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. 2019 Jan 15;234(8):12122–12132. doi: 10.1002/jcp.28048

Therapeutics for advanced hepatocellular carcinoma: Recent advances, current dilemma, and future directions

Jing Zhu 1,†, Tailang Yin 2,†, Yong Xu 3,✉, Xiao‐Jie Lu 1,✉
PMCID: PMC13484161  PMID: 30644100

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies and is a serious threat to people's health worldwide. The prognosis of advanced HCC is dim if left untreated. In the clinic, the treatment options for advanced HCC include surgery, radiotherapy, transcatheter arterial chemoembolization, and so forth. In recent years, molecular targeted therapy and immunotherapy have also made great progress, bringing new hope to patients with advanced HCC. In this study, therapeutic advances, current dilemma, and future directions of advanced HCC are reviewed, which might serve as a summary for clinicians and may stimulate future research.

Keywords: Hepatocellular carcinoma (HCC), portal vein tumor thrombosis, transcatheter arterial chemoembolization: immunotherapy

The prognosis of advanced hepatocellular carcinoma (HCC) is dim if left untreated. In the clinic, the treatment options for advanced HCC include surgery, radiotherapy, transcatheter arterial chemoembolization, and so forth. In recent years, molecular targeted therapy and immunotherapy have also made great progress, bringing new hope to patients with advanced HCC.

graphic file with name JCP-234-12122-g002.jpg

Abbreviations

3D‐CRT

3‐dimensional conformal radiation therapy

CTLA‐4

cytotoxic T‐lymphocyte‐associated protein 4

GKR

gamma knife radiosurgery

GPC3

glypican‐3

HCC

hepatocellular carcinoma

HCV

chronic hepatitis C virus

HIFU

high intensity focused ultrasound

ICR

ICAM‐1–related long noncoding RNA

IGRT

image guided radiotherapy

IL‐34

interleukin‐34

IMRT

intensity modulated radiation therapy

LA

laser ablation

MPVTT

main portal vein tumor thrombus

MWA

microwave ablation

OS

overall survival

PD‐1

programmed cell death protein 1

PD‐L1

programmed death‐ligand 1

PDX

patient‐derived xenograft

PVS

portal vein stenting

PVTT

portal vein tumor thrombus

RCT

randomized controlled trial

RFA

radio frequency ablation

RT

radiotherapy

SR

surgical resection

TACE

transcatheter arterial chemoembolization

TAMs

tumor‐associated macrophages

TCR‐T

TCR gene‐engineered human T cells

TTP

time to progression

1. INTRODUCTION

Globally, the incidence of liver cancer ranks sixth among all cancers and ranks fourth among cancer deaths (Fitzmaurice et al., 2017). Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer (European Association for the Study of the Liver, 2018). The symptoms of early HCC are often inconspicuous. Most of the HCC has developed to an advanced stage when symptoms occur. Tumors are prone to invade the portal vein and form portal vein tumor thrombus (PVTT). The incidence of PVTT is 44.0–62.2% (Z. M. Zhang et al., 2015). If not treated, the median survival time is only about 3 months (Woo & Heo, 2015). Surgical resection (SR), transcatheter arterial chemoembolization (TACE), radiotherapy, molecular targeted drug therapy, and local ablation are all options for the treatment of HCC with PVTT. However, no single treatment has achieved the desired results and the existing expert consensus recommendations lack evidence‐based medicine support. New effective treatments are urgently needed.

2. CLASSIFICATION AND PATHOGENESIS OF PVTT

The PVTT classification mainly includes the Vp classification proposed by the Liver Cancer Study Group of Japan (Liver Cancer Study Group of Japan, 1989) and the Cheng's classification (Cheng et al., 2007) proposed by Chinese professor Cheng and his coworkers. Japanese VP classification: Vp0, no tumor thrombus was found; Vp1, tumor thrombus is located in the third branch of portal vein; Vp2, tumor thrombus is located in the secondary branch of portal vein; Vp3, tumor thrombus is located in the primary branch of portal vein; Vp4, tumor thrombus is located in the portal vein or involved in the contralateral portal vein. Cheng's classification: Type I, tumor thrombus invades the portal vein branch of the liver or liver segment; Type II, tumor thrombus invades to the left or right branch of the portal vein; Type III, tumor thrombus invades to the portal vein; Type IV, tumor thrombus invades to the superior mesenteric vein; postoperative pathological diagnosis of microvascular tumor thrombus is Type I0.

