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The efficacy and safety of Radiofrequency ablation combined with Lenvatinib plus Sintilimab in Unresectable Hepatocellular Carcinoma: a real-world study

BMC Cancer volume 24, Article number: 1036 (2024) Cite this article

Abstract

Background

The combination of targeted therapy and immunotherapy has improved the clinical outcomes of unresectable hepatocellular Carcinoma (HCC). However, the overall prognosis remains suboptimal. This study aims to evaluate the efficacy and safety of a novel combination of radiofrequency ablation (RFA) with lenvatinib plus sintilimab in unresectable HCC.

Methods

In this retrospective study, patients diagnosed with unresectable HCC were included and divided into two cohorts: RFA combined with lenvatinib plus sintilimab (R-L-S group) and lenvatinib plus sintilimab (L-S group). The primary efficacy endpoints were objective response rate (ORR) and progression free survival (PFS). Adverse events were analyzed to assess the safety profiles.

Results

The median follow-up periods for the entire cohort were 14.0 months. The R-L-S group (n = 60) had a significantly higher ORR than those with L-S alone (n = 62) (40.0% vs. 20.9%; p = 0.022). Moreover, patients in the R-L-S group had improved median PFS (12 vs. 8 months; p = 0.013) and median overall survival (24 vs. 18 months; p = 0.037), as compared with lenvatinib and sintilimab alone. No significant difference in treatment related adverse event (TRAE) of any grade between the two groups. The most common TRAEs of grade ≥ 3 were fatigue 10.0% (6/60) and hand-foot skin reaction 10.0% (6/60) in the R-L-S group and hand-foot skin reaction 11.3% (7/62) in the L-S group.

Conclusion

In unresectable HCC patients, the incorporation of RFA to lenvatinib plus sintilimab demonstrated improved efficacy without compromising safety compared with lenvatinib plus sintilimab alone.

Peer Review reports

Background

Hepatocellular carcinoma (HCC) is the most prevalent and lethal type of liver cancer, ranking as the fifth most common cancer worldwide and the second leading cause of cancer death in China [1, 2]. Despite advances in disease management, its five-year survival rates remain disappointingly low [3, 4]. This is largely attributed to the fact that over half of the patients with HCC are diagnosed at an advanced stage, precluding curative interventions [5,6,7]. Targeted therapies and immunotherapies have changed the treatment paradigm of advanced HCC management [8,9,10]. Notably, the combination of immunocheckpoint inhibitors and tyrosine kinase inhibitors (TKIs) has emerged as the first-line treatment for advanced HCC [11, 12]. Recently, in the ORIENT-32 trial, significant survival benefits from sintilimab plus a bevacizumab biosimilar (IBI305) over sorafenib in Chinese cohorts were observed [13]. A retrospective study has shown superior efficacy of lenvatinib combined with sintilimab over lenvatinib alone [14]. In addition, combinations such as lenvatinib with pembrolizumab [15] and camrelizumab with rivoceranib, have also shown promising antitumor activities with manageable safety profiles [16].

Despite notable progress in the management of advanced HCC, the clinical outcomes for patients are still not satisfactory. This situation emphasizes the urgent requirement for additional research and advancement in this specific medical field. Kudo et al. recently suggested that patients with HCC at all stages could potentially benefit from the use of systemic therapies, especially TKIs, when used in conjunction with locoregional therapies [17]. Transarterial chemoembolization (TACE) or radiotherapy, combined with systemic therapies were explored in advanced HCC and significant increased ORR was observed [18,19,20,21]. A study highlighted that the ORR for a regimen of lenvatinib paired with PD‑1 inhibitor, with or without TACE, were 76.7% and 44.9%, respectively [18]. Another study corroborated that TACE, in concert with a PD-1 inhibitor and lenvatinib, facilitated improved clinical outcomes versus a combination of TACE and a PD-1 inhibitor alone in advanced HCC [21]. Similar findings have been echoed in subsequent research [22], including a study on a sequential protocol involving TACE, stereotactic body radiotherapy, and immunotherapy in locally advanced unresectable HCC, which also yielded encouraging results [23].

