https://orcid.org/0000-0002-2435-1417
Abstract
To compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with sorafenib and camrelizumab or with sorafenib alone in patients with intermediate or advanced hepatocellular carcinoma (HCC).
We retrospectively analysed 78 patients with intermediate or advanced HCC who were treated at our centres between January 2018 and December 2021. Twenty-six of them received sorafenib and camrelizumab plus TACE (the TACE + Sor + C group), while 52 received TACE and sorafenib (the TACE + Sor group). Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were evaluated. Univariate and multivariate analyses were used to determine the factors affecting survival.
The median OS (22 vs 10 months, P < .001) and median PFS (11 vs 6 months, P = .008) of the TACE + Sor + C group were significantly higher than those of the TACE + Sor group. Multivariate analysis showed that compared with TACE + Sor + C, TACE + Sor increased the risk of all-cause mortality and tumour progression. For grade I and II AEs, the incidence of skin capillary hyperplasia and hypothyroidism in the TACE + Sor + C group was significantly higher than that in the TACE + Sor group. For serious AEs (grade III or IV), there was no significant difference in any adverse reaction between the 2 groups (P > .05).
Patients with intermediate or advanced HCC appeared to benefit more in terms of survival from TACE + Sor + C than from TACE + Sor, and the AEs were tolerable.
(1) Subgroup analysis demonstrated that TACE + sorafenib + camrelizumab could benefit HCC patients regardless of whether they had portal vein tumour thrombosis, Barcelona Clinic Liver Cancer B or C, or CHILD A or B; (2) We reported the immunotherapy-related AEs occurred with a significantly higher incidence in triple treatment, but all the AEs are tolerable.
Introduction
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide and accounts for 75%-85% of primary liver cancers.1,2 Early-stage HCC can be curatively treated by local ablation, surgical resection, or liver transplantation.3 Despite advances in early detection, 70% of new patients are diagnosed with intermediate or advanced HCC and thus miss the opportunity for curative resection.4,5 Transcatheter arterial chemoembolization (TACE) and systemic therapy are the standard treatments for intermediate- and advanced-stage HCC, respectively.6–8
TACE has remained the standard treatment for patients with intermediate HCC for >15 years, prolonging patients’ overall survival (OS) and progression-free survival (PFS) compared with the best supportive care.9 However, the complete embolization rate of TACE is low, and incomplete embolization causes tumours to produce hypoxia-inducible factors and other related factors that promote tumour angiogenesis and metastasis and result in tumour recurrence and metastasis.10 Therefore, combination therapy strategies are needed to further mitigate the insufficiency of TACE and improve its survival benefit in patients.
Molecularly targeted drugs have been the first-line treatment for patients with advanced liver cancer in the past 10 years; however, some patients have low response rates, resulting in poor efficacy of molecularly targeted drugs.11 In addition, immune checkpoint inhibitors (ICIs) have rapidly progressed in the treatment of HCC, but monotherapy with programmed cell death protein-1 (PD-1) antibody only caused tumour regression in 20% of patients.12 Molecularly targeted drugs combined with immunotherapy have been widely used for the treatment of unresectable HCC in recent years and resulted in better OS and PFS outcomes compared with molecularly targeted drug monotherapy.13 However, few studies have focused on the clinical experience of a triple therapy (TACE + molecularly targeted drugs + ICIs).14,15
Sorafenib, a multiple-target tyrosine kinase inhibitor (TKI), exerts antiangiogenesis and antiproliferation effects and extends total median survival in patients with advanced HCC.16 The TACTICS (Transcatheter Arterial Chemoembolization Therapy in Combination with Sorafenib) study demonstrated that concurrent sorafenib therapy might delay tumour progression following TACE.17 Camrelizumab (Nanjing, China, AiRuiKa™) is a selective, humanized, high-affinity IgG4 kappa mAb against PD-1 developed by Jiangsu Hengrui Medicine Co. Ltd (Jiangsu Hengrui Medicine, Jiangsu, China). Camrelizumab shows promising antitumor activity and manageable toxicities and offers a new second-line drug option for patients with advanced HCC18
This retrospective study aimed to investigate the safety and efficacy of TACE + sorafenib + camrelizumab (TACE + Sor + C) and compare them with those of TACE and sorafenib in patients with intermediate or advanced HCC.
Methods
Patients and study design
This study retrospectively enrolled and analysed 78 patients with unresectable HCC who received TACE combined with sorafenib alone (TACE + Sor) or with sorafenib and camrelizumab (TACE + Sor + C) at Our centres between January 2018 and December 2021. This study was approved by the ethics committees of both hospitals, and since this was a retrospective study, the need for obtaining patients’ informed consent was waived by the ethics committees.
The inclusion criteria were as follows: (1) patients diagnosed with intermediate or advanced liver cancer by imaging and laboratory tests; (2) patients who received TACE + Sor or TACE + Sor + C; (3) patients who did not receive TACE, molecularly targeted drugs, or immunotherapy before inclusion in this study; (4) patients with an Eastern Cooperative Oncology Group score of 0 or 1; and (5) patients with a Child-Pugh classification of class A or B.
The exclusion criteria were as follows: (1) patients with diffuse liver cancer that could not be assessed; (2) patients with platelet count <60 × 109/L; and (3) patients lost to follow-up (Figure 1).
The flowchart of patient selection. Abbreviations: TACE + Sor = transcatheter arterial chemoembolization with sorafenib; TACE + Sor + C = transcatheter arterial chemoembolization with sorafenib plus camrelizumab.
TACE procedure
TACE was conducted by specialists with at least 8 years of experience in the procedures. Under local anaesthesia (induced using 1% lidocaine), the right femoral artery was punctured, a sheath was placed, a 5-F catheter (Cook, Bloomington, IN, United States) was introduced through the arterial sheath, and celiac or superior mesenteric arteriography was performed to assess arterial anatomy, tumour supply vessels, and portal vein patency. Subsequently, through the 5-F catheter, a 2.6-F microcatheter (Terumo, Japan) was introduced and the tumour-feeding arteries were superselected. The microcatheter was then sent to the port of the feeding artery of the tumour, and an emulsion of 10-20 mL of lipiodol (Lipiodol Ultrafluido, Guerbet, France) mixed with 20-40 mg of doxorubicin hydrochloride (Hisun Pharmaceutical Co. Ltd, Zhejiang, China) was slowly injected into the tumour-feeding artery. Gelatin sponge particles (300-500 µm; Cook) mixed with a contrast agent were injected into the tumour-feeding arteries until the arteries were no longer visible after angiography.
Sorafenib and ICI administration
Sorafenib (400 mg/time, twice a day) and camrelizumab were administered within 1 week after TACE. Dosage adjustment was made for sorafenib based on patient tolerance to it. If a patient developed serious adverse reactions (grade III or IV) after taking sorafenib, the dose was adjusted to 400 mg/day until the adverse reactions were relieved, after which the dose was readjusted back to normal. The patients received 200 mg of camrelizumab intravenously once every 3 weeks. The administration of sorafenib and camrelizumab should be stopped when no clinical benefits are observed or when unacceptable toxicity occurs.13
Outcomes
The end points of this study were OS and PFS. PFS was defined as the time from the initiation of treatment until the first tumour progression (based on the mRECIST criteria),19 until death was confirmed, or until the last follow-up in censored data. OS was defined as the time from the initiation of treatment until death or the last follow-up in the censored data.