The formation of PVTT is a multi‐link participation and multi‐factor synthesis process, involving various mechanisms such as body hemodynamics, anatomy, and intrinsic molecular science. It is the result of interaction between the patient itself, tumor cells, and the microenvironment. Anatomical basis: the portal vein system has no venous valve, and blood flow is slow. HCC patients often have a certain degree of cirrhosis, resulting in the portal vein system in a highly dynamic state; the main theories of hemodynamics include "portal blood countercurrent theory", due to the opening of arteriovenous fistula, portal pressure is significantly higher than usual, which leads to an increase in portal venous reflux; molecular biology basis: Yang et al. (2012) found that hepatitis B virus (HBV) infection status and the activity of TGF‐β‐miR‐34a‐CCL22 axis worked as strong etiological factors for HCC patients to develop PVTT. It is possible to promote the colonization of disseminated HCC cells in the portal system by establishing an immune‐subversive microenvironment. Zhou et al. (2016) found that the low expression of miR‐28‐5p was closely related to tumor metastasis, recurrence, and prognosis. Interleukin‐34 (IL‐34) is an important target of miR‐28‐5p, which plays a role in the regulation of tumor‐associated macrophages (TAMs) and proposes miR‐28‐5p‐IL‐34‐macrophage feedback path. Liu et al. (2012) found that the overexpression of miR‐135a promoted invasion and metastasis in vitro. In addition, miR‐135a was found to function through the upstream transcriptional gene FOXM1 and the downstream targeted tumor suppressor gene MTSS1, and finally, the FOXM1‐miR‐135a‐MTSS1 pathway was established. Guo et al. (2016) demonstrated that ICAM‐1–related long noncoding RNA (ICR) specifically regulated cancer stem cells properties of ICAM‐1(+) HCC cells. ICR contributed to PVTT development. Despite the rapid development of molecular biology technology, there is still a long way to go to find out the specific formation mechanism.

3. TREATMENT OPTIONS FOR ADVANCED HCC

3.1. Targeted therapy: Sorafenib and other molecular targeted drugs

Based on the survival benefit in large prospective randomized Phase 3 trials (Cheng et al., 2009; Llovet et al., 2008), sorafenib, a tyrosine kinase inhibitor, was recommended as standard therapy in advanced HCC patients with PVTT by the Barcelona Clinic Liver Cancer staging system (Forner, Reig, de Lope, & Bruix, 2010). It was shown to prolong median overall survival (OS) by about 3 months for advanced HCC patients (8.1 vs 4.9 months; Bruix et al., 2012). Two cases of advanced HCC as Irtan et al. (2011) reported, after 12 and 10 months of oral sorafenib treatment, tumor thrombus disappeared and the tumor shrank. Two patients were subsequently treated with surgery. Jeong et al. (2013) investigated the efficacy of sorafenib monotherapy in 30 advanced HCC patients (Vp3 or 4). Three cases (10.0%) had a partial remission of PVTT revascularization, nine cases (30.0%) had a stable condition. The disease control rate was 33.3% and the median OS rate was 3.1 months. While this efficacy of sorafenib monotherapy in treating advanced HCC was very poor, the limited proportion of patients indicated significant results.

