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Abstract

Purpose

To evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with regorafenib (hereafter, TACE-regorafenib) or camrelizumab (hereafter, TACE-camrelizumab) for treating hepatocellular carcinoma (HCC) with untreatable progression after TACE and sorafenib therapy.

Methods

The medical records of patients with HCC who received TACE-regorafenib or TACE-camrelizumab between September 2018 and December 2023 were retrospectively evaluated. Therapeutic response, overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were compared between the two groups.

Results

A total of 76 patients were enrolled in this study, with 41 and 35 patients in the TACE-regorafenib and TACE-camrelizumab groups, respectively. The objective response rates in the TACE-regorafenib and TACE-camrelizumab groups were 9.8% and 8.6%, respectively, with no statistically significant difference between the two groups (P = 0.859). Similarly, there was no statistically significant difference in disease control rates between the two groups (61.0% vs 68.6%, P = 0.838). The median OS was 11 months in the TACE-regorafenib group and 10 months in the TACE-camrelizumab group, with no significant difference between the two groups (P = 0.348). The TACE-regorafenib group had a median PFS of 7 months, which was significantly longer than that of the TACE-camrelizumab group (4 months, P = 0.004). There was no significant difference in the incidence of AEs between the two groups (P = 0.544).

Conclusions

TACE-regorafenib was safe, well-tolerated, and showed promising efficacy in patients with sorafenib-refractory advanced HCC, whereas TACE–camrelizumab demonstrated similar survival benefits.

Keywords

hepatocellular carcinoma transarterial chemoembolization refractory regorafenib camrelizumab

Introduction

Primary liver cancer is the fourth leading cause of cancer-related deaths worldwide and is particularly prevalent in Asian countries.¹ Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancers and is a major global health problem.² Most patients are diagnosed at an advanced stage, although high-risk patients are regularly monitored by ultrasonography and alpha-fetoprotein levels. Patients with HCC have poor prognosis, with 5-year standardized survival rates ranging from 10%-20%.^3-5 Therefore, improvement in the prognosis of patients, particularly those with advanced HCC, is urgently needed.

Sorafenib, approved by the United States Food and Drug Administration (FDA) in 2007, is a first-line treatment for patients with advanced HCC, but it improves the median survival by 2-3 months.^6,7 However, the drug is associated with major toxicities, and approximately 30% of patients discontinue it due to intolerance.⁶ Hence, the exploration of second-line treatment after sorafenib therapy is an effective means to improve the survival of patients with advanced HCC. In 2017, the findings of the RESORCE study led to the approval of regorafenib by the United States FDA for patients with advanced HCC who were refractory or not amenable to sorafenib.⁸ In China, regorafenib has been approved as a second-line treatment for advanced HCC. China accounts for approximately 18% of the world’s population but reports more than 50% of HCC cases worldwide. Given the biological and clinical heterogeneity of HCC, exploring different treatment strategies or options is crucial to demonstrate the overall survival (OS) benefits.

In recent years, great progress has been made with immune checkpoint inhibitors (ICI) in the treatment of HCC. Camrelizumab, an anti-PD-1 monoclonal antibody, has been approved in China as a second-line treatment for unresectable HCC. In a phase 2 trial involving patients with previously treated HCC,⁹ camrelizumab provided a median OS and progression-free survival (PFS) of 13.8 months and 2.1 months, respectively, similar to the efficacy of nivolumab and pembrolizumab for advanced HCC. Tumors with a low mutation load and fewer neoantigens are generally less immunogenic and, therefore, less responsive to ICI. Transarterial chemoembolization (TACE) promotes tumor-specific CD8⁺ T-cell responses by killing HCC cells, causing the release of tumor-associated antigens, and ultimately promoting the immune response.¹⁰ Thus, TACE combined with camrelizumab (TACE-camrelizumab) may yield promising outcomes in patients with HCC who are refractory or intolerant to sorafenib. Therefore, this study aimed to compare the efficacy and safety of TACE combined with regorafenib (TACE-regorafenib) and TACE-camrelizumab in treating sorafenib-refractory HCC.

