Elsevier

Journal of Hepatology

Volume 69, Issue 1, July 2018, Pages 182-236
Journal of Hepatology

Clinical Practice Guidelines
EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma

https://doi.org/10.1016/j.jhep.2018.03.019Get rights and content

Summary

Liver cancer is the fifth most common cancer and the second most frequent cause of cancer-related death globally. Hepatocellular carcinoma represents about 90% of primary liver cancers and constitutes a major global health problem. The following Clinical Practice Guidelines will give up-to-date advice for the clinical management of patients with hepatocellular carcinoma, as well as providing an in-depth review of all the relevant data leading to the conclusions herein.

Introduction

In 2012, the previous guidelines for the management of hepatocellular carcinoma (HCC) were published as a result of a joint effort by the European Association for the Study of the Liver (EASL) and the European Organisation for Research and Treatment of Cancer (EORTC).1 Since then several clinical and scientific advances have been achieved. Thus, an updated version of the document is needed.

Section snippets

Objectives of the guideline

These EASL Clinical Practice Guidelines (CPGs) are the current update to the previous EASL-EORTC CPGs.1 These EASL CPGs define the use of surveillance, diagnosis and therapeutic strategies recommended for patients with HCC.

The purpose of this document is to assist physicians, patients, healthcare providers and health-policy makers from Europe and worldwide in the decision making process, based on the currently available evidence. Users of these guidelines should be aware that the

Composition of the guidelines group

The guideline development group (GDG) of this guideline project is composed of international experts in the field of HCC, comprising the areas of hepatology (PRG, AF, JL, FP), surgery (VM), radiology (VV), oncology (JLR) and pathology (PS). Initially, the EASL governing board nominated a chair (PRG) and a governing board member (AF) to propose a panel of experts and finally nominated the above GDG, Additionally, a guideline methodologist was appointed to support the GDG (MF).

Funding and management of conflict of interests

This guideline

Epidemiology, risk factors and prevention

  • The incidence of HCC is increasing both in Europe and worldwide; it is amongst the leading causes of cancer death globally (evidence high).

  • Vaccination against hepatitis B reduces the risk of HCC and is recommended for all new-borns and high-risk groups (evidence high; recommendation strong).

  • Governmental health agencies should implement policies to prevent HCV/HBV transmission, counteract chronic alcohol abuse, and encourage life styles that prevent obesity and metabolic syndrome (evidence

Surveillance

  • Implementation of screening programmes to identify at-risk candidate populations should be improved. Such programmes are a public health goal, aiming to decrease HCC-related and overall liver-related deaths (evidence low; recommendation strong).

  • Patients at high risk of developing HCC should be entered into surveillance programmes. Government health policy and research agencies should address these needs. Groups at high risk are depicted (Table 3) (evidence moderate; recommendation strong).

  • The

Diagnosis

  • Diagnosis of HCC in cirrhotic patients should be based on non-invasive criteria and/or pathology (evidence high; recommendation strong).

  • In non-cirrhotic patients, diagnosis of HCC should be confirmed by pathology (evidence moderate; recommendation strong).

  • Pathological diagnosis of HCC should be based on the International Consensus recommendations using the required histological and immunohistological analyses (evidence high; recommendation strong).

  • Non-invasive criteria can only be applied to

Recall policy

  • In patients at high risk of developing HCC, nodule(s) less than 1 cm in diameter detected by ultrasound should be followed at ≤4-month intervals in the first year. If there is no increase in the size or number of nodules, surveillance could be returned to the usual six-month interval thereafter (evidence weak; recommendation weak).

  • In cirrhotic patients, diagnosis of HCC for nodules of ≥1 cm in diameter can be achieved with non-invasive criteria and/or biopsy-proven pathological confirmation (

Staging systems and treatment allocation

  • Staging systems for clinical decision making in HCC should include tumour burden, liver function and performance status (evidence high; recommendation strong).

  • The BCLC staging system (Fig. 3) has been repeatedly validated and is recommended for prognostic prediction and treatment allocation (evidence high; recommendation strong). The levels of evidence for treatments according to strength and magnitude of benefit are summarised (Fig. 9).

  • Treatment stage migration concept applies.

  • Refinement of

Response assessment

  • Assessment of response in HCC should be based on mRECIST for loco-regional therapies (evidence moderate; recommendation strong). For systemic therapies both mRECIST and RECIST1.1 are recommended (evidence moderate; recommendation weak). The use of changes in serum biomarker levels for assessment of response (i.e. AFP levels) is under investigation.

  • Multiphasic contrast-enhanced CT or MRI are recommended for assessment of response after resection, loco-regional or systemic therapies (evidence

Liver resection

  • Surgical resection is recommended as treatment of choice in patients with HCC arising on a non-cirrhotic liver (evidence low; recommendation strong).

