Treatment of intermediate-to-advanced unresectable hepatocellular carcinoma is shifting toward a multidisciplinary strategy that includes multiple modalities as needed

Abstract

In the recent issue of the World Journal of Gastroenterology, Han et al compared the efficacy of and adverse reactions to bevacizumab versus lenvatinib as molecularly targeted agents in combination with interventional therapy and immunotherapy (IMT) to treat intermediate-to-advanced unresectable hepatocellular carcinoma. No significant differences in efficacy or adverse reactions were observed between bevacizumab and lenvatinib. This study is highly promising because in some regions, e.g., Japan, the combination of molecularly targeted therapy with IMT is fixed because of insurance restrictions, and some molecularly targeted agents cannot be combined with IMT. Further studies using these three modalities are expected to be conducted in the future. Additionally, because advanced radiotherapy modalities have recently been established, the number of combinations continues to increase, and further evidence regarding combination therapy, which is the cornerstone of personalized medicine, needs to be accumulated.

Key Words: Hepatocellular carcinoma; Molecularly targeted therapy; Immunotherapy; Interventional therapy; Radiation therapy

Core Tip: Many treatment approaches for intermediate-to-advanced unresectable hepatocellular carcinoma are advancing, and there is an increasing amount of evidence regarding the use of combination therapies. Although there may be limitations on combinations in some regions, there is a growing need for research on multimodal treatments, which serve as the cornerstone of personalized medicine. Based on this evidence, we believe that effective combination therapies should be sought for each patient.

TO THE EDITOR

In this article, I comment on the article by Han et al[1] published in the recent issue of the World Journal of Gastroenterology. They reported a retrospective study to compare bevacizumab with lenvatinib in combination with sintilimab, a programmed death-1 (PD-1) inhibitor, and interventional treatment for intermediate-to-advanced unresectable hepatocellular carcinoma (HCC). They investigated the differences in clinical efficacy and safety between the two molecularly targeted agents combined with an immune checkpoint inhibitor and interventional therapy. The results revealed no significant differences in progression-free survival (PFS), which was the primary endpoint. There were also no significant differences in overall survival (OS), the objective response rate (ORR), the disease control rate, and treatment-related adverse events (TRAEs), which were the secondary endpoints. These results indicated that bevacizumab and lenvatinib exhibited comparable efficacy and acceptable adverse reactions. In the future, we should aim to further improve the outcomes by changing the type of immunotherapy (IMT) used or considering various combinations.

CURRENT STATUS OF COMBINATION THERAPY

In some regions, combining molecularly targeted therapy (MTT) with IMT and interventional treatment is impossible. For example, according to the algorithm for therapy for HCC in the 2021 edition of the Japanese Society of Hepatology's guidelines, if combined MTT and IMT are indicated, the primary drug therapy should be either atezolizumab as a programmed death ligand 1 (PD-L1) inhibitor plus bevacizumab (atezo-bev) or tremelimumab as a cytotoxic T lymphocyte-associated antigen-4 inhibitor plus durvalumab as a PD-L1 inhibitor. The complications of severe autoimmune disease may contraindicate IMT. If IMT is not indicated in such cases, monotherapy with MTTs such as sorafenib or lenvatinib is used. As PD-1 and PD-L1 inhibitors cannot be combined with sorafenib or lenvatinib under medical insurance, the use of combinations of MTTs and IMT such as checkpoint inhibitors is limited in Japan. However, combining interventional treatments is possible in Japan. A technique that combines lenvatinib and transarterial chemoembolization (TACE) as an interventional therapy is becoming more widespread in Japan. Tachiiri et al[2] reported that TACE combined with lenvatinib, which entails 4 days of lenvatinib administration before TACE without an intervening interval, was feasible and safe, had a high complete response (CR) rate (75% overall), improved lipiodol deposition after conventional TACE, and consequently prolonged the 12-month PFS rate to 75.0%. The following mechanisms are hypothesized: TACE following lenvatinib administration may order deformed tumor vasculature, consequently refining the intra-arterial drug distribution, and may also reduce the increase in vascular endothelial growth factor caused by hypoxia due to TACE[3,4]. Therefore, in regions where combinations of treatment modalities are limited, it is necessary to develop better combination regimens by optimizing the use of the modalities available.

