Sequential surgery following conversion therapy based on combination of immune checkpoint inhibitors and antiangiogenic targeted drugs as a potential approach for advanced hepatocellular carcinoma with portal vein tumor thrombus: a prospective study

Introduction

Hepatocellular carcinoma (HCC) has emerged as the sixth most common malignancy and the third leading cause of cancer-related deaths worldwide, with its global burden showing a progressive worsening trend (1). Approximately 60% of HCC patients are diagnosed at Barcelona Clinic Liver Cancer (BCLC) stage B or C, indicating intermediate to advanced disease. Portal vein tumor thrombus (PVTT), a frequent complication occurring in 44–62.2% of HCC cases (2), signifies advanced disease progression. The occurrence of PVTT can lead to systemic metastasis, portal hypertension, and increased risks of gastrointestinal hemorrhage (3,4). Previous studies demonstrated a median survival of merely 2.0–9.7 months for HCC patients with PVTT, underscoring its dismal prognosis (5-8). Currently, there remains ongoing debate between Eastern and Western medical communities regarding whether surgical intervention should be performed for HCC with PVTT. Western guidelines, including the 2026 National Comprehensive Cancer Network (NCCN) HCC Guidelines and 2025 European Society for Medical Oncology (ESMO) Clinical Practice Guidelines (9,10), consider PVTT a contraindication for surgical resection. Clinical outcomes from Eastern Asian medical centers performing direct surgery on HCC with PVTT reveal high risks of early postoperative recurrence, with survival rates ranging from 23.8% to 39.1% (7). However, existing non-surgical interventions such as hepatic artery infusion chemotherapy (HAIC), transarterial embolization (TAE), and transcatheter arterial chemoembolization (TACE) also demonstrate limited efficacy for PVTT patients. Reported objective response rates (ORRs) and disease control rates (DCRs) for these modalities range from 15.6–28.0% and 3.9–37.9% respectively (11-13), indicating suboptimal local therapeutic outcomes.

Recent advancements in immune checkpoint inhibitor (ICI) combined with anti-angiogenic targeted drug (AATD) therapies (conversion therapy) have revolutionized treatment paradigms for advanced HCC. Multiple phase III clinical trials have validated the efficacy and safety of immune-targeted conversion therapies, achieving ORR of 19.0–54.2% and median overall survival (OS) of 19.2–22.1 months (14-17), significantly surpassing targeted monotherapy outcomes. Current guidelines now prioritize immune-targeted conversion therapy as first-line treatment for advanced HCC (15,18,19). This progress has prompted the concept of conversion therapy combining targeted and immunotherapeutic agents to downstage tumors for subsequent radical resection, which is termed as sequential surgery following conversion therapy based on combination of ICIs and AATDs. Emerging evidence suggests that post-conversion surgical intervention may prolong survival and reduce recurrence risks. Our team initiated a prospective study in 2018 investigating this approach for initially unresectable HCC. Preliminary results demonstrated significantly improved 1-year and 2-year recurrence-free survival (RFS) rates of 65.4% and 56% in the conversion therapy group versus 29.4% and 21% in the surgery-only group (12), confirming survival benefits of conversion therapy.

Building upon our extensive clinical experience in sequential surgery following conversion therapy based on combination of ICIs and AATDs for advanced HCC, we conducted a prospective interventional cohort study of 76 HCC patients with PVTT. Here we report the 5-year survival outcomes in this population, with the aim of exploring the potential of sequential surgery following conversion therapy as a treatment approach for advanced HCC with PVTT. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0147/rc).

Methods

Patients

We collected data from 76 patients with HCC complicated by PVTT who underwent surgical resection after receiving conversion therapy with programmed death-1 (PD-1) inhibitors and tyrosine kinase inhibitors (TKIs) at Chinese People’s Liberation Army General Hospital between June 2019 and June 2024. A rigorous research protocol was developed prior to patient enrollment, and the study was strictly executed in accordance with the protocol. All patients met the following inclusion criteria: (I) HCC confirmed histologically or cytologically, or clinically diagnosed HCC, according to the guidelines of the American Association for the Study of Liver Diseases (AASLD); (II) PVTT confirmed by imaging, based on the criteria of the Japanese Society of Hepatology (20); (III) age 18–75 years; (IV) at least three cycles of PD-1 inhibitors combined with TKIs treatment and assessable tumor response; (V) successful surgical treatment after conversion therapy; (VI) Child-Pugh stage of A or B; (VII) Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of ≤1; (VIII) expected survival time of ≥12 weeks; (IX) no history of esophageal or gastric variceal bleeding attributable to portal hypertension within the past 6 months; (X) no prior use of PD-1 inhibitors, TKIs, or other immune or targeted therapies; (XI) at least one measurable tumor based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST).

The exclusion criteria were as follows: (I) patients with severe diseases or complications affecting other systems; (II) patients with incomplete clinical, imaging, or survival data.

This study adhered to the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of Chinese People’s Liberation Army General Hospital (No. S2018-111-01). All experiments involving human participants and the use of human tissue samples in this study were conducted in accordance with the ethical standards of the institutional and national research committee. This study has been officially registered with the registration number: ChiCTR1900023914. Written informed consent was obtained from all patients before conversion treatment and surgery.

