Efficacy of salvage surgery for hepatocellular carcinoma following conversion therapy

Abstract

BACKGROUND

Salvage surgery following conversion therapy [transcatheter arterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and anti-programmed cell death protein 1 (PD-1) antibodies] provides a chance for a cure in patients with unresectable hepatocellular carcinoma (uHCC).

AIM

To primarily analyze the efficacy and safety of salvage surgery in patients initially diagnosed with uHCC who underwent conversion therapy.

METHODS

We retrospectively collected data from patients at the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital) who met the study criteria. These patients were initially diagnosed with uHCC and received TACE combined with TKIs and anti-PD-1 antibodies as conversion therapy. The main endpoints studied were the safety of salvage surgery, overall survival (OS), and recurrence-free survival (RFS) after surgery. Secondary endpoints included postoperative complications. We performed univariate and multivariate Cox regression analyses to identify independent risk factors for postoperative RFS.

RESULTS

A total of 117 patients were enrolled in this study, including 28 patients (23.9%) who underwent curative surgery after triplet therapy conversion treatment. Among the 28 patients who underwent salvage surgery, the 1-year and 2-year RFS rates were 75.0% and 59.4%, respectively, and the 1-year and 2-year OS rates were 92.7% and 87.6%, respectively. The median follow-up time after surgery was 15.0 months (range: 1.6-37.2 months), with median OS and RFS not yet reached. Pathological complete response was achieved in 14 cases (50.0%), and postoperative complications occurred in 20 patients (71.4%). Univariate and multivariate Cox regression analyses indicated that pathological complete response and preoperative albumin levels were risk factors for postoperative RFS.

CONCLUSION

Salvage surgery following conversion therapy with TACE combined with TKIs and anti-PD-1 antibodies appears to be an effective and safe treatment option for patients with uHCC. It extends OS and may offer additional potential benefits to uHCC patients.

Key Words: Hepatocellular carcinoma; Salvage surgery; Systemic therapy; Conversion therapy; Transcatheter arterial chemoembolization

Core Tip: For patients with advanced hepatocellular carcinoma, the opportunity for radical surgical treatment is lost. Patients who receive targeted drugs, immune drugs, or localized regional therapies cannot achieve a complete cure in the clinical sense, although it may lead to remission of the tumor lesions and improve overall survival. Patients after receiving transcatheter arterial chemoembolization combined with targeted and immune drugs, the liver cancer lesions were in remission, which was in line with the indication range of surgical resection. Postoperative complications in patients treated with salvage surgery were within acceptable limits and overall survival was prolonged.

INTRODUCTION

Primary liver cancer has become one of the top three causes of cancer-related deaths globally. It ranks sixth in incidence among all malignancies, with hepatocellular carcinoma (HCC) being the most common type, accounting for 75%-85% of cases of primary liver cancer[1,2]. While surgical treatment remains the most effective curative option for early-stage HCC, unfortunately, more than 70% of HCC patients are diagnosed at an advanced stage, missing the opportunity for curative surgery due to the insidious onset and lack of typical clinical symptoms in early stages[3-5]. For these specific HCC patients, both local and systemic therapies become crucial. Studies have shown that some initial unresectable HCC (uHCC) patients can be offered the chance of salvage surgery after conversion therapy through local or systemic interventions[6,7].

Conversion therapy refers to interventions (such as local or systemic therapies) aimed at converting uHCC patients into candidates for curative surgical treatment[8]. Transcatheter arterial chemoembolization (TACE), as a primary form of local therapy, has historically been considered a first-line treatment for uHCC patients. However, standalone TACE has not consistently achieved the desired outcomes. Reports indicate tumor response rates of approximately 30% and conversion-to-resection rates as low as 9.5%-16.9% in patients with large nodular HCC treated with TACE alone[9,10]. In recent years, systemic therapies predominantly using tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) have shown significant efficacy in HCC treatment, especially when TKIs and ICIs are combined[11-13]. In a single-center, single-arm phase II study, the combination of sintilimab and lenvatinib achieved a 38% objective response rate (ORR) and a conversion-to-resection rate of 34% as conversion therapy[14]. Currently, triplet therapy is being increasingly applied in the conversion therapy of uHCC, showing promising tumor ORR. However, there is limited cohort research on the safety and prognosis of salvage surgery following successful conversion. Therefore, this study aimed to evaluate the safety of salvage surgery and assess the overall survival (OS) and recurrence-free survival (RFS) following salvage surgery treatment.

