Introduction: Accurately predicting the outcomes of conversion therapy among patients with initially unresectable hepatocellular carcinoma (uHCC) remains a challenge. Clinical complete response (cCR) has been proposed as a predictor of prognosis. However, information on its prognostic value in these patients is limited. We aimed to explore the prognostic value of cCR in patients with uHCC following conversion therapy and identify predictors of cCR. Methods: We included 241 patients with uHCC who underwent transcatheter arterial chemoembolization combined with lenvatinib and PD-1 inhibitors (triple therapy) as first-line treatment. The prognostic value of cCR, predictive factors of cCR, and the relationship between cCR and pathological complete response (pCR) were analyzed. Results: The cCR rate of the 241 patients included was 17.4%. Patients with cCR showed better overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) than those without. cCR was an independent risk factor for OS (hazard ratio [HR]: 0.11, 95% confidence interval [CI]: 0.03–0.42, p = 0.001) and PFS (HR: 0.29, 95% CI: 0.15–0.56, p < 0.001). Serum α-fetoprotein levels ≥400 ng/mL (odds ratio [OR]: 0.47, 95% CI: 0.22–0.95, p = 0.040) and extrahepatic metastasis (OR: 0.13, 95% CI: 0.01–0.62, p = 0.046) were independent negative predictors of cCR. A total of 107 patients (44.4%) underwent conversion surgery. Among these patients, cCR was associated with better OS (p = 0.009) and recurrence-free survival (p = 0.007). cCR was significantly correlated with pCR (Φ = 0.61, p < 0.001). Albumin levels ≥35 g/L (OR: 0.12, 95% CI: 0.02–0.69, p = 0.018) and cCR (OR: 30.32, 95% CI: 9.19–128.00, p < 0.001) were independent predictors of pCR. Conclusion: cCR after triple therapy has an excellent long-term survival advantage and is significantly related to pCR. cCR may be a surrogate marker for predicting prognosis and pCR in patients with uHCC receiving triple therapy.

Hepatocellular carcinoma (HCC) poses a significant global health challenge owing to its high incidence and mortality rates [1, 2]. Surgical resection remains the most effective curative treatment option for early-stage HCC [3, 4]. However, many patients with HCC are ineligible for hepatectomy because of advanced disease at initial diagnosis [3, 4].

Conversion therapies for unresectable HCC (uHCC) have undergone notable advancements and challenges in recent years [5, 6]. Current therapies now have the ability to transform uHCC into resectable HCC, thereby improving patient prognosis. Various therapies have been identified as candidates for conversion therapy, including local, systemic, and a combination of local and systemic therapies [6‒13]. Combinations of local and systemic therapies have shown promising clinical efficacies in patients with uHCC [6, 9‒13]. Among them, transcatheter arterial chemoembolization (TACE) combined with lenvatinib and PD-1 inhibitors (triple therapy) is an important conversion therapy with a high rate of tumor response (objective response rate [ORR] 46–77.4%) and converted resection (25–50%) for uHCC [11‒13].

Although conversion therapy improves the treatment outcomes in uHCC, accurately predicting the outcomes of conversion therapy remains a challenge. The complexity of HCC biology and the heterogeneity of patient populations contribute to the difficulty of prediction. Several studies have indicated that achieving pathological complete response (pCR) after conversion therapy is associated with excellent long-term outcomes [14‒17]. Allard et al. [14] showed that achieving pCR or nearly pCR after preoperative TACE resulted in better long-term survival in patients with HCC. Our previous study also demonstrated that achieving a major pathological response (MPR) or pCR could improve postoperative overall survival (OS) and recurrence-free survival (RFS) in patients who underwent conversion surgery after triple therapy [15]. Therefore, pCR after conversion therapy seems to be a promising surrogate marker for prognosis. However, pCR after conversion therapy can only be confirmed after surgical resection.

To address this, clinical complete response (cCR), defined as no residual tumor using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) and normal serum tumor markers after conversion therapy, has been proposed as a predictor of prognosis [18‒22]. Patients with uHCC who achieve cCR after conversion therapy have improved survival outcomes [18‒21]. Li et al. [19] found that in patients with uHCC who achieved cCR after conversion therapy, the watch-and-wait strategy offered survival outcomes comparable to those of surgical resection. Our previous research also indicated that surgical resection may not be necessary for uHCC after conversion therapy if cCR is achieved [18, 20]. If the prognostic value of cCR is reliably validated as a promising surrogate indicator, it can be used to predict the prognosis of patients with uHCC after conversion therapy, and the watch-and-wait strategy can be used for these patients. However, evidence regarding the prognostic value of cCR after conversion therapy with triple therapy is lacking, and the relationship between cCR and pCR remains unclear. Therefore, the clinical value of cCR as a prognostic marker of long-term survival after triple therapy requires further investigation. In this study, we aimed to clarify the prognostic value of cCR for uHCC following triple therapy and the relationship between cCR and pCR. Furthermore, we identified preoperative predictors of cCR.

Patients

In this retrospective study, patients with uHCC who underwent at least one cycle of triple therapy between January 2018 and December 2023 were collected from six high-volume institutions: Fujian Provincial Hospital, First Affiliated Hospital of Fujian Medical University, Zhongshan Hospital of Xiamen University, Zhangzhou Affiliated Hospital of Fujian Medical University, First Affiliated Hospital of Xiamen University, and Guilin Medical University. Patients were eligible if they fulfilled the following inclusion criteria: (1) diagnosis of HCC according to clinical practice guidelines, (2) diagnosed with unresectable disease and treated with triple therapy as the first-line treatment, (3) Barcelona Clinic for Liver Cancer (BCLC) stage B or C, (4) age 18–75 years, (5) Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1, and (6) Child-Pugh class A. Patients were excluded from the study if they fulfilled any of the following exclusion criteria: (1) tumor thrombus involving both the left and right branch of the portal vein or main portal vein, (2) any other previous treatments for HCC, (3) a history of other malignancies, (4) severe dysfunction of vital organs, (5) incomplete data.

uHCC was defined as a condition in which surgical removal of the tumor is not feasible owing to extrahepatic metastases, extensive bilobar liver involvement, insufficient remnant liver volume (<30% for patients without liver cirrhosis or <40% for patients with liver cirrhosis), or inadequate hepatic functional reserve. uHCC was evaluated by a multidisciplinary team (MDT).

