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Gomaa et al. Advanced HCC: current and potential therapies

patients with HCC are diagnosed with advanced 1 and B-Raf and the activity of vascular endothelial
disease [Barcelona Clinic Liver Cancer (BCLC) stage growth factor receptors (VEGFRs) 1, 2, and 3 and
C], unsuitable for surgery or loco-regional curative platelet-derived growth factor receptor β (PDGFR-β).
treatment. Prognosis of advanced HCC is poor, and Also it induces down-regulation of anti-apoptotic
the 1-, 2- and 3-year survival rates are 29%, 16%, proteins, leading to significant enhancement of the
[6]
and 8%, with median OS less than 6 months. This is cytotoxicity of tumor necrosis factor-related apoptosis
even less in low and middle income countries, where inducing ligand (TRAIL) to HCC cells. [10]
resources and access to therapy are limited.
Sorafenib improves survival compared to placebo, with
In the BRIDGE study that included data for 18,031 median OS of 6.5-10.7 months, with significant benefit
patients with HCC from 42 sites in 14 countries in Asia, in time to progression (TTP). Many molecular agents
Europe and North America, more than 50% of cases have been studied, but only the sorafenib showed
were diagnosed in advanced and terminal stages. [7] efficacy in terms of OS and TTP, based on results of
Whereas 12% of HCC patients in Japan and 17% in two phase III, randomized controlled studies [2,11] and
Taiwan present in advanced stage HCC (BCLC stage confirmed in other clinical trials comparing sorafenib
C) and only 1-2% in terminal stage (BCLC D), between to other molecules, [12-16] as well as in real life clinical
50% and 60% of HCC patients in North America, practice. [17,18]
Europe, China and South Korea present in BCLC
stages C and D. [7] Despite the approval of sorafenib in advanced-stage
HCC, several issues remain not known. An important
The proportion of HCC patients presenting in advanced concern is to identify patients who will most probably
stages is even larger in limited resource countries. A benefit from sorafenib, to avoid unnecessary toxicity
study that included 2,566 HCC patients from 21 tertiary in patients who will not. Several markers at baseline or
referral centers in 9 African countries showed that during treatment, as vascular endothelial growth factor,
only 23% presented in early and intermediate stages angiopoietin-2, hepatocyte growing factor, c-Kit or alfa-
(BCLC A and B), 49% in advanced stage (BCLC C) feto-protein (AFP) have been shown to predict OS, but
and 28% in BCLC stage D. The proportion of patients not response to sorafenib in patients with advanced
diagnosed with HCC while in advanced or terminal HCC. [19]
stage was much larger in sub-Saharan countries, with
95% of the patients diagnosed in BCLC stages C and Several reports showed that the development of some
D, and 97% of 1,315 patients with HCC did not receive adverse events as dermatological adverse events, [20-22]
HCC specific therapy because of advanced stage and diarrhea, [23] or arterial hypertension [24] are associated
unavailability of therapy. [8] with favorable outcomes. Patients who develop early
dermatological adverse events within the first 2 months
This highlights the importance of developing effective after starting sorafenib experienced a longer median
therapies for advanced HCC, and that these therapies OS, comparing to those who did not develop this
should be made available and affordable in limited adverse event (18.2 vs. 10.1 months, respectively). [20]
resource countries where most patients present in Hence, it is mandatory to closely follow the patients
advanced stage (especially sub-Saharan Africa). and to adjust the dose if needed to avoid unnecessary
This also emphasizes the importance of screening interruption of the drug in a probably responding
programs for detection of HCC in early treatable patient.
stages.
Using sorafenib in patients with Child-Pugh B cirrhosis
SYSTEMIC THERAPIES is challenging. Sorafenib was effective in Child-
Pugh class B patients as class A patients in terms of
Molecular targeted therapy progression free survival (PFS), but with lower OS. The
Advanc ed HCC has experienc ed the most median OS was 5.5 months for Child class B patients
relevant advancements in research in HCC lately. compared to 11.3 months for Child A patients. [25] The
Hepatocarcinogenesis is associated with genetic prospective GIDEON trial confirmed that the median
and epigenetic alterations that eventually lead to OS was shorter in Child-Pugh class B patients, 5.2
an alteration in the molecular pathways, leading to months compared to 13.6 months in Child A, although
uncontrolled growth of the hepatocytes. [9] the TTP and the incidence of adverse events of
sorafenib was similar across subgroups, Child-Pugh
Sorafenib class B patients experienced more serious adverse
Sorafenib inhibits the serine-threonine kinases Raf- events. The liver dysfunction in advanced cirrhosis may

Hepatoma Research ¦ Volume 3 ¦ June 15, 2017 113