Radiofrequency Ablation (RFA) was one of the regional therapies especially for curing small HCC lesions [24, 25]. It has been shown to enhance the intratumoral accumulation of drugs and immune cells by increasing tumor vascular permeability [26]. In addition, preclinical studies have demonstrated that using a PD-1 inhibitor can potentiate the T-cell-mediated immune response post-ablation [27]. This scientific rationale underpins the potential synergy between RFA and combined systemic therapies, particularly those involving targeted agents and immune checkpoint inhibitors. However, the implementation of this combined modality has been infrequently pursued in clinical practice settings. This study endeavors to bridge this gap by providing empirical evidence from a real-world clinical scenario. This study aims to evaluate the efficacy and safety of RFA combined with lenvatinib plus sintilimab in unresectable HCC.

Methods

Study design and patients

This study was a single-center, retrospective cohort study, receiving the requisite approval from the ethics committee of the First Affiliated Hospital of Army Medical University, PLA (People’s Liberation Army), known as Southwest Hospital. Informed consent was meticulously procured in written form from each participant. The study period extended from October 2018 through May 2023, targeting patients diagnosed with unresectable HCC, who had not received any prior treatments. The research encompassed two distinct patient groups: one receiving the tripartite treatment regimen of RFA, lenvatinib, and sintilimab (R-L-S) totaling 60 individuals, and the other administered a dual therapy of lenvatinib and sintilimab (L-S) involving 62 individuals.

Inclusion criteria included individuals aged between 18 and 80 years, with a clinical or histopathological confirmation of HCC at Barcelona Clinic Liver Cancer (BCLC) stage B or C. Moreover, the presence of at least one measurable lesion as determined by the modified Response Evaluation Criteria in Solid Tumors (mRECIST v1.1) was necessary. Further inclusion requisites stipulated an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 or less, alongside a Child–Pugh score within class A or B. Additionally, inclusion criteria for this study required patients to have at least one ablatable HCC lesion with a size of no more than 5 cm, even if they had additional tumors larger than 5 cm. This ensured that all patients in the R-L-S group underwent RFA for at least one lesion. Patients were included regardless of the total tumor burden, provided that they had at least one lesion suitable for RFA. Exclusion criteria included patients who did not have any ablatable lesions (i.e., all tumors larger than 5 cm), patients with any other malignancies, a history of prior treatments including RFA, TACE, hepatic arterial infusion chemotherapy (HAIC), radiotherapy, or systemic therapies, and those with significant comorbidities such as severe cardiac, pulmonary, renal, or coagulation dysfunctions.

Treatment procedure

In the R-L-S cohort, treatment commenced with RFA, followed by systemic therapy with lenvatinib and sintilimab. The sequence was specifically chosen to allow for a short recovery period after RFA before the initiation of systemic treatment to ensure optimal patient tolerance and efficacy of the treatment regimen.

RFA was performed as the initial intervention. An experienced hepatobiliary surgeon conducted the ablations under general anesthesia, guided by real-time ultrasound imaging. For lesions less than 3 cm in diameter, a single radiofrequency needle was used, applying a power of 120 watts for 3 min. For lesions between 3 cm and 5 cm, two needles were used with a power of 180 watts for 5 min. This approach helped to minimize potential complications and ensure comprehensive treatment of the target lesions.

Systemic treatment with lenvatinib and sintilimab was initiated three days post-RFA. This interval was determined to be sufficient for initial post-ablation recovery while maintaining the momentum of therapeutic impact against HCC. Lenvatinib dosing was stratified by body weight: 12 mg per day for individuals weighing over 60 kg, and 8 mg per day for those under. Sintilimab was administered via intravenous infusion at a dose of 200 mg every three weeks.

The decision to proceed with systemic therapy was contingent upon the patient’s recovery from RFA, assessed through clinical evaluation and liver function tests. This strategic sequencing and timing of treatments were designed to maximize therapeutic outcomes while minimizing the risks associated with the combined treatment modalities.

We conducted a comprehensive and systematic pre-RFA evaluation, assessing factors such as tumor size, location of lesions, overall patient health, and liver function reserve. This evaluation guided our decision on the number of lesions suitable for ablation, with the aim of optimizing therapeutic outcomes while minimizing potential risks. Specifically, we targeted 1 to 5 lesions based on their accessibility and safety for ablation, focusing on intrahepatic lesions with the largest diameter ≤ 3 cm or isolated lesions with a diameter of 3 to 5 cm that were not adjacent to major vessels or vital organs.

