Introduction

Hepatocellular carcinoma (HCC) is an aggressive malignancy and the second leading cause of cancer-related mortality globally.1 Surgical resection is the most effective treatment for patients with HCC and offers the possibility of cure and long-term survival.2,3 However, most patients are diagnosed in advanced stages and often miss the opportunity for surgical intervention, resulting in an unsatisfactory survival.1,3 Based on accumulated data, 10–37%4–8 of patients with unresectable HCC present with extrahepatic metastases (EM). With the increased rates of disease screening and improvements in imaging techniques, the detection of HCC with EM has improved.

HCC with EM has a negative prognostic impact, resulting in unsatisfactory long-term survival. In HCC patients with EM, the median overall survival (mOS) ranges between 4.9 and 10.3 months.4,6–12 In recent years, the success of several clinical studies on systemic therapy for patients with advanced HCC has resulted in improved survival prognosis. He et al13 found that FOLFOX chemotherapy combined with lenvatinib and toripalimab could elicit promising antitumor activity and manageable toxicity in HCC patients with EM. The median progression-free survival (mPFS) was 9.73 months, the mOS was 14.63 months, and the objective response rate (ORR) was 43.3%. According to Sun et al,14 combined FOLFOX4 with all-trans retinoic acid showed favorable antitumor activity and safety in HCC patients with EM, with an mPFS reaching 7.1 months, mOS of 16.2 months, and ORR of 24.5%. Kudo et al15 found that in patients with advanced HCC, the overall survival rate of lenvatinib was non-inferior to that of sorafenib in untreated advanced HCC, with an mPFS of 7.3 months and mOS of 11.5 months in the subgroup with macroscopic portal vein invasion, extrahepatic spread, or both. Furthermore, several clinical studies16–20 have assessed potential systemic therapies in patients with EM. However, data disclosure for subgroup analysis of EM remains limited, reducing the potential for guiding systemic therapy.

Several retrospective studies7,21,22 have found that in HCC patients with EM, the cause of death in most patients was due to liver failure owing to further deterioration of the primary intrahepatic lesion rather than due to metastatic lesions, thereby suggesting the need to treat the primary intrahepatic lesion more aggressively. Yoo et al21 found that in HCC patients with EM, Transcatheter arterial chemoembolization (TACE) offered a greater survival benefit than conservative treatment. Furthermore, the authors found that sorafenib combined with TACE may provide an independent survival benefit in such patients. However, its current efficacy remains unsatisfactory, and the prognosis of HCC with EM needs to be further improved.

According to Guan et al,23 hepatic arterial infusion chemotherapy can improve the efficacy of lenvatinib and anti-programmed cell death 1 (PD-1) inhibitors therapy in HCC patients with EM, with an mPFS reaching 8.0 months, mOS of 27.0 months. Additionally, TACE combined with lenvatinib and PD-1 inhibitors can prolong the survival of patients with unresectable HCC and induce deeper remission.24–26 However, the therapeutic potential of triple therapy in HCC patients with EM remains unclear. Accordingly, the objective of the current study was to evaluate the efficacy and safety of triple therapy in HCC patients with EM.

Materials and Methods Patients

In total, 60 patients with a diagnosis of HCC with EM from three high-volume institutions in China (Fujian Provincial Hospital, First Affiliated Hospital of Fujian Medical University, and First Affiliated Hospital of Xiamen University) were included. Inclusion criteria were as follows: 1) patients with a primary diagnosis of HCC with EM who underwent triple therapy as first-line therapy; 2) aged 18–75 years; 3) Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0 or 1; 4) Child-Pugh class A or B; and 5) at least one measurable lesion according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST).27 Exclusion criteria were as follows: 1) previous radical resection, radiofrequency, radiation, or other forms of antitumor treatment; 2) a history of other primary malignancies; 3) severe medical comorbidities (eg, severe heart disease, severe kidney disease, or severe pulmonary disease); and 4) incomplete data.

