EASL肝细胞肝癌诊疗指南

EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma European Association for the Study of the Liver⇑, European Organisation for Research and Treatment of Cancer Introduction EASL–EORTC Clinical Practice Guidelines (CPG) on the manage- ment of hepatocellular carcinoma (HCC) define the use of surveil- lance, diagnosis, and therapeutic strategies recommended for patients with this type of cancer. This is the first European joint effort by the European Association for the Study of the Liver (EASL) and the European Organization for Research and Treat- ment of Cancer (EORTC) to provide common guidelines for the management of hepatocellular carcinoma. These guidelines update the recommendations reported by the EASL panel of experts in HCC published in 2001 [1]. Several clinical and scien- tific advances have occurred during the past decade and, thus, a modern version of the document is urgently needed. The purpose of this document is to assist physicians, patients, health-care providers, and health-policy makers from Europe and worldwide in the decision-making process according to evidence- based data. Users of these guidelines should be aware that the recommendations are intended to guide clinical practice in cir- cumstances where all possible resources and therapies are avail- able. Thus, they should adapt the recommendations to their local regulations and/or team capacities, infrastructure, and cost– benefit strategies. Finally, this document sets out some recom- mendations that should be instrumental in advancing the research and knowledge of this disease and ultimately contribute to improve patient care. The EASL–EORTC CPG on the management of hepatocellular carcinoma provide recommendations based on the level of evi- dence and the strength of the data (the classification of evidence is adapted from National Cancer Institute [2]) (Table 1A) and the strength of recommendations following previously reported sys- tems (GRADE systems) (Table 1B). Clinical Practice Summary The clinical practice guidelines below will give advice for up to date management of patients with HCC as well as providing an in-depth review of all the relevant data leading to the conclusions. Clinical Practice Summary Surveillance • Patients at high risk for developing HCC should be entered into surveillance programs. Groups at high risk are depicted in Table 3 (evidence 1B/3A; recommendation 1A/B) • Surveillance should be performed by experienced personnel in all at-risk populations using abdominal ultrasound every 6 months (evidence 2D; recommendation 1B) Exceptions: A shorter follow-up interval (every 3-4 months) is recommended in the following cases: (1). Where a nodule of less than 1 cm has been detected (see recall policy), (2). In the follow-up strategy after resection or loco-regional therapies (evidence 3D; recommendation 2B) • Patients on the waiting list for liver transplantation should be screened for HCC in order to detect and manage tumor progression and to help define priority policies for transplantation (evidence 3D; recommendation 1B) Recall policy • In cirrhotic patients, nodules less than 1 cm in diameter detected by ultrasound should be followed every 4 months the first year and with regular checking every 6 months thereafter (evidence 3D; recommendation 2B) • In cirrhotic patients, diagnosis of HCC for nodules of 1-2 cm in diameter should be based on non-invasive criteria or biopsy-proven pathological confirmation. In the latter case, it is recommended that biopsies are assessed by an expert hepatopathologist. A second biopsy is recommended in case of inconclusive findings, or growth or change in enhancement pattern identified during follow-up (evidence 2D; recommendation 1B) • In cirrhotic patients, nodules more than 2 cm in diameter can be diagnosed for HCC based on typical features on one imaging technique. In case of uncertainty or atypical radiological findings, diagnosis should be confirmed by biopsy (evidence 2D; recommendation 1A) Journal of Hepatology 2012 vol. 56 j 908–943 Received 15 December 2011; accepted 15 December 2011 Contributors: Chairmen: Josep M. Llovet (EASL); Michel Ducreux (EORTC). Clinical Practice Guidelines Members: Riccardo Lencioni; Adrian M. Di Bisceglie; Peter R. Galle; Jean Francois Dufour; Tim F. Greten; Eric Raymond; Tania Roskams; Thierry De Baere; Michel Ducreux; and Vincenzo Mazzaferro. EASL Governing Board Repre- sentatives:Mauro Bernardi. Reviewers: Jordi Bruix; Massimo Colombo; Andrew Zhu. ⇑ Correspondence: EASL Office, 7 rue des Battoirs, CH-1205 Geneva, Switzerland. Tel.: +41 22 807 0360; fax: +41 22 328 0724. E-mail address: easloffice@easloffice.eu ( European Association for the Study of the Liver). Abbreviations: HCV, Hepatitis C virus; SNP, Single nucleotide polymorphism; PEG, Polyethylene glycol; HALT-C, Hepatitis C antiviral long-term