The second‐line targeted drugs that failed to use sorafenib have become the research focus of molecularly targeted drugs at present. The second‐line targeted drugs are represented by regorafenib, cabozantinib, and so forth. Bruix et al. (2017) conducted a randomized, double‐blind, parallel‐group, Phase 3 trial done at 152 sites in 21 countries to evaluate the safety and efficacy of regorafenib in HCC patients who progressed on sorafenib. Results showed that regorafenib improved OS. The median survival got prolonged (regorafenib vs placebo, 10.6 vs 7.8). Finn et al. (2018) carried out exploratory research on this. They found regorafenib conferred survival benefit to patients regardless of the pace of disease progression during prior sorafenib treatment and last sorafenib dose. The efficacy of receiving regorafenib after sorafenib treatment may be beyond the scope of the report. Regorafenib is expected to become a second‐line treatment of advanced HCC. Abou‐Alfa et al. (2018) conducted a randomized, double‐blind, Phase 3 trial to assess the efficacy of cabozantinib compared with placebo previously used in patients with advanced HCC. The results showed that cabozantinib treatment provided longer OS and progression‐free survival. The incidence of high‐grade adverse events was twice that of the placebo group in the cabozantinib group. Ikeda et al. (2017) conducted a Phase 2, single‐arm, open‐label multicenter study to evaluate the safety and efficacy of lenvatinib in advanced HCC. Forty‐six patients with HCC were enrolled in the study group. They took the medicine until they progressed or showed irreversible toxic reactions. Results showed that the median time to progression (TTP) was 7.49 months, the median OS was 13.9 months, 32.6% of the patients achieved partial relief, and 45.7% of the patients achieved stable disease, suggesting that lenvatinib indicated clinical activity and acceptable toxicity, but its efficacy needed further certification. Apatinib is also a tyrosine kinase inhibitor. Qin et al. (2014) conducted a multicenter randomized, non‐blind, dose‐exploratory Phase II clinical trial to explore the efficacy of apatinib as a first‐line treatment of advanced HCC patients. The results showed that patients tolerated apatinib well and most adverse events could be relieved by withdrawal or reduction of the dose. Apatinib had potential survival benefits in patients with advanced HCC. Orantinib is another multi‐kinase inhibitor. Kudo et al. (2018) did a randomized, double‐blind, placebo‐controlled, Phase 3 study, to evaluate the efficacy of orantinib combined with conventional TACE in patients with unresectable HCC. Unfortunately, it has not improved the patient's OS. There are also some antiangiogenic molecular targeted drugs such as Bevacizumab (Li et al., 2017; Pinter et al., 2015) and Endostar (Q. Zhang et al., 2014), EGFR, IGFR, HGF/c‐Met pathway‐targeted drugs, mTOR inhibitors, and other targeted drugs achieved good results in preliminary clinical trials and need further certification (Tables 1, 2).

Table 1.

VP classification

VP0 No tumor thrombus was found
VP1 The third branch of the portal vein invaded
VP2 The secondary branch of portal vein invaded
VP3 The primary branch of portal vein invaded
VP4 The portal vein or involved in the contralateral portal vein
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Table 2.

Cheng's classification

I0 Postoperative pathological diagnosis of microvascular tumor thrombus invaded
I The segmental branches of portal vein or above invaded
II The right or left portal vein invaded
III The main portal vein trunk invaded
IV The superior mesenteric vein or inferior vena cava invaded
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3.2. Recent advances

Although targeted therapies are the recommended therapeutics for advanced HCC, there remain many alternative therapeutic explorations as summarized in Table 3.

Table 3.

Main clinical trails regarding treatments beyond targeted therapy for advanced HCC