Conversion therapy and efficacy assessment

All eligible patients received a conversion treatment regimen combining PD-1 inhibitors with TKIs. The interval between a single dose of PD-1 inhibitor and the next dose was defined as one treatment cycle. Patients receiving combination therapy were followed up regularly every 3 months. At each follow-up, disease progression and drug tolerance were assessed. Any drug-related SAEs occurring during the treatment period were documented. mRECIST v1.1 was used for assessing the tumor response. Additionally, the staging of PVTT was assessed to determine if there was any downstage. The maximum tumor diameter at baseline (pre-treatment) and at the time of conversion treatment (post-treatment) was also compared. In cases of multiple tumors, the maximum diameter of the largest tumor was used for analysis.

Radical surgery

After successful conversion, all patients signed the surgical consent form and underwent sequential surgical treatment. Before undergoing radical resection, all patients were required to undergo hematological tests and contrast-enhanced magnetic resonance imaging (MRI). Tumor progression was assessed according to the mRECIST criteria (21). According to the Expert consensus on sequential surgery following conversion therapy based on combination of ICIs and AATDs for advanced HCC (15), the indications for successful conversion were as follows: (I) liver function classified as Child-Pugh A or B; (II) sufficient remnant liver volume after surgical resection. For non-cirrhotic patients, the remnant liver volume should be ≥35% of the standard liver volume; for cirrhotic patients, it should be ≥45%; (III) indocyanine green 15-minute retention rate <20%; (IV) postoperative liver vascular inflow and outflow pathways maintain structural integrity, with unobstructed blood flow; (V) no extrahepatic lesions assessed by positron emission tomography-computed tomography (PET-CT) (or lung CT, bone scan, etc.) or extrahepatic lesions can be R0 resected, or extrahepatic lesions are tend to be judged inactive by multidisciplinary team (MDT); (VI) postoperative biliary structures are intact, with unobstructed drainage; (VII) ECOG PS score of 0–1; (VIII) American Society of Anesthesiologists classification not exceeding grade III.

The radical surgical approach was selected based on comprehensive preoperative evaluation, including patient tolerance, tumor characteristics, and PVTT extent. Three principal techniques were utilized (5,22-24): (I) hepatectomy with en bloc resection of ipsilateral tumor thrombus, appropriate for Vp2–Vp3 PVTT distant from main portal branches; (II) hepatectomy with portal vein thrombectomy, primarily indicated for Vp3–Vp4 PVTT to prevent residual thrombus and reduce recurrence; (III) hepatectomy with portal vein resection and reconstruction, employed for Vp3–Vp4 PVTT with venous wall invasion where complete thrombus removal is unfeasible.

Other surgical details, such as the extent of liver resection (whether it is major hepatectomy, i.e., removal of ≥3 liver segments) or the use of laparoscopy, were determined by experienced specialist surgeons. All resected tumor specimens were subjected to pathological assessment to assess the proportion of residual viable tumor cells.

Postoperative adjuvant therapy selection

Based on the pathological necrosis status of the patient, if no residual viable tumor cells are present, the patient is determined to have achieved a pathological complete response (pCR). If the percentage of residual viable tumor cells is ≤10%, the patient is considered as major pathological response (mPR). For patients who achieve pCR, the postoperative adjuvant therapy subjected to PD-1 antibody from the previous treatment regimen for 6 months. For patients who do not meet the mPR criteria (non-mPR), the postoperative adjuvant therapy consists of PD-1 antibody plus TKIs from the previous treatment regimen for 12 months.

Evaluation of treatment safety

Adverse events (AEs) from conversion therapy were recorded at each follow-up and graded per CTCAE v5.0. Perioperative safety included postoperative complications graded by Clavien-Dindo classification (25), intraoperative blood loss, surgical duration, and Child-Pugh score at postoperative day 5. Portal vein patency was evaluated via follow-up imaging in patients undergoing thrombectomy or reconstruction, with portal vein thrombosis (PVT) classified by the Yerdel system (26).

End points

The primary follow-up end points were RFS, defined as the time from radical surgery to radiological confirmation of recurrence or death from any cause, and OS, defined as the time from initial diagnosis to death from any cause. All patients underwent regular treatment and follow-up after discharge, and those lost to follow-up were excluded from the study. To ensure data completeness, we implemented rigorous follow-up management measures, including assigning dedicated personnel for point-to-point patient contact and establishing a tiered follow-up protocol, among others. The follow-up cutoff date was September 1, 2025.