Regarding the prognostic value of the number of lesions ablated, our study found that ablation of fewer, strategically selected lesions (typically 1 to 3) was associated with better localized control and potentially enhanced survival outcomes, reflecting the importance of targeted, precision-based therapy in HCC management. We observed that ablation of more than three lesions, while feasible, did not significantly improve survival rates and was sometimes associated with increased complications due to the broader impact on liver function. The RFA needle was multipolar, internally cooled-tip CelonProSurge™ (Celon-POWER System OLYMPUS Medical®).

Follow‑up assessment

Baseline clinical profiles were meticulously compiled using the advanced Southwest Hospital Scientific Research Platform. This encompassed a broad spectrum of data points: demographic data, liver function as indicated by Child–Pugh grades, patient vitality via ECOG-PS scores, a battery of clinical metrics, including α-fetoprotein (AFP) level-a marker of hepatocellular carcinoma-along with etiology, hemoglobin (HB) concentration, white blood cell and platelet count, coagulation times (prothrombin time or PT), albumin and alanine aminotransferase (ALT) levels, and serum total bilirubin level. Peripheral blood lymphocyte counts, neutrophil-to-lymphocyte ratio (NLR), leucocyte-to-lymphocyte ratio (LLR), platelet-to-lymphocyte ratio (PLR) and aspartate aminotransferase to platelet ratio index (APRI) were measured in 60 patients of the R-L-S group on the first day before and after RFA. Additionally, tumor burden was quantified by tallying lesion counts, measuring the largest tumor dimensions, and assessing for extrahepatic spread and microvascular invasion. Tumor response assessments were rigorously scheduled, utilizing contrast-enhanced MRI or CT imaging at intervals of four to eight weeks. Follow-up visits were consistently conducted every two months, continuing until disease progression or death.

Outcomes and evaluations

The primary endpoints of this study were the objective response rate (ORR) according to the mRECIST v1.1 and progression-free survival (PFS). The secondary endpoints encompassed overall survival (OS), disease control rate (DCR), and safety. The ORR encompassed the aggregated instances of partial response (PR) and complete response (CR). DCR was defined as the collective proportion of PR, stable disease (SD), and CR. PFS was defined as the duration from the onset of the initial therapeutic regimen until the occurrence of disease progression or death. AEs were meticulously assessed using the version 5.0 criteria set forth by the National Cancer Institute Common Terminology Criteria for Adverse Events.

Statistical analysis

The statistical evaluation was executed employing SPSS software (version 20.0; SPSS Inc., Chicago, IL, USA) and GraphPad Prism software (version 9.0; GraphPad Prism Software Inc., San Diego, CA, USA). Median values, supplemented by the range, represented continuous data. The chi-square and the Fisher exact tests provided insights into categorical data, while the Mann–Whitney U test was used for the analysis of continuous data variables that deviated from normal distribution patterns. The Kaplan–Meier estimator facilitated the derivation of PFS and OS metrics, which were subsequently compared through the log-rank test. Initial exploration of prognostic variables utilized univariate Cox regression analysis, with those achieving a p-value below 0.10 undergoing further scrutiny in a multivariate Cox regression framework to discern independent predictors for OS and PFS. Descriptive statistics were utilized to portray the landscape of AE outcomes. All p-values were dual-sided, with a significant threshold established at p < 0.05.

Results

Demographic and baseline clinical characteristics

Initially, we identified 143 patients diagnosed with primary unresectable HCC, including 70 in the R-L-S group and 73 in the L-S group. In the R-L-S cohort, 10 patients were excluded due to concurrent malignancies (n = 3), previous treatments (n = 3), early mortality (n = 2), and insufficient data (n = 2). The L-S cohort had 11 patients excluded for similar reasons: concurrent malignancies (n = 3), previous treatments (n = 3), early mortality (n = 4), and insufficient data (n = 1). Finally, we included 60 patients in the R-L-S cohort and 62 in the L-S group for analysis, as delineated in Fig. 1. The baseline characteristics such as age, gender, Child-Pugh score, ECOG PS, AFP, etiology of liver disease, preoperative laboratory results, BCLC stage, tumor number, tumor size, presence of metastasis, and microvascular invasion were comparable across the R-L-S and L-S cohorts (Table 1).

