Cancer, Liver


Article Author:
Alejandro Recio-Boiles
Abdul Waheed


Article Editor:
Hani Babiker


Editors In Chief:
Hela KCHIR
Joseph Lee
Savio John


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
5/18/2019 11:20:25 PM

Introduction

Hepatocellular carcinoma is the most common form of primary liver cancer in the United States with three-quarters of primary and secondary liver cancer cases. [1][2][3]The trend for both estimated new and instances of death is increasing in parallel to the geographical underlying chronic liver disease or cirrhosis etiology.

Etiology

Hepatocellular carcinoma develops from chronic liver disease caused by multiple risk factors. Hepatocellular carcinoma has a strong association with chronic hepatitis B and C virus (HBV and HCV) infections. Chronic hepatitis infections with other associated risk factors, including coinfection hepatitis D (HDV), alcohol consumption, cigarette smoking, may have a higher liver cancer risk. [4][5][6] Patients with chronic hepatitis of any cause (e.g., hemochromatosis or alpha-1 antitrypsin deficiency) or cryptogenic cirrhosis have an increased risk of Hepatocellular carcinoma. Environmental exposure to aflatoxin, contaminated water with blue-green algal toxin and betel nut contribute to hepatocellular carcinoma. Ethanol abuse and metabolic syndrome have been linked to liver cancer with persistent liver damage leading to steatosis, steatohepatitis, cirrhosis, and ultimately hepatocellular carcinoma. Protective factors of hepatocellular carcinoma have been associated with statins and coffee. Treatment of chronic hepatitis, metabolic syndrome, iron removal, alcohol cessation to prevent the development of cirrhosis may reduce Hepatocellular carcinoma development. HBV vaccination and HCV screening can reduce hepatocellular carcinoma incidence worldwide. Hepatocellular carcinoma surveillance guidelines are indicated for high-risk populations and vary per societies/institutions and usually recommend including ultrasonography (US), with or without alpha-fetoprotein (AFP), every 6 to 12 months.

Epidemiology

Hepatocellular carcinoma is the fifth most common cancer occupying second place in cancer deaths worldwide. The majority of Hepatocellular carcinoma cases are due to chronic viral B and C hepatitis infections. In the United States, the Surveillance, Epidemiology and End Results (SEER) Database reported an increased incidence rate of 3.1% per year. Men have an incidence of 11.5 per 100,000 compared to 3.9 in women. Hepatocellular carcinoma death rates have also increased by 2.8% for males and 3.4% for females, per year. Hepatocellular carcinoma commonly presents in the older population after longstanding chronic liver disease. Regional and race/ethnical variations of hepatocellular carcinoma are dependent on the exposure risk factor. HBV is more prevalent worldwide, and HCV accounts for 30% of cases in the United States. HCV has a five-fold increased prevalence among individuals born in the United States between 1945 and 1965, raising their liver cancer-related mortality.

Pathophysiology

Although ngene sequencing studies have described multiple genes associations with hepatocellular carcinoma, most of the initiating genetic events that incite hepatocellular carcinoma remain unknown. Genomic instability, including chromosomal or single nucleotide polymorphism, could be the force of tumorigenesis in liver cancer. Recurrently somatic mutated genes (e.g., TERT promoter, TP53, CTNNB1, ARID1A, FGF) with implicated signaling pathways (JAK/STAT, WntB-catenin, PI3K-AKT-mTOR) have been identified as major drivers of the development of hepatocellular carcinoma. No potential driver or targeted therapy has emerged likely due to the genomic heterogeneity of hepatocellular carcinoma. The classical prognostic biomarkers of hepatocellular carcinoma include Ki-67 protein expression and TP53 gene mutation, which has repeatedly been demonstrated to correlate with poor prognosis.

The most important pathologic issue is the distinction between fibrolamellar variant with tumor encapsulation that presents in younger individuals. These lesions are more likely to be resectable, less frequently related to viral infection or cirrhosis, accompany normal AFP levels and an overall better prognosis, or the traditional hepatocellular cancer presenting in the older population with a chronic disease and less than 25% resectable cases.