Author, Year Study design Sample size (n) Sample (n) Outcomes
Peng, 2012 Retrospective study 603 Hepatic resection (201) versus TACE (402) 1‐, 3‐, and 5‐year overall survivals (OS): 42.0%, 14.1%, 11.1% versus 37.8%, 7.3%, 0.5%
Kojima, 2015 Cohort 52 Hepatic resection (52) The median disease‐free survival (DFS): 8.9 months; OS: 27.6 months
Kokudo, 2016 Cohort 6,474 Hepatic resection (2,093), other treatments (4,381). In the Child‐Pugh A patients, the median survival time: 2.87 years vs 1.10 years.
Chok, 2014 Retrospective study 88 Group 1 (71), with ipsilateral PVTT resected in a hepatectomy; Group 2 (10), with PVTT extending to or beyond the portal vein bifurcation, treated by en bloc resection followed by portal vein reconstruction; Group 3 (7), with PVTT extending to or beyond the portal vein bifurcation, treated by thrombectomy. The median OS durations were 10.91, 9.4, and 8.58 months. Median DFS durations were 4.21, 3.78, and 1.51 months.
Zhang, 2016 A prospective two‐arm non‐randomized study 320 Arm 1(205):immediate surgical resection; Arm 2(115): preoperative TACE. 1‐, 3‐ and 5‐year OS rates: 48.3%,18.7%,13.9% versus 61.2%, 31.7%, 25.3%.
Luo, 2011 A prospective two‐arm non‐randomized study 164 TACE group (84); conservative treatment group (80). 12‐ and 24‐month OS rates for the TACE and conservative groups: 30.9%, 9.2% versus 3.8%, 0%.
Kim, 2018 Cohort 331 HCC patients with segmental PVTT(331). Median survival: 10.7 months. Objective tumor response was achieved in 53.8% of patients.
Huang, 2016 Cohort 210 TACE‐Iodine125 group (70); TACE group (140). Median survival times: 11.0 versus 7.5 months. The survival probability at 12, 24, and 36 months was 50%, 14.5%,14.5% versus 25%, 9%,5%.
Liu, 2018 Cohort 1,004 Crude cohort: 540 patients, PS‐matched cohort: 464 patients with similar baseline characteristics. PA‐TACE was associated with longer OS (odds ratio [OR] = 0.55, p = 0.001),
Giorgio, 2016 RCT 99 sorafenib + RFA (49) versus sorafenib alone(50). 1‐, 2‐, and 3‐year survival rates: 60%, 35%, and 26% in the combination group, 1‐, 2‐year survival rates: 37% and 0%.
Long, 2016 Retrospective study 60 TACE + MWA (60). The median 3‐year OS duration: 13.5 months. 1‐ and 3‐year OS rates: 48% and 23%.
Zheng, 2014 Retrospective study 134 TACE + RFA (134). The median OS time: 29.5 months. 1, 3, and 5 year OS: 63%, 40%, 23%.
Pitton, 2015 Retrospective study 24 SIRT (12) or DEB‐TACE (12). PFS: 180 days versus 216 days. Median TTP: 371 days versus 336 days. Median OS: 592 days versus 788 days.
Lu, 2016 Retrospective study 138 Palliative group (74) versus GKR group (64). The median OS: 3.0 months versus 6.1 months
Im, 2017 Nationwide, multicenter study 985 RT (985) The response rate of the PVTT: 51.8%. RT responders had a significantly longer survival than non‐responders (15.2 vs 6.9 months). The median OS: 10.2 months.
Choi, 2014 Retrospective study 100 Chemoradiotherapy (100) Complete response (CR) and partial response (PR) were achieved in 14% and 48% of patients, yielding an objective response (OR) rate of 62%. The median OS: 11.6 months.
Sun, 2018 Retrospective study 134 TACE + 125I seed group (64); TACE group (70). The median survival time: 11 months versus 5.8 months; The 6‐, 12‐, and 18‐month OS rate: 65.4, 45.3, 20.8% versus 42.9, 15.7, 10.4%.
Sun, 2016 Retrospective study 34 PVS + 125I seed strand endovascular implantation The median survival: 147 days. The cumulative survival rates and stent patency rates at 90, 180, 360 days: 94.1%, 61.8%, 32.4%, and 97.1%, 76.9%, 29.4%.
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Note. HCC: hepatocellular carcinoma; MWA: microwave ablation; PVS: portal vein stenting; PVTT: portal vein tumor thrombus; RFA: radiofrequency ablation; TACE: transcatheter arterial chemoembolization.

