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Carr. Hepatoma Res 2019;5:3 I http://dx.doi.org/10.20517/2394-5079.2018.113 Page 7 of 10

Macroscopic PVT (visible on MRI or CT scan) is thought to be present in over 30% of HCC patients and
is likely the single worst prognostic factor. In addition to being an important portal for metastases (tumor
cells are already in the portal vein), the presence of main stem or major branch PVT impacts the ability
to perform liver transplant (high recurrence rates), resection (high recurrence rates and technical surgical
difficulties); it is also associated with worse liver function. Many studies have thus focused on the treatment
[41]
of HCC patients with PVT , as well as on treatment of the PVT itself [41,42] . Treatments include selective
TACE, SIRT [20-22,43] , sorafenib and 3-dimensional conformal radiotherapy. However, this is a heterogeneous
group of patients [44,45] . One consensus suggests hepatic resection when technically feasible for longest
[46]
survival, otherwise TACE for unresectable patients, followed by external beam radiation . Depending on
the extent of the PVT, enhanced survival has been reported in a large series for hepatectomy, TACE, TACE
[47]
plus sorafenib or TACE plus radiotherapy . There is currently no standard for therapy for PVT.

LIKELY PRACTICE SCENARIOS [Table 2]
FDA has approved both sorafenib and lenvatinib as first line therapies. If patients tolerate sorafenib well,
then FDA-approved regorafenib or nivolumab will be good second line options. If patients did not tolerate
sorafenib, then FDA-approved nivolumab might be an excellent second line option, due to its different
mechanisms than sorafenib. But so could ramucirumab, should it get approved by FDA in the second line
setting. Furthermore, ramucirumab appears to be attractive for patients in the second line setting with
elevated AFP levels.

NEW AGENTS
A variety of new agents are in current clinical trials and will likely change the clinical landscape again in
another 2-5 years. These include particularly a variety of agents inhibiting the immune checkpoint proteins
PD-1, PD-L1 and cytotoxic T lymphocyte antigen 4, as well as epigenetic control mechanisms. In addition
to further opdivo studies, other agents being tested include ipilumimab, prembrolizumab and durvalumab
and tremelimumab, amongst others. Agents against various growth factor targets such as FGF/FGFR
(fibroblast growth factor and its receptor, such as BLU 554 or dovatinib) and growth pathways (MEK, signal
transducer and activator of transcription 3, AKT-also called protein kinase B), apoptosis induction, epithelial
to mesenchymal modulation, and cytolytic viruses, are currently under way. Furthermore, the clinical
availability of curative (HCV) or highly effective (HBV) antivirals that are the ultimate cause of HCC and
hoped-for contributors to the amelioration of HCC aggressiveness. In this context, the role of inflammatory
micro-environment and anti-inflammatory agents in the development of HCC and its modulation, is
drawing increased interest.

WHERE ARE WE HEADING?
The standard of care for patients with advanced, non-curative and non metastastic HCC remains TACE or
more recently, TARE [National Comprehensive Cancer Network (NCCN) guidelines version 5.2018, HCC;
NCCN.org]. Chemoembolization is associated with 30%-60% objective response rates in various trials and
[6,7]
has some minor survival advantage . Sorafenib has minor response rates, can be given orally and has a
proven, but small survival advantage, through quite different mechanisms and different toxicity profiles than
for either TACE or TARE. Therefore, it will be rational to evaluate combinations of chemoembolization or
SIRT with sorafenib [48,49] or the more potent regorafenib or any other multikinase inhibitor. Several trials are
under way.

The same reasoning of different mechanisms, applies to combinations of immune checkpoint inhibitor with
either: (a) chemoembolization; (b) SIRT; and (c) multikinase inhibitors. In this regard, the combination
of VEGF inhibitor bevacizumab (avastin) plus atezolizumab (tecentriq) has just been given (July 2018)