Statistical analysis

The statistical analysis plan was established at the beginning of the study. Data analysis was performed using SPSS 27.0 (IBM, Armonk, NY, USA) and R 4.4.2. Categorical variables are presented as frequency (percentage), and continuous variables as mean (± standard deviation) or median (range) based on distribution. Baseline characteristics were summarized descriptively. Between-group comparisons utilized Wilcoxon signed-rank and Cochran-Mantel-Haenszel tests. Survival curves were generated via the Kaplan-Meier (K-M) method. Univariate and multivariate Cox regression analyses were conducted to identify risk factors and estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Before performing multivariate Cox regression analysis, multicollinearity among all candidate variables was assessed to evaluate whether there were strong correlations between variables. Variance inflation factor (VIF) and tolerance were used as the primary diagnostic indicators, with VIF >5 or tolerance <0.2 indicating significant collinearity. To explore differences in treatment benefit across patient subgroups with distinct clinicopathological characteristics and to identify potential predictors of efficacy, prespecified and exploratory subgroup analyses were performed. All subgroup analyses were performed using the Kaplan-Meier method to generate survival curves, and the log-rank test was used for between-group comparisons. Continuous variables were categorized to enhance model fit.The sample size of this study was estimated based on the 3-year recurrence-free survival (RFS) rate. According to published literature, the 3-year RFS rate in patients with advanced HCC and PVTT after upfront surgery is approximately 23% (P₀). We hypothesized that sequential surgery after conversion therapy would increase the 3-year RFS rate to 41% (P₁). A one-sided exact test for a single proportion (alternative hypothesis H₁: P > P₀) was used, with a significance level α =0.05 and a power (1 − β) =0.90. The sample size was calculated using PASS 15.0 software. The results showed that the minimum required sample size was 54 patients. After considering a 20% dropout rate, the required sample size was 68 patients.

Results

Baseline characteristics

One-hundred patients with advanced HCC complicated by PVTT treated at Chinese People’s Liberation Army General Hospital were assessed for eligibility between June 2019 and June 2024. After applying the inclusion and exclusion criteria, 76 patients were enrolled in the study (Figure 1). The baseline data for all patients are summarized and presented in Table 1. According to the BCLC staging system, all the 76 patients were classified as stage C. The majority of patients exhibited a significant elevation in alpha-fetoprotein (AFP) levels, with a median AFP level of 437.3 ng/mL (range, 1.7–60,500 ng/mL). The mean maximum tumor diameter was 85.6 mm (range, 49.1–122.1 mm), and PVTT was predominantly classified as Vp3 (n=39, 51.3%) and Vp4 (n=23, 30.3%) stages, indicating invasion of the main branches of the portal vein. Baseline data analysis indicates that the patients in this cohort were overall in the advanced stage of HCC.

Figure 1 Flow diagram of this study. HCC, hepatocellular carcinoma; mRECIST, the modified response evaluation criteria in solid tumors; PD-1, programmed death-1; PVTT, portal vein tumor thrombus; TKI, tyrosine kinase inhibitors.

Conversion therapy efficacy

The treatment regimens and preoperative treatment cycles are detailed in supplementary appendix online (Table S1). The median treatment cycle was 5 (range, 3–37). The most common combination regimen was sintilimab plus lenvatinib (55 patients, 72.4%), followed by pembrolizumab plus lenvatinib (8 patients, 10.5%). The most recent preoperative mRECIST evaluation results are shown in Table 2. Based on the mRECIST assessments, 13 (17.1%) patients achieved complete response (CR), 49 (64.5%) patients achieved partial response (PR), 10 (13.2%) patients achieved stable disease (SD) and only 4 (5.2%) patients were evaluated as progressive disease (PD). The median maximum tumor diameter after treatment was 57.5 mm (range, 8.0–181.0 mm), while before treatment was 85.6 mm (range, 49.1–122.1 mm). Eleven (14.5%) patients had complete disappearance of PVTT (Table 2). Compared to baseline, 32 (42.1%) patients showed a downstaging of PVTT. The serum AFP levels were also monitored during treatment. Before conversion therapy, the median AFP level was 437.3 ng/mL (range, 1.7–60,500 ng/mL), with 21 (27.6%) patients having AFP levels within the normal range (<20 ng/mL). After conversion therapy, the median AFP level decreased to 6.60 ng/mL (range, 0.74–39,464 ng/mL), and 52 (68.4%) patients had AFP levels within the normal range.

After successful conversion therapy and evaluation by a multidisciplinary surgical team, all patients underwent radical surgery resection. A total of 38 (50.0%) patients underwent en bloc resection, 29 (38.2%) underwent hepatectomy with portal vein thrombectomy, and 9 (11.8%) patients underwent hepatectomy with portal vein resection and reconstruction (Table 2). Detailed surgical information is presented in Table 2. The median proportion of residual cancer cells was 10% (range, 0–100%). Seventeen patients (22.4%) achieved pCR, 24 patients (31.6%) achieved mPR (Table 2). Thirty patients (55.6%) showed complete necrosis of the tumor thrombus. The median proportion of residual tumor cells in the thrombus was 0% (range, 0–90%).

Safety of conversion therapy and sequential surgery

During conversion therapy, 55 patients (72.4%) experienced adverse events. Twenty-one (27.6%) patients had grade 1 adverse events, 23 (30.3%) had grade 2 adverse events, and 11 (14.5%) had grade 3 adverse events. No patients experienced grade 4 or higher severe adverse events (Table 2).

The evaluation of postoperative complications revealed that 18 (23.7%) had grade II complications, and 5 (6.6%) had grade IIIa complications (Table 2). Notably, 2 (2.6%) patients experienced grade IV severe complications: one patient was admitted to the ICU attributable to severe hypoproteinemia and infection, and the other attributable to pulmonary embolism. Both patients recovered and were discharged after treatment. No patients experienced grade V complications, which would indicate death resulting from surgical complications (Table 2).