Adverse events (AEs) were monitored and recorded by experienced nurses who were blinded to the treatment, and all AEs related to treatment were recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.20
Follow-Up
All patients included in this study were followed up within 3 months after receiving TACE, once a month, and then every 2-3 months. At each follow-up visit, the patient’s laboratory and imaging findings were recorded. The imaging findings of the patients were independently assessed by an interventional physician (with 30 years of interventional diagnosis and treatment experience) and a radiologist (with 10 years of experience in diagnostic imaging readings). If a patient had a residual tumour or new tumour lesions in the liver during follow-up, TACE was recommended again. The end time of follow-up was June 30, 2022.
Statistical analysis
Continuous variables at baseline for the 2 groups were compared using the Student t-test or Mann-Whitney U test, and categorical variables were compared using the chi-square or Fisher’s exact test. The survival curve was drawn using the Kaplan-Meier method, and the OS and PFS of the 2 groups were compared using log-rank tests. Cox regression models were used for the evaluation. Factors with P-values no more than .05 in univariate analysis were included in multivariate analysis. Differences were considered statistically significant when the bilateral P-value was ≤.05. All statistical analyses were conducted using SPSS version 24.0.
Results
Patient demographics and clinical characteristics
A total of 98 patients (58 in the A centre and 40 in the B centre) with intermediate- or advanced-stage HCC who received TACE + Sor + C (n = 32) or TACE + Sor (n = 66) between January 2018 and December 2021 were considered for inclusion in this study. Twenty patients (6 in the TACE + Sor + C group and 14 in the TACE + Sor group) were excluded because they met the exclusion criteria (Figure 1). Ultimately, 78 patients were included in this study (TACE + Sor + C group, n = 26; TACE + Sor group, n = 52). The baseline characteristics of the 2 groups were not significantly different (Table 1).
Baseline characteristics of 2 groups.
| Characteristics | TACE + Sor + C (n = 26) | TACE + Sor (n = 52) | P-value |
|---|---|---|---|
| Age (years) | 52.2 ± 11.9 | 52.7 ± 10.5 | .782 |
| ALT (U/L) | 43.5 ± 28.7 | 57.4 ± 79.7 | .391 |
| AST (U/L) | 69 ± 85.5 | 74.2 ± 89.0 | .808 |
| TB (µmol/L) | 16.8 ± 9.6 | 22.0 ± 19.8 | .212 |
| Albumin (g/L) | 36.6 ± 4.6 | 37.6 ± 5.9 | .461 |
| PLT | 191.7 ± 112.1 | 155.2 ± 69.6 | .180 |
| Tumour size (cm) | 9.2 ± 5.3 | 8.2 ± 4.5 | .395 |
| Sex | >.999 | ||
| Male | 23 | 46 | |
| Female | 3 | 6 | |
| HBV infection | .722 | ||
| Yes | 18 | 38 | |
| No | 8 | 14 | |
| Number of tumours | .252 | ||
| 1 | 8 | 23 | |
| ≥2 | 18 | 29 | |
| BCLC stage | .732 | ||
| B | 9 | 16 | |
| C | 17 | 36 | |
| Cirrhosis | .411 | ||
| Yes | 19 | 31 | |
| No | 7 | 21 | |
| Ascites | .396 | ||
| Yes | 7 | 19 | |
| No | 19 | 33 | |
| Portal vein invasion | .421 | ||
| Yes | 10 | 25 | |
| No | 16 | 27 | |
| Extrahepatic metastases | .200 | ||
| Yes | 12 | 28 | |
| No | 14 | 24 | |
| AFP (ng/mL) | .747 | ||
| <400 | 14 | 30 | |
| ≥400 | 12 | 22 | |
| Child-Pugh | >.999 | ||
| A | 21 | 42 | |
| B | 5 | 10 | |
| ECOG performance | .107 | ||
| 0 | 15 | 20 | |
| 1 | 11 | 32 |
| Characteristics | TACE + Sor + C (n = 26) | TACE + Sor (n = 52) | P-value |
|---|---|---|---|
| Age (years) | 52.2 ± 11.9 | 52.7 ± 10.5 | .782 |
| ALT (U/L) | 43.5 ± 28.7 | 57.4 ± 79.7 | .391 |
| AST (U/L) | 69 ± 85.5 | 74.2 ± 89.0 | .808 |
| TB (µmol/L) | 16.8 ± 9.6 | 22.0 ± 19.8 | .212 |
| Albumin (g/L) | 36.6 ± 4.6 | 37.6 ± 5.9 | .461 |
| PLT | 191.7 ± 112.1 | 155.2 ± 69.6 | .180 |
| Tumour size (cm) | 9.2 ± 5.3 | 8.2 ± 4.5 | .395 |
| Sex | >.999 | ||
| Male | 23 | 46 | |
| Female | 3 | 6 | |
| HBV infection | .722 | ||
| Yes | 18 | 38 | |
| No | 8 | 14 | |
| Number of tumours | .252 | ||
| 1 | 8 | 23 | |
| ≥2 | 18 | 29 | |
| BCLC stage | .732 | ||
| B | 9 | 16 | |
| C | 17 | 36 | |
| Cirrhosis | .411 | ||
| Yes | 19 | 31 | |
| No | 7 | 21 | |
| Ascites | .396 | ||
| Yes | 7 | 19 | |
| No | 19 | 33 | |
| Portal vein invasion | .421 | ||
| Yes | 10 | 25 | |
| No | 16 | 27 | |
| Extrahepatic metastases | .200 | ||
| Yes | 12 | 28 | |
| No | 14 | 24 | |
| AFP (ng/mL) | .747 | ||
| <400 | 14 | 30 | |
| ≥400 | 12 | 22 | |
| Child-Pugh | >.999 | ||
| A | 21 | 42 | |
| B | 5 | 10 | |
| ECOG performance | .107 | ||
| 0 | 15 | 20 | |
| 1 | 11 | 32 |
Abbreviations: AFP = a-fetoprotein; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BCLC Barcelona Clinic Liver Cancer; ECOG = Eastern Cooperative Oncology Group; HBV = hepatitis B virus; PLT = platelet; TACE = transcatheter arterial chemoembolization; TACE + Sor + C = transcatheter arterial chemoembolization with sorafenib plus camrelizumab; TACE + Sor = transcatheter arterial chemoembolization with sorafenib; TB = total bilirubin.
