Hepatocellular carcinoma : Consensus , controversies and future directions : A report from the Canadian Association for the Study of the Liver Hepatocellular Carcinoma Meeting

1Departments of Medicine and Oncology, Division of Gastroenterology & Hepatology, Cumming School of Medicine, University of Calgary, Calgary, Alberta; 2Department of Medicine, Division of Gastroenterology, University of Toronto and University Health Network, Toronto, Ontario Correspondence: Dr Kelly Warren Burak, Rm 6D35 Teaching Research and Wellness Building, 3280 Hospital Drive Northwest, Calgary, Alberta T2N 4Z6. Telephone 403-592-5049, fax 403-592-5090, e-mail kwburak@ucalgary.ca Received for publication January 22, 2015. Accepted January 25, 2015 METHODOLOGY The present document is a report of the consensus conference on the management of hepatocellular carcinoma (HCC) sponsored by the Canadian Association for Study of the Liver (CASL), which was held in Toronto on February 11, 2014. This is not a practice guideline; however, the views expressed are those of physician experts on various aspects of the management of HCC. Where there is existing consensus, optimal management strategies are recommended, but we also sought to review controversial areas and define future direction in the management of HCC. The topics for the meeting were chosen by the organizing committee (KWB and MS), and nationally and internationally recognized experts in all aspects of HCC were invited to present (Table 1). The meeting was funded by the Canadian Liver Foundation and was endorsed by the World Gastroenterology Organization and the International Association for the Study of the Liver. Before the meeting, several statements were drafted by the organizers related to each specific topic. The level of evidence for each statement was assigned according to the Oxford System (Table 2). Individual speakers first received the particular statements related to their specific topics for feedback and modification. After editing, the full set of statements was circulated to the entire group of speakers for comments and suggested changes. The finalized statements were circulated to all speakers and other participants ahead of the meeting, along with an environmental scan of the existing HCC consensus recommendations from the Canadian Multidisciplinary HCC Consensus and the major hepatology societies globally including the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL) and the Asian Pacific Association for the Study of the Liver (APASL) (1-4). Speakers delivered 20 min presentations on their topic, which are available at <www.hepatology.ca/?page_id=542>. There was a question and answer panel discussion following each section of related presentations, after which the participants in the audience voted on their level of agreement with the corresponding statements according to a five-point Likert scale (Table 3). The meeting was attended by 65 individuals, of whom 26 voted on the statements. The profession, years in practice and volume of HCC seen by the respondents were recorded (Figure 1). The majority were hepatologists and practicing physicians, with two being from nursing. The current report presents a summary of the topics presented and the results of the voting. We highlight areas in which there appears to be a lack of consensus regarding the diagnosis and management of HCC.

Modelling studies for both hepatitis B virus (HBV) and hepatitis C virus suggest that the incidence of HCC will continue to rise for the next 15 to 20 years (7,8).Furthermore, as the obesity and diabetes epidemics continue to increase we are also likely to encounter more HCC related to nonalcoholic fatty liver disease.The incidence of HCC will, therefore, likely continue to climb for years to come.Surveillance: Evidence and populations: The evidence for HCC surveillance is supported by case-control and cohort studies, as well as one randomized controlled trial (RCT) from China involving HBVinfected individuals (9).The strength of evidence around HCC surveillance has been criticized (10); however, further RCTs are not likely to be performed.There is evidence that surveillance for HCC is cost effective, but this is highly dependent on incidence of HCC in the population under surveillance.The groups who should be offered surveillance have been previously identified (1-3).The categories of patients are broadly defined as all cirrhotic and certain noncirrhotic patients with HBV (Asian men >40, Asian women >50 and Africans >20 years of age, positive family history) (1)(2)(3).However, surveillance should not be offered to Child-Pugh (C-P) class C cirrhotic patients, unless they are awaiting liver transplantation (LT) (1-3).A large    (11).There are other risk scores for HBV and for cirrhotic patients, and these may be used to help identify those at highest risk for HCC (12).These risk scores require further validation before being routinely used to determine who should undergo surveillance and those for whom surveillance is unnecessary.Surveillance: Tests, intervals and uptake: Ultrasound (US) is effective for HCC detection with sensitivity of approximately 63%, and six months is superior to annual surveillance (13).However, US has limitations in clinical practice and can be influenced by the experience and training of technicians, and the presence of obesity, cirrhosis and/or ascites.In general, surveillance is underutilized, with <20% of cirrhotic patients receiving regular surveillance (14).The use of biomarkers, such as alpha-fetoprotein (AFP), AFP-L3 or des-gamma-carboxy prothrombin, is controversial.AFP can be combined with US to maximize early tumour detection; however, this may be associated with higher false-positive rates and costs (15).Evidence also suggests that these biomarkers are not highly sensitive to the presence of small HCCs, and are more frequently associated with aggressive or late-stage disease, making these markers unsuitable for HCC surveillance.Better biomarkers are clearly required for HCC surveillance.