MATERIALS AND METHODS

Patients

We conducted a retrospective study collecting data from patients diagnosed with uHCC who underwent triplet conversion therapy at the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital) from March 2020 to September 2023. Data included baseline demographics, clinical characteristics, tumor pathological features, and relevant prognostic outcomes.

Patients were diagnosed with HCC according to the clinical diagnostic criteria of the American Association for the Study of Liver Diseases or confirmed by histopathological examination. uHCC was defined as patients with poor general condition, insufficient residual liver volume post-surgery, or tumors deemed unsuitable for resection, as follows: (1) Extensive liver involvement with multiple tumors (> 3) not confined to the same liver lobe; (2) Concurrent extrahepatic metastasis; (3) Major vascular invasion or tumors located near major vessels precluding negative margin resection (R0 resection); and (4) Inadequate residual liver volume post-surgery (residual liver volume/standard liver volume < 40% for patients with cirrhosis, < 30% for non-cirrhotic patients) (residual liver volume was assessed by three-dimensional reconstruction of the liver).

Inclusion criteria were: (1) Patients aged between 18 years and 75 years who received triple conversion therapy and salvage surgery for uHCC; (2) No prior systemic therapy; (3) Eastern Cooperative Oncology Group performance status score ≤ 1; (4) Regular conversion therapy and follow-up according to schedule; and (5) Patients with at least one measurable target lesion according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Exclusion criteria were: (1) Severe organ failure such as liver, kidney, or heart failure not tolerable for surgical treatment; (2) Child-Pugh class C; (3) Incomplete clinical data; and (4) Extrahepatic metastases [extrahepatic metastases were ruled out by full abdominal and chest computed tomography (CT)].

This study complied with the principles of the Helsinki Declaration and was approved by the research ethics committee of the First Affiliated Hospital of the University of Science and Technology of China, Anhui Provincial Hospital, approval No. 2024-RE-186. Given the retrospective nature of the study, informed consent from patients was waived, ensuring the confidentiality of patient information.

Conversion therapy

Triple conversion therapy consisted of TACE combined with TKIs and anti-programmed cell death protein 1 (PD-1) antibodies (choice of the treatment program depends primarily on the patient’s financial situation and the presence of relevant contraindications to treatment), as follows: TACE is performed under local anesthesia by puncturing the right femoral artery using the Seldinger technique and placing a guiding sheath. Firstly, digital subtraction angiography is used to identify the arteries supplying the tumor, and a mixture of iodized oil and pirarubicin solution is injected into the corresponding arteries via a microcatheter. Secondly, gelatin sponge particles are selectively used to embolize the feeding arteries until complete cessation of arterial blood flow is observed. Finally, the microcatheter is retracted to the main hepatic artery, followed by repeat digital subtraction angiography. If persistent staining of the tumor is observed, additional embolization is performed. Repeat TACE may be considered at intervals of 4-6 weeks if subsequent imaging suggests significant arterial blood supply to the tumor.

The TKIs involved in this study include lenvatinib (12 mg for patients ≥ 60 kg or 8 mg for patients < 60 kg, orally, once daily), sorafenib (200 mg, orally, twice daily), apatinib (250 mg, orally, once daily), and regorafenib (400 mg, orally, once daily). All patients meeting the study criteria receive intravenous administration of anti-PD-1 antibody drugs every 3 weeks, including sintilimab (200 mg), tislelizumab (200 mg), camrelizumab (200 mg), and pembrolizumab (200 mg). All patients with active hepatitis B virus infection receive oral antiviral therapy (entecavir).

Clinical assessment

Each conversion therapy cycle consisted of treatments administered every 3 weeks, with contrast-enhanced magnetic resonance imaging (MRI) or 2024-RE-186 scans conducted every 8-10 weeks[15,16]. Tumor resectability was assessed jointly using radiological (enhanced MRI or CT) and laboratory data, evaluating tumor response according to mRECIST criteria. Throughout conversion therapy, close monitoring and timely management of drug-related adverse events were performed, with drug doses adjusted as necessary based on individual patient conditions.