Baseline characteristics of 2 groups.
| Characteristics | TACE + Sor + C (n = 26) | TACE + Sor (n = 52) | P-value |
|---|---|---|---|
| Age (years) | 52.2 ± 11.9 | 52.7 ± 10.5 | .782 |
| ALT (U/L) | 43.5 ± 28.7 | 57.4 ± 79.7 | .391 |
| AST (U/L) | 69 ± 85.5 | 74.2 ± 89.0 | .808 |
| TB (µmol/L) | 16.8 ± 9.6 | 22.0 ± 19.8 | .212 |
| Albumin (g/L) | 36.6 ± 4.6 | 37.6 ± 5.9 | .461 |
| PLT | 191.7 ± 112.1 | 155.2 ± 69.6 | .180 |
| Tumour size (cm) | 9.2 ± 5.3 | 8.2 ± 4.5 | .395 |
| Sex | >.999 | ||
| Male | 23 | 46 | |
| Female | 3 | 6 | |
| HBV infection | .722 | ||
| Yes | 18 | 38 | |
| No | 8 | 14 | |
| Number of tumours | .252 | ||
| 1 | 8 | 23 | |
| ≥2 | 18 | 29 | |
| BCLC stage | .732 | ||
| B | 9 | 16 | |
| C | 17 | 36 | |
| Cirrhosis | .411 | ||
| Yes | 19 | 31 | |
| No | 7 | 21 | |
| Ascites | .396 | ||
| Yes | 7 | 19 | |
| No | 19 | 33 | |
| Portal vein invasion | .421 | ||
| Yes | 10 | 25 | |
| No | 16 | 27 | |
| Extrahepatic metastases | .200 | ||
| Yes | 12 | 28 | |
| No | 14 | 24 | |
| AFP (ng/mL) | .747 | ||
| <400 | 14 | 30 | |
| ≥400 | 12 | 22 | |
| Child-Pugh | >.999 | ||
| A | 21 | 42 | |
| B | 5 | 10 | |
| ECOG performance | .107 | ||
| 0 | 15 | 20 | |
| 1 | 11 | 32 |
| Characteristics | TACE + Sor + C (n = 26) | TACE + Sor (n = 52) | P-value |
|---|---|---|---|
| Age (years) | 52.2 ± 11.9 | 52.7 ± 10.5 | .782 |
| ALT (U/L) | 43.5 ± 28.7 | 57.4 ± 79.7 | .391 |
| AST (U/L) | 69 ± 85.5 | 74.2 ± 89.0 | .808 |
| TB (µmol/L) | 16.8 ± 9.6 | 22.0 ± 19.8 | .212 |
| Albumin (g/L) | 36.6 ± 4.6 | 37.6 ± 5.9 | .461 |
| PLT | 191.7 ± 112.1 | 155.2 ± 69.6 | .180 |
| Tumour size (cm) | 9.2 ± 5.3 | 8.2 ± 4.5 | .395 |
| Sex | >.999 | ||
| Male | 23 | 46 | |
| Female | 3 | 6 | |
| HBV infection | .722 | ||
| Yes | 18 | 38 | |
| No | 8 | 14 | |
| Number of tumours | .252 | ||
| 1 | 8 | 23 | |
| ≥2 | 18 | 29 | |
| BCLC stage | .732 | ||
| B | 9 | 16 | |
| C | 17 | 36 | |
| Cirrhosis | .411 | ||
| Yes | 19 | 31 | |
| No | 7 | 21 | |
| Ascites | .396 | ||
| Yes | 7 | 19 | |
| No | 19 | 33 | |
| Portal vein invasion | .421 | ||
| Yes | 10 | 25 | |
| No | 16 | 27 | |
| Extrahepatic metastases | .200 | ||
| Yes | 12 | 28 | |
| No | 14 | 24 | |
| AFP (ng/mL) | .747 | ||
| <400 | 14 | 30 | |
| ≥400 | 12 | 22 | |
| Child-Pugh | >.999 | ||
| A | 21 | 42 | |
| B | 5 | 10 | |
| ECOG performance | .107 | ||
| 0 | 15 | 20 | |
| 1 | 11 | 32 |
Abbreviations: AFP = a-fetoprotein; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BCLC Barcelona Clinic Liver Cancer; ECOG = Eastern Cooperative Oncology Group; HBV = hepatitis B virus; PLT = platelet; TACE = transcatheter arterial chemoembolization; TACE + Sor + C = transcatheter arterial chemoembolization with sorafenib plus camrelizumab; TACE + Sor = transcatheter arterial chemoembolization with sorafenib; TB = total bilirubin.
Survival analysis
The median follow-up period was 15.6 (range 2.0-26.1) months, with a median follow-up time of 16.0 months (range 3.0-26.0) in the TACE + Sor + C group and 9.0 months (range 2.0-23.0) in the TACE + Sor group. During follow-up, 14 (53.8%) and 39 (75.0%) patients in the TACE + Sor + C and TACE + Sor groups died, respectively. The median OS (mOS) and median PFS (mPFS) of patients who received TACE + Sor + C were significantly higher than those of patients who received TACE + Sor. The mOS was 22 months (95% CI: 17.8-26.2) in the TACE + Sor + C group and 10 months (95% CI: 7.6-12.6) in the TACE + Sor group (P < .001). The mPFS was 11 months (95% CI: 9.1-12.9) in the TACE + Sor + C group and 6 months (95% CI: 4.3-7.7) in the TACE + Sor group (P = .008) (Figure 2).
The Kaplan-Meier (KM) curves for patients with intermediate or advanced hepatocellular carcinoma who received the treatment of TACE + Sor + C or TACE + Sor. (A) The KM curves of overall survival time; (B) the KM curves of progression-free time. Abbreviations: mOS = median overall survival; mPFS = median progression-free survival; TACE + Sor = transcatheter arterial chemoembolization with sorafenib; TACE + Sor + C = transcatheter arterial chemoembolization with sorafenib plus camrelizumab.
In univariate analysis, the potential factors associated with OS and PFS included portal vein invasion, extrahepatic metastasis, and treatment. In multivariate analysis, 3 independent factors affecting OS were identified: portal vein invasion (hazard ratio [HR]: 0.162; 95% CI: 0.076-0.348; P < .001), extrahepatic metastasis (HR: 0.556; 95% CI: 0.312-0.993; P = .047), and treatment (HR: 7.174; 95% CI: 3.175-16.214; P < .001) (Table 2). Two independent factors also affected PFS: portal vein invasion (HR: 0.228; 95% CI: 0.125-0.415; P < .001) and treatment (HR: 2.972; 95% CI: 1.655-5.339; P < .001) (Table 3).
Univariate and multivariate analyses of prognostic factors for OS.