Diagnosis
Very early stage HCC: The diagnosis of HCC can be established with radiology or by biopsy.The classical radiographic appearance of HCC is a lesion that exhibits higher signal intensity than the surrounding liver in the arterial phase of a contrast-enhanced study and lower signal intensity than the surrounding liver in the venous or the delayed phase of the contrast examination (so-called portal venous 'washout').
The mechanism underlying this phenomenon is that the HCC is a vascular lesion, fed principally by the hepatic artery, whereas the liver receives 80% of its blood supply from the portal vein.However, some HCCs are hypovascular, particularly if small or early.In these lesions, the arterial supply may not be fully developed, and they may present as hypovascular lesions on dynamic imaging (16).
If the radiological appearances are not typical a biopsy is required.Most often in larger lesions the interpretation of the biopsy is not difficult, but with smaller lesions the distinction between dysplastic nodule and HCC becomes more difficult.In addition to cellular features, a set of stains can reliably separate lesions into HCC or not HCC.These include glypican 3, heat shock protein 70, glutamine synthetase and clathrin heavy chain.The likelihood of HCC approaches 100% when at least two of these markers are positive (17), and these stains should be used in all cases in which the diagnosis is in doubt.Computed tomography, magnetic resonance imaging, liver imaging reporting and data system: A diagnostic algorithm for HCC has been developed and validated (Figure 2) (2).For any lesion >1 cm found on surveillance US, the diagnosis of HCC can be made if either the contrast-enhanced computed tomography (CT) scan or magnetic reonance imaging (MRI) show typical features as described above.If there is no arterial phase enhancement or no portal venous or delayed phase washout, and if the radiological appearances are not typical of another type of lesion (eg, hemangioma), a biopsy is required.All major clinical practice guidelines endorse multiphasic CT and MRI with extracellular contrast agents as the first-line modalities for diagnosis and staging of HCC (1)(2)(3)(4).
The American College of Radiology has developed liver imaging reporting and data system (LI-RADS) as a standardized system for interpretation and data collection of CT and MRI liver examinations (18).LI-RADS categorize observations along a five-point ordinal scale ranging from LR1 (definitely benign) to LR5 (definitely HCC).The application of LI-RADS has yet to be validated; however, standardized reporting should improve communication between radiologists and other clinicians caring for HCC patients.

Contrast-enhanced US:
The APASL guidelines state that contrastenhanced US (CEUS) is as sensitive as dynamic CT or dynamic MRI in the diagnosis of HCC (4); however, the EASL (3) and AASLD (2) guidelines have dropped CEUS from the diagnostic algorithm (Figure 2) because some cholangiocarcinomas on CEUS can have a pattern of arterial phase enhancement and portal venous washout similar to HCC (19).It is important to recognize that CEUS remains a valuable tool in the diagnosis and management of HCC.Unlike dynamic CT or MRI, CEUS allows for real-time scanning throughout the entire arterial phase, with a contrast agent that is purely intravascular and can be safely administered in patients with renal failure.In fact, very rapid washout on CEUS is atypical for HCC and is more likely to represent cholangiocarcinoma or metastatic disease.Furthermore, CEUS can assist in the staging of HCC by determining whether portal vein thrombosis (PVT) is bland or malignant, and may be very helpful in localizing and assessing response of small HCC undergoing percutaneous ablation (20).