Baseline characteristics, including age, sex, Child-Pugh class, BCLC stage, hepatitis B virus (HBV) infection, ECOG PS score, serum α-fetoprotein (AFP) levels, protein induced by vitamin K absence-II (PIVKA-II) levels, neutrophils count, lymphocytes count, albumin (ALB), bilirubin, alanine aminotransferase (ALT), aspartate transaminase (AST), tumor diameter, tumor number, presence of macrovascular invasion, extrahepatic metastasis, TACE sessions, and postoperative pathology, were retrospectively collected. This study was conducted in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of each center. All the patients in this study provided written informed consent prior to triple therapy.

Triple Therapy

For TACE, the microcatheter was inserted into the right femoral artery and threaded through the vascular system under radiographic guidance until it reached the arteries supplying the tumor for superselective chemoembolization. For multiple intrahepatic tumors, chemoembolization was performed by superselection of the arteries supplying arteriographically visible tumors, whereas non-visible tumors were not embolized. Pirarubicin was mixed with iodized oil and injected directly through the microcatheter into selected arteries feeding the tumor. The arteries feeding the tumor were embolized using gelatin sponge particles. Patients were followed up every 4 weeks, and AFP levels, PIVKA-II levels, and computed tomography (CT) or magnetic resonance imaging (MRI) were evaluated to determine the curative effect and vascular supply of the tumor. TACE was repeated on demand every 4–6 weeks if there was an obvious hepatic arterial blood supply to the tumor based on CT or MRI results. All patients with active HBV infections received oral antiviral therapy.

Lenvatinib was orally administered once a day at doses of 8 or 12 mg to patients with body weights <60 kg or ≥60 kg, respectively. The PD-1 inhibitor was administered intravenously every 3 weeks at a standard dose (sintilimab 200 mg, tislelizumab 200 mg, camrelizumab 200 mg, toripalimab 240 mg, and pembrolizumab 200 mg). Lenvatinib and PD-1 inhibitors were administered within 3–14 days of the first TACE treatment and were discontinued for 3 days before and after the next TACE treatment.

Evaluation of Response and Toxicity

Viable tumors with arterial phase enhancement were measured and evaluated using CT or MRI. Tumor responses were evaluated using mRECIST, including CR, partial response (PR), stable disease, and progressive disease. The ORR was defined as the proportion of patients who achieved CR and PR.

cCR was defined by the following criteria: radiological CR sustained for at least 4 weeks and normalization of tumor markers (AFP <7 ng/mL and PIVKA-II <40 mAU/mL) for at least 4 weeks [18, 20]. pCR was defined as the absence of residual viable cancer cells in the surgical tumor specimen, and MPR was defined as ≤10% viable tumor cells in the surgical tumor specimen. The toxicities of triple therapy were evaluated using the Common Terminology Criteria for Adverse Events version 5.0.

Surgical Procedures

Whether patients with uHCC met the criteria for resectability after triple therapy was determined by an MDT. The criteria for resectable HCC were as follows: (1) sufficient remnant liver volume (>30% for patients without liver cirrhosis or >40% for patients with liver cirrhosis), (2) R0 resection margins after triple therapy, (3) Child-Pugh class A or B, (4) ECOG PS score 0–1, (5) no extrahepatic lesions, and (6) no contraindication. Surgery was performed 1 month after the last TACE procedure. Lenvatinib and PD-1 inhibitors were discontinued for 1 and 4 weeks, respectively, before surgery.

Follow-Up

Follow-up included contrast-enhanced abdominal CT or MRI, AFP levels, PIVKA-II levels, and liver function assessments. Patients were followed up every 4–8 weeks. For patients who experienced PD or intolerable toxicity or withdrew consent, further treatment options were determined by the MDT after discussion with the patient. Other patients were treated until PD, symptomatic progression, intolerable toxicity, or withdrawal of consent. The choice of subsequent treatment was determined after discussions with the MDT, considering the patient’s preference. Patients who underwent surgical resection received lenvatinib and PD-1 inhibitors for 3–6 months postoperatively.

OS was defined as the time from the date of the first TACE until death. Progression-free survival (PFS) was defined as the time from the first TACE to progression or death. The primary endpoint of this study was OS after triple therapy. The secondary study endpoints were PFS and predictors of cCR. For the analysis of patients who underwent conversion surgery, OS was defined as the time from surgery to death. RFS was defined as the time from surgery to the first recurrence or death. The last follow-up date for these patients was June 30, 2024.

Statistical Analysis

Categorical variables are presented as numbers (percentages) and were compared using the chi-squared test or Fisher’s exact test. Continuous variables are presented as mean ± standard deviation or median (interquartile range [IQR]) and were compared using the Student’s t test or Mann-Whitney U test. The neutrophil-to-lymphocyte ratio (NLR) was calculated as the ratio of neutrophils to lymphocytes. The ALBI grade was calculated as log10 bilirubin × 0.66 + albumin × −0.085, and grades 1, 2, and 3 were defined as ≤–2.60, ≤–1.39, and >–1.39, respectively. Moreover, NLR and the number of TACE sessions were dichotomized based on their median values. The phi (Φ) coefficient was used to evaluate the correlation between cCR and pCR.