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Variable | HR (95% CI) | P-value | HR (95% CI) | P-value |
| Age (years) | 1.021 (0.994-1.048) | .135 | ||
| ALT | 0.999 (0.994-1.005) | .793 | ||
| AST | 1.001 (0.998-1.005) | .445 | ||
| TB | 0.986 (0.960-1.013) | .300 | ||
| Albumin | 0.974 (0.927-1.024) | .303 | ||
| PLT | 0.999 (0.996-1.002) | .688 | ||
| Tumour size (cm) | 1.019 (0.973-1.069) | .422 | ||
| Sex | ||||
| Male | 1 | |||
| Female | 1.428 (0.669-3.048) | .357 | ||
| HBV infection | ||||
| Yes | 1 | |||
| No | 0.885 (0.482-1.626) | .693 | ||
| Number of tumours | ||||
| 1 | 1 | |||
| ≥2 | 1.352 (0.767-2.383) | .297 | ||
| BCLC stage | ||||
| B | 1 | |||
| C | 1.615 (0.845-3.084) | .147 | ||
| Cirrhosis | ||||
| Yes | 1 | |||
| No | 1.027 (0.567-1.860) | .930 | ||
| Ascites | ||||
| Yes | 1 | |||
| No | 1.030 (0.570-1.863) | .922 | ||
| Portal vein invasion | ||||
| Yes | 1 | 1 | ||
| No | 0.312 (0.176-0.552) | <.001 | 0.162 (0.076-0.348) | <.001 |
| Extrahepatic metastasis | ||||
| Yes | 1 | 1 | ||
| No | 0.462 (0.265-0.805) | .006 | 0.556 (0.312-0.993) | .047 |
| AFP | ||||
| <400 | 1 | |||
| ≥400 | 1.268 (0.731-2.199) | .399 | ||
| Child-Pugh | ||||
| A | 1 | |||
| B | 1.109 (0.568-2.163) | .762 | ||
| ECOG performance | ||||
| 0 | 1 | |||
| 1 | 1.416 (0.817-2.454) | .216 | ||
| Treatment | ||||
| TACE + Sor + C | 1 | 1 | ||
| TACE + Sor | 3.757 (1.899-7.434) | <.001 | 7.174 (3.175-16.214) | <.001 |
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Variable | HR (95% CI) | P-value | HR (95% CI) | P-value |
| Age (years) | 1.021 (0.994-1.048) | .135 | ||
| ALT | 0.999 (0.994-1.005) | .793 | ||
| AST | 1.001 (0.998-1.005) | .445 | ||
| TB | 0.986 (0.960-1.013) | .300 | ||
| Albumin | 0.974 (0.927-1.024) | .303 | ||
| PLT | 0.999 (0.996-1.002) | .688 | ||
| Tumour size (cm) | 1.019 (0.973-1.069) | .422 | ||
| Sex | ||||
| Male | 1 | |||
| Female | 1.428 (0.669-3.048) | .357 | ||
| HBV infection | ||||
| Yes | 1 | |||
| No | 0.885 (0.482-1.626) | .693 | ||
| Number of tumours | ||||
| 1 | 1 | |||
| ≥2 | 1.352 (0.767-2.383) | .297 | ||
| BCLC stage | ||||
| B | 1 | |||
| C | 1.615 (0.845-3.084) | .147 | ||
| Cirrhosis | ||||
| Yes | 1 | |||
| No | 1.027 (0.567-1.860) | .930 | ||
| Ascites | ||||
| Yes | 1 | |||
| No | 1.030 (0.570-1.863) | .922 | ||
| Portal vein invasion | ||||
| Yes | 1 | 1 | ||
| No | 0.312 (0.176-0.552) | <.001 | 0.162 (0.076-0.348) | <.001 |
| Extrahepatic metastasis | ||||
| Yes | 1 | 1 | ||
| No | 0.462 (0.265-0.805) | .006 | 0.556 (0.312-0.993) | .047 |
| AFP | ||||
| <400 | 1 | |||
| ≥400 | 1.268 (0.731-2.199) | .399 | ||
| Child-Pugh | ||||
| A | 1 | |||
| B | 1.109 (0.568-2.163) | .762 | ||
| ECOG performance | ||||
| 0 | 1 | |||
| 1 | 1.416 (0.817-2.454) | .216 | ||
| Treatment | ||||
| TACE + Sor + C | 1 | 1 | ||
| TACE + Sor | 3.757 (1.899-7.434) | <.001 | 7.174 (3.175-16.214) | <.001 |
Abbreviations: AFP = alpha-fetoprotein; ALT = alanine transaminase; AST = aspartate aminotransferase; BCLC = Barcelona Clinic Liver Cancer; HBV = hepatitis B; HR = hazard ratio; OS = overall survival; PLT = platelet; TACE + Sor = transcatheter arterial chemoembolization with sorafenib; TACE + Sor + C = transcatheter arterial chemoembolization with sorafenib plus camrelizumab.
Univariate and multivariate analyses of prognostic factors for OS.
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Variable | HR (95% CI) | P-value | HR (95% CI) | P-value |
| Age (years) | 1.021 (0.994-1.048) | .135 | ||
| ALT | 0.999 (0.994-1.005) | .793 | ||
| AST | 1.001 (0.998-1.005) | .445 | ||
| TB | 0.986 (0.960-1.013) | .300 | ||
| Albumin | 0.974 (0.927-1.024) | .303 | ||
| PLT | 0.999 (0.996-1.002) | .688 | ||
| Tumour size (cm) | 1.019 (0.973-1.069) | .422 | ||
| Sex | ||||
| Male | 1 | |||
| Female | 1.428 (0.669-3.048) | .357 | ||
| HBV infection | ||||
| Yes | 1 | |||
| No | 0.885 (0.482-1.626) | .693 | ||
| Number of tumours | ||||
| 1 | 1 | |||
| ≥2 | 1.352 (0.767-2.383) | .297 | ||
| BCLC stage | ||||
| B | 1 | |||
| C | 1.615 (0.845-3.084) | .147 | ||
| Cirrhosis | ||||
| Yes | 1 | |||
| No | 1.027 (0.567-1.860) | .930 | ||
| Ascites | ||||
| Yes | 1 | |||
| No | 1.030 (0.570-1.863) | .922 | ||
| Portal vein invasion | ||||
| Yes | 1 | 1 | ||
| No | 0.312 (0.176-0.552) | <.001 | 0.162 (0.076-0.348) | <.001 |
| Extrahepatic metastasis | ||||
| Yes | 1 | 1 | ||
| No | 0.462 (0.265-0.805) | .006 | 0.556 (0.312-0.993) | .047 |
| AFP | ||||
| <400 | 1 | |||
| ≥400 | 1.268 (0.731-2.199) | .399 | ||
| Child-Pugh | ||||
| A | 1 | |||
| B | 1.109 (0.568-2.163) | .762 | ||
| ECOG performance | ||||
| 0 | 1 | |||
| 1 | 1.416 (0.817-2.454) | .216 | ||
| Treatment | ||||
| TACE + Sor + C | 1 | 1 | ||
| TACE + Sor | 3.757 (1.899-7.434) | <.001 | 7.174 (3.175-16.214) | <.001 |
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Variable | HR (95% CI) | P-value | HR (95% CI) | P-value |
| Age (years) | 1.021 (0.994-1.048) | .135 | ||
| ALT | 0.999 (0.994-1.005) | .793 | ||
| AST | 1.001 (0.998-1.005) | .445 | ||
| TB | 0.986 (0.960-1.013) | .300 | ||
| Albumin | 0.974 (0.927-1.024) | .303 | ||
| PLT | 0.999 (0.996-1.002) | .688 | ||
| Tumour size (cm) | 1.019 (0.973-1.069) | .422 | ||
| Sex | ||||
| Male | 1 | |||
| Female | 1.428 (0.669-3.048) | .357 | ||
| HBV infection | ||||
| Yes | 1 | |||
| No | 0.885 (0.482-1.626) | .693 | ||
| Number of tumours | ||||
| 1 | 1 | |||
| ≥2 | 1.352 (0.767-2.383) | .297 | ||
| BCLC stage | ||||
| B | 1 | |||
| C | 1.615 (0.845-3.084) | .147 | ||
| Cirrhosis | ||||
| Yes | 1 | |||
| No | 1.027 (0.567-1.860) | .930 | ||
| Ascites | ||||
| Yes | 1 | |||
| No | 1.030 (0.570-1.863) | .922 | ||
| Portal vein invasion | ||||
| Yes | 1 | 1 | ||
| No | 0.312 (0.176-0.552) | <.001 | 0.162 (0.076-0.348) | <.001 |
| Extrahepatic metastasis | ||||
| Yes | 1 | 1 | ||
| No | 0.462 (0.265-0.805) | .006 | 0.556 (0.312-0.993) | .047 |
| AFP | ||||
| <400 | 1 | |||
| ≥400 | 1.268 (0.731-2.199) | .399 | ||
| Child-Pugh | ||||
| A | 1 | |||
| B | 1.109 (0.568-2.163) | .762 | ||
| ECOG performance | ||||
| 0 | 1 | |||
| 1 | 1.416 (0.817-2.454) | .216 | ||
| Treatment | ||||
| TACE + Sor + C | 1 | 1 | ||
| TACE + Sor | 3.757 (1.899-7.434) | <.001 | 7.174 (3.175-16.214) | <.001 |
Abbreviations: AFP = alpha-fetoprotein; ALT = alanine transaminase; AST = aspartate aminotransferase; BCLC = Barcelona Clinic Liver Cancer; HBV = hepatitis B; HR = hazard ratio; OS = overall survival; PLT = platelet; TACE + Sor = transcatheter arterial chemoembolization with sorafenib; TACE + Sor + C = transcatheter arterial chemoembolization with sorafenib plus camrelizumab.
