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Wang et al. BMC Cancer (2024) 24:1036

https://doi.org/10.1186/s12885-024-12779-5

BMC Cancer

†

Xishu Wang and Ximin Sun contributed equally to this work.

*Correspondence:

Feng Xia

frankfxia@163.com

1

Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical

University, Chongqing 400038, China

2

Department of Surgical Anesthesiology, Southwest Hospital, Army

Medical University, Chongqing 400038, China

3

Outpatient Department, Southwest Hospital, Army Medical University,

Chongqing 400038, China

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.

Keywords Unresectable hepatocellular carcinoma, Radiofrequency ablation, Lenvatinib, Sintilimab, Locoregional

therapy

The efficacy and safety of Radiofrequency

ablation combined with Lenvatinib plus

Sintilimab in Unresectable Hepatocellular

Carcinoma: a real-world study

Xishu Wang1†, Ximin Sun1†, Yongrong Lei1

, Lingyan Fang2

, Yuedi Wang3

, Kai Feng1

and Feng Xia1*

Wang et al. BMC Cancer (2024) 24:1036 Page 2 of 12

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 [5–7]. Targeted therapies and immunotherapies

have changed the treatment paradigm of advanced HCC

management [8–10]. 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 [18–21]. 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 realworld 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.

Wang et al. BMC Cancer (2024) 24:1036 Page 3 of 12

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 preRFA 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, neutrophilto-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

Wang et al. BMC Cancer (2024) 24:1036 Page 4 of 12

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 dualsided, 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).

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

Fig. 1 Patient flowchart

Wang et al. BMC Cancer (2024) 24:1036 Page 5 of 12

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.

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).

Variable R-L-S group

(n=60)

L–S group

(n=62)

P#

Patient characteristics

Age (yr) * 51.50(30–73) 53.00(19–78) 0.376

<65 54(90.0) 56(90.3)

≥65 6(10.0) 6(9.7)

Gender 0.641

Male 53(88.3) 53(85.5)

Female 7(11.7) 9(14.5)

Child–Pugh grade 0.967

A 57(95.0) 59(95.2)

B 3(5.0) 3(4.8)

ECOG PS 0.738

0 51(85.0) 54(87.1)

1 9(15.0) 8(12.9)

AFP (ng/mL) 0.195

≥400 22(36.7) 16(25.8)

<400 38(63.3) 46(74.2)

Etiology 0.619

HBV infection 59(98.3) 59(95.2)

HCV infection 1(1.7) 3(4.8)

Hemoglobin (HB) * 137.00(95.00–

174.00)

139.00(70.00–

176.00)

0.846

White cell count (×109

/L) * 5.90

(1.23–13.75)

5.76 (3.39–14.00) 0.988

Platelet count (×109

/L) * 149(51.00–

465.00)

174(39.00–585.00) 0.077

PT (s) * 11.80(5.36–

14.90)

11.95(5.26–19.80) 0.931

Albumin (g/L) * 39.20(26.10–

68.20)

39.30(28.40–47.40) 0.667

ALT (U/L) * 33.95(5.70–

521.90)

39.55(7.40–292.80) 0.261

Serum total bilirubin

(µmol/L ) *

19.80

(5.65–87.50)

17.80

(7.50–141.40)

0.499

BCLC stage 0.966

B 37(61.7) 38(61.3)

C 23(38.3) 24(38.7)

Number of tumors

Single

Two

Three or more

26(43.3)

4(6.7)

30(50.0)

30(48.4)

11(17.7)

21(33.9)

0.078

Diameter of tumor (cm) 1.000

<3 3 4

≥ 3 57 58

Extrahepatic metastasis 0.952

Yes 6(10.0) 6(9.7)

NO 54(90.0) 56(90.3)

Microvascular invasion 0.282

Yes 25(41.7) 20(32.3)

NO 35(58.3) 42(67.7)

Major vascular invasion 0.608

Table 1 Baseline clinical characteristics of patients with

unresectable HCC Variable R-L-S group

(n=60)

L–S group

(n=62)

P#

Yes 20(33.3) 18(29.0)

NO 40(66.7) 44(71.0)

* The value expressed as the median with the range shown in parentheses.

ECOG PS:  Eastern Cooperative Oncology Group performance status,  BCLC:

In the Barcelona Clinic Liver Cancer (BCLC) classification, #

the R–L–S group

is compared with L-S group. AFP stands for α-fetoprotein; HBV for hepatitis

B virus; HCV for hepatitis C virus; PT for prothrombin time; ALT for alanine

aminotransferase

Table 1 (continued)

Wang et al. BMC Cancer (2024) 24:1036 Page 6 of 12

Table 2 Best tumor response in the R–L–S and L–S group

Investigator Assessment BICR Assessment

R–L–S (n=60) L-S (n=62) P value R–L–S (n=60) L-S (n=62) P value

CR 8(13%) 2(3%) 0.088 8(13%) 3(5%) 0.296

PR 16(27%) 11(18%) 0.235 14(23%) 9(15%) 0.213

SD 30(50%) 29(47%) 0.722 27(45%) 27(44%) 0.872

PD 6(10%) 20(32%) 0.003 8(13%) 19(31%) 0.021

UnknownII - 3(5%) 4(6%)

ORRI

(95% CI)

24(40%)

(27.6, 53.5)

13(20.9%)

(11.7, 33.2)

0.022 22(37%)

(24.6, 50.1)

12(19.4%)

(10.4,31.4)

0.033

DCRIII, No. (%) 54(90%) 42(68%) 0.003 49(82%) 39(63%) 0.021

DDC

median (95% CI)