History and Physical

Most patients are initially asymptomatic from hepatocellular carcinoma but often present with related symptoms due to chronic liver disease. Patients may complain of upper abdominal discomfort and distention, weight loss, fever, poor appetite, early satiety, diarrhea and other symptoms. Any acute liver decompensation with the development of ascites, encephalopathy, jaundice, or hematemesis should raise a suspicion for hepatocellular carcinoma. Patients with hepatocellular carcinoma may rarely present with unusual symptoms due to a paraneoplastic syndrome presentation that may include hypoglycemia, erythrocytosis, hypercalcemia, or severe watery diarrhea.

Physical examination may reveal signs of chronic liver disease or cirrhosis stigmata, including hepatomegaly, splenomegaly, ascites, jaundice, or engorgement of collateral veins (caput medusa, also known as the palm tree sign, which are dilated superficial epigastric veins) which could be a sign of cirrhosis.

Evaluation

Patients with suspected or confirmed hepatocellular carcinoma will need general laboratory workup for further risk score stratification. Laboratory testing will help to evaluate the severity of liver disease including hypoalbuminemia, hyperbilirubinemia, and hypoprothrombinemia with the clinical inclusion of ascites and encephalopathy to classify according to the Child-Pugh assessment scale. The American Association for the Study of Liver Disease (AASLD) has issued diagnostic algorithms for solid liver lesions by size. US surveillance frequently identifies high-risk patients and is further characterized by dynamic contrasted-enhanced magnetic resonance imaging (MRI) or four-phase computer tomography (CT). [7][8][9][7]Negative features for hepatocellular carcinoma on MRI should be followed by a serial ultrasound every three months. Biopsy for diagnosis is not required for patients with increased hepatocellular carcinoma risk when MRI is diagnostic (e.g., T2 signal intensity) or CT (e.g., arterial enhancement with washout). An AFP increase, especially above 500 mcg/L should raise suspicion for hepatocellular carcinoma. Other approved tumor markers not routinely used are Lens culinaris agglutinin-reactive AFP (AFP-L3) and Des-gamma-carboxy prothrombin (DCP); that in combination with AFP can have a 90% positive predictive value but can be missed in 9% of hepatocellular carcinoma patients. If the diagnosis remains unclear, a biopsy may be appropriate. Diagnosed hepatocellular carcinoma will require further staging imaging with CT to evaluate for metastasis.[10][11][12]

Liver cancer has multiple proposed prognostic staging systems, but no single system is considered ideal. The most commonly used is the Barcelona Clinic Liver Cancer system (four stages A to D) that includes a more robust evaluation of the performance status evaluation (0, 1, 2 or greater than 2), constitutional symptoms by the Child-Pugh stage (A, B, or C), and the Okuda system evaluation. The Okuda criteria include tumor size less than or greater than 50%, ascites clinically detectable or absent, albumin less than or greater than 3 mg/dL, bilirubin less than or greater than 3 mg/dL, assigning positive points that correlates with stages I, II, and III in untreated patients with median overall survival of (mOS) 8.3, 2.0, and 0.7 months, respectively. Barcelona Clinic Liver Cancer system is divided into the following:

  • Early stage (A) asymptomatic patients with tumors appropriate for radical therapies
  • Intermediate stage (B) asymptomatic patients with multi-nodular hepatocellular carcinoma may benefit from chemoembolization
  • Barcelona Clinic Liver Cancer system advanced stage (C) symptomatic patient with vascular invasion, and/or extra-hepatic spread with preserved liver function could be treated with chemotherapy
  • Barcelona Clinic Liver Cancer system terminal stage D disease should be offered systemic palliative therapy.

Very early stage (0) and early stage (A) may be considered for resection or even liver transplant with a curative rate of 30% and 5-year survival 40% to 70%. After a complete resection for hepatocellular carcinoma, based upon the 2010 TNM (tumor, node, metastasis) staging system, five-year survival rates are Stage I (55%), Stage II (37%) and Stage III (16%). Patient with advanced disease may benefit from prognostic survival evaluation by calculating the Cancer of the Liver Italian Program (CLIP) score which sums points of each of the sub-scores (Child-Pugh stage, Tumor morphology uni-nodular versus multi-nodular and extension less than or greater than 50%, AFP less than or greater than 400, and portal vein thrombosis present or absent) with a mOS of 36, 22, 9, 7, and 3 months for patients in categories 0, 1, 2, 3, and 4 to 6, respectively.