Univariate and multivariate analyses of prognostic factors for PFS.
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Variable | HR (95% CI) | P-value | HR (95% CI) | P-value |
| Age (years) | 1.004 (0.980-1.028) | .762 | ||
| ALT | 1.001 (0.998-1.004) | .568 | ||
| AST | 1.003 (1.000-1.005) | .061 | ||
| TB | 0.991 (0.973-1.010) | .371 | ||
| Albumin | 0.984 (0.945-1.023) | .413 | ||
| PLT | 1.001 (0.998-1.004) | .434 | ||
| Tumour size (cm) | 1.032 (0.987-1.079) | .168 | ||
| Sex | ||||
| Male | 1 | |||
| Female | 0.649 (0.316-1.332) | .238 | ||
| HBV infection | ||||
| Yes | 1 | |||
| No | 1.147 (0.684-1.922) | .603 | ||
| Number of tumours | ||||
| 1 | 1 | |||
| ≥2 | 1.548 (0.944-2.541) | .084 | ||
| BCLC stage | ||||
| B | 1 | |||
| C | 1.564 (0.910-2.688) | .106 | ||
| Cirrhosis | ||||
| Yes | 1 | |||
| No | 1.239 (0.754-2.035) | .397 | ||
| Ascites | ||||
| Yes | 1 | |||
| No | 0.874 (0.527-1.450) | .602 | ||
| Portal vein invasion | 1 | |||
| Yes | 1 | 0.228 (0.125-0.415) | <.001 | |
| No | 0.318 (0.193-0.524) | <.001 | ||
| Extrahepatic metastasis | 1 | |||
| Yes | 1 | 0.731 (0.445-1.199) | .214 | |
| No | 0.577 (0.358-0.931) | .024 | ||
| AFP | ||||
| <400 | 1 | |||
| ≥400 | 1.025 (0.636-1.653) | .919 | ||
| Child-Pugh | ||||
| A | 1 | |||
| B | 1.195 (0.663-2.153) | .554 | ||
| ECOG performance | ||||
| 0 | 1 | |||
| 1 | 1.256 (0.781-2.020) | .348 | ||
| Treatment | ||||
| TACE + Sor + C | 1 | 1 | ||
| TACE + Sor | 1.886 (1.128-3.154) | .016 | 2.972 (1.655-5.339) | <.001 |
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Variable | HR (95% CI) | P-value | HR (95% CI) | P-value |
| Age (years) | 1.004 (0.980-1.028) | .762 | ||
| ALT | 1.001 (0.998-1.004) | .568 | ||
| AST | 1.003 (1.000-1.005) | .061 | ||
| TB | 0.991 (0.973-1.010) | .371 | ||
| Albumin | 0.984 (0.945-1.023) | .413 | ||
| PLT | 1.001 (0.998-1.004) | .434 | ||
| Tumour size (cm) | 1.032 (0.987-1.079) | .168 | ||
| Sex | ||||
| Male | 1 | |||
| Female | 0.649 (0.316-1.332) | .238 | ||
| HBV infection | ||||
| Yes | 1 | |||
| No | 1.147 (0.684-1.922) | .603 | ||
| Number of tumours | ||||
| 1 | 1 | |||
| ≥2 | 1.548 (0.944-2.541) | .084 | ||
| BCLC stage | ||||
| B | 1 | |||
| C | 1.564 (0.910-2.688) | .106 | ||
| Cirrhosis | ||||
| Yes | 1 | |||
| No | 1.239 (0.754-2.035) | .397 | ||
| Ascites | ||||
| Yes | 1 | |||
| No | 0.874 (0.527-1.450) | .602 | ||
| Portal vein invasion | 1 | |||
| Yes | 1 | 0.228 (0.125-0.415) | <.001 | |
| No | 0.318 (0.193-0.524) | <.001 | ||
| Extrahepatic metastasis | 1 | |||
| Yes | 1 | 0.731 (0.445-1.199) | .214 | |
| No | 0.577 (0.358-0.931) | .024 | ||
| AFP | ||||
| <400 | 1 | |||
| ≥400 | 1.025 (0.636-1.653) | .919 | ||
| Child-Pugh | ||||
| A | 1 | |||
| B | 1.195 (0.663-2.153) | .554 | ||
| ECOG performance | ||||
| 0 | 1 | |||
| 1 | 1.256 (0.781-2.020) | .348 | ||
| Treatment | ||||
| TACE + Sor + C | 1 | 1 | ||
| TACE + Sor | 1.886 (1.128-3.154) | .016 | 2.972 (1.655-5.339) | <.001 |
Abbreviations: AFP = alpha-fetoprotein; ALT = alanine transaminase; AST = aspartate aminotransferase; BCLC = Barcelona Clinic Liver Cancer; HBV = hepatitis B; HR = hazard ratio; OS = overall survival; PFS, progression-free survival; PLT = platelet; TACE + Sor = transcatheter arterial chemoembolization with sorafenib; TACE + Sor + C = transcatheter arterial chemoembolization with sorafenib plus camrelizumab.
Univariate and multivariate analyses of prognostic factors for PFS.