As illustrated in Table 2, two patients developed grade 1 PVT, and 2 patients developed grade 2 PVT postoperatively. After anticoagulation therapy, the thrombus resolved completely in both patients with grade 1 PVT, while the 2 patients with grade 2 PVT exhibited cavernous transformation of the portal vein during follow-up. However, imaging assessments revealed that both patients had developed collateral circulation as a compensatory mechanism, and no severe liver dysfunction or related symptoms were observed. As of the cut-off date, the long-term portal vein patency rate was 97.4%.

Follow-up results

Survival data

As of April 1, 2025, the median follow-up duration was 39.5 months (range, 7–71 months). Recurrence occurred in 44 patients (57.9%), and 25 patients (32.9%) had died attributable to tumor. K-M curves for OS and RFS were constructed, as shown in Figure 2. The 6-month, 1-year, 2-year, and 3-year recurrence-free rates were 76.2%, 59.7%, 48.1%, and 42.5%, respectively. The 6-month, 1-year, 2-year, 3-year, and 5-year survival rates were 98.7%, 93.4%, 78.1%, 72.4%, and 45.5%, respectively. The median RFS was 21 months (Figure 2A), and the median OS was 62 months (Figure 2B).

Figure 2 The Kaplan-Meier survival curves for RFS and OS in the entire cohort and in subgroup analyses. (A) RFS curve for all the patients. (B) OS curve for all the patients. (C) RFS curves for Vp1/2 and Vp3/4 patients. (D) OS curves for Vp1/2 and Vp3/4 patients (Vp stage =1 means Vp1/2 subgroup; Vp stage =2 means Vp3/4 subgroup). (E) RFS curves for patients in mRECIST CR/PR subgroup and SD/PD group. (F) OS curves for patients in mRECIST CR/PR subgroup and SD/PD group. (G) RFS curves for patients in pathological pCR&mPR subgroup and non-mPR group. (H) OS curves for patients in pathological pCR&mPR subgroup and non-mPR group. CR, complete response; mPR, major pathological response; mRECIST, modified Response Evaluation Criteria in Solid Tumors; OS, overall survival; pCR, pathological complete response; PD, progressive disease; PR, partial response; RFS, recurrence-free survival; SD, stable disease.

Subgroup analysis

Subgroup analysis was performed based on the initial PVTT staging. Patients were divided into two groups: Vp1–2 and Vp3–4, and K-M curves for OS and RFS were plotted for each group (Figure 2C-2H). In the Vp1–2 group, the 6-month, 1-year, and 2-year recurrence-free rates were 71.4%, 57.1%, and 49.0%, respectively. In the Vp3–4 group, the 6-month, 1-year, 2-year, and 3-year recurrence rates were 77.2%, 58.6%, 45.7%, and 40.9%, respectively (Figure 2C). For OS, the 1-year, 2-year, and 3-year survival rates for the Vp1–2 group were 92.9%, 85.1%, and 75.7%, while the corresponding survival rates for the Vp3–4 group were 91.9%, 75.4%, and 69.4% (Figure 2D). No significant difference in RFS and OS was found between the two groups (P>0.05).

To assess the impact of conversion therapy on survival outcomes, subgroup analyses were conducted based on radiological and pathological responses. According to radiological evaluation, patients achieving CR/PR exhibited 1-, 2-, and 3-year recurrence-free rates of 65.8%, 55.1%, and 48.5%, respectively, compared to 6-month and 1-year rates of 57.1% and 28.6% in the SD/PD group (Figure 2E). OS rates at 1, 2, and 3 years were 91.9%, 83.6%, and 77.4% in the CR/PR subgroup versus 78.6%, 48.2%, and 40.2% in the SD/PD subgroup (Figure 2F). Significant differences were observed in both OS (P=0.004) and RFS (P<0.001) between the two subgroups. Subgroup analysis based on pathological assessment revealed that the mPR (including pCR) group showed 1-, 2-, and 3-year recurrence-free rates of 72.3%, 61.6%, and 54.5%, respectively, compared to 43.7%, 31.2%, and 18.5% in the non-mPR group (Figure 2G). OS rates at 1, 2, and 3 years were 97.5%, 89.3%, and 82.9% in the mPR group versus 84.2%, 62.9%, and 57.2% in the non-mPR group (Figure 2H). Significant differences were observed for both OS (P=0.01) and RFS (P=0.008) between the two groups.

Cox regression

Cox regression indicated that liver cirrhosis (HR =4.801; 95% CI: 1.047–22.016; P=0.043), multiple tumors (HR =4.353; 95% CI: 1.708–11.095; P=0.002), and preoperative AFP levels ≥20 ng/mL (HR =4.918; 95% CI: 1.745–13.864; P=0.003) are independent significant risk factors for patient mortality. Postoperative pathological evaluation showing non-mPR (HR =2.080; 95% CI: 1.112–3.892; P=0.02) and tumor diameter before surgery >50 mm (HR =1.938; 95% CI: 1.017–3.694; P=0.044) are independent significant risk factors for recurrence (Table 3). Multicollinearity analysis showed that all variables included in the final multivariate Cox regression model had VIF values <5 and tolerance values >0.2, indicating no significant collinearity among the variables (Table S2).

