Abstract
Background
Transcatheter arterial chemoembolization combined with lenvatinib and PD-1 inhibitors (triple therapy) is a promising therapy for unresectable hepatocellular carcinoma (uHCC). We aimed to assess the characteristics and identify predictors of long-term survival (LTS) in advanced uHCC treated with triple therapy.
Methods
Retrospectively reviewed patients with uHCC who underwent triple therapy between June 2018 and May 2023 at 8 hospitals in China. LTS was defined as an overall survival (OS) ≥ 24 months. Kaplan-Meier curves were used to estimate survival. Univariate and multivariate logistic regression analyses were performed to identify predictors of LTS.
Results
A total of 110 patients were included in this study. With a median follow-up of 31.3 months, the median OS and progression-free survival for the entire cohort were 17.9 months (95% confidence interval [CI], 13.8-21.2) and 11.8 months (95% CI, 9.9-15.3), respectively. Thirty-nine (35.5%) patients had LTS, with 36- and 48-month OS rates of 95.8% and 82.1%, respectively. In contrast, the median OS for patients with non-LTS was 10.9 months (95% CI, 9.9-13.2). The independent predictors of LTS were the absence of portal vein tumor thrombus (odds ratio [OR], 13.71; 95% CI, 3.19-88.08; p < .001), absence of extrahepatic metastasis (OR, 7.81; 95% CI, 2.76-25.82; p < .001), and platelet-albumin-bilirubin grade 1 (OR, 3.15; 95% CI, 1.17-9.15; p = .023).
Conclusions
The absence of portal vein tumor thrombus, absence of extrahepatic metastasis, and platelet-albumin-bilirubin grade 1 were significantly associated with LTS. These findings help guide treatment decisions in advanced uHCC.
Keywords: hepatocellular carcinoma, overall survival, long-term survival, predictors, combination therapy
Implications for practice.
The absence of portal vein tumor thrombus, absence of extrahepatic metastasis, and platelet-albumin-bilirubin grade 1 were significantly associated with long-term survival in patients with advanced unresectable hepatocellular carcinoma receiving triple therapy. These findings provide valuable insights for guiding clinical decision-making in unresectable hepatocellular carcinoma.
Introduction
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the sixth most prevalent malignancy worldwide.1 Most patients are unable to undergo radical surgery at diagnosis owing to its insidious onset and nonspecific symptoms.2-4 Patients with untreated advanced unresectable HCC (uHCC) have an inferior prognosis, with a median overall survival (OS) of only 7 months.5
Over the past decade, rapid advances in systemic therapies, such as molecularly targeted agents and immune checkpoint inhibitors (ICIs), have substantially improved the prognosis of patients with uHCC.6,7 The REFLECT study, a randomized phase 3 non-inferiority trial, revealed that the median OS of patients with uHCC who received lenvatinib was 13.6 months, which was non-inferior to that of 12.3 months for sorafenib.8 Furthermore, a combination of systemic agents has been reported to enhance antitumor activity and prolong the survival of patients with uHCC.9-11 Combination regimens, such as atezolizumab plus bevacizumab12 and durvalumab plus tremelimumab,13 have shown promising survival benefits, with a median OS of 19.2 and 16.4 months, respectively.
The combination of locoregional and systemic treatments has shown encouraging clinical benefits in patients with uHCC.14-18 Specifically, transcatheter arterial chemoembolization (TACE) combined with lenvatinib and PD-1 inhibitors (triple therapy) has emerged as a promising treatment option with manageable toxicity, yielding a median OS of 15.7-29.0 months.19-23 However, survival outcomes varied greatly owing to the high heterogeneity among patients with uHCC. Therefore, it is essential to identify patients who may achieve long-term survival (LTS) before treatment initiation. Although several prognostic factors for triple therapy have been identified, variables associated with LTS remain unclear. Therefore, we conducted this multicenter retrospective study to assess the characteristics and identify predictors of LTS (OS ≥ 24 months) in patients with advanced uHCC treated with triple therapy.
