Comparing the efficacy of five first-line treatment regimens for unresectable hepatocellular carcinoma: A network meta-analysis of randomized controlled trials

doi:10.21203/rs.3.rs-2817825/v1

Background: To find ideal treatment regimens in unresectable hepatocellular carcinoma (u-HCC) are clinically important. This study evaluated the efficacy of five first-line regimens in u-HCC patients at 6-, 12-, 18-, 24-, and 30-month overall survival (OS) to provide reference for rational clinical treatment.

Methods: We performed a systematic search using five databases. Screening and including qualified randomized controlled trials (RCT) regarding to the first-line regimens for unresectable HCC. Odds ratios (OR) were generated for dichotomous variants by network meta-analysis. The primary endpoint was OS, and the secondary endpoint was progression-free survival (PFS). The software implemented was STATA 17.0 MP.

Results: Eventually, a total of six RCTs with five first-line regimens were included. HAIC-FO (OR=9.78, 95%CI: 4.21 to 22.69) was significantly superior to sorafenib on OS at 18^th month. Concurrently, HAIC-FO (SUCRA=100%) had the highest ranking compared with the rest regimens. Atezolizumab plus bevacizumab (OR=5.13, 95%CI: 2.28 to 11.54) showed significantly better efficacy compared with sorafenib on PFS at 12^th month. Synchronously, atezolizumab plus bevacizumab (SUCRA=87.3%) had the highest ranking.

Conclusion: For patients with u-HCC, The optimal regimen we recommend is treating with HAIC-FO until 18^th month, followed by sequential therapy with donafenib. Furthermore, we need more head-to-head trials to confirm these findings.

unresectable HCC

first-line treatment regimens

network meta-analysis

RCT.

Primary liver cancer (PLCs) is the sixth most common malignant tumor and the fourth most common fatal tumor worldwide. Hepatocellular carcinoma (HCC) is the most common histological subtype of PLCs, accounting for 80%-85% of cases (1). Biologically, HCC has a poor overall prognosis, resulting in approximately 780,000 deaths per year. The incidence is expected to exceed 1 million cases by 2025 (2). In terms of treatment, surgical resection and liver transplantation can best remedy yielding the gratifying prognosis of HCC (3). However, the early symptoms of HCC are not conspicuous. According to reports, more than 50% of patients are diagnosed for advanced stage each year and lose surgical indications (4). For these patients, systemic treatment or local treatment of tumor is the alternative choice. Regrettably, contemporary treatment measures for unresectable HCC are still facing challenges, such as the selection of immunotherapy and molecularly targeted therapeutic regimens, biomarker studies and combinations with other therapeutic modalities. This undoubtedly brings stupendous psychological and somatic as well as economic burdens to patients. Moreover, families, society, and medical insurance were inevitably retarded.

The number of drugs approved for first-line treatment regimens for unresectable HCC has increased appreciably in the past several years, and many drugs and their combinations have been evaluated in various clinical trials (5). On the basis of the National Comprehensive Cancer Network (NCCN) guidelines and the Chinese Society of Clinical Oncology (CSCO) guidelines, although similarities in treatment allocation recommendations, some discrepancies exist between different treatment regimens.

Hence, we need multi-arm trials to compare these different remedies and comparisons among lately available first-line therapies will be of great clinical significance. Despite many studies comparing the therapeutic effects of first-line drugs in unresectable HCC, modicum of them analyzed by each time node, yielding potential bias even error owing to the omission of different follow-up periods.

Consequently, this network meta-analysis aimed to compare the efficacy on overall survival (OS) and progression-free survival (PFS) of first-line treatment regimens at 6th, 12th, 18th, 24th, and 30th month transversely and longitudinally in unresectable HCC to come up with the ideal regimens for unresectable HCC.

Search strategy

This meta-analysis was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guideline. We systematically searched the eligible studies on electronic databases including PubMed, Google Scholars, Scopus, Embase and Cochrane library. The MeSH terms were detailedly depicted in the Supplementary Materials.

Inclusion criteria

Fully open, randomized, controlled clinical trial of sorafenib, lenvatinib, donafenib, atezolizumab plus bevacizumab and 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (FOLFOX) in unresectable HCC.