Discussion

Multiple international clinical guidelines suggest that surgery is not suitable for patients with advanced PVTT (19,27,28). However, increasing evidence from studies indicates that conversion therapy can provide a potential opportunity for surgery in patients with initially unresectable advanced HCC with PVTT. As a result, sequential surgery following conversion therapy is gradually becoming an important component of the treatment strategy for advanced HCC.

To confirm the efficacy of sequential surgery following conversion therapy, as well as the long-term survival and recurrence rates, our study included 76 patients with advanced HCC complicated by PVTT who were initially considered unresectable. All patients underwent surgical resection following successful conversion therapy. Long-term follow-up demonstrated the efficacy of this treatment regimen, with a median RFS of 21 months, a median OS of 62 months (Figure 2A,2B). The 3-year recurrence-free rates were 42.5% and 5-year OS rates were 45.5%.

Further prognostic factor analysis revealed that preoperative AFP level was a significant factor influencing patient survival (29). Our team’s previous studies have demonstrated that for 50 patients with HCC and PVTT treated with sequential surgery following conversion therapy, the 1- and 2-year OS rates were 95.0% and 88.2%, respectively, in the normal AFP group, compared to 73.4% and 54.1% in the control group (30). This suggests the decrease in serum AFP to normal levels after conversion therapy can serve as a predictive marker for survival benefits from subsequent surgical resection. In our study, patients with preoperative AFP levels ≥20 ng/mL had a death risk 4.918 times higher than those with AFP <20 ng/mL (95% CI: 1.745–13.864; P=0.003) (Table 3). In the analysis of the efficacy of conversion therapy, we observed that after conversion treatment, AFP levels significantly decreased, with the median AFP dropping from 437.3 ng/mL at baseline to 6.60 ng/mL. This suggests that conversion therapy can significantly reduce AFP levels and, consequently, lower the risk of patient mortality.

Similarly, analysis of recurrence factors revealed that the preoperative maximum tumor diameter, the residual cancer cells within the tumor were significantly associated with recurrence (Table 3). We found that after treatment, the tumor maximum diameter significantly reduced, with the median size decreasing from 85.6 mm (range, 49.1–122.1 mm) to 57.5 mm (range, 8.0–181.0 mm). The proportion of residual viable cancer cells within the tumor decreased significantly, with a median proportion of only 10% (range, 0–100%); 17 patients (22.4%) achieved pCR, and 24 patients (31.6%) achieved mPR (Table 2). Additionally, subgroup analysis based on preoperative mRECIST imaging assessment showed that patients with CR/PR had higher 1-, 2-, and 3-year survival rates compared to those with SD/PD (91.9% vs. 78.6%, 83.6% vs. 48.2%, 77.4% vs. 40.2%) (Figure 2E,2F). The prognostic value of pathological response to treatment has been reported previously. Studies have shown that achieving pCR in advanced HCC patients undergoing systemic treatment is associated with better RFS (31), which is consistent with our findings.

We also observed that conversion therapy was effective against PVTT. After treatment, 32 patients (42.1%) had a downstage in PVTT stage, and 11 patients (14.5%) had complete disappearance of PVTT (Table 2). The comparison of PVTT stage before and after conversion therapy showed a significant difference (P<0.001). Pathological analysis of the residual cancer cells in PVTT from 54 patients showed 30 patients had complete necrosis of PVTT (Table 2). This suggests that conversion therapy can effectively induce necrosis and shrinkage of PVTT, reducing the risk of distant metastasis via PVTT and early postoperative recurrence. Furthermore, subgroup analysis based on PVTT staging revealed no significant differences in OS and RFS between Vp1–2 and Vp3–4 groups, suggesting that conversion therapy could provide comparable survival benefits for advanced PVTT patients to those with lower-grade PVTT (Figure 2C,2D).

Based on the aforementioned findings, we propose that from oncological perspective, conversion therapy reduces tumor cell activity and decreases the patient’s tumor burden, and from radical surgery perspective, tumor shrinkage, necrosis, and PVTT downstage increase the likelihood of successful radical resection, reduce the surgical resection scope, and minimize the need for complex surgical techniques (32). Hence, we are confident that conversion therapy reduces the risk of recurrence and mortality, further confirming its effectiveness.

Based on the results of this study and our team’s clinical experience, we believe that surgery is also an important component of the overall treatment for advanced HCC with PVTT. After conversion therapy enables initially unresectable HCC with PVTT patients to become eligible for surgical resection, radical surgery benefits patient recurrence and survival (33). Current research indicates that the ORR for advanced HCC with PVTT patients treated with conversion therapy alone ranges from 23.3% to 70%, with conversion success rates from 15.9% to 55.4% (34-38). In contrast, all patients in our study received sequential surgery after conversion therapy, with a median OS of 62 months and median RFS of 21 months. This study is the first to report a 5-year survival rate of 45.5% for advanced HCC with PVTT patients treated with this approach, confirming that sequential surgery following conversion therapy improves both OS and RFS. Moreover, surgical resection of the tumor and cancer thrombus followed by pathological evaluation provides better prognostic guidance (31). Subgroup analysis of pathological evaluation results confirmed this finding, showing that the 1-, 2-, and 3-year survival rates were higher in the mPR (including pCR) group compared to the non-mPR group (97.5% vs. 84.2%, 89.3% vs. 62.9%, 82.9% vs. 57.2%). The 1-, 2-, and 3-year RFS rates were also higher in the mPR group (72.3% vs. 43.7%, 61.6% vs. 31.2%, 54.5% vs. 18.5%) (Figure 2G,2H). These findings suggest pathological evaluation results are associated with patient prognosis.