Fig. 1
figure 1

Patient flowchart

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Table 1 Baseline clinical characteristics of patients with unresectable HCC
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Efficacy results

The median follow-up periods were 26.0 months (ranging from 6.0 to 58.0 months) for the R-L-S group and 24.0 months (ranging from 8.0 to 59.0 months) for the L-S group. The R-L-S group had a significantly higher ORR than the L-S group according to mRECIST criteria (Table 2), with rates of 40% and 17.7%, respectively (p = 0.007), by investigator assessment, and 35% and 17.7%, respectively (p = 0.030), by BICR evaluation (Table 2). Both investigator and BICR assessments showed a higher DCR in the R-L-S group than in the L-S group (p = 0.003). Moreover, the R-L-S group had a higher median duration of disease control (DDC) of 9 months versus 5 months. The target lesion changes following treatments were illustrated in the waterfall plots of Fig. 2A and B. Figure 2C shows radiological images of a patient who was treated with the combination therapy and had a CR in both ablated and non-ablated lesions. In terms of survival outcomes, the median PFS (mPFS) and median OS (mOS) were 12.0 and 24.0 months for the R-L-S group, while they were 8.0 and 18.0 months for the L-S group (p = 0.0132 and p = 0.0367, respectively), as shown in Fig. 3A and B.

Fig. 2
figure 2

Tumor response mRECIST A depicts the percentage change from baseline tumor size for 60 patients within the R-L-S group. The responses are colour-coded; CR is indic signified by yellow, Partial Response (PR) with green, Stable Disease (SD) with blue, and Progressive Disease (PD) denoted through red hues. B data for another set of 62 cases in L-S group. In both panel A and B, patient count is conveyed along horizontal axis while vertical one demonstrates the percentage change from baseline in tumor size. Bars extending above the horizontal axis denote tumor size increase, whereas bars below represent tumor size reduction. C The MRI scans of a patient with multiple HCC lesions, who received RFA in combination with lenvatinib and sintilimab and achieved CR in both RFA lesion and non-RFA lesions (follow-up at 6 months after RFA). Yellow arrows indicate RFA lesion; blue arrows indicate non-RFA lesions

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Fig. 3
figure 3

Kaplan-meier survival curves for unresectable HCC patient cohorts. A Progression-Free Survival (PFS) Curves: The blue and red lines represent the survival probabilities for the R-L-S and L-S groups, respectively. The dashed lines delineate the 95% confidence intervals, indicating the range within which the true survival curve is expected to lie with 95% certainty. The log-rank test reported a p-value of 0.0132, suggesting a statistically significant difference between two groups. B Overall Survival (OS) Curves: The survival difference is significant with a log-rank p-value of 0.0367. Additionally, the table below each graph indicates the number of patients remaining at risk at specified time intervals, providing additional context to the survival estimates

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Table 2 Best tumor response in the R–L–S and L–S group
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Changes in lymphocyte counts and systemic inflammation scores

Assessment of lymphocyte counts in the R-L-S group before and after radiofrequency ablation revealed a significant difference (p = 0.001, as shown in Fig. 4A). The peripheral blood lymphocyte counts increased notably post-ablation, with the mean value rising from 0.88 × 109/L to 1.09 × 109/L. In patients who achieved a CR, 6 out of 8 experienced an increase in lymphocyte counts following RFA, while 2 exhibited a decrease. Among the 16 patients with a PR, 14 had an increase while 2 had a decrease, as depicted in Fig. 4B. In the group of 30 patients with SD, 23 observed an increase in lymphocyte counts compared to 7 who experienced a decrease. Finally, for the PD category, half of the patients (3 out of 6) showed an increase in lymphocyte counts, and the other half displayed a decrease. Changes of NLR, LLR, PLR and APRI in the R-L-S group before and after radiofrequency ablation were shown in Fig. 4C, E, G, I (p = 0.030, < 0.001, < 0.001, < 0.001, respectively). Among the 24 patients with CR and PR, NLR had a decrease in 13 patients while had an increase in 11 patients. The LLR was decreased in 18 and elevated in 6 patients among the 24 patients reaching CR and PR. There were 17 patients elevated and 7 patients decreased in PLR among the 24 patients with CR and PR. While the numbers of patients decreased and increased in APRI were 4 and 20, respectively, among the 24 patients with CR and PR (shown in Fig. 4D, F, H, J).

