LECTURES

The Treatment Landscape for Hepatocellular Carcinoma

Partner	Topic of the training	Training description	Proposed duration of the training	Planned date
NKUA	The Treatment Landscape for Hepatocellular Carcinoma	Online course for medical students related to Training in treating patients with GI tumours and Training in surgical operational procedures aiming to treat patients with GI	Online - 1 day / 20-30 persons	26.5.2021 at 15:00 (CET)

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Histological and molecular subtypes of hepatocellular carcinoma – Prof. Dina Tiniakos

Recent classification of hepatocellular carcinoma (HCC) is based on morphology and underlying molecular alterations recognising two main HCC subgroups, the proliferative with worse prognosis (expression of stem cell markers, TP53 mutations, FGF19 amplification) and the non-proliferative (activation of JAK/STAT pathway, CTNNB1 activating mutations). New subtypes have been introduced in addition to classical HCC: massive macrotrabecular HCC (5-10% of HCC, high serum AFP, large size, trabeculae >6-cell thick in >50% of the tumour, predictor of HCC recurrence, TP53 mutations and FGF19 amplification); steatohepatitic (steatosis, ballooning or Mallory–Denk bodies, fibrosis and inflammatory foci, JAK/STAT pathway activation, more common in patients with the metabolic syndrome and steatohepatitis in the background liver); and chromophobe HCC (5% of HCC, related to HBV infection, alternative lengthening of telomere (ALT) phenotype by telomere FISH). A specific fusion transcript, DNAJB1–PRKACA, has been identiﬁed in ﬁbrolamellar carcinoma (FLC) subtype of HCC.

Locoregional therapies and patient profiling – Prof. Ioannis Elefsiniotis

Hepatocellular carcinoma (HCC) represents approximately 80% of primary liver cancers and constitutes a major health problem worldwide. The vast majority of HCC cases occur in the setting of chronic liver disease, with cirrhosis being the primary risk factor for HCC, independent of liver disease aetiology. Locoregional therapies includes the ablative techniques (mostly radiofrequency and microwave ablation) as well as intraarterial therapies (transarterial chemoembolization and radioembolizalion with yttrium-90 microspheres) and are currently recommended for patients with HCC in very early (BCLC 0) or early (BCLC A) stages, as a curative approach, and in intermediate stages (BCLC B) as a palliative treatment, as well as a bridging therapy in patients listed for liver transplantation or for down staging the disease in carefully selected patients of early BCLC-B stage in order to become candidates for surgical treatment (either resection or liver transplantation).

Ablative techniques using chemical or thermal energy have been developed and established in the loco-regional therapy of HCCs over the last three decades. They recommended in very early stage (single lesion < 2 cm) and early stage (single or 2-3 nodules < 3 cm each) cancers amongst patients who are not candidates for surgical resection or transplantation. Transcatheter arterial chemoembolization (TACE) represents the therapeutic gold-standard (evidence IA) in a subgroup of patients’ unsuitable for surgery and for percutaneous ablation techniques, with multinodular HCC and preserved liver function (intermediate stage, BCLC-B), without vascular invasion or extra-hepatic spread that both characterize the advanced HCC stage (BCLC-C). Transarterial radioembolization (TARE) has been investigating in patients with HCC of various stages (for disease downstaging in BCLC-A patients awaiting liver transplantation, in comparison with TACE in BCLC-B or with sorafenib in BCLC-C patients), showing good safety profile and local disease control but failure to show overall survival benefit, so the subgroup of patients benefitting from TARE needs to be further evaluated.

Moreover there are preliminary data suggesting the immune modulating effects of locoregional therapy and its potential synergy with systemic treatment (mainly immunotherapy) in patients with advanced HCC stages, and we are eagerly awaiting the results from many randomized controlled trials in the near future.

Surgical Treatment in HCC - Prof. Christos Dervenis

In The Treatment Landscape for Hepatocellular Carcinoma

Primary cancer of the liver that originates from the hepatocytes
Incidence is rising specially in the Western countries mostly because of new risk factors and also because of higher sensitivity of the detections methods
Risk factors for HCC are:

Diagnosis is based on medical imaging and biopsy rather than symptoms which often come when the cancer has progressed in late stages
Many cases of HCC though arise without any evident liver pathology and are called sporadic.
Cirrhotic patients or known to have a liver threatening disease are at a regular follow up and have a chance of being diagnosed at un earlier stage of cancer.
Treatment depends on the timing of diagnosis which translates in a combination of the cancer stage and the level of liver function or cirrhosis:

● Early stages benefit from surgical resection
● Later Stages benefit from local other than surgical and systemic treatment

Systemic Treatments and Immunotherapy in HCC – Prof. Ioannis Koskinas

Systemic therapies are recommended for patients in advanced disease stages (BCLC stage C) or for patients in intermediate-stage disease stages (BCLC stage B) that are not (or no longer) eligible for locoregional therapies.

Until recently, sorafenib and lenvatib (TKIs) were the first line treatment for HCC followed by regorafenib or cabozantinib as a second line in patients who developed progression or intolerance to first line drugs. TKIs‘ side effects include fatigue, diarhea, hypertension and hand-foot syndrome.

Currently immunotherapy has been introduced in the treatment of HCC based on the utility of immune checkpoint inhibitors. The first combination that has been approved (atezolizumab plus bevacizumab) when compared to sorafenib as first line treatment showed better results with up to 35% objective response rate and therefore has replaced TKIs as first line treatment.

Many studies with immunotherapy drugs in combination are underway with promising efficacy. However immune markers for identification of immunologically “hot” HCC and evaluation of treatment response in clinical practice are still lacking.