The Kaplan-Meier method was used to evaluate survival, whereas the reverse Kaplan-Meier method was used to estimate median follow-up time. The Cox proportional hazards model was used to identify prognostic factors for survival. Logistic regression analysis was conducted to detect predictors of cCR and pCR. Variables that were clinically relevant, such as HBV infection, AFP levels, ALBI grade, macrovascular invasion, and extrahepatic metastasis; or significant in the univariate analysis (p < 0.05), were included in the multivariate analysis using the forced-entry method.

To evaluate the association between cCR and survival in the entire cohort, landmark analysis and time-dependent covariate Cox regression models were employed to address immortal time bias. For the OS analysis, patients who died or were lost to follow-up before the landmark time were excluded. Similarly, for the PFS analysis, patients who had experienced disease progression or were lost to follow-up before the landmark time were excluded. Only patients achieving cCR by the landmark time were classified as cCR. Furthermore, the landmark times were set at 5 and 6 months, corresponding to the points at which 75% and 90% of patients had achieved cCR, respectively. In the analysis of patients who underwent conversion surgery, cCR status had been determined prior to surgery, thereby eliminating the concern for immortal time bias. Statistical significance was defined as p < 0.05, and all analyses were performed using the SPSS software (version 17.0; SPSS Inc., Chicago, IL, USA) and R (version 4.3.3).

Patient Characteristics

We included 241 patients with uHCC treated with triple therapy (Fig. 1). The baseline characteristics of the patients are summarized in Table 1. The mean age was 56.3 ± 11.4 years, and 207 patients (85.9%) were male. Regarding the BCLC stage, 154 patients (63.9%) were classified as stage C and 87 (36.1%) as stage B. Of the 241 patients, 117 (48.5%) had AFP levels <400 ng/mL, and 216 (89.6%) were diagnosed with HBV infection. Macrovascular invasion was observed in 130 patients (53.9%), and 185 (76.8%) had multiple lesions based on radiological evaluations. The median number of TACE sessions was 2 (IQR, 1–3). Conversion surgery was performed in 107 patients (44.4%).

Fig. 1.

Patient selection flowchart. uHCC, unresectable hepatocellular carcinoma; BCLC, Barcelona Clinic for Liver Cancer; cCR, complete clinical response; pCR, pathological complete response.

Fig. 1.

Patient selection flowchart. uHCC, unresectable hepatocellular carcinoma; BCLC, Barcelona Clinic for Liver Cancer; cCR, complete clinical response; pCR, pathological complete response.

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Table 1.