The trial reported OS and/or PFS clinical outcomes and Kaplan-Meier survival curve graphs of high resolution were given in the study.

Randomized controlled trials (RCTs) with head-to-head comparisons of at least two treatment arms.

Exclusion criteria

Non-controlled or single-arm studies.

Patients who were non-treatment-naive patients and/or received the treatment of surgery or radiotherapy.

The effective outcome data could not be extracted from the study.

Reviews, abstracts, case reports, animal experiments, expert opinions, editorials and posters, etc.

Data extraction and quality assessment

Baseline data extracted from the included literature comprised: name of first author, year of publication, number of patients, sex, median age, Child-Pugh grade, ECOG physical status score, barcelona clinical liver cancer stage, hepatitis virus infection type. All the above steps were performed independently by two investigators (JS and LJ), any discrepancy was arbitrated by a senior investigator (GR).

The quality assessment was performed using the Cochrane Risk of Bias assessment tool by Review Manager 5.3.

Endpoint

The primary endpoint was OS.

The secondary endpoint was PFS.

Statistical analysis

This network meta-analysis was implemented by Stata 17.0 MP (StataCorp, College Station, TX); Odd ratios were generated for dichotomous variants including OS rate and PFS rate at each time node by network meta-analysis based on frequentist methodology. Heterogeneity was set as I² < 50% and p > 0.01 for the fixed effect model, otherwise, the random effect model would be applied. The surface under cumulative ranking (SUCRA) curve was calculated and a higher SUCRA value indicated a higher probability of being the best treatment. However, whether the effect size of any pairwise comparison of all the regimens reached significance was judged from net-league table, literally matrix in algebra. The overall and loops inconsistency was examined to justify the robustness of all the results. Small sample effect was explored by network funnel plot. p < 0.05 was considered to be statistically significant.

Characteristics and quality assessment of the included studies

The screening procedure was shown in Fig. 1. Eventually, a total of six RCTs with five first-line regimens were included. The regimens were sorafenib, lenvatinib, donafenib, atezolizumab plus bevacizumab and hepatic arterial infusion chemotherapy of infusional FOLFOX (HAIC-FO).

The median age of patients ranged from 53 to 66 years. The baseline studies characteristics were presented in Table 1 (6–11). All studies complete outcome reports were achieved and followed the principle of random allocation. All studies were at low risk of bias. The result of detailed methodological quality assessment is shown in Supplementary Fig. 1.

The efficacy of first-line regimens compared with sorafenib

All studies were eligible for analyzing the primary endpoint. The network plot is shown in Fig. 2A-E; sorafenib versus lenvatinib was the most common comparison from the 6th to 30th months, followed by sorafenib versus atezolizumab plus bevacizumab.

With regard to OS (Table 2), the efficacy of atezolizumab plus bevacizumab (OR = 2.56, 95%CI: 1.49 to 4.40) and HAIC-FO (OR = 2.42, 95%CI: 1.13 to 5.19) were significantly more effective than the sorafenib at 6th month. HAIC-FO (OR = 3.44, 95%CI: 1.47 to 8.04) and atezolizumab plus bevacizumab (OR = 2.45, 95%CI: 1.33 to 4.55) showed significant efficacy compared with sorafenib at 12th month. Simultaneously, the rest of the regimens were not significantly different from sorafenib. At 18th month, HAIC-FO (OR = 9.78, 95%CI: 4.21 to 22.69) was significantly superior to the sorafenib. Concurrently, HAIC-FO (SUCRA = 100%) had the highest ranking deducing from its effect size compared with the rest regimens. From the 24th to 30th months, donafenib (OR = 1.63, 95%CI: 0.98 to 2.72) indicated significant effectiveness compared with sorafenib. Simultaneously, donafenib (SUCRA = 92%) had the highest ranking at 30th month.

All studies were eligible for analyzing the secondary endpoint. The network plot is shown in Supplementary Fig. 2A-E; sorafenib versus lenvatinib was the most common comparison from the 6th to 30th months, followed by sorafenib versus atezolizumab plus bevacizumab.