Treatment / Management

The only proven curative approach in most patients is surgery (resection or transplant). Unfortunately, most patients are not candidates for surgery (70%). Resectable candidates have early hepatocellular carcinoma stage (less than IIIB and liver disease Child-Pugh stage A only). Resection can achieve relapse-free survival of 40% and 5-year OS of 90%, but the surgery carries a mortality rate of 5% to 10% in patients with cirrhosis. Transplant candidates are evaluated according to the Milan criteria (single tumor smaller than 5 cm or two to three tumors none exceeding 3 cm and no vascular invasion and/or extrahepatic spread) plus High MELD-Na score to ensure that available organs are directed to transplant candidates according to urgency. A liver transplant can achieve relapse-free survival of 80% and 4-year OS 75%. Waiting time for transplant may be months, and hence bridging therapies are performed (chemoembolization, radiofrequency ablation, or partial hepatectomy). Neoadjuvant therapy is not considered a standard of care and adjuvant therapy by the Adjuvant Treatment in the Prevention of Recurrence of Hepatocellular Carcinoma (STORM) (sorafenib) trial showed no benefit. Patients should be offered enrollment in clinical trials when available. If chronic viral hepatitis is present, treatment should be included in the multidisciplinary discussion.[13][14]

For non-surgical candidates, a variety of local treatment options could be offered. Radiofrequency ablation could offer complete remission in 80% of cases (tumors less than 3 cm and 50% of tumors larger than 3 cm). Radiofrequency ablation can be performed in tumors smaller than 4 cm and Child-Pugh A/B liver disease severity. Transarterial chemoembolization is most often used for large or multifocal disease (larger than 5 cm or more than three tumors) not suitable for local ablation with early liver disease. Transarterial chemoembolization offers a survival benefit but only in selected patients with tumors that are smaller than 2 cm and CLIP1 and those cohorts of patients have a median of survival of 50 months. Transarterial chemoembolization absolute contraindications include portal vein thrombosis, encephalopathy, and biliary obstruction and other relative limiting factors. Transarterial chemoembolization plus radiofrequency ablation may be better according to a retrospective analysis with a five-year OS of 44% compared to 20% with only transarterial chemoembolization or 28% with only radiofrequency ablation. Percutaneous ethanol injection [PEI] is considered for poor Child-Pugh B/C liver stage. Other thermal ablation therapies are cryoablation or microwave. Multiple radiation therapy modalities are available (EBRT-SBRT-IMRT-Cyberknife-(90Y or 131I) radioembolization-Proton Beam) without clear guidelines or consensus.

Systemic therapy for hepatocellular carcinoma patients with advanced disease is single-agent multikinase inhibitor which is sorafenib and no role for chemotherapy. 

The Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) study, a multicenter, phase 3, double-blind, placebo-controlled trial with 602 patients with unresectable hepatocellular carcinoma compared sorafenib (at a dose of 400 mg twice per day) to placebo and results revealed time to progression of 5.5 months versus 2.8 months and mOS of 10.7 months versus 7.9 months, in favor of sorafenib and statistically significant for both outcomes. Of note, the SHARP study only included hepatocellular carcinoma patients with Child-Pugh A, and a subgroup analysis showed HCV positive patients had a longer median survival of 14 months. Sorafenib was for long the only approved hepatocellular carcinoma option in the advanced disease setting until the Regorafenib After Sorafenib in Patients with Hepatocellular Carcinoma (RESORCE) study with regorafenib (a multikinase inhibitor) revealed positive results. This was a randomized, double-blind, placebo-controlled, multicenter phase 3, that enrolled 573 patients with Hepatocellular carcinoma whose disease has progressed after treatment with sorafenib greater than 400 mg/day and CP-A (97%). The trial compared 160 mg regorafenib once daily for 3 weeks on and 1 week off, or best supportive care plus placebo, with 28 days cycles. The results revealed a statistically significant median of survival of 10.6 months in the regorafenib group when compared with 7.8 months in the control arm. The Regorafenib After Sorafenib in Patients with Hepatocellular Carcinoma (RESORCE) study included 87% of patients with hepatocellular carcinoma and a Barcelona Clinic Liver Cancer system stage C. Another option for patients with hepatocellular carcinoma whose disease progressed on sorafenib therapy is ramucirumab (a recombinant monoclonal antibody which inhibits vascular endothelial growth factor receptor 2). In the REACH study, a median of survival was improved with ramucirumab (9.2 months) compared with placebo (7.6 months) but did not reach statistical significant (p = 0.1391). Nonetheless, a sub-analysis demonstrated a significant median of survival benefit for patients with an AFP level of 400 ng/mL or greater and Child-Pugh A for 7.8 months for ramucirumab compared with 4.2 months for placebo (HR, 0.67; 95% CI; 0.51, 0.90). REACH-2 study of ramucirumab in patients with advanced hepatocellular carcinoma with underlying Child-Pugh A cirrhosis and baseline AFP levels of 400 ng/mL or more is currently recruiting to evaluate this hypothesis. Ongoing clinical trials and future therapies are focused on immunotherapy (nivolumab and durvalumab) and small molecule tyrosine kinase inhibitors (cabozantinib).[15][16][17][18]