Materials and methods
Study population
We retrospectively reviewed the data of 389 patients with uHCC who underwent triple therapy between June 2018 and May 2023 at 8 tertiary hospitals in China. The hospitals included in this study were Fujian Provincial Hospital, First Affiliated Hospital of Fujian Medical University, Fujian Medical University Union Hospital, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhongshan Hospital of Xiamen University, First Affiliated Hospital of Xiamen University, Second Affiliated Hospital of Nanchang University, and Affiliated Hospital of Guilin Medical University. This study procedure complied with the ethical guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of Fujian Provincial Hospital (approval number: K2024-09-046). Written informed consent was obtained from all patients for participation in this study.
HCC diagnosis was based on the histopathology or clinical criteria of the China Liver Cancer staging system.3 The tumor stage was determined using the Barcelona Clinic Liver Cancer (BCLC) staging system.4 The nonresectability of HCC was evaluated by a multidisciplinary team (MDT). The inclusion criteria for this study were as follows: (1) age between 18 and 75 years, (2) initial diagnosis of uHCC and treatment with triple therapy, (3) BCLC stage C, and (4) Child-Pugh class A. The exclusion criteria were as follows: (1) Eastern Cooperative Oncology Group performance status score > 1, (2) main portal vein tumor thrombus (Vp4), (3) combined with other malignancies, (4) individuals who were still alive with a follow-up < 24 months, and (5) missing critical data. In addition, an exploratory analysis of patients with BCLC stages A and B was performed (Supplementary Tables S3 and S4, and Supplementary Figures S1 and S2).
Triple therapy procedure
Conventional TACE was performed for each patient. Under local anesthesia, a right femoral artery puncture was performed using the Seldinger technique. Hepatic artery angiography was subsequently performed to determine the location, number, size, and feeding arteries of target lesions. A mixed emulsion of pirarubicin and lipiodol (5-20 mL) was infused into tumor-feeding arteries via superselective 5-F catheterization, followed by embolization using gelatin sponge granules. Subsequent TACE procedures were performed on demand every 4-6 weeks, mainly based on the hepatic function and evidence of arterial blood supply to the target lesion.
Lenvatinib and PD-1 inhibitors were administered within 3-14 days after the initial TACE procedure. The patients were treated with lenvatinib orally at a dose of 8 mg/day (body weight < 60 kg) or 12 mg/day (body weight ≥ 60 kg). PD-1 inhibitors were administered intravenously once every 3 weeks (toripalimab 240 mg, tislelizumab 200 mg, pembrolizumab 200 mg, camrelizumab 200 mg, penpulimab 200 mg or sintilimab 200 mg). Lenvatinib and PD-1 inhibitors were discontinued for at least 3 days before and after each TACE procedure. Patients with hepatitis B virus (HBV) infection received regular antiviral therapy (entecavir or tenofovir).
Follow-up
Patients were routinely followed up every 4-8 weeks throughout the treatment, and tumor resectability was evaluated by MDT at each visit. Conversion surgery was considered for patients whose tumors were converted to resectable.24 Patients were required to discontinue lenvatinib for one week and PD-1 inhibitors for 4 weeks before conversion surgery. Postoperative adjuvant therapy with lenvatinib and PD-1 inhibitors was administered for 3-12 months. Patients who did not undergo conversion surgery continued to receive triple therapy until they experienced unacceptable toxicity or disease progression or refused treatment. The subsequent treatment strategy was established through discussion with the MDT and the patient’s wishes.
Efficacy and safety
Tumor response was assessed according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST).25 The objective response rate (ORR) was defined as the proportion of patients achieving a complete or partial response as the best radiological response. The disease control rate (DCR) was defined as the proportion of patients who achieved complete response, partial response, or stable disease. Treatment-related adverse events (TRAEs) were monitored and recorded to evaluate treatment safety, based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events Version 5.0.