In terms of PFS (Table 3), the efficacy of HAIC-FO (OR = 3.53, 95%CI: 2.12 to 5.88), lenvatinib (OR = 2.38, 95%CI: 1.87 to 3.02), atezolizumab plus bevacizumab (OR = 2.07, 95%CI: 1.49 to 2.87) and donafenib (OR = 1.68, 95%CI: 1.17 to 2.41) were significantly more effective than the sorafenib at 6th month. Atezolizumab plus bevacizumab (OR = 5.13, 95%CI: 2.28 to 11.54), HAIC-FO (OR = 4.31, 95%CI: 1.80 to 10.33) and lenvatinib (OR = 2.66, 95%CI: 1.33 to 5.33) showed significant better efficacy compared with sorafenib at 12th month. Synchronously, Atezolizumab plus bevacizumab (SUCRA = 87.3%) had the highest ranking. The efficacy of HAIC-FO (OR = 7.62, 95%CI༚2.57 to 22.58) was significantly superior to the sorafenib at 18th month. Meanwhile, HAIC-FO (SUCRA = 99.9%) had the highest ranking. From the 24th to 30th months, there was no significant difference in efficacy among all regimens.

The first-echelon regimens compared to sorafenib from longitudinal prospective

With regard to OS (Table 2), atezolizumab plus bevacizumab and HAIC-FO were first-echelon regimens compared with sorafenib at 6-12th months. HAIC-FO were first-echelon regimens compared with sorafenib at 18th month. Donafenib were first-echelon regimens compared with sorafenib at 24-30th months. Compared with sorafenib, atezolizumab plus bevacizumab, HAIC-FO, and lenvatinib were first-echelon regimens at 6-12th months in PFS (Table 3). On the other hand, HAIC-FO is the most long-lasting regimen in the first-echelon in PFS. These data are summarized based on a matrix plot of each pairwise comparison of all regimens on the efficacy across all regimens from the 6th to 30th months. (Supplementary Table 1-Table 10)

Data consistency and small sample study effect

There exists no inconsistency in general and loops in any pairwise comparison of regimens on OS and PFS. From the network funnel plot, small sample effect was verified to be existing in the comparison between lenvatinib and sorafenib at 6th month (Fig. 3A), in the comparison between atezolizumab plus bevacizumab and sorafenib at 12th month (Fig. 3B), and in the comparison between HAIC-FO and sorafenib at 18th month (Fig. 3C), and in the comparison between lenvatinib and sorafenib at 24th month (Fig. 3D) in analyzing the primary endpoint; in Fig. 3A-B: A = Atezolizumab plus Bevacizumab, B = Donafenib, C = HAIC-FO, D = Lenvatinib, E = Sorafenib; in Fig. 3C: A = Donafenib, B = HAIC-FO, C = Lenvatinib, D = Sorafenib; in Fig. 3D-E: A = Donafenib, B = Lenvatinib, C = Sorafenib. Small sample effect was also verified to be existing in the comparison between atezolizumab plus bevacizumab and sorafenib at 6th month (Supplementary Fig. 3A), in the comparison between lenvatinib and sorafenib at 24-30th month (Supplementary Fig. 3D-E) in analyzing the secondary endpoint.

To the best of our knowledge, this is the first meta-analysis to make comparisons among the first-line treatment regimens on OS and PFS in unresectable HCC by each time node.

With regard to the targeted therapy of HCC, sorafenib is a multi-target tyrosine kinase Inhibitor (TKI) that not only inhibits vascular endothelial growth factor receptor (VEGFR), fibroblasts growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR), but also inhibits RAS/RAF/ERK signaling and proto-oncogene c-kit. Thus, it can block tumor angiogenesis and inhibit the proliferation of HCC cells (12). Nevertheless, its high cost, frequent adverse reactions and unsatisfactory efficacy have greatly limited its use (13). Afterwards, lenvatinib is a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFR α, RET and KIT, giving it superior anti-tumor activity similar to sorafenib in a variety of pathologic mechanisms (14,15). Lenvatinib has been approved for the treatment of solid tumors such as thyroid cancer, kidney cancer and HCC (16,17). Kudo et al. (6) found no statistically significant difference in OS between the lenvatinib group and the sorafenib group, which was consistent with our results.