Materials and Methods

Study Design and Patient Selection

A retrospective analysis was conducted on all patients with HCC who received TACE regorafenib or camrelizumab at our center between September 2018 and December 2023. The criteria for patient selection were as follows: (1) age >18 years with HCC confirmed via pathological or clinical diagnosis according to the EASL criteria²; (2) refractory to TACE; (3) refractory or intolerant to sorafenib; (4) Child-Pugh class A or B; and (5) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The exclusion criteria were as follows: (1) concurrent ablation, resection, radiotherapy, or systemic therapies for HCC; (2) hepatic dysfunction (Child-Pugh class C) or renal impairment; (3) malignancies other than HCC; and (4) loss to follow-up.

Untreatable progression after TACE was defined as major progression (such as extensive hepatic involvement, extrahepatic metastasis, or vascular invasion) and minor intrahepatic progression associated with impaired liver function and performance status.^2,11,12 Sorafenib-refractory HCC was defined as two successive instances of radiological progression to confirm real disease progression and eliminate the possibility that sorafenib was ineffective due to insufficient treatment time.^13,14 Sorafenib intolerance was defined as the occurrence of grade 4 or higher hematological toxicities, grade 3 or higher non-hematological toxicities, or grade 2 or higher toxicities that were considered unacceptable by the investigator.¹⁵

This retrospective study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Ethics Committee of the Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (UHCT-IEC-SOP-006-02-01). The need for informed consent was waived by the Institutional Review Board because the clinical data were analyzed retrospectively and anonymously. The reporting of this study conforms to the STROBE guidelines,¹⁶ and all patient information was de-identified.

TACE Procedure

TACE was performed according to the institutional standard protocol as previously reported.^17,18 TACE was performed by placing a 5-F catheter (Cook, Bloomington, Indiana, USA) or a 2.7-F microcatheter (Progreat, Terumo, Tokyo, Japan) into the hepatic tumor donor arteries. First, an emulsion of 2-20 mL lipiodol (Lipiodol Ultra-Fluid; Laboratoire Andre Guerbet, Aulnay-sous-Bois, France) and 20-60 mg epirubicin was administered to the tumor vessels. The doses of lipiodol and epirubicin were determined based on tumor size, vascularity, presence of an arterioportal shunt, and underlying liver function. Next, the target vessels were embolized with gelatin sponge particles (350-560 μm or 560-710 μm, Alicon, Hangzhou, China). Embolization was performed under fluoroscopic guidance until arterial flow stasis was observed. Finally, reexamination angiography of the hepatic artery was performed to validate devascularization.

Treatment Protocol

In the present study, all treatment strategies were recommended by a multidisciplinary tumor board. All patients in this study had BCLC stage B at initial diagnosis and were treated with TACE; however, with an increase in the number of TACE procedures, patients developed untreatable progression. The patients were then treated with sorafenib as recommended; however, as the disease progressed, all patients developed refractoriness or intolerance to sorafenib. Subsequently, regorafenib or camrelizumab was recommended by the multidisciplinary tumor board as a second-line treatment for these patients.

Regorafenib (160 mg) was orally administered once daily, and the dose was reduced based on toxicity. If patients developed grade 3 or 4 adverse events (AEs), such as hematotoxicity, skin toxicity, gastrointestinal toxicity, and hypertension, the dose needed to be adjusted (80 or 120 mg once daily) or even discontinued until these AEs were alleviated or eliminated.

Camrelizumab was administered intravenously at a dose of 200 mg every 3 weeks. If patients experienced serious AEs, camrelizumab was interrupted or discontinued, and symptomatic treatment, such as glucocorticoids or immunosuppressant agents, was administered depending on the severity and the involved organs.