Outcomes
OS was calculated from the date of triple therapy initiation to the date of death from any cause. Progression-free survival (PFS) was calculated from the date of triple therapy initiation to the date of disease progression or death from any cause. Patients who had experienced no events at the last follow-up date were right-censored. The primary outcome was LTS, defined as OS ≥ 24 months, irrespective of censoring status. Patients with OS < 24 months were classified into the non-LTS group, and censored patients were excluded from this classification. The secondary outcomes were ORR, DCR, and TRAEs. The data cutoff date was April 30, 2024.
Statistical analysis
Continuous data are expressed as median (interquartile range [IQR]), and categorical data are expressed as frequency (%). Continuous data were compared using the Student’s t test or Mann-Whitney test, and categorical data were compared using Pearson chi-square test or the Fisher exact test. The platelet-albumin-bilirubin (PALBI) score was calculated as 2.02 × log10 bilirubin—0.37 × (log10 bilirubin)² - 0.04 × albumin—3.48 × log10 platelets + 1.01 × (log10 platelets)². The PALBI grade was classified as follows: grade 1 (PALBI score ≤-2.53), grade 2 (-2.53 < PALBI score ≤-2.09), and grade 3 (PALBI score >-2.09).26 Owing to the small number of patients with PALBI grade 3 in the LTS group, grades 2 and 3 were combined into one group. In addition, to facilitate clinical interpretation, age, α-fetoprotein (AFP) levels, protein induced by vitamin K absence-II (PIVKA-II) levels, maximum tumor size, and tumor number were dichotomized during the analysis according to the clinically applicable cutoff values.
Kaplan-Meier curves were used to estimate survival, and the log-rank test was used to compare differences in survival between the groups. The median follow-up time was calculated using the reverse Kaplan-Meier method. Univariate and multivariate logistic regression analyses were performed to identify the predictive factors of LTS. Firth penalized-likelihood multivariate logistic regression was used to reduce the risk of bias due to the small number of events and the sparse distribution of variables.27,28 Variables included in the multivariate analysis were carefully selected based on their statistical significance in the univariate model, clinical relevance, and the number of events available to ensure parsimony in the final model. Multicollinearity was assessed using the variance inflation factor before determining the final model; no multicollinearity was detected among the independent variables. Two sensitivity analyses were conducted after adjusting for more confounding factors. A p-value < .05 was adopted as the threshold for statistical significance. All statistical analyses were performed using R Studio, version 2024.04.2 + 764 (R Studio Inc.).
Results
Patient characteristics
After screening all 389 patients with uHCC treated with triple therapy, 110 were included (Figure 1). The demographic and clinical characteristics of the patients are summarized in Table 1. All patients were diagnosed with advanced stage (BCLC stage C), with a median age of 57.0 (IQR, 50.0-65.8) years, and 94 (85.5%) patients were male. Most patients had HBV infection (96/110, 87.3%). A total of 56 (50.9%) patients had a maximum tumor size of ≥10 cm, and 75 (68.2%) patients had at least 3 tumor lesions. Portal vein tumor thrombus (PVTT) was identified in 22 (20.0%) patients, and extrahepatic metastasis was detected in 40 (36.4%) patients. More than two-thirds of the patients (74/110, 67.3%) were classified as PALBI grade 2 or 3.
Figure 1.
Patient flowchart. Abbreviations: BCLC, Barcelona Clinic for Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; LTS, long-term survival; uHCC, unresectable hepatocellular carcinoma.
Table 1.
Baseline demographic and clinical characteristics of patients.
