Page 63 - Read Online

Page 10 of 15 Wu et al. Hepatoma Res 2023;9:6 https://dx.doi.org/10.20517/2394-5079.2022.37

evaluated the efficacy and safety of RFA and TACE combined with postoperative cytokine-induced killer
[72]
(CIK) cell immunotherapy in Child-Pugh class A or B cirrhotics with HCC meeting Milan’s criteria . The
median OS of patients was 42.1 ± 5.6 months and 37.8 ± 4.8 months and the 5-year OS rate was 29.3% and
[72]
13.8% in RFA + TACE + CIK vs. RFA + TACE, respectively . The study found that RFA and TACE
combined with postoperative autologous CIK cell reinfusion have significant efficacy in the treatment of
primary HCC, enhancing the immune function, improving the postoperative quality of life, and raising the
patient’s survival rate with tolerable adverse reactions . Multiple studies to assess the efficacy of TACE and
[72]
other immunotherapies are underway. Two trials are set to study the combined effects of TACE and
Nivolumab (NCT03143270 and NCT03572582). Another trial (NCT03397654) is exploring the sequential
[73]
use of TACE and Pembrolizumab . The combination of 2 immunotherapies (Durvalumab and
Bevacizumab) with TACE is considered in another emerging study (NCT03937830). Using the combination
of LRTs and immune checkpoint inhibitors may provide promising options for patients with HCC.

HAIC with sorafenib
A couple of studies were conducted to evaluate the effect of adding HAIC to sorafenib therapy in advanced
HCC. A recent single-arm phase II study demonstrated favorable outcomes of OS and PFS in HAIC with 5-
FU and sorafenib in HCC ineligible for curative treatment . In a phase II trial by Ikeda, patients with
[74]
[75]
advanced HCC were randomized to receive sorafenib with HAIC with cisplatin or sorafenib alone . There
was a significant improvement in OS with HR 0.6. Both studies had tolerable adverse events. More
randomized trials need to be conducted to further evaluate the efficacy of this combined method.

FUTURE CONSIDERATION AND STUDIES
With the emergence of multiple new tyrosine kinase inhibitors along with immunotherapy, the future
perspective is focusing on finding combination therapies and the best sequential therapeutic options
[Table 1]. The success with Atezolizumab/ Bevacizumab combination therapy has led to new perspectives.
Currently, multiple different combination therapies are being studied. For example, a German multicenter
phase II trial is evaluating Pembrolizumab and Lenvatinib in patients with advanced HCC who failed
Atezolizumab/ Bevacizumab (NCT05101629). Toripalimab with Bevacizumab is being evaluated for first-
line therapy for HCC (NCT04605796). The combination of TACE with sorafenib and Tislelizumab is also
being studied (NCT04599777). The START-FIT trial is currently examining sequential transarterial
chemoembolization and stereotactic radiotherapy with immunotherapy; the study is being done in China
and recruiting patients (NCT03817736). Arginine hydrochloride is a new anticancer drug that is being
evaluated for the treatment of HCC. Levamisole may play an antitumor role by inhibiting the reverse TCA
cycle (NCT03950518). The results of multiple ongoing trials will be unexpected to be revealed in the
upcoming years, and it is anticipated to have guidelines-changing outcomes.

CONCLUSION
HCC is a devastating disease with grim outcomes, as it is often diagnosed during an advanced stage. For
many decades, the treatment options for patients with HCC who are not transplant or surgical candidates
were limited to bridging-to-transplant or palliative therapy. Currently, we have LRT for early to
intermediate-stage HCC and sorafenib for advanced HCC. Awareness of the shortcomings of each modality
and the potential for increasing their efficacy has prompted the exploration of combined therapy, most
notably LRT and systemic treatment. The intent of combining LRT with MTAs is to reduce the post-
ischemia upregulation of angiogenic antigens with MTAs. More and larger studies need to be conducted to
see if MTA administration after RFA results in improved survival benefits. TACE had probably been the
most studied agent in combination with MTAs, mainly sorafenib. Although past studies have largely
demonstrated no improvement in OS or PFS in combined therapy, the recent TACTICS trial did show