Follow-Up and Evaluation

All patients were followed-up until May 2024. Laboratory examinations, abdominal contrast-enhanced CT, and MR were performed every 6-8 weeks after the initial regorafenib or camrelizumab treatment. Abdominal contrast-enhanced CT or MR at 2-3 months after initial regorafenib or camrelizumab treatment was compared with pretreatment imaging to identify the objective response (ORR) and disease control rates (DCR) based on Modified Response Evaluation Criteria in Solid Tumors.¹⁹ ORR was defined as complete or partial response (CR or PR, respectively). The DCR was defined as complete response (CR), partial response (PR), or stable disease (SD).

OS was defined as the time from the start of regorafenib or camrelizumab treatment to death or the last follow-up. PFS was defined as the time interval from the initial regorafenib or camrelizumab treatment to the date of progression in patients who displayed radiologic evidence of disease progression, date of death, or last follow-up. AEs were recorded and assessed using The Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Furthermore, post-embolization syndromes, such as fever, pain, nausea, and vomiting, are not considered an AE in itself but rather an expected outcome of TACE therapy.²⁰

Statistical Analyses

All analyses were performed using SPSS software (version 24.0; IBM, Armonk, New York, USA), and statistical significance was set at P < 0.05. The chi-square, Student’s t-, and Mann–Whitney U tests were used to compare baseline characteristics between the two groups. OS and PFS were plotted using the Kaplan-Meier method. The univariate logistic regression was used to analyze the correlation between the postoperative fever and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the two groups. The 95% confidence interval (CI) was calculated for the median OS, median PFS, and hazard ratio (HR).

Results

Study Population and Patient Characteristics

In this study, 113 patients with HCC refractory or intolerant to sorafenib were treated with TACE-regorafenib or TACE-camrelizumab, of which 37 were excluded from the study because they did not meet the inclusion criteria, as shown in Figure 1. Seventy-six patients were enrolled in this study: 41 in the TACE-regorafenib group and 35 in the TACE-camrelizumab group. There were no significant differences in the baseline characteristics between the two groups (Table 1).

Figure 1.

Flow chart shows the screening procedure for sorafenib refractory advanced HCC patients treated with TACE-regorafenib or TACE-camrelizumab.

Table 1.

Baseline Characteristics.

Characteristics	TACE-Regorafenib Group (N = 41)(No, %; Mean ± SD)	TACE-Camrelizumab Group (N = 35)(No, %; Mean ± SD)	P Value
Gender			0.486
Male	34 (82.9%)	31 (88.6%)
Female	7 (17.1%)	4 (11.4%)
Age (years)	55.7 ± 10.2	54.9 ± 10.4	0.732
ECOG performance			0.385
0	17 (41.5%)	18 (51.4%)
1	24 (58.5%)	17 (48.6%)
Hepatitis			0.335
Hepatitis B	33 (80.5%)	31 (88.6%)
Other	8 (19.5%)	4 (11.4%)
Child-pugh score			0.084
A	12 (29.3%)	17 (48.6%)
B	29 (70.7%)	18 (51.4%)
TB (μmol/L)	17.4 ± 9.0	21.3 ± 10.9	0.094
Albumin (g/L)	34.7 ± 4.1	33.9 ± 3.7	0.371
PT(s)	14.0 ± 1.1	14.2 ± 1.8	0.401
AST (μmol/L)	47.5 ± 38.7	45.5 ± 27.2	0.798
ALT (μmol/L)	64.1 ± 62.9	62.6 ± 28.6	0.896
PLR	178.6 ± 124.1	152.6 ± 97.4	0.320
NLR	3.9 ± 3.9	3.4 ± 1.6	0.559
Tumor size (cm)	8.7 ± 4.3	8.4 ± 3.6	0.768
Tumor number			0.330
≤3	5 (12.2%)	2 (5.7%)
>3	36 (87.8%)	33 (94.3%)
α-Fetoprotein level			0.403
>400 ng/mL	16 (39.0%)	17 (48.6%)
≤400 ng/mL	25 (61.0%)	18 (51.4%)
Macrovascular invasion			0.085
Absent	17 (41.5%)	8 (22.9%)
Present	24 (58.5%)	27 (77.1%)
Extrahepatic spread			0.709
Absent	17 (41.5%)	16 (45.7%)
Present	24 (58.5%)	19 (54.3%)
Ascites			0.210
Absent	28 (68.3%)	19 (54.3%)
Present	13 (31.7%)	16 (45.7%)