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Variable | HR (95% CI) | P-value | HR (95% CI) | P-value |
| Age (years) | 1.004 (0.980-1.028) | .762 | ||
| ALT | 1.001 (0.998-1.004) | .568 | ||
| AST | 1.003 (1.000-1.005) | .061 | ||
| TB | 0.991 (0.973-1.010) | .371 | ||
| Albumin | 0.984 (0.945-1.023) | .413 | ||
| PLT | 1.001 (0.998-1.004) | .434 | ||
| Tumour size (cm) | 1.032 (0.987-1.079) | .168 | ||
| Sex | ||||
| Male | 1 | |||
| Female | 0.649 (0.316-1.332) | .238 | ||
| HBV infection | ||||
| Yes | 1 | |||
| No | 1.147 (0.684-1.922) | .603 | ||
| Number of tumours | ||||
| 1 | 1 | |||
| ≥2 | 1.548 (0.944-2.541) | .084 | ||
| BCLC stage | ||||
| B | 1 | |||
| C | 1.564 (0.910-2.688) | .106 | ||
| Cirrhosis | ||||
| Yes | 1 | |||
| No | 1.239 (0.754-2.035) | .397 | ||
| Ascites | ||||
| Yes | 1 | |||
| No | 0.874 (0.527-1.450) | .602 | ||
| Portal vein invasion | 1 | |||
| Yes | 1 | 0.228 (0.125-0.415) | <.001 | |
| No | 0.318 (0.193-0.524) | <.001 | ||
| Extrahepatic metastasis | 1 | |||
| Yes | 1 | 0.731 (0.445-1.199) | .214 | |
| No | 0.577 (0.358-0.931) | .024 | ||
| AFP | ||||
| <400 | 1 | |||
| ≥400 | 1.025 (0.636-1.653) | .919 | ||
| Child-Pugh | ||||
| A | 1 | |||
| B | 1.195 (0.663-2.153) | .554 | ||
| ECOG performance | ||||
| 0 | 1 | |||
| 1 | 1.256 (0.781-2.020) | .348 | ||
| Treatment | ||||
| TACE + Sor + C | 1 | 1 | ||
| TACE + Sor | 1.886 (1.128-3.154) | .016 | 2.972 (1.655-5.339) | <.001 |
| Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|
| Variable | HR (95% CI) | P-value | HR (95% CI) | P-value |
| Age (years) | 1.004 (0.980-1.028) | .762 | ||
| ALT | 1.001 (0.998-1.004) | .568 | ||
| AST | 1.003 (1.000-1.005) | .061 | ||
| TB | 0.991 (0.973-1.010) | .371 | ||
| Albumin | 0.984 (0.945-1.023) | .413 | ||
| PLT | 1.001 (0.998-1.004) | .434 | ||
| Tumour size (cm) | 1.032 (0.987-1.079) | .168 | ||
| Sex | ||||
| Male | 1 | |||
| Female | 0.649 (0.316-1.332) | .238 | ||
| HBV infection | ||||
| Yes | 1 | |||
| No | 1.147 (0.684-1.922) | .603 | ||
| Number of tumours | ||||
| 1 | 1 | |||
| ≥2 | 1.548 (0.944-2.541) | .084 | ||
| BCLC stage | ||||
| B | 1 | |||
| C | 1.564 (0.910-2.688) | .106 | ||
| Cirrhosis | ||||
| Yes | 1 | |||
| No | 1.239 (0.754-2.035) | .397 | ||
| Ascites | ||||
| Yes | 1 | |||
| No | 0.874 (0.527-1.450) | .602 | ||
| Portal vein invasion | 1 | |||
| Yes | 1 | 0.228 (0.125-0.415) | <.001 | |
| No | 0.318 (0.193-0.524) | <.001 | ||
| Extrahepatic metastasis | 1 | |||
| Yes | 1 | 0.731 (0.445-1.199) | .214 | |
| No | 0.577 (0.358-0.931) | .024 | ||
| AFP | ||||
| <400 | 1 | |||
| ≥400 | 1.025 (0.636-1.653) | .919 | ||
| Child-Pugh | ||||
| A | 1 | |||
| B | 1.195 (0.663-2.153) | .554 | ||
| ECOG performance | ||||
| 0 | 1 | |||
| 1 | 1.256 (0.781-2.020) | .348 | ||
| Treatment | ||||
| TACE + Sor + C | 1 | 1 | ||
| TACE + Sor | 1.886 (1.128-3.154) | .016 | 2.972 (1.655-5.339) | <.001 |
Abbreviations: AFP = alpha-fetoprotein; ALT = alanine transaminase; AST = aspartate aminotransferase; BCLC = Barcelona Clinic Liver Cancer; HBV = hepatitis B; HR = hazard ratio; OS = overall survival; PFS, progression-free survival; PLT = platelet; TACE + Sor = transcatheter arterial chemoembolization with sorafenib; TACE + Sor + C = transcatheter arterial chemoembolization with sorafenib plus camrelizumab.
Subgroup analysis
The mOS of patients with portal vein tumour thrombosis (PVTT) in the TACE + Sor + C and TACE + Sor groups was 13 (95% CI: 10.1-15.9) and 7 (95% CI: 4.7-9.3) months, respectively (P = .047). The corresponding mPFS was 8 (95% CI: 4.6-11.4) and 4 (95% CI: 1.7-6.4) months in the TACE + Sor + C and TACE + Sor groups, respectively (P = .023) (Figures S1A and S2A). The mOS of patients without PVTT in the TACE + Sor + C and TACE + Sor groups was 22 (95% CI: 15.9-28.1) and 13 (95% CI: 10.3-15.7) months, respectively (P < .001). The corresponding mPFS was 12 (95% CI: 9.1-14.9) and 9 (95% CI: 7.1-10.9) months in the TACE + Sor + C and TACE + Sor groups, respectively (P = .145) (Figures S1B and S2B). The mOS of patients with Barcelona Clinic Liver Cancer (BCLC) stage B in the TACE + Sor + C and TACE + Sor groups was 26 (95% CI: 18.8-29.8) and 13 (95% CI: 9.8-16.2) months, respectively (P < .001). The corresponding mPFS was 13 (95% CI: 11.5-14.5) and 9 (95% CI: 5.6-12.4) months in the TACE + Sor + C and TACE + Sor groups, respectively (P = .014) (Figures S1C and S2C). The mOS of patients with BCLC stage C in the TACE + Sor + C and TACE + Sor groups was 16 (95% CI: 9.7-22.3) and 9 (95% CI: 6.5-11.5) months, respectively (P = .011). The corresponding mPFS was 10 (95% CI: 7.6-12.4) and 5 (95% CI: 3.1-6.9) months in the TACE + Sor + C and TACE + Sor groups, respectively (P = .077) (Figures S1D and S2D). The mOS of patients with CHILD A in the TACE + Sor + C and TACE + Sor groups was 19 (95% CI: 13.9-24.1) and 10 (95% CI: 6.8-13.8) months, respectively (P = .001). The corresponding mPFS was 11 (95% CI: 8.0-14.0) and 6 (95% CI: 3.0-9.0) months in the TACE + Sor + C and TACE + Sor groups, respectively (P = .011) (Figures S1E and S2E). The mOS of patients with CHILD-B in the TACE + Sor + C and TACE + Sor groups was 22 (95% CI: 0-48.1) and 7 (95% CI: 0.4-14.0) months, respectively (P = .033). The corresponding mPFS was 11 (95% CI: 6.7-15.3) and 2 (95% CI: 0-4.5) months in the TACE + Sor + C and TACE + Sor groups, respectively (P = .445) (Figures S1F and S2F).