| Characteristics | All | Non-LTS | LTS | p-Value |
|---|---|---|---|---|
| (n = 110) | (n = 71) | (n = 39) | ||
| Age, years | 57.0 (50.0-65.8) | 54.0 (48.5-63.5) | 62.0 (53.5-68.0) | .003 |
| Age | .011 | |||
| < 55 years | 49 (44.5) | 38 (53.5) | 11 (28.2) | |
| ≥ 55 years | 61 (55.5) | 33 (46.5) | 28 (71.8) | |
| Sex | .853 | |||
| Female | 16 (14.5) | 10 (14.1) | 6 (15.4) | |
| Male | 94 (85.5) | 61 (85.9) | 33 (84.6) | |
| HBV infection | .767 | |||
| Absent | 14 (12.7) | 10 (14.1) | 4 (10.3) | |
| Present | 96 (87.3) | 61 (85.9) | 35 (89.7) | |
| ECOG PS score | .124 | |||
| 0 | 75 (68.2) | 52 (73.2) | 23 (59.0) | |
| 1 | 35 (31.8) | 19 (26.8) | 16 (41.0) | |
| AFP | .167 | |||
| < 400 ng/mL | 44 (40.0) | 25 (35.2) | 19 (48.7) | |
| ≥ 400 ng/mL | 66 (60.0) | 46 (64.8) | 20 (51.3) | |
| PIVKA-II | .401 | |||
| < 400 mAU/mL | 34 (30.9) | 20 (28.2) | 14 (35.9) | |
| ≥ 400 mAU/mL | 76 (69.1) | 51 (71.8) | 25 (64.1) | |
| Maximum tumor size | .020 | |||
| < 10 cm | 54 (49.1) | 29 (40.8) | 25 (64.1) | |
| ≥ 10 cm | 56 (50.9) | 42 (59.2) | 14 (35.9) | |
| Tumor number | .496 | |||
| < 3 | 35 (31.8) | 21 (29.6) | 14 (35.9) | |
| ≥ 3 | 75 (68.2) | 50 (70.4) | 25 (64.1) | |
| PVTT | .004 | |||
| Absent | 88 (80.0) | 51 (71.8) | 37 (94.9) | |
| Present | 22 (20.0) | 20 (28.2) | 2 (5.1) | |
| Extrahepatic metastasis | .003 | |||
| Absent | 70 (63.6) | 38 (53.5) | 32 (82.1) | |
| Present | 40 (36.4) | 33 (46.5) | 7 (17.9) | |
| PALBI grade | .008 | |||
| 1 | 36 (32.7) | 17 (23.9) | 19 (48.7) | |
| 2 and 3 | 74 (67.3) | 54 (76.1) | 20 (51.3) | |
| Total bilirubin, μmol/L | 14.9 (11.1-18.7) | 15.5 (11.4-18.6) | 14.5 (9.00-19.9) | .156 |
| Albumin, g/L | 40.1 (34.4-43.2) | 40.0 (34.0-43.0) | 40.2 (37.2-44.0) | .290 |
| Alanine aminotransferase, IU/L | 36.8 (25.0-63.0) | 40.0 (28.5-63.5) | 30.2 (21.4-58.8) | .054 |
| Aspartate transaminase, IU/L | 53.5 (36.2-85.9) | 65.0 (46.1-90.7) | 40.9 (27.0-64.2) | .003 |
| Hemoglobin, g/L | 138 (124-153) | 138 (122-153) | 138 (132-152) | .340 |
| Platelet count, 10^9/L | 198 (145-248) | 215 (174-257) | 171 (122-208) | .003 |
| INR | 1.06 (0.99-1.11) | 1.06 (1.00-1.10) | 1.05 (0.99-1.12) | .582 |
Abbreviations: AFP, alpha-fetoprotein; ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; INR, international normalized ratio; LTS, long-term survival; PALBI, platelet-albumin-bilirubin; PIVKA-II, protein induced by vitamin K absence-II; PVTT, portal vein tumor thrombus.
Data are presented as median (interquartile range) or number (%).
Thirty-nine (35.5%) patients were included in the LTS group (Table 1). The median age (62.0 years vs 54.0 years, p = .003) and percentage of patients aged ≥ 55 years (71.8% vs 46.5%, P = .011) were higher in the LTS group than in those without LTS. A maximum tumor size ≥10 cm was less common in patients with LTS than those without LTS (35.9% vs 59.2%, P = .020). Additionally, PVTT (5.1% vs 28.2%, P = .004) and extrahepatic metastasis (17.9% vs 46.5%, P = .003) were significantly less common in patients with LTS. More patients in the LTS group were classified as PALBI grade 1 than those in the non-LTS group (48.7% vs 23.9%, P = .008). Aspartate transaminase levels (40.9 vs 65.0 IU/L, P = .003) and platelet counts (171 vs 215 * 109/L, P = .003) were significantly lower in patients with LTS.