Note. TACE: Transarterial chemoembolization; SD: Standard deviation; ECOG: Eastern Cooperative Oncology Group; TB: Total bilirubin; PT: Prothrombin time; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; PLR: Platelet-to-lymphocyte ratio; NLR: Neutrophil-to-lymphocyte ratio.

The median follow-up period for both the TACE-regorafenib and TACE-camrelizumab groups was 9 months (ranges, 3-20 months and 3-17 months, respectively). Twenty-six patients (63.4%) in the TACE-regorafenib group and twenty-three patients (65.7%) in the TACE-camrelizumab group died during the observation period.

Safety Assessment

In the TACE-regorafenib group, 23 patients (56.1%) developed fever (n = 14), abdominal pain (n = 10), and nausea and vomiting (n = 16) within 1 week of TACE. There was no significant correlation between postoperative fever and elevated ALT (P = 1.00) and AST (P = 0.295) levels. In the TACE-camrelizumab group, 20 patients (57.1%) developed fever (n = 13), abdominal pain (n = 9), and nausea and vomiting (n = 9) within 1 week of TACE. Similarly, postoperative fever was not significantly associated with elevated ALT (P = 0.405) or AST (P = 0.981) levels. All patients’ symptoms improved significantly after symptomatic treatment during hospitalization. Furthermore, no serious TACE-related AEs related to TACE such as liver abscesses or bilomas, were observed in this study.

AEs associated with regorafenib treatment are listed in Table 2. A total of 47 AEs occurred in 32 (78.0%) of 41 patients in the TACE-regorafenib group. In this study, six patients developed grade 3 AEs and none developed grade 4 or 5 AEs. The symptoms in these patients were relieved or eliminated after symptomatic treatment, drug reduction, or temporary discontinuation.

Table 2.

Adverse Events Related to Regorafenib Administration in the TACE-Regorafenib Group.

Adverse Event	All Events	CTCAE Grade
Adverse Event	All Events	1	2	≥3
Hand-foot skin reactions	26 (63.4%)	8 (19.5%)	16 (39.0%)	2 (11.1%)
Hypertension	9 (21.9%)	2 (4.9%)	5 (12.2%)	2 (4.9%)
Diarrhea	4 (9.8%)	2 (4.9%)	2 (4.9%)	0 (0%)
Fatigue	5 (12.2%)	1 (2.4%)	4 (9.8%)	0 (0%)
Increased bilirubin	3 (7.3%)	2 (4.9%)	0 (0%)	1 (2.4%)

Note. CTCAE: Common Terminology Criteria for Adverse Events.

The AEs associated with camrelizumab are shown in Table 3. During the follow-up period, 23 (71.9%) patients developed at least one type of AEs after camrelizumab treatment, and none of the patients developed severe AEs (grade >3). There was no significant difference in the incidence between the two groups (P = 0.544). In addition, one patient who developed myositis after camrelizumab treatment showed significant improvement after receiving glucocorticoids and temporarily discontinuing camrelizumab. In this study, no drug-related mortality was observed.

Table 3.

Adverse Events Related to Camrelizumab Administration in the TACE-Camrelizumab Group.