  • Indications for resection of HCC in cirrhosis should be based on multi-parametric composite assessment of liver function, portal hypertension, extent of hepatectomy, expected volume of the future liver remnant, performance status and patients’ co-morbidities (evidence high; recommendation strong).

  • Perioperative mortality of liver resection in

Liver transplantation

  • LT is recommended as the first-line option for HCC within Milan criteria but unsuitable for resection (evidence high; recommendation strong). Milan criteria are the benchmark for selection of patients with HCC for LT and the basis for comparison with other suggested criteria.

  • Consensus on expanded criteria for LT in HCC has not been reached. Patients beyond the Milan criteria can be considered for LT after successful downstaging to within Milan criteria, within defined protocols (evidence

Local ablation and external radiation

  • Thermal ablation with radiofrequency is the standard of care for patients with BCLC 0 and A tumours not suitable for surgery (evidence high; recommendation strong). Thermal ablation in single tumours 2 to 3 cm in size is an alternative to surgical resection based on technical factors (location of the tumour), hepatic and extrahepatic patient conditions.

  • In patients with very early stage HCC (BCLC-0) radiofrequency ablation in favourable locations can be adopted as first-line therapy even in

Transarterial therapies

  • TACE is recommended for patients with BCLC stage B and should be carried out in a selective manner (evidence high; recommendation strong). The use of drug-eluting beads has shown similar benefit to conventional TACE (cTACE; gelfoam-Lipiodol® particles) and either of the two can be utilised (evidence high; recommendation strong). TACE should not be used in patients with decompensated liver disease, advanced liver and/or kidney dysfunction, macroscopic vascular invasion or extrahepatic spread (

Systemic therapies

  • Sorafenib is the standard first-line systemic therapy for HCC. It is indicated for patients with well-preserved liver function (Child-Pugh A) and with advanced tumours (BCLC–C) or earlier stage tumours progressing upon or unsuitable for loco-regional therapies (evidence high; recommendation strong).

  • Lenvatinib has been shown to be non-inferior to sorafenib and is also recommended in first-line therapy for HCC given its approval. It is indicated for patients with well-preserved liver function

Palliative and best supportive care

  • In HCC on cirrhosis, acetaminophen (paracetamol) up to 3 g/day can be utilised for the management of pain of mild intensity. Non-steroidal anti-inflammatory drugs should be avoided whenever possible in patients with underlying cirrhosis. Opioids can be utilised for the management of pain of intermediate or severe intensity, paying attention to proactively avoid constipation (evidence low; recommendation weak).

  • Bone metastases causing pain or at significant risk of spontaneous secondary fracture

Trial design and endpoints

  • For phase III clinical trials testing primary treatments (either loco-regional or systemic therapies) the primary endpoint should be OS, while for adjuvant therapies after resection/ablation it should be recurrence-free survival or time to response (recommendation strong).

  • When testing neoadjuvant treatments for patients on the liver transplantation waiting list, OS, cancer-related deaths and waiting list drop-out rates are recommended as endpoints (recommendation strong).

  • There are no optimal

Future directions

Hepatocellular carcinoma (HCC) is the result of underlying and well-defined liver disease in most patients. Thus, it is preventable. The rising incidence of HCC in most European countries suggests an insufficient awareness of liver disease in general, calling for public health policies aiming to prevent, detect and treat liver disease – not only for HCC prevention. It is particularly frustrating to see most patients with HCC diagnosed at a stage no longer amenable to curative treatment,

Disclosures

These guidelines reflect the state of knowledge, current at the time of publication, on effective and appropriate care, as well as clinical consensus judgments when knowledge is lacking. The inevitable changes in the state of scientific information and technology mandate that periodic review, updating, and revisions will be needed. These guidelines do not apply to all patients, and each must be adapted and tailored to each individual patient. Proper use, adaptation modifications or decisions to

Conflict of interest

Peter R. Galle reports grant/research support from Bayer, Eli Lilly, BMS, MSD, SillaJen, Merck, Blueprint Medicines, Arqule, Gilead, AbbVie, WAKO; consultant/advisory roles with Bayer, Eli Lilly, BMS; sponsored lectures for Bayer, Lilly, WAKO. Fabio Piscaglia reports grant/research support from ESAOTE; consultant/advisory roles for Bayer, Eisai; sponsored lectures for Bayer, Bracco, Meda Pharma. Jean-Luc Raoul reports consultant/advisory roles for Bayer SP, BTG, MSD; sponsored lectures for

Acknowledgement

The logistical and editorial support from the EASL office is greatly appreciated.

We would like to thank the reviewers of this Clinical Practice Guideline for their time and critical reviewing: EASL Governing Board, Tim Meyer, Gregory Gores, Jean-François Dufour.

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