However, a previous meta-analysis comparing TACE combined with MTT and IMT (TACE-MTT-IMT) versus TACE combined with MTT (TACE-MTT) revealed that add-on IMT provided additional clinical merits and survival benefits in unresectable HCC[5]. Feng et al[5] suggested the following reasons for the greater survival benefit of TACE-MTT-IMT than of TACE-MTT: TACE causes considerable local tumor necrosis and thereby increases antitumor immune responses through PD-1 inhibitors, which results in comprehensive treatment synergy[6]. The antiproliferative and antiangiogenic effects of multikinase inhibitors as MTT can act against hypoxia-induced angiogenesis due to TACE[7]. Additionally, they can regulate the tumor immune microenvironment and magnify the immune response to PD-1 inhibitors in HCC[8,9]. This synergistic antitumor activity improves the prognosis of HCC patients[5]. TACE-MTT-IMT exerts immunostimulatory effects on local and systemic immune activation by decreasing the tumor burden, increasing CD8+ T-cell infiltration, and reducing the suppressive effects of CD8+ T cells, thereby prolonging survival in HCC patients[10].

Notably, advances in therapy for HCC have been made, from conventional external beam radiotherapy (EBRT) techniques to advanced modalities such as intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and innovative particle therapies such as proton therapy and carbon-ion radiation therapy[11], which can be combined with TACE-MTT-IMT to provide personalized treatment for each patient. A review by Kim and Kim[11] synthesized the results of the following clinical studies. A multicenter phase II trial conducted in Korea evaluated the combination of nivolumab that is a PD-1 inhibitor and EBRT in advanced HCC patients with macrovascular invasion[12]. The primary endpoints were PFS and safety[12]. The median PFS was 5.6 (90%CI: 3.6-9.9) months. Among the 50 patients included in this study, 40 (80.0%) and 6 (12.0%) patients experienced any grade TRAEs and grade 3/4 TRAEs, respectively[12]. Pruritus (38.0%) and rash (16.0%) were common TRAEs, and there were no deaths associated with the therapy[12]. Thus, the combination of nivolumab and EBRT was associated with favorable PFS and safety[12]. Additionally, a study conducted in Hong Kong compared the combination of SBRT and nivolumab in locally advanced HCC patients with TACE alone[13]. The primary outcome was PFS[13]. The 12- and 24-month PFS rates were significantly greater in the combination group than in the TACE alone group (93.3% vs 16.7% and 77.8% vs 2.1%, respectively, P < 0.001)[13]. The 12- and 24-month OS rates, which were secondary outcomes, were also better in the combination group than in the TACE alone group (93.8% vs 31.3% and 80.4% vs 8.3%, respectively, P < 0.001)[13]. There were fewer discontinuation of treatment (25% vs 12.5%, P = 0.295) because of adverse events (AEs) and ≥ grade 3 TRAEs (60.4% vs 18.8%, P = 0.004) in the combination group than in the TACE alone group[13]. Thus, the combination of SBRT and nivolumab was associated with significantly longer survival and fewer AEs than TACE alone[13]. As a safety-focused study, Zhang et al[14] compared the frequency of radiation-induced hepatic toxicity (RIHT) associated with RT plus PD-1 inhibitors with that associated with RT alone in patients with unresectable HCC[14]. After propensity score matching, aspartate aminotransferases ≥ grade 1 developed more often in the combination group (P = 0.020), and other hepatotoxicity metrics were not significantly different between the two groups[14]. They concluded that the incidence of RIHT in the combination therapy group was comparable to that in the RT alone group and was considered tolerable[14]. Thus, the combination of RT and IMT has considerable potential for further development in the treatment of HCC.