The diagnosis of HCC was based on the typical imaging features or liver biopsy pathology (when necessary). EM was diagnosed using computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, positron emission tomography-computed tomography (PET-CT), and biopsy of metastatic lesions. Baseline data, medical history, laboratory results, radiological results, and histological results were retrospectively collected from all patients.

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Ethics Committee of Fujian Provincial Hospital (No: K2024-09-111). Informed consent was obtained from all patients for their data to be used for research purposes.

Treatment Procedure

The targeted drugs included oral lenvatinib (8 mg for body weight <60 kg or 12 mg for body weight ≥60 kg once daily). Immunotherapeutic drugs included intravenous carelizumab (200 mg once every 3 weeks), sintilimab (200 mg once every 3 weeks), tislelizumab (200 mg once every 3 weeks), toripalimab (240 mg once every 3 weeks), pembrolizumab (15 mg/kg once every 3 weeks), and penpulimab (200 mg once every 3 weeks). TACE was performed under sterile conditions via the right femoral artery using the Seldinger technique. After identifying the tumor-feeding arteries, the radiologist mixed iodized oil and pirarubicin and slowly injected the solution through a microcatheter into the tumor-feeding artery. Gelatin sponge particles were then injected until complete stasis of the tumor arterial blood flow was achieved. The decision to proceed with or repeat TACE depended on the recommendations of the multidisciplinary team. Treatment with lenvatinib and anti-PD-1 inhibitors was suspended for three days before and after TACE. All patients with hepatitis B virus (HBV) infection received oral antiviral treatment (entecavir or tenofovir).

Patients with resectable HCC were identified based on the following criteria: 1) R0 resection with sufficient preservation of residual liver function and volume was achievable; 2) ECOG-PS score of 0–1; 3) Child-Pugh class A; 4) EM lesions has achieved radiological complete responseand can be removed intact during surgery and could be removed intact during surgery; 5) no contraindications to salvage hepatectomy.

The multidisciplinary team was consulted to decide the course of second-line therapy when disease progression was detected.

Efficacy and Safety Assessments

According to the mRECIST criteria,27 tumor response was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The ORR was calculated by adding the CR and PR rates, whereas the disease control rate (DCR) was obtained by adding the CR, PR, and SD rates. Treatment-related adverse events (TRAEs) were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.28

Follow-Up

All HCC patients with EM who received triple therapy were followed up every 4–8 weeks to collect survival data, physical examination results, radiological data (chest enhanced CT, abdominal enhanced CT, and/or MRI), alpha-fetoprotein (AFP) level, and laboratory data. Disease progression was defined as an increase in the intrahepatic tumor burden or the appearance of new arterial-enhancing lesions documented in radiological reports. The primary endpoint of this study was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and TRAEs. OS was defined as the period from treatment initiation to either death or the latest follow-up. PFS was defined as the period from treatment initiation to the first radiologically confirmed progression, death, or latest follow-up. All patients were followed up until death or the end of December 2023.

Statistical Analysis

Continuous data are expressed as mean (standard deviation) or median (range), as appropriate. Categorical data are expressed as numbers (percentages) and compared using the chi-square test or Fisher’s exact test. PFS and OS were plotted using the Kaplan–Meier method for survival curves and compared using the Log rank test. Univariate analysis was performed to determine the risk factors for PFS and OS, and the variables that were significant in the univariate analyses were introduced into Cox proportional risk regression models for multivariate analysis to identify independent risk factors that affect prognosis. All P-values were two-tailed, and values <0.05 indicated that the difference was statistically significant. Statistical analyses were performed using IBM SPSS Statistics version 26.0 (IBM Corp., Armonk, NY, USA).