Safety
The treatment-related AEs are presented in Table 4. No treatment-related mortalities were observed. One hundred and thirty and 204 adverse reactions occurred in the TACE + Sor + C and TACE + Sor groups, respectively. The incidence of common TACE-related adverse reactions (nausea, vomiting, decreased appetite, abdominal pain, and fever) was similar between the 2 groups, with no statistical difference. Grades III and IV AEs, with an incidence of >5% in both groups, were nausea and decreased appetite. For drug-related AEs, there was a higher incidence of grade I or II AEs in skin capillary hyperplasia (P = .034) and hypothyroidism (P = .001) in the TACE + Sor + C group. Regarding grade III and IV AEs, only fatigue had an incidence of >5% in both groups (7.7% in the TACE + Sor + C group and 9.6% in the TACE + Sor group).
The adverse events of patients after receiving TACE + Sor + C or TACE + Sor.
| Grade I or II | Grade III or IV | |||||
|---|---|---|---|---|---|---|
| Adverse events | TACE + Sor + C (N,%) | TACE + Sor (N,%) | P-value | TACE + Sor + C (N,%) | TACE + Sor (N,%) | P-value |
| Nausea | 14 (53.8) | 21 (40.4) | .260 | 2 (7.7) | 3 (5.4) | .747 |
| Vomiting | 6 (23.1) | 11 (21.2) | .846 | 1 (3.8) | 1 (1.9) | >.999 |
| Decreased appetite | 20 (76.9) | 38 (73.1) | .714 | 3 (11.5) | 4 (7.7) | .582 |
| Abdominal pain | 10 (38.5) | 17 (32.7) | .614 | 1 (3.8) | 1 (1.9) | >.999 |
| Fever | 9 (34.6) | 15 (28.8) | .603 | 0 (0) | 1 (1.9) | >.999 |
| Hand-foot skin reaction | 11 (42.3) | 24 (46.2) | .747 | 5 (19.2) | 9 (17.3) | .835 |
| Hypertension | 10 (38.5) | 10 (19.2) | .067 | 1 (3.8) | 0 (0) | .333 |
| Fatigue | 15 (57.7) | 30 (57.7) | >.999 | 2 (7.7) | 5 (9.6) | .758 |
| Headache | 4 (15.4) | 9 (17.3) | .829 | 0 (0) | 0 (0) | >.999 |
| Proteinuria | 2 (7.7) | 4 (7.7) | >.999 | 0 (0) | 0 (0) | >.999 |
| Skin capillary hyperplasia | 3 (11.5) | 0 (0) | .034 | 1 (3.8) | 0 (0) | .333 |
| Hypothyroidism | 7 (26.9) | 1 (1.9) | .001 | 0 (0) | 0 (0) | >.999 |
| Myositis | 2 (7.7) | 0 (0) | .108 | 0 (0) | 0 (0) | >.999 |
| Pneumonia | 1 (3.8) | 0 (0) | .333 | 0 (0) | 0 (0) | >.999 |
| Grade I or II | Grade III or IV | |||||
|---|---|---|---|---|---|---|
| Adverse events | TACE + Sor + C (N,%) | TACE + Sor (N,%) | P-value | TACE + Sor + C (N,%) | TACE + Sor (N,%) | P-value |
| Nausea | 14 (53.8) | 21 (40.4) | .260 | 2 (7.7) | 3 (5.4) | .747 |
| Vomiting | 6 (23.1) | 11 (21.2) | .846 | 1 (3.8) | 1 (1.9) | >.999 |
| Decreased appetite | 20 (76.9) | 38 (73.1) | .714 | 3 (11.5) | 4 (7.7) | .582 |
| Abdominal pain | 10 (38.5) | 17 (32.7) | .614 | 1 (3.8) | 1 (1.9) | >.999 |
| Fever | 9 (34.6) | 15 (28.8) | .603 | 0 (0) | 1 (1.9) | >.999 |
| Hand-foot skin reaction | 11 (42.3) | 24 (46.2) | .747 | 5 (19.2) | 9 (17.3) | .835 |
| Hypertension | 10 (38.5) | 10 (19.2) | .067 | 1 (3.8) | 0 (0) | .333 |
| Fatigue | 15 (57.7) | 30 (57.7) | >.999 | 2 (7.7) | 5 (9.6) | .758 |
| Headache | 4 (15.4) | 9 (17.3) | .829 | 0 (0) | 0 (0) | >.999 |
| Proteinuria | 2 (7.7) | 4 (7.7) | >.999 | 0 (0) | 0 (0) | >.999 |
| Skin capillary hyperplasia | 3 (11.5) | 0 (0) | .034 | 1 (3.8) | 0 (0) | .333 |
| Hypothyroidism | 7 (26.9) | 1 (1.9) | .001 | 0 (0) | 0 (0) | >.999 |
| Myositis | 2 (7.7) | 0 (0) | .108 | 0 (0) | 0 (0) | >.999 |
| Pneumonia | 1 (3.8) | 0 (0) | .333 | 0 (0) | 0 (0) | >.999 |
Abbreviations: TACE + Sor = transcatheter arterial chemoembolization with sorafenib; TACE + Sor + C = transcatheter arterial chemoembolization with sorafenib plus camrelizumab.
The adverse events of patients after receiving TACE + Sor + C or TACE + Sor.
| Grade I or II | Grade III or IV | |||||
|---|---|---|---|---|---|---|
| Adverse events | TACE + Sor + C (N,%) | TACE + Sor (N,%) | P-value | TACE + Sor + C (N,%) | TACE + Sor (N,%) | P-value |
| Nausea | 14 (53.8) | 21 (40.4) | .260 | 2 (7.7) | 3 (5.4) | .747 |
| Vomiting | 6 (23.1) | 11 (21.2) | .846 | 1 (3.8) | 1 (1.9) | >.999 |
| Decreased appetite | 20 (76.9) | 38 (73.1) | .714 | 3 (11.5) | 4 (7.7) | .582 |
| Abdominal pain | 10 (38.5) | 17 (32.7) | .614 | 1 (3.8) | 1 (1.9) | >.999 |
| Fever | 9 (34.6) | 15 (28.8) | .603 | 0 (0) | 1 (1.9) | >.999 |
| Hand-foot skin reaction | 11 (42.3) | 24 (46.2) | .747 | 5 (19.2) | 9 (17.3) | .835 |
| Hypertension | 10 (38.5) | 10 (19.2) | .067 | 1 (3.8) | 0 (0) | .333 |
| Fatigue | 15 (57.7) | 30 (57.7) | >.999 | 2 (7.7) | 5 (9.6) | .758 |
| Headache | 4 (15.4) | 9 (17.3) | .829 | 0 (0) | 0 (0) | >.999 |
| Proteinuria | 2 (7.7) | 4 (7.7) | >.999 | 0 (0) | 0 (0) | >.999 |
| Skin capillary hyperplasia | 3 (11.5) | 0 (0) | .034 | 1 (3.8) | 0 (0) | .333 |
| Hypothyroidism | 7 (26.9) | 1 (1.9) | .001 | 0 (0) | 0 (0) | >.999 |
| Myositis | 2 (7.7) | 0 (0) | .108 | 0 (0) | 0 (0) | >.999 |
| Pneumonia | 1 (3.8) | 0 (0) | .333 | 0 (0) | 0 (0) | >.999 |
| Grade I or II | Grade III or IV | |||||
|---|---|---|---|---|---|---|
| Adverse events | TACE + Sor + C (N,%) | TACE + Sor (N,%) | P-value | TACE + Sor + C (N,%) | TACE + Sor (N,%) | P-value |
| Nausea | 14 (53.8) | 21 (40.4) | .260 | 2 (7.7) | 3 (5.4) | .747 |
| Vomiting | 6 (23.1) | 11 (21.2) | .846 | 1 (3.8) | 1 (1.9) | >.999 |
| Decreased appetite | 20 (76.9) | 38 (73.1) | .714 | 3 (11.5) | 4 (7.7) | .582 |
| Abdominal pain | 10 (38.5) | 17 (32.7) | .614 | 1 (3.8) | 1 (1.9) | >.999 |
| Fever | 9 (34.6) | 15 (28.8) | .603 | 0 (0) | 1 (1.9) | >.999 |
| Hand-foot skin reaction | 11 (42.3) | 24 (46.2) | .747 | 5 (19.2) | 9 (17.3) | .835 |
| Hypertension | 10 (38.5) | 10 (19.2) | .067 | 1 (3.8) | 0 (0) | .333 |
| Fatigue | 15 (57.7) | 30 (57.7) | >.999 | 2 (7.7) | 5 (9.6) | .758 |
| Headache | 4 (15.4) | 9 (17.3) | .829 | 0 (0) | 0 (0) | >.999 |
| Proteinuria | 2 (7.7) | 4 (7.7) | >.999 | 0 (0) | 0 (0) | >.999 |
| Skin capillary hyperplasia | 3 (11.5) | 0 (0) | .034 | 1 (3.8) | 0 (0) | .333 |
| Hypothyroidism | 7 (26.9) | 1 (1.9) | .001 | 0 (0) | 0 (0) | >.999 |
| Myositis | 2 (7.7) | 0 (0) | .108 | 0 (0) | 0 (0) | >.999 |
| Pneumonia | 1 (3.8) | 0 (0) | .333 | 0 (0) | 0 (0) | >.999 |
Abbreviations: TACE + Sor = transcatheter arterial chemoembolization with sorafenib; TACE + Sor + C = transcatheter arterial chemoembolization with sorafenib plus camrelizumab.