Salvage surgery

Criteria for surgical treatment eligibility after successful conversion therapy include: (1) Sufficient residual liver volume (residual liver volume/standard liver volume > 40% for patients with cirrhosis, > 30% for non-cirrhotic patients); (2) No extrahepatic metastases; (3) Complete or partial resolution of intrahepatic tumor lesions; and (4) Absence of contraindications for surgical treatment (the main contraindications include: Insufficient residual liver volume, Child-Pugh-C class, bilateral lower extremity deep vein thrombosis, etc.). Upon meeting the surgical criteria and obtaining informed consent from the patient and family members, curative surgery is performed. TKIs and anti-PD-1 antibodies are discontinued for at least 1 week and 3 weeks before surgery. The specific surgical approach for each patient is determined based on their general condition, degree of liver cirrhosis, tumor size, tumor location, and hepatic functional reserve. The Clavien-Dindo classification system is used to categorize complications occurring after salvage surgery.

Follow-up

Patients undergo examinations at 1 month after salvage surgery and subsequently every 3 months. The main examination items include alpha-fetoprotein and contrast-enhanced CT or MRI of the abdomen. If HCC recurrence is detected, specific diagnosis and treatment plans can be formulated based on the patient's general condition and characteristics of the recurrent tumor, such as TACE, microwave ablation, or systemic therapy.

Study endpoints

The primary endpoints of our study were the safety of salvage surgery, OS, and RFS. Secondary endpoints included postoperative complications. We conducted univariate and multivariate Cox regression analyses to identify independent risk factors for postoperative RFS. OS was defined as the time from salvage surgery to death or the last follow-up date. RFS was defined as the time from salvage surgery to tumor recurrence, death, or the last follow-up date. Pathological tumor outcomes primarily refer to pathological complete response (PCR), defined as the absence of viable tumor cells in hematoxylin-eosin-stained specimens of resected tumors. The study endpoint was March 1, 2024.

Statistical analysis

Continuous variables are presented as mean ± SD or median [interquartile range (IQR)], and categorical variables as frequency (percentage). OS and RFS were calculated using Kaplan-Meier curves. Univariate and multivariate Cox regression analyses were used to determine independent risk factors for RFS. In the univariate analysis, variables with P < 0.05 were included in the multivariate Cox proportional hazards model. A P-value < 0.05 was considered statistically significant. All statistical analyses are performed using the SPSS software (version 25, SPSS, Inc., Chicago, IL, United States).

RESULTS

Baseline characteristics

This study included 117 patients diagnosed with uHCC who attended our hospital between March 2020 and September 2023. All patients underwent conversion therapy with TACE combined with TKIs and anti-PD-1 antibodies (Figure 1). Of these patients, 106 (90.6%) were male and 11 (9.4%) were female, with a mean age of 58.79 ± 10.48 years. The majority of patients (n = 106, 90.6%) had a history of hepatitis B infection, and 82 (70.1%) patients had vascular invasion. Barcelona Clinic Liver Cancer stage C was present in 85 (72.6%) patients, and the mean diameter of the largest tumor was 8.46 ± 3.57 cm (Supplementary Table 1).

Figure 1 Flowchart of the study. uHCC: Unresectable hepatocellular carcinoma; PCR: Pathological complete response.

Among the 28 patients who underwent salvage surgery, 25 (89.3%) were male and 3 (10.7%) were female, with a mean age of 57.18 ± 12.46 years. Twenty-two (78.6%) patients had a history of hepatitis B infection, and one (3.6%) patient had a history of hepatitis C infection. Barcelona Clinic Liver Cancer stages A, B, and C were observed in 1 (3.6%), 10 (35.7%), and 17 (60.7%) patients, respectively. Vascular invasion was observed in 17 (60.7%) patients, and the mean diameter of the largest tumor was 7.38 ± 3.67 cm. Sixteen (57.1%) patients received adjuvant therapy postoperatively (Table 1).

Table 1 Demographic and baseline characteristics of patients, n (%).