3.2.1. Resection

Previously, patients with advanced HCC had poor prognosis and high mortality, which was a contraindication of surgery and interventional therapy. With the development of medical technology and surgical technology, SR has played its own value in the treatment of PVTT. The meta‐analysis made by Liang et al. (2018) demonstrated that SR resulted in better OS than TACE and other Non‐SR treatments for patients with advanced HCC. It ought to be considered in selected patients with resectable HCC accompanied by PVTT. Peng et al. (2012) and X. P. Zhang et al. (2017) drew the same conclusion especially in patients with Type I or II PVTT. Kokudo et al. (2016) performed a multicenter, nationwide study to evaluate the survival benefit of liver resection in HCC patients with PVTT using propensity score‐based matching. They found that so long as the PVTT was limited to the first‐order branch, liver resection may reach a longer OS than nonsurgical treatment. Kojima et al. (2015) retrospectively analyzed the disease‐free survival and OS in 52 consecutive patients who operated SR for HCC. Macroscopically curative resection was found probably beneficial to patients with advanced HCC, even if tumor thrombi were in the first branch or trunk of the portal vein. Chok et al. (2014) investigated the outcomes of three different surgical approaches in patients with advanced HCC. They found the three approaches had similar outcomes in terms of complication, survival, and recurrence. Effective adjuvant treatments are required to be developed to lower the high incidence of recurrence. However, Bruix et al. (2015) undertook a Phase 3, double‐blind, placebo‐controlled study to evaluate the safety and efficacy of sorafenib versus placebo as adjuvant therapy in patients with HCC who undertook SR or local ablation. Their data indicated that sorafenib was not an adjuvant therapy with effective intervention for HCC following resection or ablation.

3.2.2. TACE

TACE is a commonly used nonsurgical treatment. Recent studies have confirmed the feasibility of TACE in the treatment of HCC with PVTT. Y. F. Zhang et al. (2016) made a comparative study to assess the outcomes of preoperative TACE for resectable HCC with PVTT. They found preoperative TACE appeared to offer a survival benefit to resectable HCC with PVTT, particularly to Types I and II PVTT. Luo et al. (2011) conducted a prospective two‐arm nonrandomized study to assess the efficacy of TACE for patients with HCC and PVTT. Data showed TACE was safe and feasible in selected patients. It had a survival benefit compared to conservative treatment. A retrospective controlled study made by Zhu et al. (2014) evaluated the safety and efficacy of TACE combined with sorafenib. They found the side effects of TACE‐Sorafenib were acceptable, and this treatment may prolong OS in patients with HCC and first‐order or lower‐branch PVTT compared with patients underwent TACE alone. Kim et al. (2018) assessed survival outcomes and prognostic factors in a large cohort of 331 patients with HCC and segmental PVTT who undertook TACE. Researchers found TACE well‐tolerated and effective. Four risk factors were related to decrease the length of OS after TACE: a major tumor burden, extrahepatic spread, Child‐Pugh class B liver function, and nonregression to TACE. For patients with 2–4 risk factors, TACE may not be recommended because of the poor survival outcome. Huang et al. (2016) performed a retrospective matched cohort study to investigate the survival benefit of TACE plus Iodine125 seed implantation (TACE‐Iodine125) to hepatitis B‐related HCC patients along with PVTT, The median survival times of the TACE and TACE‐Iodine125 groups were 7.5 and 11.0 months, respectively (p < 0.001). The survival probability of TACE‐Iodine125 and TACE group at 12, 24, and 36 months was 50%, 14.5%, 14.5% versus 25%, 9%, 5%, respectively (p < 0.001), suggesting that for patients with HCC‐PVTT, TACE‐Iodine125 was more effective than TACE. Furthermore, TACE associated with a lower risk of death particularly in selected patients with PVTT involving left/right or main portal vein (Liu et al., 2018).