Fig. 4
figure 4

Lymphocyte Count and Systemic Inflammation Scores Changes Pre- and Post-RFA in the R-L-S Group. A represents the change in lymphocyte counts among 60 patients before and after RFA in the R-L-S group. A Wilcoxon two-sided test indicated a statistically significant increase with a p-value of 0.001. B shows the change in lymphocyte counts in patients achieving CR and PR in the R-L-S group. C, E, G, I represent the change in NLR, LLR, PLR, APRI among 60 patients before and after RFA in the R-L-S group. A Wilcoxon two-sided test indicated a statistically significant increase with a p-value of 0.030, < 0.001, < 0.001, < 0.001, respectively. D, F, H, J show the change in NLR, LLR, PLR, APRI in patients achieving CR and PR in the R-L-S group

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Prognostic factors analysis

In the analysis of prognostic factors associated with survival in HCC patients (Table 3), multivariate analysis revealed that the Child–Pugh class and the treatment regimen were significant predictors of both OS and PFS. Patients classified as Child–Pugh class B had a markedly higher risk of decreased OS (HR = 5.24, p < 0.001) and PFS (HR = 3.97, p = 0.003) compared to those classified as class A. Regarding treatment options, R-L-S treatment was associated with a statistically significant improvement in OS (HR = 1.63, p = 0.047) and PFS (HR = 1.68, p = 0.017) compared to L-S treatments. The BCLC stage also held prognostic value for PFS; patients with a BCLC stage C had a 63% higher risk of disease progression compared to stage B (HR = 1.63, 95% CI 1.01–2.65, p = 0.045). Other variables, including sex, age, AFP levels, the number of tumors, the size of the largest tumor, extrahepatic metastasis, and major vascular invasion, did not display a significant impact on OS or PFS in the multivariate analysis (Table 3). The ECOG PS also showed no significant difference in outcomes.

Table 3 Univariate and multivariate analyses of prognosis factors (baseline) for OS and PFS
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Safety results

The most common TRAEs of any grade in the R-L-S group included diarrhea (51.7%, 31/60), fatigue (40%, 24/60), and hand–foot skin reaction (40%, 24/60) as shown in Table 4. In the L-S group, the most common TRAEs of any grade included diarrhea (45.2%, 28/62), hand–foot skin reaction (37.1%, 23/62), and oral ulcer (33.9%, 21/62) (Table 4). There was no significant difference in TRAEs between the two groups (p ≥ 0.05). In the R-L-S group, the most common TRAEs of grade ≥ 3 included fatigue (10.0%, 6/60) and hand–foot skin reaction (10.0%, 6/60). For the L-S group, the most common TRAEs of grade ≥ 3 were hand–foot skin reaction (11.3%, 7/62). No differences in the frequency of TRAEs of grade ≥ 3 between the two groups were observed (Table 4). In the R-L-S group, the most common RFA-related AEs included abdominal pain (41.7%, 25/60), increased ALT (33.3%, 20/60), increased AST (25.0%, 15/60), increased blood bilirubin (16.7%, 10/60), and fever (16.7%, 10/60). Most RFA-related AEs resolved quickly with or without interventions. No SAEs or TRAEs of grades 4 or 5 were reported in any cohort. Additionally, no deaths related to treatment were reported during the study. There were 15 patients who discontinued taking lenvatinib: 8 patients were in the R-L-S group and 7 in the L-S group. The primary reasons for treatment discontinuation were disease progression and gastrointestinal hemorrhage. Additionally, 10 patients received local treatments including TACE, HAIC, and SBRT, while 5 patients chose palliative treatment.

Table 4 Treatment related adverse events
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Discussion

To the best of our knowledge, this is the first study to retrospectively evaluate the efficacy and safety of a novel combination of RFA with lenvatinib plus sintilimab in unresectable HCC in a real-world setting. Our study has shown that adding RFA to systemic therapy with a multi-target TKI and an ICI targeting PD-1 significantly improves clinical outcomes compared to systemic therapy alone, while maintaining an acceptable safety profile. It highlights the potential positive value of RFA in managing unresectable HCC.