Characteristics	Total cohort (n = 28)
Age (year), mean ± SD	57.18 ± 12.46
Age, years
< 65	19 (67.9)
≥ 65	9 (32.1)
Gender
Male	25 (89.3)
Female	3 (10.7)
Etiology
HBV	22 (78.6)
HCV	1 (3.6)
Non-viral	5 (17.9)
ECOG-PS
0	25 (89.3)
1	3 (10.7)
Child-Pugh class
A	23 (82.1)
B	5 (17.9)
Pre-treatment AFP (ng/mL)
< 400	7 (25.0)
≥ 400	21 (75.0)
BCLC staging system
A	1 (3.6)
B	10 (35.7)
C	17 (60.7)
Vascular invasion
Present	17 (60.7)
Absent	11 (39.3)
Maximum tumor diameter (cm), mean ± SD	7.38 ± 3.67
Number of tumors
1	9 (32.1)
2	4 (14.3)
3	2 (7.1)
≥ 4	13 (46.4)
irAEs
Yes	6 (21.4)
No	22 (78.6)
Post-operative complications
Yes	4 (14.3)
No	24 (85.7)
Post-operative adjuvant therapy
Yes	16 (57.1)
No	12 (42.9)
ALT level (IU/L)
< 40	20 (71.4)
≥ 40	8 (28.6)
AST level (IU/L)
< 40	15 (53.6)
≥ 40	13 (46.4)

HBV: Hepatitis B virus; HCV: Hepatitis C virus; ECOG-PS: Eastern Cooperative Oncology Group performance status; Child-Pugh: Child-Pugh score; AFP: Alpha-fetoprotein; BCLC: Barcelona Clinic Liver Cancer; irAEsA: Immune-related adverse events; ALT: Alanine transaminase; AST: Aspartate transaminase.

Conversion therapy

All 28 patients who underwent salvage surgery in this study received at least one cycle of conversion therapy (Table 2). The median number of cycles of anti-PD-1 antibody therapy was 1 (IQR: 1-1), and the median number of TACE treatments was 4 (IQR: 3-5.75). The anti-PD-1 antibodies used in this study included sintilimab (n = 12, 42.9%), camrelizumab (n = 7, 25.0%), tislelizumab (n = 6, 21.4%), and pembrolizumab (n = 3, 10.7%). TKIs included lenvatinib (n = 19, 67.9%), sorafenib (n = 5, 17.9%), apatinib (n = 3, 10.7%), and regorafenib (n = 1, 3.6%). During the application of triple therapy conversion treatment, liver tumors were evaluated according to mRECIST criteria, with 14 (50.0%) patients achieving complete response (CR) and 14 (50.0%) achieving partial response.

Table 2 Treatment regimens and hepatic tumor response, n (%).

Variable	Patients (n = 28)
Anti-PD-antibody treatment cycle, median (IQR)	1 (1-1)
Number of TACE treatments, median (IQR)	4 (3-5.75)
Anti-PD-1 antibody class
Tislelizumab	6 (21.4)
Sintilimab	12 (42.9)
Camrelizumab	7 (25.0)
Pembrolizumab	3 (10.7)
TKI class
Lenvatinib	19 (67.9)
Donafenib	5 (17.9)
Apatinib	3 (10.7)
Sorafenib	1 (3.6)
Optimal tumor response according to mRECIST
PR	14 (50.0)
CR	14 (50.0)

PD-1: Programmed cell death protein 1; TACE: Transarterial chemoembolization; IQR: Interquartile range; ICI: Immune checkpoint inhibitor; TKI: Tyrosine kinase inhibitor; mRECIST: Modified Response Evaluation Criteria in Solid Tumors; PR: Partial response; CR: Complete response.