Immunotherapy orchestrated with targeted therapy has significant synergistic anti-tumor effects, highlighting the characteristics and advantages of immunotherapy, and also gradually changing the existing clinical standard and treatment paradigm of HCC (18). Immune Checkpoint Inhibitors (ICI) such as anti-programmed cell death protein 1 (PD-1) drugs and anti-programmed death ligand 1 (PD-L1) drugs, can block the inhibitory effect of tumor cells on immune cells by blocking the interaction between tumor cells expressing immune checkpoints and immune cells (19).

Most of these immunotherapy drugs exert anti-neoplastic effects by inhibiting the immune checkpoint PD-1/PD-L1 pathway. Concerning the mechanism of its occurrence, CD8⁺T cells express PD1 receptor, while tumor cells and peritumoral cells express their PD-L1, inactivating CD8⁺T cells and leading to immune tolerance (20). Hence, immunotherapy to reshape the tumor microenvironment and reverse tumor immune tolerance is a promising strategy for the treatment of unresectable HCC (21). There are many combinations of immunotherapy and targeted therapy, for example, since the Chinese brand names of lenvatinib plus pembrolizumab sounds like “Cola”, therefore, we usually call the regimen as “Cocacola band”. Two years ago, The Food and Drug Administration (FDA) has approved anti-PD-L1 drugs atezolizumab combined with anti-VEGF targeted drugs bevacizumab for first-line treatment of unresectable HCC.

The anti-tumor strategy based on immunotherapy combined with targeted therapy could prolong the tail of the survival curve, which was consistent with our results. The IMbrave150 research manifested that atezolizumab plus bevacizumab remarkably increased the survival time of patients by reducing the risk of death by 42% compared to sorafenib and increasing the 12 months OS to 67.2% compared to sorafenib's 54.6% (11).

Imperfectly, atezolizumab plus bevacizumab was not applied to the total population with unresectable HCC. The updated IMbrave150 recently showed that atezolizumab plus bevacizumab has limited benefit in high-risk patients (Vp4, and/or bile duct invasion and/or tumor occupancy of ≥ 50% of the liver) with a median OS of 7.6 months (22). Furthermore, the total cost of atezolizumab plus bevacizumab amounted to $95,928, significantly increasing the financial burden on patients (23).

In addition to Immunotherapy combined with targeted therapy, HAIC-FO is also worthy of consideration. FOLFOX is normally deemed to the most common first-line chemotherapy regimen for metastatic colorectal cancer and has been widely implemented in the treatment of colorectal cancer (24).

HAIC-FO is a local regional therapy that can deliver chemotherapy drugs directly to the tumor-associated artery branches in the case of increased local drug concentration to achieve the purpose of anti-tumor. Currently, HAIC-FO has been approved for the treatment of unresectable HCC and shown to be more effective than systemic chemotherapy under certain conditions (25), which is listed in the guidelines of the Pan-Asian-Operative European Society for Medical Oncology (26). In a phase III randomized clinical trial comparing HAIC-FO and sorafenib in the treatment of unresectable HCC (8), the median OS of the HAIC-FO group was better than the sorafenib group (13.9 months vs. 8.2 months). Furthermore, it is worth mentioning that the median OS was significantly longer with HAIC-FO than with sorafenib (10.8 months v 5.7 months) in high-risk subpopulations.

In our study, HAIC-FO was more effective than sorafenib at 6-18th months in OS and PFS. Mechanistically, (1) Oxaliplatin exerts its anti-tumour effects by platinum-adduct formation, binding to cellular proteins and possibly interfering with RNA synthesis as well (27). (2) 5-FU exerts its antitumor effects mainly through the inhibition of thymidylate synthase (TS) leading to disrupting the intracellular deoxynucleotide pools required for DNA replication, LV directly provides the activated form of folic acid in the body and increases the antitumor effect of 5-FU (28). Moreover, in our study, HAIC-FO was in the first-echelon regimens from the 6th to 18th months in OS and PFS and had a faster onset of action compared with sorafenib. From 2007 to 2018, sorafenib was the only first-line targeted agent of unresectable HCC, which had achieved considerable curative effect (29). While, the incidence of grade 3 or worse adverse events (AEs) of sorafenib was higher than HAIC-FO during therapeutic process; what is more, HAIC-FO has the superiority of the shorter treatment period and better compliance than the sorafenib (8). Due to these evidences, HAIC-FO could be selected as a sorafenib alternative of the first-line regimen in unresectable HCC.