9(6.5, 11.5) 5 (2.6, 7.4) 0.230 8(6.1 to 9.9) 5 (3.2 to 6.8) 0.346

Note All confidence intervals (CIs) are calculated using the Clopper-Pearson method

Abbreviations: R–L–S, radiofrequency ablation and lenvatinib plus sintilimab; L-S, Lenvatinib plus sintilimab; BICR, blinded independent central review; ORR,

objective response rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. DCR, disease control rate; DDC, duration of disease

control

I

CR+PR

IIThe reasons for being unable to determine by BICR are as follows:

- In the R–L–S group, one patient passed away before the disease assessment, and two patients did not have a follow-up radiologic image available

- In the L-S group, two patients lacked a follow-up radiologic image, and two patients did not have a reported best overall response for the BICR assessment

IIICR+PR+SD

Fig. 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

Wang et al. BMC Cancer (2024) 24:1036 Page 7 of 12

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.

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 RFArelated 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.

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

Fig. 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

Wang et al. BMC Cancer (2024) 24:1036 Page 8 of 12

Fig. 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

Wang et al. BMC Cancer (2024) 24:1036 Page 9 of 12

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

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

Overall survival Progression-free survival

Variables Univariate analysis Multivariate analysis Univariate analysis Multivariate

analysis

HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) P

Sex

(Male vs. Female)

0.713(0.34–1.49) 0.368 0.764(0.40–1.1.44) 0.408

Age (years)

(<60 vs. ≥60)

0.729(0.37–1.43) 0.359 0.652(0.35–1.20) 0.171

Child–Pugh class (B vs. A) 4.508(1.89–10.70) 0.001 5.24

(2.06–13.283)

<0.001 4.224(1.77–10.04) 0.001 3.97

(1.62–9.72)

0.003

AFP level (mg/L) (<400 vs. ≥400) 1.256(0.76–2.05) 0.364 1.301(0.84–2.00) 0.235

Number of tumors

(>3 vs. ≤3)

1.581(0.95–2.62) 0.075 1.373(0.85–2.20) 0.188

Largest tumor size (cm)

(≥10 vs. <10)

1.25(0.76–2.04) 0.374 1.303(0.83–2.03) 0.243

BCLC stage

(C vs. B)

2.267(1.41–3.63) 0.001 1.723(1.11–2.65) 0.014 1.63

(1.01–2.65)

0.045

Extrahepatic metastasis

(No vs. Yes)

0.481(0.28–0–0.94) 0.034 0.515(0.27–0–0.98) 0.044

Major vascular invasion (No/Yes) 0.544(0.33–0–0.88) 0.014 0.699(0.44–1.10) 0.123

Microvascular invasion

(No/Yes)

0.727(0.44–1.17) 0.194 0.918(0.58–1.43) 0.705

Treatment option (L-S vs. R–L–S) 1.606(0.99–2.58) 0.051 1.63

(1.006–2.666)

0.047 1.657(1.08–2.53) 0.020 1.68

(1.09–2.57)

0.017

ECOG PS (0 vs. 1) 0.582(0.26–1.27) 0.177 0.611(0.30–1.22) 0.163

Table 4 Treatment related adverse events

Any Grade n (%) Grade3 n (%)

TRAEs of any grade (≥10%) R–L–S

group (n=60)

L-S group (n=62) P R–L–S group (n=60) L-S group (n=62) P

Diarrhea 31(51.7%) 28(45.2%) 0.472 5(8.3%) 3(4.8%) 0.488

Fatigue 24(40.0%) 17(27.4%) 0.141 6(10.0%) 5(8.1%) 0.709

Hand–foot skin reaction 24(40.0%) 23(37.1%) 0.742 6(10.0%) 7(11.3%) 0.817

Weight decreased 21(35.0%) 19(30.6%) 0.608 3(5.0%) 4(6.5%) 1.000

Oral ulcer. 19(31.7%) 21(33.9%) 0.795 5(8.3%) 3(4.8%) 0.488

Increased AST 16(26.7%) 16(25.8%) 0.914 0(0.0%) 0(0.0%) -

Increased ALT 15(25.0%) 17(27.4%) 0.761 0(0.0%) 0(0.0%) -

Nausea 15(25.0%) 13(20.9%) 0.596 0(0.0%) 0(0.0%) -

Increased blood bilirubin 14(23.3%) 20(32.3%) 0.272 0 (0.0%) 0(0.0%) -

Hypothyroidism 13(21.7%) 15(24.2%) 0.740 1(1.7%) 2(3.2%) 1.000

Arthrodynia 11(18.3%) 12(19.4%) 0.957 1(1.7%) 3(4.8%) 0.619

Hypertension 11(18.3%) 10(16.1%) 0.747 3(5.0%) 2(3.2%) 0.677

RFA related Adverse Events

Abdominal pain 25(41.7%) - -

Increased ALT 20(33.3%) - -

Increased AST 15(25.0%) - -

Increased blood bilirubin 10(16.7%) - -

Fever 10(16.7%) - -

Wang et al. BMC Cancer (2024) 24:1036 Page 10 of 12

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 [37–39]. 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.

Abbreviations

HCC Hepatocellular carcinoma

PD-1 Programmed death-1

Wang et al. BMC Cancer (2024) 24:1036 Page 11 of 12

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-tolymphocyte 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

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.

Author 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.

Funding

This research is supported by Chongqing Natural Science Foundation of China

general project (CSTB2023NSCQ-MSX0563).

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.

Declarations

Consent for publication

Not applicable.

Competing interests

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.

Received: 23 February 2024 / Accepted: 7 August 2024

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