Salvage surgery treatment

Regarding the surgical procedures, 7 patients (25.0%) underwent laparoscopic surgery, while the remaining 21 patients (75.0%) underwent open surgery. The median duration of surgery was 245 minutes (IQR: 182.5-370.0), and the median intraoperative blood loss was 200 mL (IQR: 100.0-475.0). Thirteen patients (46.4%) received intraoperative blood transfusions. Postoperatively, 14 patients (50.0%) achieved PCR. Among the patients, 20 (71.4%) experienced postoperative complications, with 16 patients (57.1%) experiencing Clavien-Dindo grade I-II complications and 4 patients (14.3%) experiencing Clavien-Dindo grade III-V complications. Postoperative complications included pleural effusion (n = 15, 53.6%), abdominal fluid (n = 13, 46.4%), intra-abdominal infection (n = 7, 25.0%), liver dysfunction (n = 6, 21.4%), bile leakage (n = 4, 14.3%), and intra-abdominal bleeding (n = 1, 3.6%) (Table 3). Postoperative complications varied between patients undergoing different surgical procedures (Supplementary Table 2). Unfortunately, one patient died 1.6 months after surgery in our study. This uHCC patient underwent right hemihepatectomy, resection of the hepatic caudate lobe, and cholecystectomy following TACE, camrelizumab, and apatinib combination therapy. The patient was discharged smoothly postoperatively but was found to have liver cancer recurrence with minimal ascites and liver function abnormalities during follow-up. Despite supportive care, the patient's condition deteriorated.

Table 3 Perioperative clinical data, n (%).

Salvage operation	Patients (n = 28)
Type of surgery
Laparoscopy	7 (25.0)
Open	21 (75.0)
Operative time, median (IQR), minutes	245 (182.5-370.0)
Intraoperative blood loss, median (IQR), mL	200 (100.0-475.0)
Intraoperative blood transfusion
Yes	13 (46.4)
No	15 (53.6)
Pathological reaction
PCR	14 (50.0)
Non-PCR	14 (50.0)
Post-operative hospitalization days, median (IQR), days	16 (7.5-23.8)
Post-operative complication
Present	20 (71.4)
Absent	8 (28.6)
Clavien-Dindo class
I-II	16 (57.1)
III-V	4 (14.3)
Post-operative complication
Liver failure	6 (21.4)
Abdominal fluid	13 (46.4)
Bile leakage	4 (14.3)
Abdominal infection	7 (25.0)
Abdominal hemorrhage	1 (3.6)
Pleural effusion	15 (53.6)

IQR: Interquartile range; PCR: Pathological complete response.

Treatment outcomes

The study’s cutoff date was March 1, 2024, and all study subjects were followed up until death or the study cutoff date. During the follow-up period, tumor recurrence occurred in 10 patients (35.7%), mainly manifesting as intrahepatic recurrence (5 cases, 17.9%). The primary treatment modalities for recurrent tumors included systemic therapy combined with targeted therapy (7 cases, 25.0%) (Table 4). The median follow-up time was 15.0 months (range: 1.6-37.2 months), with median OS and RFS not reached. The 1-year and 2-year RFS rates were 75.0% and 59.4%, respectively. The 1-year and 2-year OS rates were 92.7% and 87.6%, respectively (Figure 2).

Figure 2 Kaplan-Meier curves of patients who underwent salvage surgery. A: Kaplan-Meier curve for overall survival; B: Kaplan-Meier curve for recurrence-free survival. OS: Overall survival; RFS: Recurrence-free survival.

Table 4 Outcomes of salvage surgery, n (%).

Treatment outcome	Patients (n = 28)
Follow-up time, median (range), months	14.6 (1.3-42.1)
Number of relapsed patients	13 (46.4)
Recurrence
Intrahepatic	7 (25.0)
Extrahepatic	2 (7.1)
Intrahepatic combined with extrahepatic	4 (14.3)
Therapeutic measures after relapse
Microwave	1 (3.6)
Systemic therapy + targeted therapy	7 (25.0)
Systemic therapy + targeted therapy + TACE	2 (7.1)

TACE: Transcatheter arterial chemoembolization.

Risk factors for postoperative RFS

Single-variable Cox proportional hazard models were used to analyze risk factors associated with RFS to identify covariates related to RFS. Following data analysis, factors significantly affecting RFS included Eastern Cooperative Oncology Group performance status (P = 0.003), Child-Pugh classification (P = 0.010), postoperative pathology (P = 0.026), hemoglobin level (P = 0.013), red blood cell count (P = 0.038), and albumin (ALB) level (P = 0.005). These six factors were included in a multivariable Cox proportional hazards model analysis, which indicated that PCR (hazard ratio = 0.073, 95% confidence interval: 0.009-0.571, P = 0.013) and higher ALB level (hazard ratio = 0.022, 95% confidence interval: 0.001-0.594, P = 0.023) were significant independent factors affecting RFS (Table 5).