Enhancing Healthcare Team Outcomes

Managing liver cancer requires a multidisciplinary team that includes an oncologist, hepatobiliary surgeon, pathologist, radiologist, gastroenterologist, palliative care nurses, dietitian, and an internist. Unfortunately, the majority of patients are not candidates for surgery. Many local treatments are available but they only increase life span by 6-18 months. Biological agents are available but most are prohibitively expensive and do not affect survival significantly. Most patients may benefit from palliative care and it is important to involve the team early on. The surgeon and radiologist may be consulted to manage some of the complications of metastatic liver disease. The overall outlook for patients with liver cancer is very poor.[19][20][21]

 

 

 


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Cancer, Liver - Questions

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Which has not been associated with liver cancer?



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Which of the following is false about hepatocellular cancer?



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Hepatocellular carcinoma has been linked to:



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Which of the following has not been implicated as a cause of liver cancer?



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The use of alpha-fetoprotein and des gamma carboxy prothrombin have been used as markers for:



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What is the chemical associated with carcinoma of the liver?



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Epidemiologic studies clearly show a relationship between hepatocellular carcinoma and:



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Widespread cancer was diagnosed in a 48-year-old Asian immigrant. Serologic studies revealed a high level of alpha-fetoprotein. What is the primary carcinoma diagnosis that favors this laboratory finding?



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A 56-year-old presents with mild right upper quadrant pain and elevated alkaline phosphatase. He is not jaundiced but his bilirubin levels are elevated. Gallstones are not present. Liver biopsy reveals intrahepatic cholestasis. What is the most likely diagnosis?



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A 55-year-old male from Africa presents with a fever and weight loss. He says that over the past 3 months he has become very tired and has no energy. He denies the use of any drugs or smoking. Blood work reveals an elevated level of serum alpha-fetoprotein. CT scan reveals a mass in the liver. The tumor pathology will most likely reveal which condition?



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Liver cancer is associated with which of the following?



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Widespread cancer is diagnosed in a 34-year-old Vietnamese immigrant. Serologic studies reveal a high level of alpha-fetoprotein. This laboratory finding favors the diagnosis of a primary carcinoma of which organ?



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In a middle-aged Asian male with weight loss and elevated levels of alpha-fetoprotein, one would suspect a malignancy of which of the following?



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What is the most common primary neoplasm of the liver?



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Which of the following statements is incorrect about hepatocellular carcinoma?



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Which of the viral hepatitides is associated with a notably increased risk of hepatocellular carcinoma?



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A 55 year old female with chronic hepatitis C complains of right upper quadrant pain is found to have a 6 by 6 cm mass in the liver. Alpha fetoprotein is elevated and CT guided biopsy confirms hepatocellular carcinoma. Which of the following would not be appropriate management?



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What is the most common cause of hepatocellular carcinoma in North America associated with end-stage liver disease?



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Which is true regarding liver cancer?



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Which does not contribute to hepatocellular carcinoma?



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Which behaviors would decrease the risk of liver cancer?



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A 50 year old female with chronic hepatitis B presents with weight loss and jaundice. There is ascites and peripheral edema. Transaminases are 4 times normal and alkaline phosphatase is 250 U/L. Alpha fetoprotein is 7200 ng/mL and ultrasound shows a 4 x 5 cm mass in the liver. CT guided biopsy was done. What is the most probable diagnosis?



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Choose the false statement about hepatocellular carcinoma (HCC) found in a non-cirrhotic liver compared to HCC in a cirrhotic patient.