Regarding the combination of RT and MTT (RT-MTT), a systematic review and meta-analysis on the combined treatment of external RT and sorafenib in the treatment of HCC were conducted on the basis of 11 studies[15]. This study revealed that the median OS and PFS as the primary observation endpoints were 19.45 months and 8.20 months, respectively[15]. The incidence of AEs as the secondary observation endpoint was 0.34 (95%CI: 0.25-0.44)[15]. The study concluded that the survival of patients receiving combination therapy was significantly prolonged, and few severe AEs were observed[15]. Another systematic review and meta-analysis of 46 studies examined the use of sorafenib plus other therapeutic modalities for the treatment of advanced unresectable HCC[16]. OS, PFS, and AEs were set as the primary observation endpoints. Compared with sorafenib alone, SOF plus TACE, SOF plus RT, and SOF plus hepatic artery infusion chemotherapy were associated with improved OS and PFS (HR and 95%CI: 0.58, 0.48-0.70; 0.31, 0.21-0.47; 0.53, 0.45-0.62; HR and 95%CI: 0.69, 0.56-0.84; 0.44, 0.27-0.73; 0.45, 0.38-0.54), respectively[16]. Among these three combination therapies, a network of pairwise comparisons among seven studies revealed that SOF plus RT significantly improved OS and PFS[16]. SOF alone and SOF with combination therapies caused numerous AEs, although the frequency of AEs was lower in the SOF plus RT group[16]. Therefore, RT-MTT can be considered a promising treatment.

In terms of the combination of RT and TACE, a meta-analysis of nine studies compared SBRT plus TACE (SBRT-TACE) with TACE monotherapy for unresectable HCC with portal vein tumor thrombus[17]. Compared with TACE monotherapy, combination therapy resulted in significantly better 1-year OS rates [RR, 1.52 (95%CI: 1.33-1.74)], 2-year OS rates [RR, 2.00 (95%CI: 1.48-2.70)], ORRs [RR = 1.22 (95%CI: 1.08-1.37)], and a decreased rate of disease progression (PD) [RR = 0.45 (95%CI: 0.26-0.79)]. CR, partial response (PR), and stable disease were not significantly different between the two groups[17]. No significant differences in AEs were observed[17]. A phase 2 trial (NCT02513199) conducted SBRT-TACE for Barcelona Clinic Liver Cancer early-stage A patients with a solitary HCC ranging from 4 to 7 cm[18]. The primary endpoint was the best ORR[18]. Among the 30 patients who were enrolled, 91% had an ORR for the target lesion: 63% CR (n = 20), 28% PR (n = 9), and 3% PD (n = 1), while few toxic effects were observed[18]. Additionally, a single-center, prospective, randomized, controlled, parallel-group superiority trial (NCT02323360)[19] compared SBRT following incomplete transarterial embolization (TAE)/TACE with exclusive TAE or TACE for the treatment of unresectable HCC. The primary endpoint was 1-year local control (LC)[19]. LC was better in the group that switched treatment to SBRT than in the standard TAE/TACE rechallenge group (median not reached vs 8 months, P = 0.0002)[19]. No grade > 3 AEs were observed in either group[19]. Thus, SBRT-TACE is considered very promising.

There have been studies on the combination of RT and two other therapeutic modalities. Compared with sorafenib monotherapy, atezo-bev has been proven to achieve better 1-year OS and median PFS outcomes[20]. A retrospective study[21] compared concurrent atezo-bev and high-dose EBRT (atezo-bev-ERBT) to atezo-bev alone for highly advanced HCC with Vp4 portal vein thrombosis or tumors. The primary endpoints were ORR, OS, and safety[21]. The atezo-bev-ERBT group had a better ORR (50.0% vs 11.8%, P < 0.01) and a longer OS (not reached vs 5.5 months, P = 0.01)[21]. The rates of any-grade AEs (78.6% vs 58.8%, P = 0.19) and grade ≥ 3 AEs (14.3% vs 14.7%, P = 0.97) were not significantly different between the combination group and the atezo-bev alone group[21]. The combination of TACE, IMRT, with sorafenib (TACE-IMRT-sorafenib) was compared with the combination without sorafenib (TACE-IMRT) for advanced HCC patients with macrovascular invasion retrospectively[22]. The TACE-IMRT-sorafenib group had longer median PFS and OS than did the TACE-IMRT group (17.2 vs 9.4 months; P < 0.001, 24.1 vs 17.3 months; P < 0.001), respectively[22]. Although the TACE-IMRT-sorafenib group presented a significantly greater frequency of grade 1 to 2 AEs, such as hand-foot syndrome, no grade 4 or higher AEs were observed in either group[22]. Thus, the combination of TACE-IMRT and MTT is also worth considering in the future.