Discussion
Our study showed that compared with TACE + Sor, TACE + Sor + C conferred a more significant survival benefit in patients with intermediate or advanced HCC. The mOS increased from 10 to 22 months (P < .001), and the corresponding mPFS increased from 6 to 11 months (P = .008). In multivariate analyses, the combination of PD-1 inhibitors was also an independent predictor of better PFS and OS. The results demonstrated that this therapeutic strategy could provide a new option for patients with intermediate or advanced HCC.
The efficacy of TACE is related to tumour blood supply, lesion location, and tumour size. Therefore, it is difficult to achieve complete tumour necrosis using TACE alone, and recurrence and metastasis often occur after treatment.21 Therefore, many combination therapies have been developed to improve patient survival benefits (such as the combination of TACE and local or systemic therapy) and have demonstrated encouraging results.22–26 In addition, the tumour microenvironment in HCC is strongly immunosuppressive, expressing a high level of ICIs and calling for a combination of ICIs. Among the immuno-oncology combinations for advanced HCC, the most extensively tested combination regimen comprises anti-PD1/anti-PDL1 plus antiangiogenic agents.27 Therefore, we collected and described our clinical experience regarding the TACE + Sor + C combination in the 2 study centres.
The underlying mechanism may be greatly enhanced antitumor immunity. The key points of immunotherapy are the recognition of tumour foreignness by the immune system, the immune status of the patient, the infiltration of effective T cells, and the response of tumour cells to T cells.28 A previous study showed that TACE may induce “immunogenic cell death” by releasing tumour antigens from dying cancer cells and eliciting damage-associated molecular patterns, such as calreticulin, ATP release, and type I interferon response, to facilitate antitumor immunity.29 In addition, in vivo and in vitro studies have demonstrated that sorafenib may enhance antitumor immunity by increasing the M1 polarization of tumour-associated macrophages,30,31 enhancing CD4+ and CD8+ T-cell infiltration and function,32,33 suppressing Treg numbers, or reversing the function of Myeloid-derived suppressor cells in the tumour microenvironment.34,35 Camrelizumab, a PD-1 inhibitor, can alleviate the immunosuppressive state of CD8+ T cells. All these factors promote antitumour immunity, allowing patients to delay tumour progression and obtain survival benefits.
PVTT, BCLC stage, and Child-Pugh score are prognostic factors affecting the survival of patients with HCC.36–38 Therefore, we conducted a subgroup analysis of PVTT, BCLC stage, and Child-Pugh score and found that patients can obtain survival benefits from triple therapy regardless of whether they had PVTT, BCLC B or C, or CHILD A or B. However, only patients with PVTT, BCLCB, and Child A treated with triple therapy had better PFS. The results indicated that triple therapy deserves consideration in all these situations and that patients can obtain more survival benefits from TACE + Sor + C than from TACE + Sor in these situations.
Univariate and multivariate analyses were used to deduce the impact of other factors on patient survival in this study. Multivariate analysis showed that portal vein invasion, extrahepatic metastasis, and treatment were independent prognostic factors for OS and that portal vein invasion and treatment were predictors of PFS. The results showed that patients with portal vein invasion had an increased risk for all-cause mortality and tumour progression compared with patients without portal vein invasion and that patients with extrahepatic metastasis had an increased risk for all-cause mortality compared to patients without extrahepatic metastasis. However, after excluding factors that might influence the outcomes, we found that TACE + Sor + C reduced tumour progression and all-cause mortality risks better than TACE + Sor, indicating that patients with intermediate or advanced HCC could benefit more from TACE + Sor + C than from TACE + Sor.
This study suggests that both TACE + Sor + C and TACE + Sor are tolerable and have a well-managed safety profile. Postembolization syndrome (nausea, vomiting, decreased appetite, abdominal pain, and fever) had a similar incidence in both groups. However, there was a significantly higher incidence of immunotherapy-related AEs (irAEs) such as skin capillary hyperplasia and hypothyroidism. These irAEs should be carefully considered, as triple therapy may elicit strong immune responses that elicit stronger irAEs. Further studies should focus on irAEs associated with the combination of TACE + TKI + ICIs.
This study has several limitations. First, as a retrospective study, the comparison of TACE + Sor + C and TACE + Sor may have been subject to selection bias, and no matched-pair analysis between the 2 groups was performed because of the small sample size. Instead, multivariate and subgroup analyses were conducted to correct for confounding factors.
Second, the sample size of this study was relatively small. The results of subgroup analyses should be cautiously interpreted, and validation by further studies is needed.
In conclusion, patients appeared to benefit more from TACE + Sor + C and showed better PFS and OS than those treated with TACE + Sor. All treatment-related AEs were tolerable. TACE + Sor + C is an effective and safe treatment strategy for patients with intermediate or advanced HCC.
Author contributions
Drs B. Sun, L. Chen, and L. Yu contributed equally.
Supplementary material
Supplementary material is available at BJR online.
Funding
This study was supported by the National Natural Science Foundation of China (No. 81873919), the National Key Research and Development Program of China (2023YFC2413500) and China Scholarship Council (NO. CSC202206165023).
Conflicts of interest
None declared.