Results Patient Characteristics

From July 2019 to January 2023, 60 patients diagnosed with HCC and EM who received triple therapy at three high-volume institutions in China were enrolled in this study. According to Table 1, the median patient age was 57 years (range: 26–76 years), and the study population included 47 males and 13 females. HBV infection was observed in 54 (90.0%) patients. Regarding the hepatic functional reserve, 49 patients (81.7%) were Child-Pugh grade A and 11 (18.3%) were Child-Pugh grade B. Regarding tumor markers, 39 (65.0%) patients had AFP levels of > 400 ng/mL. Regarding tumor burden, 47 (78.3%) patients had multiple intrahepatic tumors; 33 (55.0%) patients had tumors with a maximum diameter >10 cm; and 33 (55.0%) patients had concomitant macrovascular invasion.

Table 1 Characteristics of Metastatic HCC

Metastatic Sites

In this study, 27 patients (45.0%) presented with lung metastasis, which was the most common site of metastasis. The other major metastatic sites were lymph nodes in 22 patients (36.7%), bones in 10 patients (16.7%), and adrenal glands in 6 (10.0%). Diaphragm metastases were detected in 2 patients (3.3%), and metastases in the brain, pancreas, mesentery, gallbladder, peritoneum, and abdominal wall were detected in 1 patient each. EM was detected in two or more organs in 10 patients (15.5%) (Table 2).

Table 2 Site of Extrahepatic Metastases in 60 Metastatic HCC

Triple Therapy

All patients received the triple therapy as first-line treatment. The median number of TACE treatment cycles was 2 times (range, 1–8 times), the median duration of lenvatinib treatment was 12.1 months (range, 0.9–32.0 months). The median number of cycles of PD-1 inhibitors received was 10 cycles (range, 1–21 cycles).

Tumor Response Assessment

We assessed the degree of tumor response in the intrahepatic lesions of patients receiving triple therapy. CR was achieved in 3 (5%) patients, PR in 30 (50%) patients, SD in 18 (30%) patients, and PD in 9 (15%) patients. The ORR was 55%, and the DCR was 85% (Table 3).

Table 3 Best Intrahepatic Tumor Response According to the mRECIST

Prognosis of HCC with EM

Figure 1 presents the Kaplan–Meier curves for all patients considering the follow-up data cut-off (December 2023). The mPFS was 6.0 months (range: 0.5–34 months), and the mOS was 18.63 months (range: 1.0–34 months), with a 6-month survival rate of 87.7%, a 1-year survival rate of 68.6%, and a 2-year survival rate of 26.8%. Survival data did not differ between patients with metastases at different sites (overall comparison P = 0.747).

Figure 1 Kaplan-Meier curves of PFS and OS in HCC with EM. (A) PFS of HCC with EM. (B) OS of HCC with EM.

Abbreviations: PFS, progression-free survival; OS, overall survival; HCC, hepatocellular carcinoma; EM, extrahepatic metastases.

Risk Factor Analysis of HCC with EM

The univariate analysis revealed that sex (female, P = 0.002), baseline AFP level (≥400 ng/mL, P = 0.006), and maximum tumor diameter (≥10 cm, P = 0.034) were significant risk factors that could negatively impact PFS. Furthermore, multivariate analysis confirmed that sex (female, P = 0.019, hazard ratio [HR] = 2.439, 95% confidence interval [CI] = 1.156-5.155) and baseline AFP level (≥400 ng/mL, P = 0.014, HR = 2.523, 95% CI = 1.203–5.291) were independent risk factors for PFS (Table 4).

Table 4 Univariate and Multivariate Analysis of Prognostic Factors for PFS

For OS, the univariate analysis showed that neutrophil to lymphocyte ratio (NLR) (≥4, P = 0.013), AFP level (≥400 ng/mL, P = 0.039), and macrovascular invasion (positive, P = 0.023) were significant risk factors that could adversely impact OS. The multivariate analysis confirmed that NLR (≥4, P = 0.003, HR = 3.773, 95% CI = 1.569–9.074) and AFP level (≥400 ng/mL, P = 0.046, HR = 2.889, 95% CI = 1.021–8.180) were independent risk factors for OS (Table 5).