Additionally, some other regimens also belong to the first-echelon in our study, Although the direct comparative study of lenvatinib versus sorafenib reported the longest OS and PFS, with the time up to 30 months, its comparative results were not statistically significant. The direct comparative study of HAIC-FO versus sorafenib reported the OS and PFS, with the time up to 18 months. Despite the follow-up time was not long, all results showed statistically significant. Another important point is that, in China, HAIC-FO is approximately $76,140 lower than the total cost of atezolizumab plus bevacizumab, which greatly reduces the financial burden of this patient and the pressure on medical insurance (30). Consequently, atezolizumab plus bevacizumab would not possibly be considered a cost-effective treatment option in unresectable HCC.

Donafenib, an oral small molecule multikinase inhibitor, is a deuterium derivative of sorafenib. In terms of drug mechanism, donafenib exerts its anti-neoplastic effect in two ways: (1) directly by inhibiting serine/threonine kinase and therefore blocking the Raf/MEK/ERK signal transmission pathway; (2) indirectly by inhibiting VEGFR and PDGFR, blocking tumour angiogenesis (31). In the field of safety, the incidence of drug-related grade ≥ 3 AEs was significantly lower with donafenib than sorafenib treatment (9). Although the current price of donafinib is high, it was only recently approved, there may be much room for price reductions in the future. A reduction in price in future will increase the probability of it being cost effective (32). In our study, the efficacy of donafenib is comparable to that of sorafenib at 6th month in OS. Nevertheless, at 24th and 30th months, donafenib showed better efficacy than sorafenib. Therefore, donafenib could give patients a longer and higher quality life expectancy compared to sorafenib. These findings indicated that although donafenib was not to show significant advantages to other regimens at 6th, 12th, 18th, months in OS, they may be related to better long-term survival benefits of some patients with unresectable HCC.

In accordance with these studies and our results, given the conducive findings in OS, PFS, safety, compliance, economic cost, onset time and drug maintenance time of patients, the optimal regimen we recommend is to treat with HAIC-FO until 18th month, followed by sequential therapy with donafenib.

The highlight of our study was the inclusion of several kinds of different first-line treatment regimens in unresectable HCC, covering a variety of therapeutic methods, including targeted therapy, immunotherapy and transarterial infusion of cytotoxic drugs. Taking six months as a node, we observed the OS and PFS by the first-line regimens at each node. However, the issue that still remains to be addressed in this study is whether sequential therapy with donafenib after treating with HAIC-FO requires an elution period or can be seamlessly integrated with HAIC-FO, because after treating with HAIC-FO, the tumor target and tumor biological behavior may be changed, and may affect the efficacy of donafenib. Hence, we look forward to more relevant studies to confirm this concept in the future.

Limitations

Firstly, most original studies did not fully report outcomes such as objective response rates (ORR) and time to progression (TTP). This led to the lack of richness of our study endpoints.

Secondly, patients in the original study had different tumor sites at baseline, which may have led to differences in response to treatment regimens.

Thirdly, owing to the limited number of studies that met our inclusion criteria, we were unable to perform subgroup analyses by the specific site of the tumor.

Lastly, there was no placebo in our study, so we could not determine whether any regimen was superior to placebo at certain time node, even it showed superiority over sorafenib.

Immunotherapy combined with targeted therapy, such as atezolizumab plus bevacizumab, as a novel therapeutic strategy to inhibit tumor growth activity, has excellent benefits for prolonging OS.

Notwithstanding, few drugs have been shown to improve unresectable HCC patients' long-term quality of life, therefore, after much deliberation on our part, considering the efficacy, safety, compliance, economic profiles, onset time and drug maintenance time collectively, the optimal regimen we recommend is treating with HAIC-FO until 18^th month, followed by sequential therapy with donafenib, which may maximize the longevity of unresectable HCC patients.

Conflicts of Interest

The authors have declared that no conflict of interest exists.

Author's Contribution：

Shan Jiang and Ximing Xu wrote the main manuscript text and Yangtao Xu, Xin Liu, Wenliang Chen prepared figures 1-3, table 1-3 and supplementary materials. All authors reviewed the manuscript.