Figure 2) Algorithm for the diagnosis of hepatocellular carcinoma (HCC) after identification of a lesion on a surveillance ultrasound. CT Computed tomography; MRI Magnetic resonance imaging. Adapted with permission from reference 2
Gd-EOB-DPTA MRI: Gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) is a liver-specific contrast agent that has been evaluated in the diagnosis of liver lesions, including HCC (21).It is more sensitive than CT scan for detecting HCC.However, it is more expensive than regular gadolinium contrast, has weaker arterial phase enhancement, and requires a delayed phase (usually performed at 20 min).Nodules without classic features for HCC on dynamic MRI, that remain hypointense on the delayed phase following administration of Gd-EOB-DPTA, may represent HCC.Whether it should used as the sole diagnostic agent in all cases or only used in specific cases of diagnostic difficulty has yet to be clarified.

Staging and prognosis Barcelona Clinic Liver Cancer System:
There are several ways to assess the severity of disease in patients with HCC.Liver function can be assessed by the C-P score or the Model for End-stage Liver Disease score.The TNM (tumour-node-metastasis) system assesses the anatomical extent of the cancer.Performance scores such as the Karnovsky or the Eastern Cooperative Oncology Group performance status assess the functional limitations of the patient due to the cancer.However, none of these are adequate on their own for HCC, and none give any guidance as to treatment.There are several HCC staging systems that attempt to take some of these factors into account, but the only the Barcelona Clinic Liver Cancer (BCLC) system uses performance status, liver function and tumour burden together to recommend specific therapies.Furthermore, the BCLC staging system has been validated externally for predicting prognosis.The current iteration of the BCLC staging system is shown in Figure 3 (22).
Some have suggested that the intermediate stage (BCLC B) could be further stratified into four categories (B1 to B4), but this needs external validation (23).
Predicting recurrence: Within five years of curative therapy, recurrence of HCC occurs in approximately 70% of patients treated with surgery or RFA compared with <15% of patients undergoing LT.Size and number of tumours predict vascular invasion and subsequent recurrence after LT, and thereby form the basis of the Milan criteria (single tumour ≤5 cm, or ≤3 lesions each ≤3 cm) (24).AFP has been shown to predict recurrence after RFA and resection.Furthermore, a high AFP, especially if climbing, predicts recurrence after LT.In the near future, both Canada and the United States will be adopting an AFP <400 ng/mL as a listing requirement for LT.In the future, genomic signatures of the tumour and surrounding liver may help provide further prognostication about risk of recurrence (25).