A phase I/II trial assessed the safety and efficacy of local ablation plus PD-1 inhibitor toripalimab in previously treated unresectable HCC [28]. This study suggested that compared with toripalimab alone, RFA plus toripalimab produced a higher ORR (33.8% vs. 16.9%; P = 0.027), longer mPFS (7.1 vs. 3.8 months; P < 0.001) and extended mOS (18.4 vs. 13.2 months; P = 0.005). The addition of RFA to the systemic therapy extended mPFS from 8 months to 12 months and mOS from 12 months to 15 months, alongside elevating the ORR from 17.7 to 40% and the DCR from 68 to 90%. The ORR observed here outpaced that of previous studies, where lenvatinib and sintilimab alone were administered to unresectable HCC [29]. Our investigation also attests to the favorable safety profile of the combined RFA treatment. No SAEs due to RFA were observed, and the incidence of TRAEs was comparable between both treatment groups. The absence of additional toxicities suggests that the strategic integration of RFA and systemic therapies is both a viable and secure approach in a clinical setting. Together with the RFA plus toripalimab study, incorporating RFA into the systematic treatment regimen may represent an enhanced therapeutic modality for unresectable HCC with an acceptable safety profile.

The enhanced clinical outcomes by this novel approach may be attributed to several factors. Primarily, RFA induces partial tumor necrosis, effectively reducing tumor mass in HCC patients. Subsequently, a variety of antigens are released through the necrotic process along with heat shock proteins and exosomes [26, 30, 31]. These elements work in synergy with anti-PD-1 monoclonal antibodies to bolster the T-cell response towards specific tumor antigens [32, 33]. RFA significantly increased the postoperative peripheral blood lymphocyte count in the R-L-S group, and the lymphocytes played an important role in tumor immunity, which is consistent with previous findings. Duffy et al. explored the application of tremelimumab in combination with ablation in patients with advanced HCC and found an increase in the number of activated CD4 + and CD8 + T cells [34]. Previous studies have also shown that RFA appears to aid in the maturation of dendritic cells while enhancing the ratio of CD8 + T cells to regulatory T cells (Tregs) [35, 36], cumulatively magnifying antitumor immunity mediated by CD8 + T-cells [27]. Furthermore, RFA may enhance tumor vascular permeability, which in turn could bolster the concentration of drugs and immune cells within the tumor tissue [26], potentially magnifying the effects of lenvatinib and sintilimab on tumors. The systemic inflammation scores, including NLR, LLR, and PLR, showed a decreasing trend after RFA compared with values before RFA, which is related to the increase in peripheral blood lymphocyte count following radiofrequency ablation. The decrease in these values suggests that patients have a better prognosis, consistent with the conclusions of previous studies [37,38,39]. Studies have demonstrated that high APRI levels are associated with a worse prognosis in HCC patients [40]. Furthermore, the aspartate aminotransferase level increases instantly after RFA, which directly contributes to the increase in APRI in the R-L-S group. The transient increase in APRI level did not adversely affect patient outcomes in the R-L-S group, further demonstrating that RFA enhances the efficacy of targeted and immunotherapy.

In addition, we performed strategizing lesion selection based on the potential for complete ablation in this trial. Unlike many previous studies where only a single lesion was targeted for local treatment, the approach used in this study was to treat one to five preselected lesions. Furthermore, if too many lesions were ablated, this may affect the patient’s liver function and subsequently the effectiveness of targeting and immunotherapy. Half of the patients with unresectable HCC presented with more than three lesions [41]. It has been shown that incompletely ablated lesions may become more aggressive and develop resistance to anti-PD-1 therapy [42]. To mitigate this, lesions amenable to complete ablation were targeted, aligning with methods employed in similar studies [34, 43]. This tactic aims to maximize the effectiveness of the treatment by focusing on lesions that are most likely to be fully ablated, thereby potentially reducing the risk of invasive and resistant residual tumors. Moreover, a substantial proportion of patients included in the study were classified as BCLC B, and this subset of patients had insufficient liver reserve function or volume, making them unsuitable for resection. Additionally, we found that post-TACE deterioration in liver function could delay the initiation of systemic therapy in clinical practice. Therefore, we chose to administer systemic therapy with or without RFA. In addition, multivariate analyses in our study identified Child–Pugh grade as significant predictors of survival outcomes in patients. Notably, patients undergoing the R-L-S treatment were predominantly of Child-Pugh A classification, indicative of optimal liver function reserve. This suggested these patients could better tolerate the dual stresses of local and systemic therapy, culminating in improved survival outcomes. This may help with patient selection and treatment planning of this novel treatment combination.