3.2.3. Ablation

Local ablation has the characteristics of small trauma, quick response, strong repeatability, and can accurately act on tumor tissue. Methods of local ablation for PVTT include percutaneous ethanol injection, radio frequency ablation (RFA), laser ablation (LA), high intensity focused ultrasound (HIFU), and so forth. Giorgio et al. (2014) compared the long‐term results of percutaneous radiofrequency ablation and no treatment in both HCC single nodule (up to 5 cm in diameter) and neoplastic main portal vein tumor thrombus (MPVTT). RFA significantly prolonged survival compared to no‐treatment in HCC with MPVTT. Mearini (2013) reported that HIFU was an effective treatment of HCC with PVTT, with minimal trauma, rapid recovery, and reduced damage to normal liver tissue. However, local ablation has the potential to damage the portal vein wall and bile duct. PVTT can be formed again in the short term, which affects the long‐term efficacy. It can be combined with other treatments. Giorgio et al. (2016) carried out a study to compare 3‐year survival in a randomized controlled trial (RCT) in cirrhotic patients with HCC and PVTT treated with sorafenib plus percutaneous RFA or sorafenib alone. Results showed that compared to sorafenib alone, use of RFA plus sorafenib significantly increased 3‐year survival. Long, Zheng, Sun, and Lu (2016) prospectively evaluated the use of microwave ablation (MWA) in treating HCC with PVTT after TACE, and to assess factors that significantly affect survival outcomes. They found this combination therapy may confer a survival benefit for patients with HCC + PVTT Type I, II, or partial III and Child‐Pugh Class A or B via reducing the tumor burden. Zheng et al. (2014) retrospectively evaluated the safety and survival benefit of TACE combined with RFA in 134 HCC patients with PVTT, and assessed factors that significantly affect survival outcomes. The average median survival time was 30 months. The 1‐, 3‐, and 5‐year survival rates were 63%, 40%, and 23%, respectively; suggesting that TACE combined with RFA may be an effective therapy.

3.2.4. Radiotherapy

External radiotherapy (RT) was not used in the treatment of HCC because of poor tolerance of liver tissue to RT exposure and concerns about radiation‐induced liver disease. However, with the rapid development of precision radiotherapy technology, including three‐dimensional conformal radiation therapy (3D‐CRT), image‐guided radiotherapy, intensity modulated radiation therapy, proton beam radiation therapy, RT has become an effective treatment option of HCC (Klein & Dawson, 2013). Pitton et al. (2015) reported 284 cases of HCC with PVTT treated with 3D‐CRT combined with TACE. The remission rate was 41.6%, and the progression‐free rate was 87.8%. X. J. Lu et al. (2016) found that gamma knife radiosurgery (GKR) was well tolerated in selected patients with HCC accompanied by PVTT and can provide survival benefit in a retrospective study of 138 patients. Im et al. (2017) conducted a nationwide, multicenter study to investigate survival outcomes for patients with HCC and PVTT. Data displayed that the response rate of was 51.8%. RT responders had a significantly longer OS than non‐responders. The median OS was 10.2 months. Choi, Kim, Cha, Han, and Seong (2014) treated 100 PVTT patients using radiotherapy combined with intravenous chemotherapy. The complete and partial remission rates were 14% and 48%, respectively. The median OS time was 11.6 months. External radiation therapy has become an important and effective treatment of patients with HCC and PVTT. However, there is no uniform standard for the dose of external radiation therapy for HCC and tumor thrombus. Internal radiation therapy uses minimally invasive techniques such as interventional therapy or percutaneous liver puncture to place radionuclides such as 125I, 133I, 32p, 90Y at the treatment site, which not only achieves the therapeutic effect of continuously killing tumor cells, but also avoids the adverse reactions caused by systemic irradiation. H. Sun et al. (2018) found that 125I seed implantation combined with TACE treatment can prolong the median survival time compared with the TACE treatment alone for HCC patients with PVTT. J. H. Sun et al. (2016) retrospectively evaluated the survival benefit of portal vein stenting (PVS) combined with 125I seed strand endovascular implantation followed by TACE in treating patients with HCC and PVTT. The median survival was 147 days. The cumulative survival rates and stent patency rates at 90, 180, and 360 days were 94.1%, 61.8%, and 32.4% and 97.1% (33/34), 76.9% (24/34), and 29.4% (10/34), respectively.

However, current evidence mostly generated from retrospective studies or inferred from subgroup analyses of prospective clinical trials. The issue of these treatment strategies for HCC with PVTT remains controversial. More high‐level evidence is needed (Figure 1).

Figure 1.