Baseline demographic and clinical characteristics of patients

CharacteristicsAll (n = 241)Non-cCR (n = 199)cCR (n = 42)p value
Age, mean (±SD), years 56.3 (11.4) 56.1 (11.4) 57.4 (11.3) 0.505 
Age, n (%)    0.986 
 <65 years 181 (75.1) 150 (75.4) 31 (73.8)  
 ≥65 years 60 (24.9) 49 (24.6) 11 (26.2)  
Sex, n (%)    0.487 
 Female 34 (14.1) 30 (15.1) 4 (9.5)  
 Male 207 (85.9) 169 (84.9) 38 (90.5)  
BCLC stage, n (%)    0.815 
 B 87 (36.1) 73 (36.7) 14 (33.3)  
 C 154 (63.9) 126 (63.3) 28 (66.7)  
HBV infection, n (%)    0.268 
 No 25 (10.4) 23 (11.6) 2 (4.8)  
 Yes 216 (89.6) 176 (88.4) 40 (95.2)  
ECOG PS score, n (%)    >0.999 
 0 188 (78.0) 155 (77.9) 33 (78.6)  
 1 53 (22.0) 44 (22.1) 9 (21.4)  
AFP, n (%)    0.083 
 <400 ng/mL 117 (48.5) 91 (45.7) 26 (61.9)  
 ≥400 ng/mL 124 (51.5) 108 (54.3) 16 (38.1)  
PIVKA-II, n (%)    0.610 
 <400 mAU/mL 68 (28.2) 58 (29.1) 10 (23.8)  
 ≥400 mAU/mL 173 (71.8) 141 (70.9) 32 (76.2)  
Tumor diameter, n (%)    >0.999 
 <10 cm 149 (61.8) 123 (61.8) 26 (61.9)  
 ≥10 cm 92 (38.2) 76 (38.2) 16 (38.1)  
Tumor number, n (%)    0.270 
 Single 56 (23.2) 43 (21.6) 13 (31.0)  
 Multiple 185 (76.8) 156 (78.4) 29 (69.0)  
Macrovascular invasion, n (%)    0.190 
 No 111 (46.1) 96 (48.2) 15 (35.7)  
 Yes 130 (53.9) 103 (51.8) 27 (64.3)  
Extrahepatic metastasis, n (%)    0.017 
 No 203 (84.2) 162 (81.4) 41 (97.6)  
 Yes 38 (15.8) 37 (18.6) 1 (2.4)  
NLR, n (%)    0.447 
 <2.6 119 (49.4) 101 (50.8) 18 (42.9)  
 ≥2.6 122 (50.6) 98 (49.2) 24 (57.1)  
Tbil, n (%)    0.281 
 <34 μmol/L 235 (97.5) 195 (98.0) 40 (95.2)  
 ≥34 μmol/L 6 (2.5) 4 (2.0) 2 (4.8)  
ALB, n (%)    0.469 
 <35 g/L 47 (19.5) 41 (20.6) 6 (14.3)  
 ≥35 g/L 194 (80.5) 158 (79.4) 36 (85.7)  
ALT, n (%)    0.163 
 <40 IU/L 124 (51.5) 107 (53.8) 17 (40.5)  
 ≥40 IU/L 117 (48.5) 92 (46.2) 25 (59.5)  
AST, n (%)    0.641 
 <40 IU/L 85 (35.3) 72 (36.2) 13 (31.0)  
 ≥40 IU/L 156 (64.7) 127 (63.8) 29 (69.0)  
ALBI grade, n (%)    >0.999 
 1 137 (56.8) 113 (56.8) 24 (57.1)  
 2 104 (43.2) 86 (43.2) 18 (42.9)  
TACE sessions, median (IQR) 2 (1–3) 2 (1–3) 1 (1–2) 0.067 
TACE sessions, n (%)    0.181 
 1 118 (49.0) 93 (46.7) 25 (59.5)  
 ≥2 123 (51.0) 106 (53.3) 17 (40.5)  
Conversion surgery, n (%)    0.002 
 No 134 (55.6) 120 (60.3) 14 (33.3)  
 Yes 107 (44.4) 79 (39.7) 28 (66.7)  
CharacteristicsAll (n = 241)Non-cCR (n = 199)cCR (n = 42)p value
Age, mean (±SD), years 56.3 (11.4) 56.1 (11.4) 57.4 (11.3) 0.505 
Age, n (%)    0.986 
 <65 years 181 (75.1) 150 (75.4) 31 (73.8)  
 ≥65 years 60 (24.9) 49 (24.6) 11 (26.2)  
Sex, n (%)    0.487 
 Female 34 (14.1) 30 (15.1) 4 (9.5)  
 Male 207 (85.9) 169 (84.9) 38 (90.5)  
BCLC stage, n (%)    0.815 
 B 87 (36.1) 73 (36.7) 14 (33.3)  
 C 154 (63.9) 126 (63.3) 28 (66.7)  
HBV infection, n (%)    0.268 
 No 25 (10.4) 23 (11.6) 2 (4.8)  
 Yes 216 (89.6) 176 (88.4) 40 (95.2)  
ECOG PS score, n (%)    >0.999 
 0 188 (78.0) 155 (77.9) 33 (78.6)  
 1 53 (22.0) 44 (22.1) 9 (21.4)  
AFP, n (%)    0.083 
 <400 ng/mL 117 (48.5) 91 (45.7) 26 (61.9)  
 ≥400 ng/mL 124 (51.5) 108 (54.3) 16 (38.1)  
PIVKA-II, n (%)    0.610 
 <400 mAU/mL 68 (28.2) 58 (29.1) 10 (23.8)  
 ≥400 mAU/mL 173 (71.8) 141 (70.9) 32 (76.2)  
Tumor diameter, n (%)    >0.999 
 <10 cm 149 (61.8) 123 (61.8) 26 (61.9)  
 ≥10 cm 92 (38.2) 76 (38.2) 16 (38.1)  
Tumor number, n (%)    0.270 
 Single 56 (23.2) 43 (21.6) 13 (31.0)  
 Multiple 185 (76.8) 156 (78.4) 29 (69.0)  
Macrovascular invasion, n (%)    0.190 
 No 111 (46.1) 96 (48.2) 15 (35.7)  
 Yes 130 (53.9) 103 (51.8) 27 (64.3)  
Extrahepatic metastasis, n (%)    0.017 
 No 203 (84.2) 162 (81.4) 41 (97.6)  
 Yes 38 (15.8) 37 (18.6) 1 (2.4)  
NLR, n (%)    0.447 
 <2.6 119 (49.4) 101 (50.8) 18 (42.9)  
 ≥2.6 122 (50.6) 98 (49.2) 24 (57.1)  
Tbil, n (%)    0.281 
 <34 μmol/L 235 (97.5) 195 (98.0) 40 (95.2)  
 ≥34 μmol/L 6 (2.5) 4 (2.0) 2 (4.8)  
ALB, n (%)    0.469 
 <35 g/L 47 (19.5) 41 (20.6) 6 (14.3)  
 ≥35 g/L 194 (80.5) 158 (79.4) 36 (85.7)  
ALT, n (%)    0.163 
 <40 IU/L 124 (51.5) 107 (53.8) 17 (40.5)  
 ≥40 IU/L 117 (48.5) 92 (46.2) 25 (59.5)  
AST, n (%)    0.641 
 <40 IU/L 85 (35.3) 72 (36.2) 13 (31.0)  
 ≥40 IU/L 156 (64.7) 127 (63.8) 29 (69.0)  
ALBI grade, n (%)    >0.999 
 1 137 (56.8) 113 (56.8) 24 (57.1)  
 2 104 (43.2) 86 (43.2) 18 (42.9)  
TACE sessions, median (IQR) 2 (1–3) 2 (1–3) 1 (1–2) 0.067 
TACE sessions, n (%)    0.181 
 1 118 (49.0) 93 (46.7) 25 (59.5)  
 ≥2 123 (51.0) 106 (53.3) 17 (40.5)  
Conversion surgery, n (%)    0.002 
 No 134 (55.6) 120 (60.3) 14 (33.3)  
 Yes 107 (44.4) 79 (39.7) 28 (66.7)  

cCR, clinical complete response; SD, standard deviation; BCLC, Barcelona Clinic for Liver Cancer; HBV, hepatitis B virus; ECOG PS, Eastern Cooperative Oncology Group performance status; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II; NLR, neutrophil-to-lymphocyte ratio; Tbil, total bilirubin; ALB, albumin; ALT, alanine aminotransferase; AST, aspartate transaminase; ALBI, albumin-bilirubin; TACE, transcatheter arterial chemoembolization; IQR, interquartile range.

There were no significant differences between the cCR and non-cCR groups in terms of age, sex, BCLC stage, HBV infection, ECOG PS score, AFP levels, PIVKA-II levels, tumor diameter, tumor number, macrovascular invasion, NLR, total bilirubin, ALB, ALT, AST, ALBI grade, or TACE sessions. The cCR group had a lower proportion of patients with extrahepatic metastasis (2.4% vs. 18.6%, p = 0.017) and a higher proportion of patients who underwent conversion surgery (66.7% vs. 39.7%, p = 0.002).