Current curative therapies
The therapies that are considered to be curative include resection, local ablation with RFA, microwave ablation or percutaneous ethanol injection (PEI) for small lesions, and LT.Resection: Whether resection is possible depends largely on liver function.Patients should have C-P class A cirrhosis, no significant portal hypertension and a normal serum bilirubin level (26).In addition, the amount of liver to be removed and the volume of the remaining liver are important.Anatomical resection refers to removal of one or more segments, and is always preferable because disease-free and overall survival are improved (27).Hepatic resection can be accomplished by laparoscopy with considerable reduction in morbidity, but requires adequate training.RFA/PEI: RFA can be suitable for patients with small lesions (ideally <3 cm) who have liver function that does not allow resection.RFA can also be used for local control of the HCC as bridging therapy before LT.RFA is clearly superior to PEI for lesions between 2 cm and 5 cm (28).Multifocal HCC is also associated with a higher rate of incomplete response to RFA.
A meta-analysis of RCTs and non-RCTs comparing RFA and resection found that RFA is better tolerated than resection, with similar short-term outcomes (29).Recurrence rates are higher with RFA, and this translates into lower overall survival at five years for RFA compared with surgery (29).However, for smaller lesions (<2 cm), recurrence rates and overall survival are comparable, making RFA an acceptable substitute for surgery in selected patients (29).LT: LT has traditionally been limited to patients who fell within the 'Milan criteria', namely, one HCC lesion <5 cm or fewer than three lesions, none larger than 3 cm in diameter (24).However, there are clearly patients within the Milan criteria who develop recurrence posttransplantation, and there are also many patients with HCC beyond the Milan criteria who can be cured by LT.There have been several proposals to extend these criteria, including the University of California San Francisco criteria, the "up to seven" criteria or total tumour volume (TTV).Any expansion of the listing criteria is associated with a higher drop-out rate on the LT waitlist and higher posttransplant recurrence rates.TTV <115 cm 3 and AFP <400 ng/mL predict survival after LT, and they have been prospectively validated as selection criteria for LT in Canada (30).

Current palliative therapies
There are only two palliative forms of therapy that have been shown to improve survival in randomized clinical trials: transarterial chemoembolization (TACE) and sorafenib.TACE: Conventional TACE for BCLC stage B HCC is associated with a median survival of approximately two years; unfortunately, the TACE procedure is not standardized (31).TACE has been used to keep patients within selection criteria while awaiting LT, although the exact impact of this on post-LT recurrence requires further study.TACE should be avoided in decompensated cirrhosis and patients with PVT.
A more recent innovation is TACE delivered by drug-eluting beads (DEBs).These have been compared head-to-head with conventional TACE, with no difference in survival, but less toxicity when using the DEBs (32).Cohort studies are now reporting fouryear median survival for TACE using doxorubicin-loaded DEBs in carefully selected patients (33).Combination of sorafenib and TACE does not offer a survival advantage.Sorafenib: Sorafenib for BCLC stage C disease provides a median improvement in survival of approximately three months.This has been demonstrated in two large RCTs (34,35).The survival benefit of sorafenib is only established in patients with preserved liver function (C-P class A cirrhosis).Sorafenib is generally well tolerated but is associated with hand/foot skin reaction, fatigue, gastrointestinal symptoms and hypertension.The standard dose is 400 mg twice daily; however, dose escalation is frequently used in clinical practice.Sorafenib has no advantage when used as adjuvant treatment after any of resection, RFA or TACE.

Statements on palliative therapies:
• TACE is standard of care for patients with large single HCC who are not candidates for resection or ablation (BCLC stage A) or for multifocal HCC without evidence of portal vein invasion or extrahepatic spread (BCLC stage B) (Level 1A).Mean rating 1.27 (1=17, 2=4, 3=1, 4=0, 5=0).• TACE can be used to bridge patients to LT (Level 4).

DISCUSSION
Overall, there was good agreement on the consensus statements presented, with only four statements having a mean rating of ≥2.0 on the five-point Likert scale.The first of these concerned LI-RADS and may reflect an unfamiliarity of clinicians with this new reporting system.LI-RADS is currently undergoing modifications and has not been widely implemented in Canada.However, it has recently been endorsed by the United Network of Organ Sharing and will be a requirement for reporting CT and MRI of HCC patients awaiting LT in the United States.
Second, several participants were not comfortable recommending surgery as the first-line therapy in HCC patients with C-P class A cirrhosis.This may be reflective of the fact that the majority of the audience consisted of hepatologists, who may be more comfortable arranging RFA or LT evaluation for these patients.Similarly, many disagreed with the statement that recurrence rates are lower following surgical resection of early stage HCC compared with RFA.Although this is Level 1B evidence, many in the audience may have recognized the methodological flaws in the three RCTs from China on which this recommendation is based, including significant cross-over between groups after randomization.
Finally, there was significant reservation around a statement that TARE may be more likely to downstage large tumours compared with TACE.Again, there may be a lack of familiarity with TARE because this is only available in a few Canadian centres, or perhaps it is recognition that this recommendation is largely based on a single casecontrol study from Chicago (Illinois, USA).