Treatment protocol
TACE procedure was administered for a median of 2 times (IQR, 1-3). Six different PD-1 inhibitors were used during treatment: camrelizumab (n = 47), sintilimab (n = 27), tislelizumab (n = 24), toripalimab (n = 7), pembrolizumab (n = 3), and penpulimab (n = 2). The median cycle number of PD-1 inhibitors was 14 (IQR, 8-26), and the median duration of lenvatinib treatment was 11.2 months (IQR, 7.1-18.9 months). A total of 28 (25.5%) patients underwent conversion surgery. In addition, 41 (37.3%) patients received subsequent systemic and/or locoregional treatment. Among them, 12 received regorafenib, 9 underwent hepatic arterial infusion chemotherapy, 6 underwent TACE, 5 received radiofrequency ablation, 4 received radiotherapy, 4 continued with triple therapy, and 1 underwent iodine-125 seed implantation.
Tumor response
Based on the mRECIST, complete response was observed in 18 (16.4%) patients, partial response in 59 (53.6%), stable disease in 17 (15.5%), and progressive disease in 16 (14.5%) patients. ORR and DCR were 70.0% and 85.5%, respectively. The ORR was not statistically different between patients with LTS and non-LTS (82.1% vs 63.4%, P = .068), whereas the DCR was significantly higher in the LTS group (97.4% vs 78.9%, P = .018).
Safety profile
As shown in Supplementary Table S1, 88.2% (97/110) of the patients experienced TRAEs of any grade, and 30.0% (33/110) of the patients reported grade 3-5 TRAEs. The most frequent grade 3-5 TRAEs were abnormal liver function (19.1%), pyrexia (7.3%), hypertension (2.7%), hand-foot syndrome (1.8%), thrombocytopenia (1.8%), fatigue (0.9%), skin rash (0.9%), diarrhea (0.9%), and proteinuria (0.9%). No statistically significant difference was observed in the incidence of TRAEs with any grade (84.6% vs 90.1%, P = .538) and grades 3-5 (23.1% vs 33.8%, P = .240) between patients with LTS and non-LTS.
A total of 10 (9.1%) patients experienced TRAEs leading to dose reduction or interruption of lenvatinib. Interruption of PD-1 inhibitors was observed in 4 patients (3.6%). Moreover, 4 (3.6%) and 6 (5.5%) patients discontinued PD-1 inhibitors and lenvatinib, respectively, due to TRAEs. Treatment-related death occurred in 2 (1.8%) patients: 1 patient died of immune-related hepatitis, and 1 died of upper gastrointestinal bleeding.
Survival outcomes
The median follow-up time for the entire cohort was 31.3 months (95% confidence interval [CI], 29.8-35.8). The median OS and PFS were 17.9 months (95% CI, 13.8-21.2; Figure 2A) and 11.8 months (95% CI, 9.9-15.3; Figure 2B), respectively. In addition, patients with LTS had a median OS (not reached) superior to that of patients without LTS (10.9 months, 95% CI, 9.9-13.2; P < .001; Fig. 3). The 36- and 48-month OS rates in the LTS group were 95.8% and 82.1%, respectively.
Figure 2.
Kaplan-Meier curves for all patients. (A) Overall survival. (B) Progression-free survival.
Figure 3.
Kaplan-Meier curves for overall survival in patients with LTS and non-LTS. LTS, long-term survival.
Predictors of long-term survival
In univariate analysis, age (P = .012), maximum tumor size (P = .021), PVTT (P = .010), extrahepatic metastasis (P = .004), PALBI grade (P = .009), aspartate transaminase levels (P = .016), and platelet counts (P = .005) were associated with LTS (Table 2).
Table 2.