Clinical Responses and Toxicity to Triple Therapy

The ORR in patients with uHCC treated with triple therapy was 78.4% (189/241); 42 patients (17.4%) achieved cCR. The treatment-related adverse events (TRAEs) are detailed in Supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000543602). Although 212 patients (88.0%) experienced TRAEs, only 13 (5.4%) experienced grade 4/5 adverse events. The most common TRAEs were abnormal liver function, fever, decreased appetite, fatigue, hypothyroidism, hypertension, hand-foot syndrome, thrombocytopenia, skin rash, diarrhea, weight loss, decreased hemoglobin levels, abdominal pain, and proteinuria. Grade 4/5 adverse events included abnormal liver function (2.1%), hypertension (1.2%), thrombocytopenia (1.2%), and skin rashes (0.8%). Most TRAEs were manageable with symptomatic treatment; 7 patients discontinued lenvatinib and PD-1 inhibitors because of grade 4/5 adverse events.

Sixty-five patients (27.0%) progressed from Child-Pugh class A to class B after 8 weeks of triple therapy. Among these, 58.5% (38/65) experienced interruptions in triple therapy, whereas 7.7% (5/65) discontinued it. Notably, 1 patient progressed to Child-Pugh class C after 6 weeks of triple therapy and discontinued treatment. Patients who remained in Child-Pugh class A exhibited significantly longer median OS (not reached vs. 18.8 months, p < 0.001) and median PFS (20.8 vs. 11.3 months, p = 0.002) compared to those who progressed to Child-Pugh class B (online suppl. Fig. 1).

Survival Outcomes and Prognosis according to cCR

The median follow-up period was 25.3 months (95% confidence interval [CI]: 22.8–27.7). The median OS was 35.5 months (95% CI: 28.0–not evaluable), and the median PFS was 18.9 months (95% CI: 16.4–26.1; online suppl. Fig. 2). In the cCR group, the 1- and 3-year OS rates were 97.4% and 94.0%, respectively, compared to 79.5% and 38.7%, respectively, in the non-cCR group (p < 0.001, Fig. 2a). The 1- and 3-year PFS rates were 97.6% and 74.7%, respectively, in the cCR group and 59.6% and 29.6%, respectively, in the non-cCR group (p < 0.001, Fig. 2b). Patients who achieved cCR demonstrated a statistically significant improvement in OS and PFS in the landmark analysis at 5 and 6 months (online suppl. Fig. 3). Similar findings were observed in the BCLC stage B and C subgroups (online suppl. Fig. 4–6).

Fig. 2.

Kaplan-Meier curves showing survival according to cCR in the entire cohort. OS (a) and PFS (b) according to cCR. cCR, complete clinical response.

Fig. 2.

Kaplan-Meier curves showing survival according to cCR in the entire cohort. OS (a) and PFS (b) according to cCR. cCR, complete clinical response.

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Risk Factor Analysis for OS and PFS

In this analysis, cCR was treated as a time-dependent covariate to address immortal time bias. Univariate analysis identified AFP levels (p = 0.014), tumor diameter (p = 0.027), extrahepatic metastasis (p < 0.001), and cCR (p < 0.001) as significant risk factors for OS (Table 2), whereas AFP levels (p = 0.001), tumor diameter (p = 0.033), extrahepatic metastasis (p < 0.001), TACE sessions (p = 0.035), and cCR (p < 0.001) were identified as significant risk factors for PFS (Table 3).

Table 2.

Univariate and multivariate analysis for OS

VariablesUnivariate analysisMultivariate analysis
HR95% CIp valueHR95% CIp value
Age ≥65 years 0.96 0.60–1.54 0.855    
Male 0.92 0.51–1.65 0.772    
HBV infection 0.77 0.41–1.44 0.413 0.77 0.43–1.36 0.365 
ECOG PS score of 1 0.87 0.53–1.43 0.570    
AFP ≥400 ng/mL 1.71 1.12–2.61 0.014 1.37 0.90–2.08 0.138 
PIVKA-II ≥400 mAU/mL 0.92 0.59–1.44 0.727    
Tumor diameter ≥10 cm 1.59 1.05–2.41 0.027 1.49 0.99–2.26 0.057 
Multiple tumors 1.45 0.82–2.57 0.202    
Macrovascular invasion 1.19 0.78–1.80 0.414 1.23 0.79–1.90 0.360 
Extrahepatic metastasis 4.15 2.66–6.46 <0.001 3.57 2.23–5.72 <0.001 
NLR ≥2.6 1.21 0.80–1.83 0.373    
Tbil ≥34 μmol/L 0.64 0.16–2.61 0.533    
ALB ≥35 g/L 0.70 0.43–1.13 0.148    
ALT ≥40 IU/L 1.07 0.71–1.62 0.733    
AST ≥40 IU/L 1.36 0.87–2.14 0.179    
ALBI grade 2 0.98 0.65–1.49 0.931 1.07 0.69–1.66 0.747 
TACE sessions ≥2 1.51 0.98–2.32 0.060    
cCR 0.09 0.02–0.36 <0.001 0.11 0.03–0.42 0.001 
VariablesUnivariate analysisMultivariate analysis
HR95% CIp valueHR95% CIp value
Age ≥65 years 0.96 0.60–1.54 0.855    
Male 0.92 0.51–1.65 0.772    
HBV infection 0.77 0.41–1.44 0.413 0.77 0.43–1.36 0.365 
ECOG PS score of 1 0.87 0.53–1.43 0.570    
AFP ≥400 ng/mL 1.71 1.12–2.61 0.014 1.37 0.90–2.08 0.138 
PIVKA-II ≥400 mAU/mL 0.92 0.59–1.44 0.727    
Tumor diameter ≥10 cm 1.59 1.05–2.41 0.027 1.49 0.99–2.26 0.057 
Multiple tumors 1.45 0.82–2.57 0.202    
Macrovascular invasion 1.19 0.78–1.80 0.414 1.23 0.79–1.90 0.360 
Extrahepatic metastasis 4.15 2.66–6.46 <0.001 3.57 2.23–5.72 <0.001 
NLR ≥2.6 1.21 0.80–1.83 0.373    
Tbil ≥34 μmol/L 0.64 0.16–2.61 0.533    
ALB ≥35 g/L 0.70 0.43–1.13 0.148    
ALT ≥40 IU/L 1.07 0.71–1.62 0.733    
AST ≥40 IU/L 1.36 0.87–2.14 0.179    
ALBI grade 2 0.98 0.65–1.49 0.931 1.07 0.69–1.66 0.747 
TACE sessions ≥2 1.51 0.98–2.32 0.060    
cCR 0.09 0.02–0.36 <0.001 0.11 0.03–0.42 0.001 