Table 5 Analysis of postoperative recurrence-free survival-related risk factors.

Risk factor	Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)	P value
Age (≥ 65 years)	3.475 (0.889-13.586)	0.073	-	-
HBsAg (positive)	1.117 (0.237-5.272)	0.889	-	-
EOCG-PS (1)	11.943 (2.310-61.743)	0.003	0.406 (0.027-6.115)	0.515
Child-Pugh class (B)	5.810 (1.521-22.185)	0.010	3.748 (0.390-35.980)	0.252
Vascular invasion (present)	1.676 (0.433-6.487)	0.455	-	-
Conversion therapy cycle (≥ 5 times)	1.567 (0.436-5.637)	0.491	-	-
Number of TACE (≥ 2 times)	2.326 (0.481-11.245)	0.294	-	-
irAEs (present)	0.446 (0.056-3.566)	0.446	-	-
Surgical type (open)	4.256 (0.533-34.003)	0.172	-	-
Surgery time (≥ 200 minutes)	1.580 (0.335-7.448)	0.563	-	-
Intraoperative blood loss (≥ 500 mL)	0.821 (0.174-3.869)	0.803	-	-
Intraoperative blood transfusion (yes)	0.917 (0.257-3.278)	0.894	-	-
Clavien-Dindo class (IIIa-V)	0.037 (0.000-71.508)	0.394	-	-
Post-operative pathology (PCR)	0.171 (0.036-0.811)	0.026	0.073 (0.009-0.571)	0.013
Maximum tumor diameter (≥ 10 cm)	1.537 (0.392 -6.028)	0.537	-	-
Number of tumors (≥ 3)	1.088 (0.306-3.861)	0.897	-	-
WBC count (≥ 4 × 109/L)	1.201 (0.310-4.653)	0.791	-	-
HGB level (≥ 120 g/L)	0.072 (0.009-0.571)	0.013	0.51 (0.018-14.854)	0.701
RBC count (≥ 4.3 × 1012/L)	0.194 (0.041-0.916)	0.038	1.816 (0.190-17.317)	0.604
PLT count (≥ 100 × 109/L)	2.200 (0.650-40.842)	0.120	-	-
ALB level (≥ 35 g/L)	0.052 (0.007-0.412)	0.005	0.022 (0.001-0.594)	0.023
ALT level (≥ 40 IU/L)	0.602 (0.127-2.860)	0.523	-	-
AST level (≥ 40 IU/L)	0.777 (0.219-2.756)	0.696	-	-
AFP level (≥ 400 ng/mL)	1.415 (0.365-5.477)	0.615	-	-
Postoperative adjuvant therapy (present)	0.746 (0.213-2.606)	0.646	-	-

HR: Hazard ratio; CI: Confidence interval; HbsAg: Hepatitis B surface antigen; ECOG-PS: Eastern Cooperative Oncology Group performance status; TACE: Transcatheter arterial chemoembolization; irAEs: Immune-related adverse events; PCR: Pathological complete response; WBC: White blood cell count; HGB: Hemoglobin; RBC: Red blood cell count; PLT: Platelet count; ALB: Albumin; ALT: Alanine transaminase; AST: Aspartate transaminase; AFP: Alpha-fetoprotein.

Comparison between PCR and non-PCR groups

Twenty-eight patients were stratified into the PCR (n = 14) and non-PCR (n = 14) groups. The PCR group demonstrated a trend toward superior OS compared to the non-PCR group (P = 0.406; Figure 3A), while significantly better RFS was observed in the PCR group (P = 0.012; Figure 3B). Furthermore, no statistically significant differences in postoperative complications were identified between the two groups (Table 6).

Figure 3 Survival analysis between the pathological complete response and non-pathological complete response groups. A: Kaplan-Meier curves for overall survival between the two groups; B: Kaplan-Meier curves for recurrence-free survival between the two groups.

Table 6 Postoperative complications in the pathological complete response group vs non-pathological complete response group.