Funding Declaration：

This study was supported by grants from the National Nature Science Foundation of China (No. 31971166).

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Table 1 Characteristics of included studies.
											Number of survival
			Sample	Median age，		Child–Pugh	ECOG performance	BCLC
Author	Year	Group	Size	years	Sex, M/F	(A/B)	status (0/1)	B/C	HBV	HCV	6 mths	12 mths	18 mths	24 mths	30 mths
Kudo et al. ^[6]	2018	Lenvatinib	478	/	405/73	475/3	304/174	104/374	251	91	388	269	201	151	108
		Sorafenib	476	/	401/75	471/5	301/175	92/384	228	126	361	245	182	134	110
Qin et al. ^[7]	2021	Atezolizumab plus Bevacizumab	133	57（29-82）	116/17	132/1	78/55	15/115	117	10	115	102	/	/	/
		Sorafenib	61	60（31-82）	49/12	61/0	31/30	3/57	47	7	39	27	/	/	/
Lyu et al. ^[8]	2022	HAIC-FO	130	54（45-61）	115/15	88/42	15/83	5/125	120	2	109	72	46	/	/
		Sorafenib	132	53（45-62）	123/9	93/39	14/95	9/123	114	4	90	35	7	/	/
Qin et al. ^[9]	2021	Donafenib	328	53（46-62）	281/47	324/4	127/201	42/286	293	7	244	166	116	86	67
		Sorafenib	331	53（46-61）	291/40	318/13	110/221	41/290	301	5	240	151	94	66	45
Yamashita et al. ^[10]	2020	Lenvatinib	81	/	65/16	81/0	76/5	31/50	23	37	66	51	39	32	23
		Sorafenib	87	/	72/15	87/0	75/12	34/53	19	49	74	53	42	27	18
Finn et al. ^[11]	2020	Atezolizumab plus Bevacizumab	336	64（56-71）	277/59	333/0	209/127	52/276	164	72	285	226	/	/	/
		Sorafenib	165	66（59-71）	137/28	165/0	103/62	26/133	76	36	120	90	/	/	/
Abbreviations: HAIC-FO, hepatic arterial infusion chemotherapy of infusional fluorouracil, leucovorin, and oxaliplatin; BCLC, Barcelona Clinic Liver Cancer; HBV, hepatitis B virus; HCV, hepatitis C virus.

Table 2. Odds ratios of first-line regimens compared with sorafenib at 6^thto 30^th months OS.
	Atezolizumab plus Bevacizumab	HAIC-FO	Donafenib	Lenvatinib
6 month	2.56(1.49,4.40)^*	2.42(1.13,5.19)^*	×	×
12 month	2.45(1.33,4.55)^*	3.44(1.47,8.04)^*	×	×
18 month	-	9.78(1.47,22.69)^*	×	×
24 month	-	-	1.43(0.99,2.06)^*	×
30 month	-	-	1.63(0.98,2.72)^*	×
*: first-echelon regimens.

Table 3. Odds ratios of first-line regimens compared with sorafenib at 6^thto 30^thmonths PFS.
	Atezolizumab plus Bevacizumab	HAIC-FO	Donafenib	Lenvatinib
6 month	2.07(1.49,2.87)*	3.53(2.12,5.88)*	1.68(1.17,2.41)	2.38(1.87,3.02)*
12 month	5.13(2.28,11.54)*	4.31(1.80,10.33)*	×	2.66(1.33,5.33)*
18 month	-	7.62(2.57,22.58)*	×	×
24 month	-	-	×	×
30 month	-	-	×	×
*: first-echelon regimens.

No competing interests reported.

supplementarymaterials.docx

Comparing the efficacy of five first-line treatment regimens for unresectable hepatocellular carcinoma: A network meta-analysis of randomized controlled trials

Status:

Version 1

Abstract

Figures

Introduction

Methods

Search strategy

Data extraction and quality assessment

Endpoint

Statistical analysis

Results

Characteristics and quality assessment of the included studies

The efficacy of first-line regimens compared with sorafenib

The first-echelon regimens compared to sorafenib from longitudinal prospective

Data consistency and small sample study effect

Discussion

Limitations

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1