Identifying patients at risk of cirrhosis, improved hepatocellular carcinoma (HCC) surveillance and management within an expert multidisciplinary team  are cornerstones of new GESA recommendations for the management of HCC.

A summary of the 31 recommendations has been published in the MJA while the full, living document (published here) also provides more comprehensive guidance.

The GESA statement covers surgical therapies, liver transplantation, locoregional therapies and the use of the rapidly growing systemic therapies available for advanced HCC. These include the recently PBS listed PD-L1 immunotherapy and anti-VEGF combination therapy atezolizumab (Tecentriq) and bevacizumab (Avastin), which were listed on the PBS on November 01 last year.

Discussing the statement on behalf of the Recommendation Steering Committee, GESA president Associate Professor Simone Strasser told the limbic that factors crucial to improving patient outcomes included patient selection, improved rates of screening, and appropriate identification of patients with small hepatic nodules that may be responsive to curative therapies such as hepatic resection or liver transplantation and additional non currative therapies.

She noted that in Australia, despite improvements in treatment, the overall five‐year survival for HCC sits at around 20%. With new treatments available and HCC becoming the most rapidly rising cancer in Australia, Professor Strasser said it was time for an Australian consensus statement.

“Liver cancer related to alcohol and obesity is progressively increasing and there’s still a lack of awareness for the risk factors that cause liver disease amongst the community but also amongst primary care so there’s heterogeneity in terms of screening for liver cancer, referring to appropriate care – and therefore appropriate treatment,” she said.

In terms of surveillance, the Committee recommended screening high-risk patients with alpha-fetoprotein and hepatic ultrasound every six months. The screening interval was based on the doubling time of tumours and cost effectiveness: ‘annually is not enough’, said Professor Strasser.

“If you leave it for a year then you can already have quite significant tumours with lower chance for survival – it’s cheap and its’ ultrasound based so it doesn’t require x ray exposure.”

Target groups

GESA recommendations highlighted several target groups for surveillance – people with cirrhosis of any aetiology and some non-cirrhotic patients with hepatitis B including Aboriginal and Torres Strait Islander people older than 50 years; Asian men older than 40 years and Asian women older than 50 years; and people born in sub-Saharan Africa older than 20 years.

“It’s really important in fatty liver particularly to identify which patients might have cirrhosis, said Professor Strasser. This could be done by either doing a blood test or ultrasound and by referring for specialist review in people who may be at risk of cirrhosis – and then they should be entered into surveillance.

Meanwhile, although surveillance for HCC in non-cirrhotic patients with NAFLD was not supported by current evidence, patients with NAFLD and advanced-stage fibrosis (F3) did have increased risk, and surveillance could be considered in that group.

The other group to identify, according to Professor Strasser, was those who are drinking to excess.

“[They’re] exposed to liver disease and cirrhosis and therefore liver cancer so there’s a lot more that needs to be done in primary care to assess the large numbers of people and appropriately refer them to specialist review and liver cancer surveillance.

Avoiding the metabolic risk factors, alcohol exposure and viral hepatitis – and treating them if present – were the first steps. “But once you’ve done that then the next is early diagnosis so that patients can get access to curative therapy – that being ablation, resection or potentially even transplantation,” she said.

Management of HCC

Recommendations around treatment also included a big push for a multidisciplinary team (MDT) approach. While all major liver centres had MDTs for HCC, Professor Strasser said not all patients were being referred to them.

“Some patients will still get referred straight from one doctor to a surgeon and get resected without ever coming for an MDT, which is not ideal,” she said. The benefit of an MDT came from having  expertise in looking at the problem from many different angles, being able to reassess the patient at each stage of their journey and change tack when necessary.

“It provides appropriate care but it also reduces inappropriate care – inappropriate surgery where other treatments  might have better outcomes, for instance. Surgeons have a tendency to operate – it’s not necessarily right that every patient needs an operation and other treatments might be appropriate or you might do another treatment first – reduce the bulk of disease and then an operation becomes more effective so it really provides that opportunity to optimise the care for each patient on an individual basis.”

Professor Strasser said it was a very strong recommendation because an MDT framework had been clearly associated with improved survival even in patients with advanced disease who had a poor overall prognosis.

The guidelines also address the three first-line therapies now PBS listed for HCC – sorafenib, lenvatinib and combination atezolizumab and bevacizumab. The Committee said the decision about which agent to start and when to transition therapy will become increasingly complex as additional first-line and second-line therapies continue to show positive results in phase III clinical trials.

Results of a large Phase III clinical trial evaluating sorafenib versus nivolumab as firstline therapy was negative and combination studies of multikinase inhibitors plus immuno-oncology agents or combination immuno-oncology agents are underway and look promising, Professor Strasser adds also noting that the recommendations would be a living document so that, as new treatments come through, the guidance will updated.

For now decisions to initiate systemic therapies should be undertaken within an MDT, she said. First-line systemic therapy should be discontinued when there is radiological progression and if the patient was eligible to proceed to second-line systemic therapy. Meanwhile for patients who are not suitable for second line systemic therapy, first-line treatment was suggested to be continued until clinical progression of the disease.

Speaking on new immunotherapy for HCC, Professor Strasser said patients and clinicians were ‘very grateful’ for its rapid approval.

“It’s early days but the results from the clinical trials suggest that about 75% of people will have disease control on that treatment and that survival is significantly improved  – we don’t even know how long survival is improved by because the median survival was not reached in the clinical trials.”

She also noted that resources would need to be ‘upscaled’ to ensure appropriate delivery of the new treatment.

“The treatment throws up a whole lot of logistical issues because its an infusion that’s given every three weeks. So in Australia, with our geographical challenges, that’s difficult and we’ll have to upscale our resources to be able to deliver that treatment wherever a patient lives.”

“TKI treatments will remain appropriate to some patients where geography precludes them from having infusions or where they have a contraindication to infusion therapy – so it means we’ve got more options and can tailor therapy to the individual patient, their circumstances and their disease,” she concluded.