Figure 1

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Several pathways related to the formation mechanism of PVTT. Downregulation of miR‐28‐5p in HCC is associated with tumor metastasis and recurrence. Its effects are dependent on IL‐34‐mediated TAM infiltration. In addition, TAMs induced by miR‐28‐5p‐IL‐34 signaling pathway inhibits the expression of miR‐28‐5p on HCC cells via transforming growth factor β1, resulting in positive miR‐28‐5p‐IL‐34‐macrophages Feedback loop (Zhou et al., 2016). mirR‐135a is transcribed from the forkhead M1 (FOXM1) and metastasis suppressor 1 (MTSS1) is a direct and functional target of miR‐135a. Overexpression of miR‐135a is conducive to the development of PVTT (Liu et al., 2012). The persistence of HBV infection in liver tissue leads to an increase in TGF‐β activity, inhibition of microRNA‐34a expression, resulting in increased production of the chemokine CCL22, which recruits regulatory T (Treg) cells to promote immune escape (Yang et al., 2012). HBV: hepatitis B virus; HCC: hepatocellular carcinoma; PVTT: portal vein tumor thrombus; TAM: tumor‐associated macrophages [Color figure can be viewed at wileyonlinelibrary.com]

4. EXPLORATION OF IMMUNOTHERAPY

Immunotherapy can enhance the immune rejection of tumor, inhibit and/or kill tumor cells by regulating the specific immune response, thereby reducing the ability of tumor recurrence and metastasis. Immune dysfunction is an important factor in the development and metastasis of HCC. Possible immunotherapeutic modalities are summarized in Figure 2. Over the last decade, drug development was disappointing. Many drugs failed in Phase 3 trials while they had good theoretical basis and promising Phase II data. As an alternative therapy, Immunotherapy has achieved great success in many different cancer types (Barata & Rini, 2017; Forde et al., 2018; X. Lu et al., 2017; Turajlic & Larkin, 2018). In particular, with the approval of immunological checkpoint inhibitors, the prospects for immunotherapy have changed dramatically (Greten & Sangro, 2017).

Figure 2.

Figure 2

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Immunotherapy in HCC. Nucleoside analogs and interferons block the pathway by which HBV destroys hepatocytes. ACI (advanced cellular immunotherapy) includes LAK (Lymphokine‐activated killer cells), TIL (Tumor‐infiltrating lymphocyte), CD3AK (Anti‐CD3 McAb activated killer cells), CIK (Cytokines‐induced killers), CTL (Cytotoxic T lymphocyte), DC (Dendritic cells), NK (Natural killer cell), TCR‐T (T‐cell Receptor therapy), CAR‐T (Chimeric Antigen Receptor T‐Cell Immunotherapy) and the like, delivering sensitized lymphocytes or their products to patients to obtain antitumor immunity. Tumor vaccines, checkpoint blockers, IL (Interleukins), and so forth, use the body's own immune system to kill tumors by activating and modulating immune cells. In addition, there are methods to eliminate the inhibitory state of the immune system by eliminating or neutralizing immunosuppressive cytokines, MDSCs (myeloid‐derived suppressor cells), and Tregs. HBV: hepatitis B virus; HCC: hepatocellular carcinoma [Color figure can be viewed at wileyonlinelibrary.com]

4.1. CTLA‐4 inhibitor tremelimumab used in HCC

In the treatment of HCC, clinical development focuses on cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) and programmed cell death protein 1/ programmed death‐ligand 1 (PD‐1/PD‐L1) pathways. Tremelimumab, a monoclonal antibody that blocks CTLA‐4, was the first immunotherapy assessed in HCC. Sangro et al. (2013) conducted a pilot clinical trial to test the antitumor and antiviral effect of tremelimumab on patients with HCC and chronic hepatitis C virus (HCV) infection, evaluating the safety of tremelimumab in cirrhotic patients. They found that the partial response rate was 17.6% and disease control rate was 76.4%. A significant decrease in viral load was observed too. A study conducted by Duffy et al. (2017) demonstrated the safety and feasibility of Tremelimumab combined with ablation in 32 HCC patients enrolled. Of the 14 patients with quantifiable HCV, 12 had a significant reduction in viral load. Six weeks of tumor biopsy showed that CD8+T cells increased significantly in patients. The 6‐ and 12‐month progression‐free survival rates were 57.1% and 33.1%, respectively. The median tumor progression time was 7.4 months and the median OS was 12.3 months, suggesting that combined with ablation may be a new treatment of advanced HCC. These results indicated that tremelimumab had an encouraging antitumor activity and good safety in advanced HCC, providing a strong reason for the detection of other checkpoint inhibitors.