Table 5 Univariate and Multivariate Analysis of Prognostic Factors for OS

Salvage Hepatectomy

Of the 60 HCC patients with EM, 11 patients met the resectability criteria after triple therapy, and 7 underwent salvage hepatectomy, all of whom had localized lymph node metastases of HCC. The postoperative pathological results revealed a major pathological response (MPR) in three patients. Patients who underwent salvage surgery after reaching the resection criteria did not show a statistically significant difference in PFS and OS when compared with those in the non-surgery group (P = 0.360 and 0.382, respectively) (Figure 2).

Figure 2 Kaplan-Meier curves of PFS and OS for HCC with EM who underwent salvage or non-salvage surgery. (A) PFS of HCC with EM. (B) OS of HCC with EM.

Abbreviations: PFS, progression-free survival; OS, overall survival; HCC, hepatocellular carcinoma; EM, extrahepatic metastases.

Safety

All TRAEs that were monitored or followed are shown in Table 6. Of the 60 patients who received triple therapy, 49 (81.6%) experienced TRAEs. The most common symptoms were abnormal liver function (58.3%), fatigue (41.6%), and weight loss (30.0%). Seven patients (11.6%) experienced grade 3/4 TRAEs, and no treatment-related deaths occurred during the follow-up period.

Table 6 Treatment-Related Adverse Events Occurred in ≥10% of Total Patients

Discussion

In our study of 60 HCC patients with EM undergoing triple therapy, the common EM sites were lung, lymph nodes, bone, and adrenal gland, aligning with previous studies.7,8,21,29 After treatment, the median PFS was 6.0 months, and the OS rates at 6 months, 1 year, and 2 years were 87.7%, 68.6%, and 26.8%, with a median OS of 18.63 months. During follow-up, 81.6% of patients had treatment-related adverse events (TRAEs), with 11.6% being grade 3/4; all were manageable with no occurrence of treatment-related deaths.

The clinical prognosis of HCC patients with EM is extremely poor, with only a few clinical studies exploring optimal treatments. In recent years, with the rapid progress in local therapy combined with tyrosine kinase inhibitors plus anti-PD-1 inhibitors therapy, improvements in long-term survival have been attained for patients with intermediate and advanced HCC; however, there are few reports on the application of this therapy in HCC patients with EM. To the best of our knowledge, this study is the first to investigate the prognosis of HCC with EM under triple therapy, achieving the longest OS reported to date (mOS, 18.63 months). After triple therapy, 11 (11.7%) patients met the resection criteria, of whom 7 with localized lymph node metastases underwent salvage hepatectomy, and the postoperative pathology showed a MPR in 3 patients.

In this study, the multivariate analysis revealed that sex and AFP were significant determinants of progression, and NLR and AFP were significant determinants of survival after the initial diagnosis of EM. AFP is a tumor biomarker for HCC and is associated with increased cell proliferation, angiogenesis, and cellular resistance to tumor necrosis factor-associated apoptosis. Higher AFP levels have also been associated with a more aggressive HCC phenotype, and numerous studies have reported that high AFP levels are a marker of tumor progression and poor prognosis.30–33 Consistently, the present study found that high AFP levels substantially impacted the prognosis of HCC patients with EM after triple therapy.

Notably, we found that high NLR was an independent predictor of survival in HCC with EM. Various markers of systemic inflammatory response have been explored for their roles in cancer prognosis, and the NLR is one of the simplest markers of inflammation and has been associated with poor prognosis in various types of cancer.34 The precise link between high NLR and poor prognosis has not been fully elucidated, and several studies have confirmed that NLR promotes tumor progression and metastasis through multiple pathways. As a possible explanation, high neutrophil levels may lead to HCC with a growth advantage by increasing pro-angiogenic factors, and relative lymphopenia leads to a weaker lymphocyte-mediated immune response to tumors, thereby resulting in increased EM and decreased survival in patients with HCC.34,35 Thus, a high NLR is strongly associated with poor prognosis in HCC patients with EM receiving triple therapy.