Adverse Event	All Events	CTCAE Grade
Adverse Event	All Events	1	2	≥3
RCCEP	15 (42.9%)	10 (28.6%)	5 (14.3%)	0 (0%)
Hypothyroidism	7 (20.0%)	5 (14.3%)	2 (5.7%)	0 (0%)
Asthenia	4 (11.4%)	2 (5.7%)	2 (5.7%)	0 (0%)
Rash	4 (11.4%)	1 (2.8%)	3 (8.6%)	0 (0%)
Myositis	1 (2.8%)	0 (0%)	1 (2.8%)	0 (0%)

Note. CTCAE: Common Terminology Criteria for Adverse Events; RCCEP: Reactive cutaneous capillary endothelial proliferation.

Treatment Response

In the TACE-regorafenib group, no patients achieved CR, 4 (9.8%) achieved PR, and 25 (61.0%) achieved SD. Therefore, the ORR and DCR were 9.8% and 70.7%, respectively. Similarly, in the TACE-camrelizumab group, no patients achieved CR, 3 patients achieved PR (8.6%), and 21 patients (60.0%) achieved SD. The ORR and DCR in the TACE-camrelizumab group were 8.6% and 68.6%, respectively. There was no significant difference in the ORR (P = 0.859) or DCR (P = 0.838) between the two groups.

Survival

In the TACE-regorafenib group, the median OS was 11 months (95%CI: 8.9 months, 13.1 months) (Figure 2). In the TACE-camrelizumab group, the median OS was 10 months (95%CI: 7.5 months, 12.5 months) (P = 0.348). Median PFS was 7 months (95%CI: 5.3 months, 8.7 months) in the TACE-regorafenib group and 4 months (95%CI: 2.4 months, 5.6 months) in the TACE-camrelizumab group (Figure 3) (P = 0.004).

Figure 2.

Kaplan-Meier curves of cumulative survival in sorafenib refractory advanced HCC patients treated with TACE-regorafenib or TACE-camrelizumab.

Figure 3.

Kaplan-Meier curves of cumulative PFS in sorafenib refractory advanced HCC patients treated with TACE-regorafenib or TACE-camrelizumab.

Discussion

Results from two randomized controlled trials indicated that most patients did not respond to sorafenib, and more than half of the patients were resistant to sorafenib.^6,7 Hence, the management of sorafenib-refractory advanced HCC is a priority because these patients have a very poor prognosis. In this study, we compared the efficacy of two second-line treatments in patients with sorafenib-resistant advanced HCC refractory to sorafenib. The most important finding of this study was that both treatments significantly improved the median OS and PFS in these patients.

Specifically, in the present study, the median OS of patients in the TACE-regorafenib group was 11 months, higher than the median OS reported by Goldstein (median OS: 6.3 months) and Ogasawara (median OS: 7.2 months) for patients with sorafenib-refractory advanced HCC.^21,22 This was longer than that reported by Zhang et al (median OS: 8 months),²³ which may be due to the combination of TACE and regorafenib used in this study. Previous studies have shown that TACE combined with sorafenib or apatinib demonstrates good efficacy in the treatment of advanced HCC^24,25; however, no study has reported the efficacy of TACE-regorafenib. The results of this study suggest that TACE with regorafenib can improve treatment efficacy in patients with advanced HCC.

A recent meta-analysis indicated that regorafenib is the best second-line treatment.²⁶ The present study also confirmed the efficacy of regorafenib and the similar efficacies of TACE-camrelizumab and TACE-regorafenib. Camrelizumab has high affinity for PD-1, a high receptor occupancy rate for circulating T lymphocytes, and a different binding epitope than nivolumab and pembrolizumab.²⁷ In addition, changes in T cell populations after TACE have been demonstrated, providing an impetus for exploring immunotherapy after TACE.^28,29 Based on these advantages, this preliminary study confirmed the efficacy of TACE-camrelizumab in patients with advanced HCC refractory to sorafenib treatment.