Based on the above discussion regarding the efficacy of conversion therapy and sequential surgery, it is evident that both approaches confer survival benefits to patients. Conversion therapy significantly reduces tumor burden and creates surgical opportunities, while sequential surgery enables radical tumor removal, achieving a tumor-free state and providing pathological prognostic insights (39). This study has some heterogeneity in treatment regimens, mainly reflected in the variety of drug combinations, which represents a potential limitation. However, on the one hand, this heterogeneity reflects the diversity of real-world clinical practice. On the other hand, from the perspective of drug mechanisms, the immunotherapeutic agents used in this study are all ICIs, and the targeted agents are all multitargeted TKIs, sharing a unified theoretical basis for synergistic antitumor activity (40,41). The subgroup analysis of different regimens also supports this conclusion: comparing the sintilimab plus lenvatinib group (n=55) with the other regimens group (n=21) showed no statistically significant difference between the two groups (RFS: P=0.60; OS: P=0.80) (Figure S1), suggesting that, in this study population, the difference in efficacy among different treatment regimens is limited. Therefore, sequential surgery following conversion therapy should be considered as an integrated treatment strategy, which can significantly improve patient prognosis.

Regarding the safety of conversion therapy followed by sequential surgery in advanced HCC with PVTT patients, both our team’s previous studies and external research have shown that the combination of TKIs and PD-1 inhibitors can lead to adverse events, including bleeding tendencies and fulminant myocarditis, but these risks are generally manageable (42,43). Our study confirms this finding. In this study, the incidence of adverse events during conversion therapy was 72.4%, but no patients experienced grade 4 or higher severe adverse events (Table 2). Additionally, some researchers suggest that radical surgery following conversion therapy may be more challenging attributable to the need for large liver volume resection, higher rates of portal vein reconstruction, and extensive lymphadenectomy, which may lead to insufficient future liver remnant (FLR) (44). These factors increase the complexity of surgery compared to direct resection, potentially leading to greater blood loss, longer operation times, and more complications. In our study, 82.9% patients underwent open surgery, with a median operation time of 235 minutes and a median intraoperative blood loss of 300 mL (Table 2). Among the 76 patients, 51 experienced grade I complications, and only 2 patients had severe grade IV postoperative complications, but neither patient died from these complications (Table 2). On postoperative day 5, 58 patients (76.3%) had Child-Pugh grade A liver function suggesting that the surgery did not significantly impair liver function (Table 2). Furthermore, a high long-term portal vein patency rate (97.4%) also indicates that surgery restore the integrity and stability of portal vein blood flow, effectively removing PVTT while maintaining the patency of the portal vein. Although the surgery following conversion therapy for advanced HCC is more complex, it remains generally safe and feasible.

The primary strengths of this study include its extended follow-up period with rigorous monitoring, resulting in no patient lost to follow-up. Additionally, the sample size (n=76) exceeded the calculated requirement, providing adequate statistical power and enabling the report of 5-year survival outcomes for this specific cohort. However, several limitations should be acknowledged. The main limitation of this study is its single-arm design. The single-arm design precludes direct comparisons with a parallel control group due to potential population heterogeneity. This study excluded patients who failed conversion therapy and only included those who achieved successful conversion. Therefore, our conclusions apply to patients who completed the entire treatment pathway and should not be generalized to all patients with advanced HCC and PVTT receiving conversion therapy. Furthermore, there is some heterogeneity in the treatment regimens used in this study. Although the sintilimab plus lenvatinib regimen was predominant, the potential differences in efficacy among different PD-1 plus TKIs combinations cannot be completely ruled out. Another limitation of this study is the very small number of patients with metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC (only 1 patient met the diagnostic criteria for pure MASLD). Therefore, we were unable to perform subgroup analyses stratified by etiology or include MASLD as a covariate in the multivariate model. Given that the tumor microenvironment and response to immunotherapy may differ according to the underlying etiology, our findings cannot be directly extrapolated to Western populations with MASLD-predominant HCC, which limits the external validity of this study. Future validation through larger-scale, multi-center studies and unified medication regimen is warranted to confirm these findings and to identify the specific subpopulations that benefit from this treatment.