Univariate and multivariate logistic analyses for long-term survival.
| Variables | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | p-value | OR | 95% CI | p-value | |
| Age (< 55 vs. ≥ 55 years) | 0.34 | 0.14-0.77 | .012 | 0.40 | 0.15-1.04 | .061 |
| Sex (female vs male) | 1.11 | 0.35-3.26 | .853 | |||
| HBV infection (absent vs present) | 0.70 | 0.18-2.26 | .566 | |||
| ECOG PS score (0 vs 1) | 0.53 | 0.23-1.20 | .127 | |||
| AFP (< 400 vs. ≥ 400 ng/mL) | 1.75 | 0.79-3.89 | .168 | |||
| PIVKA-II (< 400 vs ≥ 400 mAU/mL) | 1.43 | 0.61-3.29 | .402 | |||
| Maximum tumor size (< 10 vs ≥ 10 cm) | 2.59 | 1.17-5.91 | .021 | 2.67 | 0.97-7.88 | .058 |
| Tumor number (< 3 vs. ≥ 3) | 1.33 | 0.58-3.05 | .497 | |||
| PVTT (absent vs present) | 7.25 | 1.95-47.22 | .010 | 13.71 | 3.19-88.08 | <.001 |
| Extrahepatic metastasis (absent vs present) | 3.97 | 1.62-10.87 | .004 | 7.81 | 2.76-25.82 | <.001 |
| PALBI grade (1 vs 2 and 3) | 3.02 | 1.32-7.03 | .009 | 3.15 | 1.17-9.15 | .023 |
| Total bilirubin, μmol/L | 0.96 | 0.91-1.01 | .189 | |||
| Albumin, g/L | 1.05 | 0.98-1.12 | .207 | |||
| Alanine aminotransferase, IU/L | 1.00 | 0.98-1.00 | .364 | |||
| Aspartate transaminase, IU/L | 0.99 | 0.97-1.00 | .016 | |||
| Hemoglobin, g/L | 1.01 | 0.99-1.03 | .374 | |||
| Platelet count, 10^9/L | 0.99 | 0.99-1.00 | .005 | |||
| INR | 0.16 | 0.00-4.99 | .313 | |||
Abbreviations: AFP, alpha-fetoprotein; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; INR, international normalized ratio; OR, odds ratio; PALBI, platelet-albumin-bilirubin; PIVKA-II, protein induced by vitamin K absence-II; PVTT, portal vein tumor thrombus.
The final variables entered into the multivariate analysis were age, maximum tumor size, PVTT, extrahepatic metastasis, and PALBI grade. Multivariate analysis revealed that the absence of PVTT (odds ratio [OR], 13.71; 95% CI, 3.19-88.08; P < .001), absence of extrahepatic metastasis (OR, 7.81; 95% CI, 2.76-25.82; P < .001), and PALBI grade 1 (OR, 3.15; 95% CI, 1.17-9.15; P = .023) were independent predictors of LTS.
Two sensitivity analyses were performed. Model 1 was adjusted for aspartate transaminase levels and platelet counts, while model 2 was adjusted for AFP and PIVKA-II levels (Supplementary Table S2). After adjusting for different confounding factors, the results showed that PVTT, extrahepatic metastasis, and PALBI grade remained independent predictors of LTS.
Discussion
Studying a unique cohort of patients with uHCC with LTS may aid in screening the dominant population and selecting personalized treatment approaches. In this study, we included 110 patients with advanced uHCC who received triple therapy, of whom 39 (35.5%) had LTS. Notably, the 48-month OS rate of patients with LTS reached 82.1%. The long-term prognostic benefits are likely due to the enhanced anticancer activity resulting from the synergistic effect of triple therapy. TACE leads to tumor necrosis and increases the release of tumor antigens, which may boost the efficacy of PD-1 inhibitors.29-31 Lenvatinib not only counteracts post-TACE angiogenesis but also improves the antitumor efficacy of PD-1 inhibitors by immunomodulatory effects.32-34 However, the specific mechanisms require further investigation.