treatment against cirrhosis; EPIC, Evaluation of PegIntron in control of hepatitis C cirrhosis; CT, Computed tomography; MR, Magnetic resonance; MRI, Magnetic resonance imaging; EpCAM, Epithelial cell adhesion molecule; PPV, Positive predictive value; qRT-PCR, Real-time reverse-transcription polymerase chain reaction; CUPI, Chinese university prognostic index; CLIP, Cancer of the Liver Italian program; SHARP, Sorafenib hepatocellular carcinoma assessment randomised protocol. These Guidelines were developed by the EASL and the EORTC and are published simultaneously in the Journal of Hepatology (volume 56, issue 4) and the European Journal of Cancer (volume 48, issue 5). Clinical Practice Guidelines Clinical Practice Summary Diagnosis • Diagnosis of HCC is based on non-invasive criteria or pathology (evidence 2D; recommendation 1A) • Pathological diagnosis of HCC is based on the recommendations of the International Consensus Panel. Immunostaining for GPC3, HSP70, and glutamine synthetase and/or gene expression (GPC3, LYVE1 and survivin) are recommended to differentiate high grade dysplastic nodules from early HCC (evidence 2D; recommendation 2B) Additional staining can be considered to detect progenitor cell features (K19 and EpCAM) or assess neovascularisation (CD34) • Non-invasive criteria can only be applied to cirrhotic patients and are based on imaging techniques obtained by 4-phase multidetector CT scan or dynamic contrast-enhanced MRI. Diagnosis should be based on the of the typical hallmark of HCC (hypervascular in the arterial phase with washout in the portal venous or delayed phases). While one imaging technique is required for nodules beyond 1 cm in diameter (evidence 2D; recommendation 2B), a more conservative approach with 2 techniques is recommended in suboptimal settings. The role of contrast-enhanced ultrasound (CEUS) and angiography is controversial. PET-scan is not accurate for early diagnosis Staging systems • Staging systems in HCC should outcome prediction and treatment assignment. They should facilitate exchange of information, prognosis prediction and trial design. Due to the nature of HCC, the main prognostic variables are tumor stage, liver function and performance status • The BCLC staging system is recommended for prognostic prediction and treatment allocation (evidence 2A; recommendation 1B) This staging system can be applied to most HCC patients, as long as considerations for special subpopulations (liver transplantation) are incorporated • Other staging systems applied alone or in combination with BCLC are not recommended in clinical practice • Molecular of HCC based on gene signatures or molecular abnormalities is not ready for clinical application (evidence 2A; recommendation 1B) Treatment • Treatment allocation is based on the BCLC allocation system Resection • Resection is the treatment option for patients with solitary tumors and very well-preserved liver function, as normal bilirubin with either hepatic venous pressure gradient ≤10 mmHg or platelet count ≥100,000 (evidence 2A; recommendation 1B) Anatomical resections are recommended (evidence 3A; recommendation 2C) • Additional indications for patients with multifocal tumors meeting Milan criteria (≤3 nodules ≤3 cm) or with mild portal hypertension not suitable for liver transplantation require prospective comparisons with loco-regional treatments (evidence 3A; recommendation 2C) • Peri-operative mortality of liver resection in cirrhotic patients is expected to be 2-3% • Neo-adjuvant or adjuvant therapies have not proven to improve outcome of patients treated with resection (or local ablation) (evidence 1D; recommendation 2C) • Tumor recurrence represents the major complication of resection and the pattern of recurrence subsequent therapy allocation and outcome. In case of recurrence, the patient will be re-assessed by BCLC staging, and re-treated accordingly Liver Transplantation • Liver transplantation is considered to be the treatment option for patients with single tumors less than 5 cm or ≤3 nodules ≤3 cm (Milan criteria) not suitable for resection (evidence 2A; recommendation 1A) • Peri-operative mortality and one-year mortality are expected to be approximately 3% and ≤10%, respectively • Extension of tumor limit criteria for liver transplantation for HCC has not been established. Modest expansion of Milan criteria applying the “up-to-seven” in patients without microvascular invasion achieves competitive outcomes, and thus this indication requires prospective validation (evidence 2B; recommendation 2B) • Neo-adjuvant treatment can be considered for loco-regional therapies if the waiting list exceeds 6 months due to good cost-effectiveness data and tumor response rates, even though impact on long-term outcome is uncertain (evidence 2D; recommendation 2B) • Down-staging policies for HCCs exceeding