HR, hazard ratio; CI, confidence interval; HBV, hepatitis B virus; ECOG PS, Eastern Cooperative Oncology Group performance status; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II; NLR, neutrophil-to-lymphocyte ratio; Tbil, total bilirubin; ALB, albumin; ALT, alanine aminotransferase; AST, aspartate transaminase; ALBI, albumin-bilirubin; TACE, transcatheter arterial chemoembolization; cCR, clinical complete response.

Table 3.

Univariate and multivariate analysis for PFS

VariablesUnivariate analysisMultivariate analysis
HR95% CIp valueHR95% CIp value
Age ≥65 years 0.92 0.62–1.37 0.675    
Male 0.93 0.57–1.51 0.763    
HBV infection 0.99 0.56–1.76 0.973 1.08 0.58–1.98 0.815 
ECOG PS score of 1 0.87 0.57–1.32 0.513    
AFP ≥400 ng/mL 1.83 1.28–2.60 0.001 1.55 1.05–2.29 0.028 
PIVKA-II ≥400 mAU/mL 1.31 0.88–1.95 0.182    
Tumor diameter ≥10 cm 1.46 1.03–2.07 0.033 1.36 0.96–1.94 0.087 
Multiple tumors 1.39 0.89–2.17 0.143    
Macrovascular invasion 1.03 0.73–1.46 0.848 0.93 0.63–1.37 0.716 
Extrahepatic metastasis 2.68 1.80–3.98 <0.001 2.11 1.44–3.10 <0.001 
NLR ≥2.6 1.14 0.81–1.61 0.454    
Tbil ≥34 μmol/L 1.16 0.43–3.14 0.770    
ALB ≥35 g/L 0.80 0.53–1.21 0.288    
ALT ≥40 IU/L 1.21 0.86–1.72 0.272    
AST ≥40 IU/L 1.27 0.88–1.84 0.196    
ALBI grade 2 1.04 0.73–1.47 0.835 1.06 0.74–1.50 0.764 
TACE sessions ≥2 1.46 1.03–2.07 0.035 1.14 0.80–1.63 0.477 
cCR 0.25 0.13–0.50 <0.001 0.29 0.15–0.56 <0.001 
VariablesUnivariate analysisMultivariate analysis
HR95% CIp valueHR95% CIp value
Age ≥65 years 0.92 0.62–1.37 0.675    
Male 0.93 0.57–1.51 0.763    
HBV infection 0.99 0.56–1.76 0.973 1.08 0.58–1.98 0.815 
ECOG PS score of 1 0.87 0.57–1.32 0.513    
AFP ≥400 ng/mL 1.83 1.28–2.60 0.001 1.55 1.05–2.29 0.028 
PIVKA-II ≥400 mAU/mL 1.31 0.88–1.95 0.182    
Tumor diameter ≥10 cm 1.46 1.03–2.07 0.033 1.36 0.96–1.94 0.087 
Multiple tumors 1.39 0.89–2.17 0.143    
Macrovascular invasion 1.03 0.73–1.46 0.848 0.93 0.63–1.37 0.716 
Extrahepatic metastasis 2.68 1.80–3.98 <0.001 2.11 1.44–3.10 <0.001 
NLR ≥2.6 1.14 0.81–1.61 0.454    
Tbil ≥34 μmol/L 1.16 0.43–3.14 0.770    
ALB ≥35 g/L 0.80 0.53–1.21 0.288    
ALT ≥40 IU/L 1.21 0.86–1.72 0.272    
AST ≥40 IU/L 1.27 0.88–1.84 0.196    
ALBI grade 2 1.04 0.73–1.47 0.835 1.06 0.74–1.50 0.764 
TACE sessions ≥2 1.46 1.03–2.07 0.035 1.14 0.80–1.63 0.477 
cCR 0.25 0.13–0.50 <0.001 0.29 0.15–0.56 <0.001 

HR, hazard ratio; CI, confidence interval; HBV, hepatitis B virus; ECOG PS, Eastern Cooperative Oncology Group performance status; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II; NLR, neutrophil-to-lymphocyte ratio; Tbil, total bilirubin; ALB, albumin; ALT, alanine aminotransferase; AST, aspartate transaminase; ALBI, albumin-bilirubin; TACE, transcatheter arterial chemoembolization; cCR, clinical complete response.

In the multivariate analysis, extrahepatic metastasis (hazard ratio [HR]: 3.57, 95% CI: 2.23–5.72, p < 0.001) was independently associated with poorer OS, whereas cCR (HR: 0.11, 95% CI: 0.03–0.42, p = 0.001) was associated with improved OS (Table 2). Additionally, AFP levels ≥400 ng/mL (HR: 1.55, 95% CI: 1.05–2.29, p = 0.028) and extrahepatic metastasis (HR: 2.11, 95% CI: 1.44–3.10, p < 0.001) were independent factors for worse PFS, whereas cCR (HR: 0.29, 95% CI: 0.15–0.56, p < 0.001) was independently associated with better PFS (Table 3).