In recent years, research on ICI combined with targeted therapies for HCC has been in full swing. NCCN Clinical Practice Guidelines in Hepatobiliary Cancers clearly stated that atezolizumab combined with bevacizumab is the first-line therapy for HCC, which marks the beginning of the immunological era of first-line therapy for advanced HCC. The mechanism of the combined treatment of HCC is that proangiogenic factors, especially VEGF, can interfere with the activation, infiltration, and function of T cells, thereby destroying the anticancer immune response. Therefore, VEGF-mediated immunosuppression provides a solid therapeutic basis for ICI in combination with antiangiogenic drugs.³⁰ Hence, for patients with sorafenib intolerance, ICI combined with targeted therapy and TACE therapy may further improve the efficacy in patients with HCC, which is also worthy of further study.

The safety of regorafenib and camrelizumab for HCC treatment is also a concern, especially in patients with advanced HCC who develop untreatable progression after TACE and sorafenib treatment. Similar to a report by Bruix,⁸ hand-foot skin reactions, hypertension, diarrhea, and fatigue were the most common AEs, most of which were grade 1 or 2. Symptoms improved significantly after symptomatic treatment. Unlike nivolumab and pembrolizumab, reactive cutaneous capillary endothelial proliferation (RCCEP) is more common after camrelizumab treatment.³¹ In this study, seven patients developed RCCEP, which was the most common AEs in the TACE-camrelizumab group. In addition, the incidence of AEs in the TACE-regorafenib group was higher than that in the TACE-camrelizumab group, although the difference was not statistically significant. Compared with the TACE-regorafenib group, patients in the TACE-camrelizumab group did not develop severe AEs (grade 3 or above). Thus, the present study indicated that TACE-camrelizumab treatment for patients with advanced HCC refractory to sorafenib was relatively safe.

This retrospective study has several limitations. First, it was conducted at a single institution with a small sample size. Granito et al³² showed that transient aminotransferase elevation after TACE was associated with an objective radiological response; however, this study failed to reach similar conclusions because of the small sample size. Consequently, to increase the generalizability of the results of this study, an adequately powered prospective randomized trial is necessary. Second, in the TACE–camrelizumab group, more than half of the patients had no outcome events by the end of the study; therefore, it is necessary to explore its long-term efficacy in patients. Third, patients and tumors may have different characteristics in different countries. Larger studies or meta-analyses in different regions are required to demonstrate the efficacy of TACE regorafenib and camrelizumab in treating patients with advanced HCC refractory to sorafenib.

Conclusion

In conclusion, TACE-regorafenib may have promising efficacy and tumor control in patients with advanced sorafenib-refractory HCC, whereas TACE–camrelizumab has demonstrated similar survival benefits.

Footnotes

Acknowledgments

We are very grateful to Ms. Tingting Qin for her help in the statistical analysis of this study.

Author Contributions

Yanqiao Ren, PhD and Yiming Liu, PhD contributed equally to this article. Y.R., Y.L., conceived and designed the project. Y.R., Y.L., collected the data. S.S. and C.Z. analyzed and interpreted the data. Y.R. and Y.L. drafted the manuscript. S.S. and C.Z. revised the manuscript. All authors read and approved the final manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the grants from National Key R&D Program of China (No.2023YFC2413500) and National Natural Science Foundation of China (No.81873919).

Ethical Statement

Data Availability Statement

All data that support the findings of this study are available from the corresponding author on reasonable request.*

Appendix

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Efficacy and Safety of TACE Combined with Regorafenib versus TACE Combined with Camrelizumab in Hepatocellular Carcinoma With Untreatable Progression After TACE Combined with Sorafenib Therapy: A Case Control Study

Abstract

Purpose

Methods

Results

Conclusions

Keywords

Introduction

Materials and Methods

Study Design and Patient Selection

TACE Procedure

Treatment Protocol

Follow-Up and Evaluation

Statistical Analyses

Results

Study Population and Patient Characteristics

Safety Assessment

Treatment Response

Survival

Discussion

Conclusion

Footnotes

Acknowledgments

Author Contributions

Declaration of Conflicting Interests

Funding

Ethical Statement

Data Availability Statement

Appendix

References