There is no generally accepted definition for LTS in patients with advanced uHCC. Similar to our study, Reis et al35 defined LTS as OS ≥ 24 months in a retrospective study of sorafenib-treated patients with advanced uHCC. Twenty-five (32.5%) patients were identified as LTS in their study. The research conducted by Chen et al.36 included 181 patients with uHCC with PVTT who underwent TACE; LTS was defined as survival > 12 months and was observed in 31 (17.1%) patients. Monge et al.37 considered patients who survived more than 3 years as LTS in patients with advanced uHCC treated with ICI therapy, and 5 (8.5%) had LTS. Evidence shows that the median OS for untreated uHCC was 7 months, and it was 15.7-29.0 months in uHCC treated with triple therapy.5,23 Based on previous similar studies and the reported median OS of triple therapy, we think the cutoff of 24 months was reasonable and clinical conformity. Establishing a dichotomous system for OS may aid daily clinical practice by facilitating the selection of suitable patients for triple therapy and predicting the estimated survival outcomes.
Although several studies have reported the prognosis of triple therapy and its predictive factors, to the best of our knowledge, no study has focused on identifying a subgroup of patients with durable survival. In this study, 3 baseline variables were identified as predictors of LTS: the absence of PVTT, the absence of extrahepatic metastasis, and PALBI grade 1. These predictors remained significant even after adjusting for different confounders. These findings may assist in guiding clinical decisions and in facilitating more personalized therapeutic regimens in advanced uHCC. Similar to our study, Reis et al35 found that the absence of PVTT and Child-Pugh class A were predictors of LTS in sorafenib-treated patients with advanced uHCC. In patients with uHCC treated with triple therapy, PVTT and extrahepatic metastasis were 2 significant factors associated with survival.38-40 Liu et al39 discovered that PVTT and extrahepatic metastasis were independent predictors of shorter OS in patients with advanced HCC who were treated with triple therapy. Our previous study also found that the presence of extrahepatic metastasis was associated with inferior OS in patients with uHCC treated with triple therapy.40 Therefore, the evaluation of the status of PVTT and extrahepatic metastasis at diagnosis is important for advanced uHCC when selecting a treatment strategy.
In addition to the tumor burden, liver functional reserve is also an important factor in determining the prognosis of HCC.41,42 A meta-analysis of triple therapy in advanced HCC showed that Child-Pugh class B was significantly associated with poor OS and PFS.22 PALBI grade is an objective method to estimate liver function in HCC and has been demonstrated to be a predictor of survival.43-46 The PALBI grade was developed based on the albumin–bilirubin grade, with platelet count added as a surrogate marker for portal hypertension. Several studies revealed that the PALBI grade provided a better predictive value of survival than the albumin-bilirubin grade in patients with HCC receiving different therapies.47-49 In this study, we found that patients with PALBI grade 1 are more likely to achieve LTS. Similar to our study, Hu et al45 found that patients with PALBI grade 1 had a more favorable survival outcome among patients with HCC and Child-Pugh class A undergoing TACE combined with sorafenib. These findings highlight the importance of assessing liver functional reserve in patients with uHCC.
Monge et al37 found that the occurrence of grade 3/4 immune-related adverse events was associated with LTS in patients with advanced HCC treated with ICIs. Contrary to their finding, we observed that patients with LTS tended to have a lower incidence of TRAEs than those with non-LTS (any grade: 84.6% vs 90.1%; grades 3-5: 23.1% vs 33.8%), although this was not statistically significant. A possible reason may be that the most frequent TRAEs for this study were abnormal liver function, which is commonly associated with inferior survival in patients with uHCC. Shimose et al.50 investigated the association between adverse events and prognosis in patients with HCC treated with atezolizumab plus bevacizumab. They found that the development of liver injury was significantly correlated with shorter OS. Shen et al51 discovered that the presence of liver injury is associated with poor prognosis in patients with HBV-related HCC-treated with triple therapy. Therefore, regular liver function examinations and appropriate management of TAREs are needed in patients with advanced uHCC-treated with triple therapy.