Conclusions

This study demonstrates that for HCC patients with PVTT who achieve successful conversion and undergo radical surgery, sequential surgery following conversion therapy based on combination of ICIS and AATDs can significantly prolong patient’s RFS and OS, and provide a safe and effective treatment option. This regimen may represent a promising approach for this specific patient subgroup. However, further high-quality studies are needed to validate these findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0147/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0147/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0147/prf

Funding: This study was supported by the Beijing Natural Science Foundation (No. L244027); Young Elite Scientists Sponsorship Program of the Beijing High Innovation Plan (No. 20250936).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0147/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study adhered to the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of Chinese People’s Liberation Army General Hospital (No. S2018-111-01). All experiments involving human participants and the use of human tissue samples in this study were conducted in accordance with the ethical standards of the institutional and national research committee. Written informed consent was obtained from all patients before conversion treatment and surgery.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Chan SL, Sun HC, Xu Y, et al. The Lancet Commission on addressing the global hepatocellular carcinoma burden: comprehensive strategies from prevention to treatment. Lancet 2025;406:731-78. [Crossref] [PubMed]
2. Marzi L, Sacco R, Siciliani L, et al. Immunotherapy in Hepatocellular Carcinoma with Portal Vein Tumour Thrombosis: From Poor Prognosis to Curative-Intent Strategies. Cancers (Basel) 2026;18:627. [Crossref] [PubMed]
3. Chu HH, Chun SY, Kim JH, et al. A prediction model for overall survival after transarterial chemoembolization for hepatocellular carcinoma invading the hepatic vein or inferior vena cava. Eur Radiol 2021;31:4232-42. [Crossref] [PubMed]
4. Galasso L, Cerrito L, Termite F, et al. The Molecular Mechanisms of Portal Vein Thrombosis in Hepatocellular Carcinoma. Cancers (Basel) 2024;16:3247. [Crossref] [PubMed]
5. Gavriilidis P, Pawlik TM, Azoulay D. Comprehensive review of hepatocellular carcinoma with portal vein tumor thrombus: State of art and future perspectives. Hepatobiliary Pancreat Dis Int 2024;23:221-7. [Crossref] [PubMed]
6. Giannini EG, Bucci L, Garuti F, et al. Patients with advanced hepatocellular carcinoma need a personalized management: A lesson from clinical practice. Hepatology 2018;67:1784-96. [Crossref] [PubMed]
7. Kokudo T, Hasegawa K, Matsuyama Y, et al. Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion. J Hepatol 2016;65:938-43. [Crossref] [PubMed]
8. Jiang M, Chen C, Hu Y, et al. Locoregional therapy combined with targeted therapy and immunotherapy for hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis. Sci Rep 2025;15:39494. [Crossref] [PubMed]
9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Hepatocellular Carcinoma, Version 1.2026. Available online: Available online: https://www.nccn.org/professionals/physician_gls/pdf/hcc.pdf
10. Vogel A, Chan SL, Dawson LA, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2025;36:491-506. [Crossref] [PubMed]
11. Gorodetski B, Chapiro J, Schernthaner R, et al. Advanced-stage hepatocellular carcinoma with portal vein thrombosis: conventional versus drug-eluting beads transcatheter arterial chemoembolization. Eur Radiol 2017;27:526-35. [Crossref] [PubMed]
12. Tang H, Cao Y, Jian Y, et al. Conversion therapy with an immune checkpoint inhibitor and an antiangiogenic drug for advanced hepatocellular carcinoma: A review. Biosci Trends 2022;16:130-41. [Crossref] [PubMed]
13. Lee SW, Lee TY, Peng YC, et al. The therapeutic benefits of combined sorafenib and transarterial chemoembolization for advanced hepatocellular carcinoma. J Dig Dis 2020;21:287-92. [Crossref] [PubMed]
14. Xu J, Shen J, Gu S, et al. 983P Camrelizumab (C) in combination with apatinib (A) in patients with advanced hepatocellular carcinoma (RESCUE): An open-label, multi-center, phase II trial. Ann Oncol 2020;31:S689.
15. Tang H, Zhang W, Cao J, et al. Chinese expert consensus on sequential surgery following conversion therapy based on combination of immune checkpoint inhibitors and antiangiogenic targeted drugs for advanced hepatocellular carcinoma (2024 edition). Biosci Trends 2025;18:505-24. [Crossref] [PubMed]
16. Zhou J, Bai L, Luo J, et al. Anlotinib plus penpulimab versus sorafenib in the first-line treatment of unresectable hepatocellular carcinoma (APOLLO): a randomised, controlled, phase 3 trial. Lancet Oncol 2025;26:719-31. [Crossref] [PubMed]
17. Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol 2021;22:977-90. [Crossref] [PubMed]
18. Llovet JM, Pinyol R, Yarchoan M, et al. Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma. Nat Rev Clin Oncol 2024;21:294-311. [Crossref] [PubMed]
19. Gordan JD, Kennedy EB, Abou-Alfa GK, et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update. J Clin Oncol 2024;42:1830-50. [Crossref] [PubMed]