conventional criteria cannot be recommended and should be explored in the context of prospective studies aimed at survival and disease progression end-points (evidence 2D; recommendation 2C) Assessment of downstaging should follow RECIST criteria • Living donor liver transplantation is an alternative option in patients with a waiting list exceeding 6-7 months, and offers a suitable setting to explore extended indications within research programs (evidence 2A; recommendation 2B) Local ablation • Local ablation with radiofrequency or percutaneous ethanol injection is considered the standard of care for patients with BCLC 0-A tumors not suitable for surgery (evidence 2A; recommendation 1B) Other ablative therapies, such as microwave or cryoablation, are still under investigation • Radiofrequency ablation is recommended in most instances as the main ablative therapy in tumors less than 5 cm due to a significantly better control of the disease (evidence 1iD; recommendation 1A) Ethanol injection is recommended in cases where radiofrequency ablation is not technically feasible (around 10-15%) • In tumors <2 cm, BCLC 0, both techniques achieve complete responses in more than 90% of cases with good long-term outcome. Whether they can be considered as competitive alternatives to resection is uncertain (evidence 1iA; recommendation 1C) Chemoembolization and transcatheter therapies • Chemoembolization is recommended for patients with BCLC stage B, multinodular asymptomatic tumors without vascular invasion or extra-hepatic spread (evidence 1iiA; recommendation 1A) The use of drug-eluting beads has shown similar response rates than gelfoam-lipiodol particles associated with less systemic adverse events (evidence 1D; recommendation 2B) Chemoembolization is discouraged in patients with decompensated liver disease, advanced liver dysfunction, macroscopic invasion or extrahepatic spread (evidence 1iiA; recommendation 1B) Bland embolization is not recommended • Internal radiation with 131I or 90Y glass beads has shown promising anti-tumoral results with a safe but cannot be recommended as standard therapy. Further research trials are needed to establish a competitive role in this population (evidence 2A; recommendation 2B) • Selective intra-arterial chemotherapy or lipiodolization are not recommended for the management of HCC (evidence 2A; recommendation 2B) • External three-dimensional conformal radiotherapy is under investigation, and there is no evidence to support this therapeutic approach in the management of HCC (evidence 3A; recommendation 2C) modified efficacy profile, first-line profiles identification define specific classification first-line defined influences JOURNAL OF HEPATOLOGY Journal of Hepatology 2012 vol. 56 j 908–943 909 Epidemiology, risk factors, and prevention • The incidence of HCC is increasing in Europe and worldwide. • Vaccination against hepatitis B is recommended to all newborns and high risk groups (evidence: 2D; recommendation 1A) • Governmental health agencies should recommend policies for preventing HCV/HBV transmissions, encourage life styles preventing obesity and alcohol abuse (evidence 3A; recommendation 1A) and controlling metabolic conditions, such as diabetes (evidence 3; recommendation 2B) • In patients with chronic hepatitis, antiviral therapies leading to maintained HBV suppression in chronic hepatitis B and sustained viral response in hepatitis C are recommended since they have been shown to prevent progression to cirrhosis, and hence HCC development (evidence 1A; recommendation 1A). The application of antiviral therapies should follow the EASL guidelines for management of chronic hepatitis B and C infection • therapy in preventing HCC development are not robustly demonstrated (evidence 1D; recommendation 2B) Once cirrhosis is established, the benefits of anti-viral Epidemiology The burden of cancer is increasing worldwide. Each year there are 10.9 million new cases of cancer and 6.7 million cancer-related deaths. The most commonly diagnosed cancers are lung, breast, and colorectal while the most common causes of cancer death are lung, stomach, and liver [3,4]. Liver cancer is the sixth most common cancer (749,000 new cases), the third cause of cancer- related death (692,000 cases), and accounts for 7% of all cancers [4]. HCC represents more than 90% of primary liver cancers and is a major global health problem. The incidence of HCC increases progressively with advancing age in all populations, reaching a peak at 70 years [5]. In Chinese and in black African populations, the mean age of patients with the tumor is appreciably younger. This is in sharp contrast to Japan, where the incidence of HCC is highest in the cohort of men aged 70–79 years [6]. HCC has a strong male preponderance with a male to female ratio estimated to be 2.4 [4]. The pattern of HCC