However, there are limitations with respect to the use of ERBT in combination with other therapeutic modalities. For example, contraindications for SBRT include Eastern Cooperative Oncology Group performance status score ≥ 3, hepatic decompensation, albumin-bilirubin grade 3, Child-Pugh score C, hepatic encephalopathy, bowel infiltration, significant ascites, and pregnancy[23]. Additionally, the liver and adjacent gastrointestinal organs or structures such as the stomach, duodenum, and bowel are susceptible to radiation-induced toxicity, which may cause ulcers, fistulas, bleeding, and rupture[23]. SBRT may cause radiation-induced liver disease, which is recognized as the most severe form of RIHT[14,24], and central hepatobiliary tract toxicity, which is characterized by complications such as biliary stenosis, biliary obstruction, cholangitis, and sepsis[23]. Additionally, intermediate-to-advanced unresectable HCC is likely associated with deteriorated liver function. Thus, the indications for RT must be carefully determined on a case-by-case basis.

Table 1[25-43] presents a summary of ongoing prospective trials of EBRT combined with TACE and/or MTT and/or IMT. Single-arm studies or SBRT-based treatments are common. The target diseases are not necessarily limited to unresectable HCC. Safety or tolerability as well as efficacy are selected as the primary endpoints. Notably, studies using combinations of these four modalities are also currently underway.

Table 1 Ongoing prospective trials of external beam radiotherapy combined with transarterial chemoembolization and/or molecular targeted therapy and/or immunotherapy.