Postoperative complications	PCR group (n = 14)	Non-PCR group (n = 14)	P value
Liver failure, no/yes	12/2	10/4	0.645
Abdominal fluid, no/yes	7/7	8/6	0.705
Bile leakage, no/yes	11/3	13/1	0.589
Abdominal infection, no/yes	11/3	10/4	1.000
Abdominal hemorrhage, no/yes	13/1	14/0	1.000
Pleural effusion, no/yes	6/8	7/7	0.705

PCR: Pathological complete response.

DISCUSSION

Internationally, there are numerous randomized controlled trials on the treatment of HCC using TACE in combination with ICIs and TKIs, such as LEAP-012 and EMERAD-3, but these studies are still in the experimental stage and their results have not yet been published[17-19]. Currently, only a few reports exist on uHCC patients successfully transitioning to surgical treatment. In this study, 28 patients underwent successful salvage surgery following conversion therapy, which is of significant importance for studying the efficacy and safety of salvage surgery. Recent research indicates that for uHCC patients, TACE combined with TKIs and anti-PD-1 antibodies shows considerable effectiveness in controlling tumor progression, reducing tumor burden, and improving patient OS[20]. Wu et al[21] reported that among 62 uHCC patients treated with TACE combined with lenvatinib and anti-PD-1 antibodies, the ORR reached 80.6%. They reported a total of 33 patients (53.2%) meeting the criteria for surgical treatment, with 29 patients (46.8%) undergoing salvage surgery, with a median surgical time and blood loss of 235 minutes and 300 mL, respectively. Yang et al[22] demonstrated that combination therapy is a feasible conversion therapy for turning uHCC patients into suitable for resection and potentially improving long-term survival rates. These studies collectively suggest that salvage surgery following conversion therapy is safe and feasible for uHCC patients.

Systemic therapy with TKIs and ICIs as monotherapy shows tumor response rates below 20%[23], and TACE alone has a relatively low conversion rate for uHCC patients. However, the conversion rate significantly improves with local treatment combined with systemic therapy, and is markedly superior to monotherapy[24,25]. The synergy of triple therapy can be attributed to several reasons: (1) TACE treatment creates a hypoxic tumor microenvironment, promoting the release of factors such as vascular endothelial growth factor and hypoxia-inducible factor-1α, thereby inducing tumor neovascularization; (2) TACE induces tumor cell death and activates the release of tumor-specific antigens, enhancing the efficacy of ICIs against tumors; and (3) Both ICIs and TKIs inhibit tumor neovascularization, with TKIs additionally altering the immunosuppressive tumor microenvironment[26,27]. This synergistic combination not only counters the vascular regeneration effects post-TACE but also enhances the effectiveness of ICIs, thereby increasing the clinical benefits of TACE and ICIs. The synergistic effects among TACE, TKIs, and anti-PD-1 antibodies provide better treatment outcomes for uHCC patients, highlighting their crucial therapeutic role.

In our study, the safety of triple conversion therapy and salvage surgery was evaluated. Among the 28 patients who received TACE combined with TKIs and anti-PD-1 antibodies treatment, assessment of liver tumor based on mRECIST revealed that 14 patients (50.0%) achieved CR, while 14 patients (50.0%) achieved partial response, consistent with the tumor regression observed in postoperative pathology. During combination therapy, although 6 patients (21.4%) experienced immune-related adverse events, their symptoms were effectively managed with appropriate treatment. Post-operatively, 20 patients (71.4%) experienced complications, with 4 patients (14.3%) classified as Clavien-Dindo grade III-IV. The predominant types of complications were pleural effusion (53.6%), ascites (46.4%), intra-abdominal infections (25.0%), and liver dysfunction (21.4%). Although the majority of patients (71.4%) experienced postoperative complications, effective control was achieved through relevant medical interventions. Studies have reported postoperative liver function failure rates ranging from 14.6% to 50% after conversion therapy followed by salvage surgery[28], consistent with the occurrence rate of 21.4% observed in this study. The median surgical time and intraoperative blood loss were 245 minutes and 200 mL, respectively. These data indicate that salvage surgery is an effective and feasible treatment option for successfully converted uHCC patients. It is noteworthy that postoperative liver function failure can sometimes be fatal, thus clinicians should formulate diagnostic and therapeutic strategies more cautiously.