Predictors of cCR

Univariate analysis indicated that extrahepatic metastasis (p = 0.030) was significantly associated with cCR (Table 4). After adjusting for HBV infection, AFP levels, macrovascular invasion, and ALBI grade, multivariate analysis confirmed that AFP levels ≥400 ng/mL (odds ratio [OR]: 0.47, 95% CI: 0.22–0.95, p = 0.040) and extrahepatic metastasis (OR: 0.13, 95% CI: 0.01–0.62, p = 0.046) were independent negative predictors of cCR.

Table 4.

Univariate and multivariate analysis for clinical complete response

VariablesUnivariate analysisMultivariate analysis
OR95% CIp valueOR95% CIp value
Age ≥65 years 1.09 0.49–2.27 0.831    
Male 1.69 0.62–5.92 0.352    
HBV infection 2.61 0.73–16.7 0.205 2.90 0.77–19.04 0.172 
ECOG PS score of 1 0.96 0.41–2.09 0.923    
AFP ≥400 ng/mL 0.52 0.26–1.02 0.059 0.47 0.22–0.95 0.040 
PIVKA-II ≥400 mAU/mL 1.32 0.63–2.98 0.486    
Tumor diameter ≥10 cm 1.00 0.49–1.96 0.991    
Multiple tumors 0.61 0.30–1.32 0.195    
Macrovascular invasion 1.68 0.85–3.41 0.141 1.95 0.95–4.15 0.072 
Extrahepatic metastasis 0.11 0.01–0.52 0.030 0.13 0.01–0.62 0.046 
NLR ≥2.6 1.37 0.70–2.72 0.353    
Tbil ≥34 μmol/L 2.44 0.33–12.93 0.313    
ALB ≥35 g/L 1.56 0.65–4.33 0.351    
ALT ≥40 IU/L 1.71 0.88–3.41 0.120    
AST ≥40 IU/L 1.26 0.63–2.66 0.520    
ALBI grade 2 0.99 0.50–1.92 0.966 1.02 0.50–2.06 0.946 
TACE sessions ≥2 0.60 0.30–1.17 0.134    
VariablesUnivariate analysisMultivariate analysis
OR95% CIp valueOR95% CIp value
Age ≥65 years 1.09 0.49–2.27 0.831    
Male 1.69 0.62–5.92 0.352    
HBV infection 2.61 0.73–16.7 0.205 2.90 0.77–19.04 0.172 
ECOG PS score of 1 0.96 0.41–2.09 0.923    
AFP ≥400 ng/mL 0.52 0.26–1.02 0.059 0.47 0.22–0.95 0.040 
PIVKA-II ≥400 mAU/mL 1.32 0.63–2.98 0.486    
Tumor diameter ≥10 cm 1.00 0.49–1.96 0.991    
Multiple tumors 0.61 0.30–1.32 0.195    
Macrovascular invasion 1.68 0.85–3.41 0.141 1.95 0.95–4.15 0.072 
Extrahepatic metastasis 0.11 0.01–0.52 0.030 0.13 0.01–0.62 0.046 
NLR ≥2.6 1.37 0.70–2.72 0.353    
Tbil ≥34 μmol/L 2.44 0.33–12.93 0.313    
ALB ≥35 g/L 1.56 0.65–4.33 0.351    
ALT ≥40 IU/L 1.71 0.88–3.41 0.120    
AST ≥40 IU/L 1.26 0.63–2.66 0.520    
ALBI grade 2 0.99 0.50–1.92 0.966 1.02 0.50–2.06 0.946 
TACE sessions ≥2 0.60 0.30–1.17 0.134    

OR, odds ratio; CI, confidence interval; HBV, hepatitis B virus; ECOG PS, Eastern Cooperative Oncology Group performance status; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II; NLR, neutrophil-to-lymphocyte ratio; Tbil, total bilirubin; ALB, albumin; ALT, alanine aminotransferase; AST, aspartate transaminase; ALBI, albumin-bilirubin; TACE, transcatheter arterial chemoembolization.

Characteristics of Patients after Conversion Surgery

Of the 241 patients, 107 (44.4%) underwent successful conversion surgery. The baseline characteristics of these patients are presented in online supplementary Table 2. There were no significant differences in age, sex, BCLC stage, HBV infection, ECOG PS score, AFP levels, PIVKA-II levels, tumor diameter, tumor number, macrovascular invasion, NLR, total bilirubin, ALB, AST, ALBI grade, or TACE sessions. The cCR group exhibited a higher proportion of patients with ALT ≥40 IU/L (71.4% vs. 40.5%, p = 0.010), pCR (85.7% vs. 19.0%, p < 0.001), and MPR (96.4% vs. 68.4%, p = 0.007).

Among the 107 patients who underwent conversion surgery, 39 (36.4%) achieved pCR. Of the patients who did not achieve pCR, 94.1% (64/68) did not achieve cCR before conversion surgery, whereas 61.5% (24/39) of the patients who achieved pCR had also achieved cCR. The chi-square test showed a significant association between cCR and pCR (χ2 = 36.91, df = 1, p < 0.001). Furthermore, the phi (Φ) coefficient confirmed a strong correlation between cCR and pCR (Φ = 0.61, p < 0.001).

