists met on 15 January 2014 to review current evidence on the management of intrahepatic cholangiocarcinoma (ICC) in order to establish practice guidelines and to agree on consensus statements. The treatment of ICC requires a coordinated, multidisciplinary approach to optimize survival. Biopsy is not necessary if the surgeon suspects ICC and is planning curative resection, although biopsy should be obtained before systemic or locoregional therapies are initiated. Assessment of resectability is best accomplished using cross-sectional imaging [computed tomography (CT) or magnetic resonance imaging (MRI)], but the role of positron emission tomography (PET) is unclear. Resectability in ICC is defined by the ability to completely remove the disease while leaving an adequate liver remnant. Extrahepatic disease, multiple bilobar or multicentric tumours, and lymph node metastases beyond the primary echelon are contraindications to resection. Regional lymphadenectomy should be considered a standard part of surgical therapy. In patients with high-risk features, the routine use of diagnostic laparoscopy is recommended. The preoperative diagnosis of combined hepatocellular carcinoma and cholangiocarcinoma (cHCC–CC) by imaging studies is extremely difficult. Surgical resection remains the mainstay of treatment, but survival is worse than in HCC alone. There are no adequately powered, randomized Phase III trials that can provide definitive recommendations for adjuvant therapy for ICC. Patients with high-risk features (lymphovascular invasion, multicentricity or satellitosis, large tumours) should be encouraged to enrol in clinical trials and to consider adjuvant therapy. Cisplatin plus gemcitabine represents the standard-of-care, front-line systemic therapy for metastatic ICC. Genomic analyses of biliary cancers support the development of targeted therapeutic interventions.

Intrahepatic Cholangiocarcinoma: expert consensus statement

IMPORTANCE: Intrahepatic cholangiocarcinoma (ICC) is a primary cancer of the liver that is increasing in incidence, and the prognostic factors associated with outcome after surgery remain poorly defined. OBJECTIVE: To combine clinicopathologic variables associated with overall survival after resection of ICC into a prediction nomogram. DESIGN, SETTING, AND PARTICIPANTS: We performed an international multicenter study of 514 patients who underwent resection for ICC at 13 major hepatobiliary centers in the United States, Europe, and Asia from May 1, 1990, through December 31, 2011. Multivariate Cox proportional hazards regression modeling with backward selection using the Akaike information criteria was used to select variables for construction of the nomogram. Discrimination and calibration were performed using Kaplan-Meier curves and calibration plots. INTERVENTIONS: Surgical resection of ICC at a participating hospital. MAIN OUTCOMES AND MEASURES: Long-term survival, effect of potential prognostic factors, and performance of proposed nomogram. RESULTS: Median patient age was 59.2 years, and 53.1% of the patients were male. Most patients (74.7%) had a solitary tumor, and median tumor size was 6.0 cm. Patients were treated with an extended hepatectomy (202 [39.3%]), a hemihepatectomy (180 [35.0%]), or a minor liver resection (<3 segments) (132 [25.7%]). Most patients underwent R0 resection (87.9%), and 35.7% of patients had N1 disease. Using the backward selection of clinically relevant variables, we found that age at diagnosis (hazard ratio [HR], 1.31; P < .001), tumor size (HR, 1.50; P < .001), multiple tumors (HR, 1.58; P < .001), cirrhosis (HR, 1.51; P = .08), lymph node metastasis (HR, 1.78; P = .01), and macrovascular invasion (HR, 2.10; P < .001) were selected as factors predictive of survival. On the basis of these factors, a nomogram was created to predict survival of ICC after resection. Discrimination using Kaplan-Meier curves, calibration curves, and bootstrap cross-validation revealed good predictive abilities (C index, 0.692). CONCLUSIONS AND RELEVANCE: On the basis of an Eastern and Western experience, a nomogram was developed to predict overall survival after resection for ICC. Validation revealed good discrimination and calibration, suggesting clinical utility to improve individualized predictions of survival for patients undergoing resection of ICC.

https://jamanetwork.com/journals/jamasurgery/articlepdf/1838298/soi130137.pdf

A Nomogram to Predict Long-term Survival After Resection for Intrahepatic Cholangiocarcinoma: An Eastern and Western Experience

Primary liver cancer-including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC)-incidence is increasing and is an important source of cancer-related mortality worldwide. Management of these cancers, even when localized, is challenging due to the association with underlying liver disease and the complex anatomy of the liver. Although for ICC, surgical resection provides the only potential cure, for HCC, the risks and benefits of the multiple curative intent options must be considered to individualize treatment based upon tumor factors, baseline liver function, and the functional status of the patient. The principles of surgical resection for both HCC and ICC include margin-negative resections with preservation of adequate function of the residual liver. As the safety of surgical resection has improved in recent years, the role of liver resection for HCC has expanded to include selected patients with preserved liver function and small tumors (ablation as an alternative), tumors within Milan criteria (transplant as an alternative), and patients with large (>5 cm) and giant (>10 cm) HCC or with poor prognostic features (for whom surgery is infrequently offered) due to a survival benefit with resection for selected patients. An important surgical consideration specifically for ICC includes the high risk of nodal metastasis, for which portal lymphadenectomy is recommended at the time of hepatectomy for staging. For both diseases, onco-surgical strategies including portal vein embolization and parenchymal-sparing resections have increased the number of patients eligible for curative liver resection by improving patient outcomes. Multidisciplinary evaluation is critical in the management of patients with primary liver cancer to provide and coordinate the best treatments possible for these patients.

https://journals.sagepub.com/doi/pdf/10.1177/1073274817744621

Liver Resection and Surgical Strategies for Management of Primary Liver Cancer.

https://repositorio.chlc.min-saude.pt/bitstream/10400.17/1291/1/Surgery%202013%20811.pdf

Recurrence After Operative Management of Intrahepatic Cholangiocarcinoma

Stokes JB, Nolan NJ, Stelow EB, et al. Preoperative capecitabine and concurrent radiation for borderline resectable pancreatic cancer. Ann Surg Oncol. 18:(3): 619-627

Dustin M. Walters

Papers

Recurrence After Operative Management of Intrahepatic Cholangiocarcinoma

Stokes JB, Nolan NJ, Stelow EB, et al. Preoperative capecitabine and concurrent radiation for borderline resectable pancreatic cancer. Ann Surg Oncol. 18:(3): 619-627