20. Kudo M, Kawamura Y, Hasegawa K, et al. Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update. Liver Cancer 2021;10:181-223. [Crossref] [PubMed]
21. Llovet JM, Lencioni R. mRECIST for HCC: Performance and novel refinements. J Hepatol 2020;72:288-306. [Crossref] [PubMed]
22. Peng SY, Wang XA, Huang CY, et al. Better surgical treatment method for hepatocellular carcinoma with portal vein tumor thrombus. World J Gastroenterol 2018;24:4527-35. [Crossref] [PubMed]
23. Chinese Association of Liver Cancer and Chinese Medical Doctor Association. Guidelines for diagnosis and treatment of hepatocellular carcinoma with portal vein tumor thrombus in China(2026 edition). Zhonghua Yi Xue Za Zhi 2026;106:41-55. [Crossref] [PubMed]
24. Chok KS, Cheung TT, Chan SC, et al. Surgical outcomes in hepatocellular carcinoma patients with portal vein tumor thrombosis. World J Surg 2014;38:490-6. [Crossref] [PubMed]
25. Clavien PA, Strasberg SM. Severity grading of surgical complications. Ann Surg 2009;250:197-8. [Crossref] [PubMed]
26. Yerdel MA, Gunson B, Mirza D, et al. Portal vein thrombosis in adults undergoing liver transplantation: Risk factors, screening, management, and outcome. Transplantation 2000;69:1873-81. [Crossref] [PubMed]
27. Reig M, Sanduzzi-Zamparelli M, Forner A, et al. BCLC strategy for prognosis prediction and treatment recommendations: The 2026 update. J Hepatol 2026;84:631-54. [Crossref] [PubMed]
28. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. Journal of Hepatology 2025;82:315-74.
29. Zeng Y, Gu J, He W, et al. Dynamic changes in serum alpha-fetoprotein predict prognosis in hepatocellular carcinoma treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Ther Adv Gastroenterol 2025;18:17562848251387501. [Crossref] [PubMed]
30. Cao YB, Li JF, Tang HW, et al. Serum alpha-fetoprotein in predicting survival of patients with BCLC C hepatocellular carcinoma treated by salvage surgery after downstaging therapy. Chinese Journal of Hepatobiliary Surgery. Chin J Hepatobiliary Surg 29:22-7.
31. Zhu XD, Huang C, Shen YH, et al. Hepatectomy After Conversion Therapy Using Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy for Patients with Unresectable Hepatocellular Carcinoma. Ann Surg Oncol 2023;30:2782-90. [Crossref] [PubMed]
32. Lau WY, Lai ECH. Salvage Surgery Following Downstaging of Unresectable Hepatocellular Carcinoma—A Strategy to Increase Resectability. Ann Surg Oncol 2007;14:3301-9. [Crossref] [PubMed]
33. Shi XJ, Jin X, Wang MQ, et al. Effect of resection following downstaging of unresectable hepatocelluar carcinoma by transcatheter arterial chemoembolization. Chin Med J (Engl) 2012;125:197-202.
34. Chi QY, Liu QY, Wang SJ, et al. Lenvatinib combined with anti-PD-1 antibodies plus locoregional treatment for initial unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a multicenter real-world study. BMC Cancer 2025;25:1162. [Crossref] [PubMed]
35. Xu H, Zhang H, Li B, et al. Systemic conversion therapies for initially unresectable hepatocellular carcinoma: a systematic review and meta-analysis. BMC Cancer 2024;24:1008. [Crossref] [PubMed]
36. Sun H, Zhu X, Gao Q, et al. Sintilimab combined with bevacizumab biosimilar as a conversion therapy in potentially resectable intermediate stage hepatocellular carcinoma (HCC): A phase II trial. Ann Oncol 2022;33:S867-8.
37. Wang LJ, Wang HW, Cui Y, et al. Sintilimab plus lenvatinib as conversion therapy in patients with unresectable locally intermediate to advanced hepatocellular carcinoma: A single-arm, single-center, open-label, phase 2 study. J Clin Oncol 2022;40:449.
38. Zhang W, Tong S, Hu B, et al. Lenvatinib plus anti-PD-1 antibodies as conversion therapy for patients with unresectable intermediate-advanced hepatocellular carcinoma: a single-arm, phase II trial. J Immunother Cancer 2023;11:e007366. [Crossref] [PubMed]
39. Chen Z, Chen X, Hu H, et al. The combination of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), interventional hepatoma therapy, targeted therapy, and immunotherapy: a case series of a novel AITI conversion therapy model. J Gastrointest Oncol 2025;16:1736-48. [Crossref] [PubMed]
40. Guo X, Nie H, Zhang W, et al. Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer. Cancer Cell 2025;43:248-268.e9. [Crossref] [PubMed]
41. Dai S, Chen Y, Cai W, et al. Combination immunotherapy in hepatocellular carcinoma: synergies among immune checkpoints, TKIs, and chemotherapy. J Hematol Oncol 2025;18:85. [Crossref] [PubMed]
42. Dai L, Duan Y, Xiong Q. From tumor immunotherapy to myocardial injury: A mechanistic discussion of immune checkpoint inhibitor-related myocarditis Molecular Medicine Reports 2025;32:332. (Review).
43. Zhang W, Hu B, Han J, et al. Surgery After Conversion Therapy With PD-1 Inhibitors Plus Tyrosine Kinase Inhibitors Are Effective and Safe for Advanced Hepatocellular Carcinoma: A Pilot Study of Ten Patients. Front Oncol 2021;11:747950. [Crossref] [PubMed]
44. Zhang ZF, Luo YJ, Lu Q, et al. Conversion therapy and suitable timing for subsequent salvage surgery for initially unresectable hepatocellular carcinoma: What is new? World J Clin Cases 2018;6:259-73. [Crossref] [PubMed]