This study had some limitations. First, triple therapy is not a standard first-line treatment for patients with uHCC according to current treatment guidelines. However, an increasing number of studies have demonstrated the efficacy and safety of triple therapy, leading to its widespread use as a first-line therapy for uHCC in China.17,18,23 Further phase III clinical trials are ongoing and are likely to produce positive results.52 Second, a selection bias might exist owing to the retrospective study design; thus, the results should be validated in future prospective controlled studies. Third, most patients included in the present study had HBV infection, and it is unknown whether the results can be generalized to patients with uHCC of other etiologies. Fourth, 6 different PD-1 inhibitors were used in this study; therefore, consistency of efficacy may not be guaranteed. Finally, potential prognostic biomarkers at the gene or molecular level have not yet been explored. However, given the high cost of biomarker tests, the variables included in this study are more commonly used and easier to apply clinically.
Conclusions
In patients with advanced uHCC who received triple therapy, the absence of PVTT, absence of extrahepatic metastasis, and PALBI grade 1 independently predicted LTS. Patients with these baseline characteristics may be more eligible for triple therapy. However, further prospective controlled studies with long-term follow-up are required to validate these findings.
Supplementary Material
Acknowledgments
None.
Contributor Information
Zhen-Xin Zeng, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China.
Hua-Chun Song, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China.
Yi-Nan Li, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China.
Jia-Yi Wu, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian Province, People’s Republic of China.
Dong Liang, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian Province, People’s Republic of China; Department of General Surgery, Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People’s Republic of China.
Shu-Qun Li, Department of Hepatobiliary Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Province, People’s Republic of China.
Zhi-Bo Zhang, Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China.
Shao-Wu Zhuang, Department of Interventional Radiology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian Province, People’s Republic of China.
Bin Li, Department of Hepato-Biliary-Pancreatic and Vascular Surgery, First Affiliated Hospital of Xiamen University, Xiamen, Fujian Province, People’s Republic of China.
Jian-Yin Zhou, Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian Province, People’s Republic of China.
De-Yi Liu, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China.
Han Li, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China.
Xiang-Ye Ou, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China.
Rong-Jian Pan, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China.
Jun-Yi Wu, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian Province, People’s Republic of China.
Mao-Lin Yan, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; Department of Hepatobiliary Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian Province, People’s Republic of China.
Authors contributions
Conceptualization: Zhen-Xin Zeng, Hua-Chun Song, Yi-Nan Li, Jun-Yi Wu, and Mao-Lin Yan. Material preparation, data collection, and analysis: Jia-Yi Wu, Dong Liang, Shu-Qun Li, Zhi-Bo Zhang, Shao-Wu Zhuang, Bin Li, and Jian-Yin Zhou. Investigation and visualization: De-Yi Liu, Han Li, Xiang-Ye Ou, and Rong-Jian Pan. Funding acquisition: Jia-Yi Wu, Dong Liang, Jun-Yi Wu, and Mao-Lin Yan. Writing-Original Draft: Zhen-Xin Zeng, Hua-Chun Song, and Yi-Nan Li. Writing-Review & Editing: All authors. All authors read and approved the final manuscript.
Funding
This study was funded by the Medical Innovation Project of Fujian Provincial Health Commission (Grant number: 2022CXA002, 2023CXA005), the Fujian Provincial Health Technology Project of Fujian Provincial Health Commission (Grant number: 2023GGA006), and the Natural Science Foundation of Fujian Province (Grant number: 2022J011021, 2023J01839). Funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Conflicts of interest
The authors declare no potential conflicts of interest.
Data availability
The data underlying this article cannot be shared publicly due to the privacy of individuals who participated in the study. The data will be shared on reasonable request to the corresponding author.
Ethics approval
This study was conducted in accordance with the Declaration of Helsinki with approval from the Institutional Review Board of Fujian Provincial Hospital (approval number: K2024-09-046).
Patient consent
Written informed consent was obtained from all patients for participation in this study.
Conflict of Interest
None declared.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data underlying this article cannot be shared publicly due to the privacy of individuals who participated in the study. The data will be shared on reasonable request to the corresponding author.