We have also expanded on the details of subsequent treatments administered after disease progression. The prognostic value of these treatments was analyzed, revealing that patients who received subsequent lines of therapy, such as second-line systemic therapies orlocal treatments including TACE, HAIC, and SBRT, tended to have better survival outcomes compared to those who did not receive further treatment after progression.

However, the study is not without limitations. The single-center retrospective design may introduce selection biases, underlining the necessity for validation through larger-scale, multi-center, prospective, randomized controlled trials. Furthermore, given that over 95% of participants had a history of chronic hepatitis B, the applicability of these results to populations with diverse etiologies of HCC may be limited. Thus, expansive clinical trials are imperative to thoroughly evaluate the effectiveness and safety of various immune checkpoint inhibitors across a broader patient demographic.

Conclusion

In summary, the RFA in combination with lenvatinib and sintilimab regimen emerges as a safe and potent treatment alternative for unresectable HCC, highlighting its potential as a valuable addition to the existing therapeutic arsenal.

Data availability

The datasets analyzed during the current study are not publicly available as they contain information that are sensitive to the study institution. They may be made available from the corresponding author on reasonable request.

Abbreviations

HCC:

Hepatocellular carcinoma

PD-1:

Programmed death-1

VEGF:

Vascular endothelial growth factor

TKIs:

Tyrosine kinase inhibitors

TACE:

Transarterial chemoembolization

RFA:

Radiofrequency ablation

BCLC:

Barcelona Clinic Liver Cancer

mRECIST v1.1:

modified Response Evaluation Criteria in Solid Tumors version 1.1

ECOG PS:

Eastern Cooperative Oncology Group performance status

AFP:

α-fetoprotein

HB:

Hemoglobin

PT:

Prothrombin time

ALT:

Alanine aminotransferase

NLR:

neutrophil-to-lymphocyte ratio, LLR: leucocyte-to-lymphocyte ratio, PLR: platelet-to-lymphocyte ratio, APRI: aspartate aminotransferase to platelet ratio index, MRI: Magnetic Resonance Imaging

CT:

Computed Tomography

ORR:

Objective response rate

PFS:

Progression-free survival

OS:

Overall survival

DCR:

Disease control rate

AEs:

Adverse events

CR:

Complete response

PR:

Partial response

SD:

Stable disease

PD:

Progressive disease

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Acknowledgements

We acknowledge that this manuscript has been meticulously revised by native English-speaking expert in the field of cancer and further enhanced with advanced language processing technologies (Large Language Models) for final validation.

Funding

This research is supported by Chongqing Natural Science Foundation of China general project (CSTB2023NSCQ-MSX0563).

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Author notes

  1. Xishu Wang and Ximin Sun contributed equally to this work.

Authors and Affiliations

  1. Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, 400038, China

    Xishu Wang, Ximin Sun, Yongrong Lei, Kai Feng & Feng Xia

  2. Department of Surgical Anesthesiology, Southwest Hospital, Army Medical University, Chongqing, 400038, China

    Lingyan Fang

  3. Outpatient Department, Southwest Hospital, Army Medical University, Chongqing, 400038, China

    Yuedi Wang

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  1. Xishu Wang
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Contributions

X. W. and X. S.: Conceived and designed the experiments; Analyzed and interpreted the data; Wrote the original draft. Y. L., L. F., and Y. W.: Performed the experiments; Wrote the original draft. F. K.: Performed the experiments; Conceived and designed the experiments; Analyzed and interpreted the data; Wrote the original draft. F. X.: Conceived and designed the experiments; Analyzed and interpreted the data; Writing-review & editing; Supervision; Funding acquisition; Wrote the original draft; Project administration.

Corresponding author

Correspondence to Feng Xia.

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The authors declare no competing interests.

Ethics approval and consent to participants

This study protocol was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Army Medical University, PLA (People’s Liberation Army), known as Southwest Hospital. The decision reference number for this approval is KY2024004. Written informed consent was meticulously procured from each participant. This consent process was conducted in compliance with the ethical guidelines set by the Ethics Committee of the First Affiliated Hospital of Army Medical University.

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Wang, X., Sun, X., Lei, Y. et al. The efficacy and safety of Radiofrequency ablation combined with Lenvatinib plus Sintilimab in Unresectable Hepatocellular Carcinoma: a real-world study. BMC Cancer 24, 1036 (2024). https://doi.org/10.1186/s12885-024-12779-5

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Keywords

BMC Cancer

ISSN: 1471-2407

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