occurrence has a clear geographical distri- bution, with the highest incidence rates in East Asia, sub-Saharan Africa, and Melanesia, where around 85% of cases occur [3,4]. In developed regions, the incidence is low with the exception of Southern Europe where the incidence in men (10.5 age-standardized Clinical Practice Summary Systemic therapies • Sorafenib is the standard systemic therapy for HCC. It is indicated for patients with well-preserved liver function (Child-Pugh A class) and with advanced tumors (BCLC C) or those tumors progressing upon loco-regional therapies (evidence 1iA; recommendation 1A) • There are no clinical or molecular biomarkers available to identify the best responders to sorafenib (evidence 1A; recommendation 2A) • Systemic chemotherapy, tamoxifen, immunotherapy, anti- androgen, and herbal drugs are not recommended for the clinical management of HCC patients (evidence 1-2A; recommendation 1A/B) • There is no available second-line treatment for patients with intolerance or failure to sorafenib. Best supportive care or the inclusion of patients in clinical trials is recommended in this setting (recommendation 2B) • In circumstances, radiotherapy can be used to alleviate pain in patients with bone metastasis (evidence 3A; recommendation 2C) • Patients at BCLC D stage should receive palliative support including management of pain, nutrition and psychological support. In general, they should not be considered for participating in clinical trials (recommendation 2B) specific Table 1A. Levels of evidence according to study design and end-points National Cancer Institute: PDQ Levels of Evidence for Adult and Pediatric Cancer Treatment Studies. Bethesda [2]–. Strength of evidence according to study design: Level 1: Randomized controlled clinical trials or meta- analyses of randomized studies* (i) Double-blinded (ii) Non-blinded treatment delivery Level 2: Non-randomized controlled clinical trials** Level 3: Case series*** (i) Population-based, consecutive series (ii) Consecutive cases (not population-based) (iii) Non-consecutive cases Strength of evidence according to end-points: C. Carefully assessed quality of life D. Indirect surrogates# (i) Event-free survival (ii) Disease-free survival (iii) Progression-free survival (iv) Tumor response rate A. Total mortality (or overall survival from a defined time) B. Cause-specific mortality (or cause-specific mortality from a defined time) –National Cancer Institute: PDQ� Levels of Evidence for Adult and Paediatric Cancer Treatment Studies. Bethesda, MD: National Cancer Institute. Date last modified 26/August/2010. Available at: http://cancer.gov/cancertopics/pdq/lev- els-evidence-adult-treatment/HealthProfessional. Accessed . ⁄The randomized, double-blinded controlled clinical trial (1i) is the gold standard of study design. Meta-analyses of randomized studies are placed in the same category of strength of evidence as are randomized studies. ⁄⁄This category includes trials in which treatment allocation was made by birth date, chart number (so-called quasi randomized studies) or subset analyses of randomized studies (or randomized phase II studies). ⁄⁄⁄All other prospective (cohort studies) or retrospective studies (case–control studies, case series). #These end-points may be subjected to investigator interpretation. More importantly, they may, but do not automatically, translate into direct patient benefit such as survival or quality of life. Nevertheless, it is rational in many circumstances to use a treatment that improves these surrogate end-points while awaiting a more definitive end-point to support its use. Clinical Practice Guidelines 910 Journal of Hepatology 2012 vol. 56 j 908–943 Nation M F Albania 5.8 2.9 Austria 9.3 2.9 Belgium 3.3 1.5 Bosnia-Erzegovina 4.3 1.5 Bulgaria 5.6 2.2 Croatia 7.7 2.4 Czech Republic 5.9 2.4 Denmark 4.0 1.3 Estonia 3.5 1.5 Finland 5.8 2.4 France 10.5 2.2 Germany 6.2 2.2 Great Britain 3.8 1.7 Greece 5.2 2.0 Netherland 2.0 0.8 Hungary 7.5 2.0 Ireland 3.4 1.5 Italy 13.4 4.4 Latvia 4.6 1.8 Lithuania 4.1 1.4 Luxembourg 9.8 3.8 Macedonia 5.3 2.3 Moldova 14.2 4.6 Montenegro 5.3 2.5 Norway 2.2 1.0 Poland 3.1 1.5 Portugal 3.5 1.2 Romania 8.1 3.0 Russia 4.4 1.9 Serbia 4.8 2.6 Slovenia 5.4 1.8 Spain 9.6 2.5 Sweden 3.2 1.4 Switzerland 7.8 2.3 Ukraine 3.2 1.6 Fig. 1. Incidence rates of primary liver cancer according to geographical distribution in Europe. Age-adjusted incidence rates per 100,000 of liver cancer in Europe in 2008. The color intensity is proportional to the magnitude of incidence. M, males; F, females. (Data from: Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr.) Table 1B. Grading evidence and recommendations (adapted from GRADE system). Grading of evidence Notes Symbol High quality A Moderate quality of effect and may change the estimate B Low or very low quality estimate of effect a