Ref.	Clinical trial name	Countries	Start year	Design	Target diseases	Actual or estimated enrollment	Interventions	Primary endpoints
Dawson[25]	NCT01730937	United States, Australia, Canada, China, and Korea	2013	Randomized, two-arm, phase 3	HCC	193	Sorafenib vs SBRT followed by sorafenib	OS
Knox[26]	NCT03316872	Canada	2018	Single-arm, phase 2	Advanced HCC	19	Pembrolizumab (PD-1 inhibitor) and SBRT	ORR
Hong[27]	NCT03482102	United States	2018	Single-arm, phase 2	HCC or biliary tract cancer	70	Tremelimumab (CTLA-4 inhibitor), Durvalumab (PD-L1 inhibitor), and RT	Best ORR
Lock[28]	NCT03895359	Canada	2019	Randomized, two-arm, phase 3	Primary or secondary liver carcinoma	128	TACE vs TACE and SBRT	OS
Chan[29]	NCT04988945	China	2020	Single-arm, phase 2	Unresectable HCC	33	TACE, SBRT, Durvalumab, and Tremelimumab	Downstaging for liver resection
Sun[30]	NCT04387695	China	2020	Randomized, two-arm, phase 3	Unresectable HCC with PVTT	54	SBRT, TACE, and Sorafenib vs Sorafenib	PFS rate
Wo[31]	NCT04857684	United States	2021	Single-arm, early phase 1	Resectable HCC	20	Atezolizumab (PD-L1 inhibitor), Bevacizumab, and SBRT	Proportion of patients with grade 3-4 TRAE
[32]	NCT05010434	China	2021	Single-arm, phase 2	Advanced HCC	46	Sintilimab (PD-1 inhibitor), Bevacizumab, and RT	ORR
Welsh[33]	NCT04785287	United States	2021	Randomized, two-arm, phase 1/2	Advanced solid malignancies including Stage III/IV or metastatic liver cancer	13	Anti-CTLA4 monoclonal antibody BMS-986218 and SBRT with Nivolumab vs those without	Incidence of AE
Zhao[34]	NCT05185531	China	2022	Single-arm, phase 1b	Resectable HCC	20	Tislelizumab (PD-1 inhibitor) and SBRT	Delay to surgery, ORR, pathologic response rate on evaluation of the resected specimen, and TEAE
Ben-Josef[35]	NCT05488522	United States	2022	Single-arm, phase 1	Advanced HCC	18	SBRT, Atezolizumab, and Bevacizumab	Tolerability and safety
Wo[36]	NCT05096715	United States	2022	Single-arm, phase 1	Unresectable HCC	20	Atezolizumab, Bevacizumab, and SBRT	Dose limiting toxicity rate
[37]	NCT05225116	China	2023	Single-arm, phase 1	HCC with PVTT	20	Sintilimab, Lenvatinib, and RT	Safety and number of patients who complete pre-op treatment and proceed to surgery
[38]	NCT05917431	China	2023	Single-arm, phase 2	Unresectable or oligometastatic HCC	39	SBRT, Tislelizumab, and Regorafenib	PFS
Xi[39]	NCT06261125	China	2024	Two-arm, phase 2	HCC with abdominal lymph node metastases	60	SBRT, Adebrelimab (PD-L1 inhibitor), and Lenvatinib	PFS
Wei[40]	NCT06561399	China	2024	Single-arm, phase 2	Unresectable HCC	28	TACE, Lenvatinib, Sintilimab, and RT	ORR
[41]	NCT06664996	China	2024	Single-arm, phase 2	Resectable HCC with PVTT	33	SBRT and Sintilimab	1-year DFS rate
Zeng[42]	NCT06349317	China	2024	Single-arm, phase 2	Resectable HCC with PVTT	33	IMRT, Camrelizumab (PD-1 inhibitor), and Apatinib	1-year EFS rate
[43]	NCT06349044	China	2024	Randomized, two-arm, phase 2 (liver adenocarcinoma)	Advanced digestive system malignancies including liver adenocarcinoma	120 (overall)	Hypo-RT/SBRT, Sintilimab, and Bevacizumab with Probio-M9 microbial agents vs those with placebo	ORR

AE: Adverse event; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; DFS: Disease-free survival; EFS: Event-free survival; HCC: Hepatocellular carcinoma; Hypo-RT: Hypofractionated radiotherapy; IMRT: Intensity-modulated radiation therapy; ORR: Overall response rate; OS: Overall survival; PD-1: Programmed cell death 1; PD-L1: Programmed death-ligand 1; PFS: Progression-free survival; PVTT: Portal vein tumor thrombus; pre-op, preoperative; RT: Radiation therapy; SBRT: Stereotactic body radiation therapy; TACE: Transarterial chemoembolization; TEAE: Treatment-emergent adverse event; TRAE: Treatment-related adverse event.

CONCLUSION

In conclusion, a multidisciplinary approach in which each patient is treated individually via a multimodal approach, such as combining TACE-MTT-IMT with RT and/or other modalities, is expected to further improve the prognosis of intermediate-to-advanced unresectable HCC patients (Figure 1). Improvements in the selection of combination modalities, the ordering of interventions, the timing of interventions, and the development of better regimen choices in areas where combination therapy is restricted should be investigated in many retrospective and prospective studies in the future.

Figure 1 Multidisciplinary strategy for intermediate-to-advanced unresectable hepatocellular carcinoma. Currently, it is possible to select individual or combinations of four representative treatment modalities-i.e., transarterial chemoembolization, molecularly targeted therapy, immunotherapy, and radiotherapy-to treat intermediate-to-advanced unresectable hepatocellular carcinoma. However, the combinations may be limited in some regions. The optimal choice of the type of combination, the order of therapies used, and the timing of intervention can be expected to reduce the size of the tumor, make the tumor resectable, or even eliminate the tumor. HCC: Hepatocellular carcinoma; TACE: Transarterial chemoembolization; MTT: Molecularly targeted therapy; IMT: Immunotherapy; RT: Radiotherapy.