Studies have also shown that combination therapy has a synergistic effect in increasing tumor response rate and toxicity is within a manageable range. Liu et al[29] first reported on 22 uHCC patients treated with TACE combined with camrelizumab and lenvatinib conversion therapy in 2021, demonstrating improved median OS and progression-free survival without severe adverse reactions during treatment. Although OS in uHCC patients improved significantly after conversion therapy, post-operative RFS remains a significant challenge for achieving favorable outcomes from salvage surgery. In a recent studyinvolving 83 uHCC patients who successfully underwent salvage surgery following triple conversion therapy, 24 patients (29.2%) experienced tumor recurrence post-operatively, and 56 patients (67.5%) received adjuvant therapy[30]. The median RFS was 25.4 months, with 1-year and 2-year RFS rates of 68.2% and 61.8%, respectively. Wu et al[31] reported on 70 uHCC patients undergoing salvage surgery, with all patients receiving adjuvant therapy post-operatively; 21 patients (30.0%) experienced tumor recurrence. Statistical analysis showed that the median RFS was not reached, with 1-year and 2-year RFS rates of 68.9% and 54.4%, respectively. In our study, 10 patients (35.7%) experienced tumor recurrence post-operatively, and 16 patients (57.1%) received post-operative adjuvant therapy. The 1-year and 2-year RFS rates were 75.0% and 59.4%, respectively. These results indicate that the proportion of patients experiencing tumor recurrence post-operatively and the 1-year and 2-year RFS rates in our study are similar to those reported in the aforementioned studies. It is worth noting that current expert consensus recommends maintaining partial or preoperative systemic therapy for patients undergoing salvage surgery after conversion[32]. Furthermore, in our study, both univariate and multivariate Cox analyses revealed that PCR patients had better RFS compared to non-PCR patients. This finding underscores the special significance of tumor response for post-operative RFS. The more complete the tumor response, the longer the post-operative RFS is likely to be.

Previous studies have suggested that PCR and intraoperative blood transfusion may serve as independent risk factors for postoperative RFS[30]. However, our univariate and multivariate Cox regression analyses revealed that ALB levels emerged as an independent risk factor for postoperative RFS in patients undergoing salvage surgery. Notably, this phenomenon may be potentially associated with the treatment duration of the ICIs-TKIs-TACE combination therapy. On the one hand, sustained ICIs administration may reduce recurrence risk by maintaining antitumor immune responses. On the other hand, TKIs could induce sinusoidal endothelial cell injury via inhibition of the vascular endothelial growth factor receptor signaling pathway in hepatocytes, while TACE may provoke ischemic alterations in non-tumorous liver parenchyma. The cumulative effects of these therapies on hepatic synthetic function may explain the significant decline in ALB levels observed in patients achieving radiographic CR[33,34]. This finding carries important clinical implications: A multidimensional evaluation system integrating tumor response severity and hepatic functional reserve should be established when assessing the benefit-risk ratio of salvage surgery. Particularly, the anti-recurrence benefits of continued ICIs therapy must be carefully weighed against its potential hepatotoxicity risks during the formulation of postoperative adjuvant treatment strategies.

Our study has several limitations. Firstly, it is a retrospective, single-center, and single-arm study, which may restrict a comprehensive evaluation of the safety of salvage surgery. The lack of a control group prevents direct comparison of the effectiveness of different combination therapies. Secondly, there is a risk of selection bias due to the relatively short follow-up time and small sample size. Thirdly, most patients in this study had a history of hepatitis B, and it remains unclear how effective triple therapy is for uHCC patients with other etiologies. Therefore, future research should employ prospective designs with larger sample sizes to enhance the level of evidence, thereby providing a more comprehensive assessment of the safety of salvage surgery and its long-term survival benefits for uHCC patients.

CONCLUSION

Salvage surgery after receiving conversion therapy with TACE combined with TKIs and anti-PD-1 antibodies is an effective and safe treatment option for patients with uHCC. It can prolong the OS of patients and may bring more potential benefits to uHCC patients.