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If macroscopic fat is seen in a liver lesion on computerized topography or MRI, which of the following lesions can be excluded?



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Which of the following epidemiological statements about hepatocellular carcinoma (HCC) is false?



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When considering treatment, which of the following is not a key point in a radiology report on hepatocellular carcinoma (HCC)?



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Which of the following is not a recent problem revealed in computerized topography/magnetic resonance evaluations of liver lesions in diagnosing hepatocellular carcinoma (HCC)?



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American College of Radiology has developed liver imaging reporting and data system. Its goal includes all but which of the following?



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Liver imaging reporting and data system has _______ categories, of which category _____ is "Intermediate Probability for hepatocellular carcinoma"?



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You image a solitary mass in a cirrhotic liver that measures 1.9 cm in diameter and shows hyper-enhancement during arterial phase imaging. Last year at this time, it measured 8 mm in diameter. This should be classified as which level in liver imaging reporting and data system?



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An arterial phase hyper-enhancing mass in a cirrhotic liver measures 2.1 cm and shows portal vein enhancing thrombus. This is a liver imaging reporting and data system LI-RADS _____ lesion.



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Which of the following ancillary features suggests hepatocellular carcinoma?



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From benign to malignant, order the evolution of cirrhotic nodules using the Sakamoto hypothesis.



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Distinctive features of hepatocellular carcinoma (HCC) include which of the following?



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What percentage of hepatocellular carcinoma (HCC) is hypervascular?



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Which of these have been implicated in the pathogenesis of hepatocellular carcinoma?



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Which of the hepatocellular carcinoma risk factors is consider the most predominant in developing countries?



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A 54-year-old man with chronic hepatitis C virus cirrhosis is undergoing yearly monitoring according to guidelines and found to have an alpha-fetoprotein (AFP) of 440mg/mL (prior 10) and a new 5 cm nodule by ultrasound. What will be the next best step?



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Examination of a 53-year-old female with alcohol use disorder reveals cirrhosis and mild ascites (Childs-Pugh A). She has an alpha-fetoprotein level of 1340 mg/mL. An MRI identified multinodular, enhancing lesions in the liver of more than 50% with characteristic features of a hepatocellular carcinoma and portal vein thrombosis. The patient is classified as grade 1 on the Eastern Cooperative Oncology Group (ECOG) scale and stage N1. What should be the initial approach?



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A 64-year-old man with recently treated hepatitis C on sustained virological response who developed cirrhosis (Childs-Pugh B) has an alpha-fetoprotein level of 300 mg/mL. An MRI identified ring-enhancing lesions, up to 4 cm, in the liver with characteristic features of a hepatocellular carcinoma. Patient has an ECOG score of 0 and Okuda 1, and staging did not reveal nodules or metastasis. What should be the initial approach?



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Cancer, Liver - References

References

Arias-Flórez JS,Martínez-Delgado AM,Alarcón-Tarazona ML,Insuasty-Enriquez JS,Díaz-Martínez LA, [Conventional serum tumor markers in liver cancer. Retrospective analysis of 118 patients]. Revista medica de Chile. 2018 Dec;     [PubMed]
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Benson AB 3rd,D'Angelica MI,Abbott DE,Abrams TA,Alberts SR,Saenz DA,Are C,Brown DB,Chang DT,Covey AM,Hawkins W,Iyer R,Jacob R,Karachristos A,Kelley RK,Kim R,Palta M,Park JO,Sahai V,Schefter T,Schmidt C,Sicklick JK,Singh G,Sohal D,Stein S,Tian GG,Vauthey JN,Venook AP,Zhu AX,Hoffmann KG,Darlow S, NCCN Guidelines Insights: Hepatobiliary Cancers, Version 1.2017. Journal of the National Comprehensive Cancer Network : JNCCN. 2017 May;     [PubMed]
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Kuo KL,Stenehjem D,Albright F,Ray S,Brixner D, Treatment Patterns and Outcomes in Patients With Hepatocellular Carcinoma Stratified by Stage-Guided Treatment Categories. Journal of the National Comprehensive Cancer Network : JNCCN. 2015 Aug;     [PubMed]
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Adam R,Kitano Y, Multidisciplinary approach of liver metastases from colorectal cancer. Annals of gastroenterological surgery. 2019 Jan;     [PubMed]
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