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Gomaa et al. Advanced HCC: current and potential therapies

(NCT01655693). without improvement in OS or PFS. [65]

S-1, an oral mixture of tegafur, gimeracil and oteracil, The phase III SILIUS trial included 210 patients with
that increases the effect of 5-fluorouracil through advanced HCC, and compared sorafenib to sorafenib
increasing its serum concentration while decreasing its in combination with low dose cisplatin/fluorouracil
gastrointestinal effects, was evaluated as second line hepatic arterial infusion chemotherapy (HAIC). OS was
therapy in a phase III trial in patients with advanced HCC equal in both arms (11.8 months). However, sorafenib
refractory to sorafenib (S-CUBE). OS was not different plus HAIC significantly improved OS in the subset of
from placebo, but PFS was better (80 vs. 42 days). [53] patients with major portal-vein invasion (11.4 months
vs. 6.5 months). [66]
In a phase III study, 371 patients with advanced HCC
were randomly assigned to receive either FOLFOX4 LOCOREGIONAL THERAPY
(infusional fluorouracil, leucovorin, and oxaliplatin) or
doxorubicin (EACH trial). OS was higher in patients The presence of portal vein thrombosis (PVT)
who received FOLFOX4 compared to doxorubicin is a relative contraindication for trans-arterial
(6.4 vs. 4.97 months, P = 0.07) and reached statistical chemo-embolization (TACE) in most international
significance after extension of follow up 7 more guidelines, [6,67,68] TACE may be recommended for
months (P = 0.04). FOLFOX4 treatment prolonged the HCC patients with vascular invasion if radiologic portal
median PFS in comparison to doxorubicin (2.93 vs. invasion is distal to, or in the second-order branches of,
1.77 months, P < 0.001), the response rate was 8.15% the portal vein (Vp1 or Vp2). [69,70] Real life studies have
vs. 2.67% (P = 0.02), and the DCR was 31.55% vs. confirmed the safety and efficacy of TACE in patients
52.17% (P < 0.0001) respectively. [54] FOLFOX4 was with PVT. [71]
well tolerated, although the incidence of neutropenia
and neurotoxicity was slightly higher in the FOLFOX4 Combination of targeted therapy with loco-
group. regional therapy
Several studies compared sorafenib plus TACE to
Oxaliplatin (OXA)-based chemotherapy may be an sorafenib or TACE [72-78] [Supplementary Table 4]. A
effective first line treatment for patients with advanced meta-analysis of sorafenib in combination with TACE
HCC. In a meta-analysis [55] that included 13 studies, that included data of 1,254 patients found that the
6 studies on gemcitabine, 6 studies on 5-flurouracil or combination improved OS and TTP in advanced
capecitabine and 1 study on doxorubicin in addition to HCC, but not PFS, with higher rate of severe adverse
OXA, the PFS was 3.3 and 4 months in capecitabine- reaction in the combination group. [79] This combination
based studies and OXA-based studies, respectively. is being further evaluated in phase III study (STAH
OS was 6.47 months in capecitabine-based studies trial, NCT01829035) to evaluate combined sorafenib
compared to 11 months in OXA-based studies. [56] with conventional TACE vs. sorafenib in patients with
TACE-refractory and advanced-stage HCC.
Combination of sorafenib with systemic
chemotherapy Randomized, controlled studies to evaluate the
Combination of sorafenib with doxorubicin, [57] efficacy and safety of sorafenib combined with TACE
octreotide, [58] 5-fluorouracil, [59] tegafur/uracil, [60] in advanced HCC patients compared with sorafenib
cisplatin and gemcitabine, [61] gemcitabine/oxaliplatin alone (SELECT) (NCT01906216) or TACE alone
(GEMOX), [62,63] and capecitabine/oxaliplatin (SECOX) [64] (NCT02150317) are ongoing. The safety and efficacy
have been investigated [Supplementary Table 3]. of superselective drug-eluting chemoembolization
Currently, modified FOLFOX plus sorafenib is under with hepasphere in patients with unresectable
investigation (NCT01775501). advanced HCC is under investigation (SUPER-China,
NCT02743065).
A randomized, double-blind phase II trial that included
96 patients with advanced HCC evaluated the efficacy A phase II randomized controlled trial (RCT) conducted
of sorafenib in combination with doxorubicin vs. to explore the efficacy of sorafenib and TACE in
doxorubicin, and resulted in better OS (13.7 vs. 6.5 advanced HCC patients with major portal vein invasion
months). The median TTP was 6.4 vs. 2.8 months, and (NCT01480817) has been terminated and the results
PFS was 6.0 vs. 2.7 months, respectively. [57] On the are awaited. Combination of TACE with apatinib
other hand, a phase III randomized study of sorafenib (NCT03066557) or axitinib (NCT01352728) in patients
plus doxorubicin compared to sorafenib (CALGB with advanced HCC are under investigation. Also,
80802) showed higher toxicity for the combination comparing TACE plus sunitinib against TACE plus
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