Macrovascular invasion is a well-known predictor of poor survival in patients with HCC, and patients with coexisting macrovascular invasion and EM tend to have larger tumor burdens, more severe cirrhosis, and poorer performance statuses. However, in the current study, macrovascular invasion was not identified as a risk factor. In our previous study,36 we reported that in patients with VP4 grade portal vein thrombus, TACE and lenvatinib plus anti-PD-1 inhibitors could be an effective conversion strategy for unresectable HCC with Vp4, given the presence of deeper tumor response rates and improved prognosis in these patients. Accordingly, triple therapy can be effective in treating HCC with macrovascular invasion, which may explain why macrovascular invasion does not affect prognosis. Although the prognosis of patients with both EM and macrovascular invasion is unfavorable, triple therapy may be an effective treatment option.

It is worth noting that of these 60 patients, 7 underwent salvage hepatectomy. In all 7 patients, metastatic sites were localized lymph node metastases, and lymph node dissection was performed simultaneously during the course of salvage hepatectomy. Kobayashi et al37 retrospectively analyzed the data of 18 patients who underwent hepatectomy and metastatic lymph node dissection, concluding that elective lymph node dissection may provide a survival benefit, especially in patients with only a single lymph node metastasis. However, only a few patients met the criteria for surgical treatment owing to poor hepatic functional reserve and intrahepatic tumor staging. In the current study, triple therapy enabled some patients with HCC and lymph node metastases to undergo salvage hepatectomy. Although our prognostic univariate analysis revealed that subsequent treatment with salvage hepatectomy did not significantly improve the PFS and OS of the patients, we believe that this is a bias, which can be attributed to the small number of patients who underwent salvage hepatectomy after triple therapy, and that the efficacy of salvage surgery needs to be further explored.

This study had some limitations. First, this was a retrospective analysis with a small sample size and limited follow-up time. Thus, further long-term randomized controlled trials are required to confirm our findings. However, to our knowledge, this is the first study to analyze HCC with EM treated with triple therapy. Second, our study did not have a control group; however, we had a better long-term prognosis than reported previously. Third, the choice and duration of anti-PD-1 inhibitors were inconsistent in our study. Although there is no evidence in the literature to suggest that different anti-PD-1 inhibitors exert distinct effects, this could impact patient prognosis. Fourth, most patients in this study had HBV-related HCC, and our findings may warrant judicious application in HCC patients with EM of other etiologies.

Conclusions

In conclusion, our study showed that HCC patients with EM treated with triple therapy had promising survival outcomes. AFP level and NLR are prognostic risk factors for triple therapy in these patients.

Abbreviation

AFP, alpha-fetoprotein; CR, complete response; CT, computed tomography; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; EM, extrahepatic metastases; HCC, hepatocellular carcinoma; mPFS, median progression-free survival; MPR, major pathological response; mOS, median overall survival; mRECIST, modified Response Evaluation Criteria in Solid Tumors; MRI, magnetic resonance imaging; NLR, neutrophil-to-lymphocyte ratio; ORR, objective response rate; PET-CT, positron emission tomography-computed tomography; PD-1, programmed cell death 1; PD, progressive disease; PR, partial response; SD, stable disease; TACE, transcatheter arterial chemoembolization; TRAEs, treatment-related adverse events.

Data Sharing Statement

The data supporting the findings of this study are available within the article.

Acknowledgments

We thank all the staff of the participating hospitals for their efforts, as well as all of the patients for their participation. Mao-lin Yan and Jun-yi Wu should be considered joint corresponding author.

Funding

This study was funded by the Medical Innovation Project of Health and Family Planning Commission of Fujian Province (Grant number: 2022CXA002); the Fujian Provincial Department of Finance (Grant number: 2023GGA006); the Fujian Provincial Health Technology Project (Grant number: 2023CXA005) and the Natural Science Foundation of Fujian Province (Grant number: 2022J011021).

Disclosure

All authors declare that they have no competing interests.

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