ACKNOWLEDGEMENTS:
The authors thank the speakers (listed in Table 1) for their significant contributions to the meeting, especially Dr Jordi Bruix (CASL Gold Medal recipient) for his critical review and feedback on the consensus statements.We recognize the efforts of Allison Bollieu (CASL secretariat) and BUKSA for meeting organization, and thank Karen Seto and the Canadian Liver Foundation for their assistance in raising funds for this meeting through unrestricted educational grants.

CONCLUSIONS
HCC is rapidly increasing in Canada and its incidence is expected to continue to rise for years to come.Surveillance with US alone every six months is currently recommended for high-risk populations.The diagnosis of HCC can usually be achieved with CT or MRI, although CEUS and Gd-EOB-DTPA MRI may assist in the diagnosis in some cases.The management of HCC is complex and must be performed in a multidisciplinary team setting.The BCLC system is recommended for staging and for treatment allocation.In carefully selected patients, resection, RFA and LT can offer a cure, whereas TACE and sorafenib extend life but are palliative therapies.Further research is required on TARE and SBRT before they become standard of care.New, more-effective therapies are needed for advanced-stage HCC.

Figure 3 )
Figure 3) Barcelona Clinic Liver Cancer stages and allocation of treatment.CP Child-Pugh class; LT Liver transplantation; PS Eastern Cooperative Oncology Group performance status; TACE Transarterial chemoembolization.Adapted with permission from reference 22

TABLE 2 Oxford system for grading level of evidence Level Type of evidence
1A Systematic review of randomized clinical trials 1B Individual RCTs with narrow confidence intervals 1C All or none studies 2A Systematic reviews of cohort studies 2B Individual cohort study including low-quality RCTs

TABLE 3 Likert scale used to assess degree of consensus to statements
Figure 1) Demographics of voters.GI Gastroenterology; HCC Hepatocellular carcinoma; yrs Years

TABLE 1 Sessions, topics and speakers for the Canadian Association for the Study of the Liver hepatocellular carcinoma meeting
cohort study of ambulatory cirrhotic patients from the University of Toronto (Toronto, Ontario) has shown that the risk of HCC is highest for viral hepatitis, followed by steatohepatitis and other causes of cirrhosis (38)tments are considered to be experimental if outcome data are lacking or if there is inadequate comparison with current standard treatments.This is includes TARE and SBRT.TARE: TARE involves infusing radioactive particles, either glass beads or resin, via the hepatic artery directly into the tumour.This technique has been shown to produce substantial tumour necrosis, is safe, and can be administered to patients with PVT(36).TARE is well tolerated and has less impact on liver function than TACE.Although it has not been compared directly with TACE in a randomized trial, it does appear to have similar outcomes to TACE(37).In a single nonrandomized trial(38), TARE achieved better downstaging than TACE, but long-term post-LT outcomes were not reported.The addition of TARE to sorafenib for advanced-stage HCC is being evaluated in the ongoing phase III Efficacy Evaluation of TheraSphere in Systemic chemotherapy has not been shown to significantly enhance survival and, therefore, should not be used outside of clinical trials.Sorafenib with or without doxorubicin is currently being evaluated in the Sorafenib Tosylate With or Without Doxorubicin Hydrochloride in Treating Patients With Locally Advanced or Metastatic Liver Cancer (HEC.1)trial (NCT01015833).
(45)re directions: Several targeted therapies, including sunitinib(40)and brivanib(41), have failed when compared with sorafenib in RCTs.The addition of erlotinib to sorafenib was not beneficial in advanced HCC(42).Brivanib(43)and everolimus(44)have recently failed to show benefit as second-line therapy after sorafenib.Currently, many drugs are under study for HCC; there remains an unmet need for new first-and second-line therapies(45).