4.2. PD‐1 inhibitor nivolumab applied in advanced HCC

PD‐1/PD‐L1 inhibitors can specifically bind to PD‐L1 on tumor cells to inhibit the expression of PD‐L1, thereby restoring the recognition function of suppressed T cells to tumor cells and achieving anticancer effect through autoimmunity. El‐Khoueiry et al. (El‐Khoueiry et al., 2017) assessed the safety and efficacy of the PD‐1 inhibitor nivolumab in advanced HCC patients. In this Phase II clinical trial involving 262 patients worldwide, nivolumab alone was effective at 15–20%, disease control was over 60%, 9‐month survival was 74%, and Grade 3–4 side effects were 20%. Nivolumab had controllable safety and no new signals. Despite the need for randomized comparisons, these findings strongly suggested that first‐line or second‐line treatment with nitrobenzene monoclonal antibody can control advanced liver cancer (Killock, 2017). Due to considerable test results, Nivolumab received accelerated approval for second‐line treatment of advanced HCC in 2017 (American Association for Cancer Research, 2017) and is awaiting the results of Phase 3.

4.3. CAR‐T or TCR‐T utilized in HCC

In addition, cell‐based therapies such as Chimeric Antigen Receptor T‐Cell Immunotherapy (CAR‐T) and T‐cell Receptor therapy (TCR‐T) cells made a breakthrough in tumors (Abramson et al., 2017; Brown et al., 2016; Park et al., 2018; Zacharakis et al., 2018). They used genetic modification to improve the ability of T cell receptors to recognize and attack specific cancer cell antigens. Gao et al. (2014) found that CAR T cells targeting Glypican‐3 (GPC3) can effectively eliminate GPC3 positive HCC cells, thus offering a promising therapeutic intervention to GPC3 positive HCC. Jiang et al. (2016) transplanted CAR T cells into an HCC patient‐derived xenograft (PDX) model to study the antitumor effect of GPC3 specific CAR‐T cells on HCC. It was found that these CAR‐T cells significantly inhibited the growth of GPC3 high expression PDX tumor, and had a clear inhibitory effect on GPC3 tumor with relatively low expression. Dargel et al. (2015) generated and used T cells with GPC3‐specific receptors that recognized HCC to eliminate GPC3‐expressing xenograft tumors grown from human liver cancer cells in mice. A GPC3367‐specific T cell receptor was identified. T cells expressed this receptor, enabling them to identify and kill GPC3‐positive hepatoma cells. This discovery can be used to promote the development of HCC adoptive T cell therapy.

4.4. Problems and challenges

Although many achievements have been achieved, there are still many challenges to overcome to better utilize the benefits of immunotherapy. How to promote the activation of T cells, improve the killing power and proliferation efficiency of immune cells on tumors, reduce the side effects of drugs on the liver (Ringelhan, Pfister, O'Connor, Pikarsky, & Heikenwalder, 2018), improve patients selection (Inarrairaegui, Melero, & Sangro, 2018), select the best therapeutic effect of immune cells, immune test spot monoclonal antibodies and tumor vaccines. Further clinical research are needed. Immunotherapy combined with other antitumor treatments such as surgery, chemotherapy, molecular targeted therapy, and other comprehensive treatment models deserve further exploration.

5. FUTURE DIRECTIONS

The treatment of HCC with PVTT is still a major clinical problem. In addition to SR, nonsurgical clinical treatment is diversified, but the specific efficacy needs to be further confirmed by prospective RCT studies. The treatment of HCC with PVTT should adopt the multi‐disciplinary comprehensive treatment cooperation group model to explore the individualized treatment and improve the efficacy. Meanwhile, in‐depth basic research, further clarify the molecular mechanism of the occurrence and development of PVTT, establish the possible predictive indicators and therapeutic targets of cancer thrombus to provide a theoretical basis for clinical prevention and treatment of portal vein cancer thrombus.

CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest.

Contributor Information

Yong Xu, Email: xuyong_ey@163.com.

Xiao‐Jie Lu, Email: 189@whu.edu.cn.

References

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