Normalization of Tumor Markers in cCR after Conversion Surgery

Among the patients who underwent conversion surgery, 28 (26.2%) achieved a cCR. In this subset, the median change (Δ) in AFP levels from triple therapy initiation to achieving cCR was 311 ng/mL (IQR, 25.6–12,561), whereas the median change (Δ) in PIVKA-II levels was 6,528 mAU/mL (IQR, 49.2–33,772; online suppl. Table 3). The median time from triple therapy initiation to achieving cCR was 3.18 months (IQR, 2.25–4.68). There were no significant differences between the pCR and non-pCR groups in terms of the median change (Δ) in AFP or PIVKA-II levels or the median time to cCR.

Prognosis according to cCR and pCR after Conversion Surgery

In the cCR group after conversion surgery, the 1- and 3-year OS rates were 95.7%; in the non-cCR group, they were 87.6% and 50.7%, respectively (p = 0.009, Fig. 3a). The 1- and 2-year RFS rates were 88.0% and 74.5% in the cCR group, respectively, whereas they were 56.6% and 52.2%, respectively, in the non-cCR group (p = 0.007, Fig. 3b).

Fig. 3.

Kaplan-Meier curves showing survival according to cCR among patients who underwent conversion surgery. OS (a) and RFS (b) according to cCR. cCR, complete clinical response.

Fig. 3.

Kaplan-Meier curves showing survival according to cCR among patients who underwent conversion surgery. OS (a) and RFS (b) according to cCR. cCR, complete clinical response.

Close modal

In the pCR group, the 1- and 3-year OS rates were 100%, whereas they were 84.0% and 42.1%, respectively, in the non-pCR group (p < 0.001, Fig. 4a). The 1- and 2-year RFS rates were 91.5% and 77.9%, respectively, in the pCR group, and they were 48.4% and 46.0%, respectively, in the non-pCR group (p < 0.001, Fig. 4b). Prognosis according to cCR and pCR after conversion surgery in the BCLC stage B or C subgroups is shown in online supplementary Figures 7–8.

Fig. 4.

Kaplan-Meier curves showing survival according to pCR among patients who underwent conversion surgery. OS (a) and RFS (b) according to pCR. pCR, pathological complete response.

Fig. 4.

Kaplan-Meier curves showing survival according to pCR among patients who underwent conversion surgery. OS (a) and RFS (b) according to pCR. pCR, pathological complete response.

Close modal

Risk Factor Analysis for OS and RFS after Conversion Surgery

Univariate analysis revealed that cCR (p = 0.030) was associated with OS (online suppl. Table 4), whereas ECOG PS score (p = 0.012), AFP levels (p = 0.025), TACE sessions (p = 0.009), and cCR (p = 0.011) were associated with RFS (online suppl. Table 5). Multivariate analysis identified cCR (HR: 0.10, 95% CI: 0.01–0.77, p = 0.027) as an independent risk factor for OS. In addition, ECOG PS score of 1 (HR = 2.57, 95% CI: 1.23–5.35, p = 0.012), TACE sessions ≥2 (HR: 1.99, 95% CI: 1.03–3.87, p = 0.042), and cCR (HR: 0.34, 95% CI: 0.13–0.88, p = 0.026) were independent risk factors for RFS.

Predictors of pCR after Conversion Surgery

Univariate analysis revealed that AFP levels (p = 0.040), ALB levels (p = 0.029), and cCR (p < 0.001) were associated with pCR (Table 5). Multivariate analysis demonstrated that ALB levels ≥35 g/L (OR: 0.12, 95% CI: 0.02–0.69, p = 0.018) and cCR (OR: 30.32, 95% CI: 9.19–128.00, p < 0.001) were independent predictors of pCR.

Table 5.

Univariate and multivariate analysis for pCR

VariablesUnivariate analysisMultivariate analysis
OR95% CIp valueOR95% CIp value
Age ≥65 years 1.20 0.43–3.23 0.715    
Male 1.83 0.51–8.65 0.387    
HBV infection 1.16 0.29–5.76 0.839 2.09 0.29–22.23 0.498 
ECOG PS score of 1 1.43 0.47–4.21 0.512    
AFP ≥400 ng/mL 0.43 0.19–0.95 0.040 0.33 0.10–1.03 0.063 
PIVKA-II ≥400 mAU/mL 0.55 0.23–1.31 0.173    
Tumor diameter ≥10 cm 0.95 0.42–2.12 0.899    
Multiple tumors 0.77 0.34–1.75 0.523    
Macrovascular invasion 1.11 0.49–2.54 0.810 1.26 0.42–3.91 0.683 
NLR ≥2.6 1.44 0.65–3.22 0.371    
Tbil ≥34 μmol/L 0.57 0.03–4.63 0.632    
ALB ≥35 g/L 0.24 0.06–0.83 0.029 0.12 0.02–0.69 0.018 
ALT ≥40 IU/L 1.64 0.74–3.66 0.222    
AST ≥40 IU/L 1.49 0.66–3.45 0.343    
ALBI grade 2 1.28 0.56–2.87 0.556 1.02 0.30–3.38 0.969 
TACE sessions ≥2 0.84 0.37–1.87 0.672    
cCR 25.60 8.46–97.53 <0.001 30.32 9.19–128.00 <0.001 
VariablesUnivariate analysisMultivariate analysis
OR95% CIp valueOR95% CIp value
Age ≥65 years 1.20 0.43–3.23 0.715    
Male 1.83 0.51–8.65 0.387    
HBV infection 1.16 0.29–5.76 0.839 2.09 0.29–22.23 0.498 
ECOG PS score of 1 1.43 0.47–4.21 0.512    
AFP ≥400 ng/mL 0.43 0.19–0.95 0.040 0.33 0.10–1.03 0.063 
PIVKA-II ≥400 mAU/mL 0.55 0.23–1.31 0.173    
Tumor diameter ≥10 cm 0.95 0.42–2.12 0.899    
Multiple tumors 0.77 0.34–1.75 0.523    
Macrovascular invasion 1.11 0.49–2.54 0.810 1.26 0.42–3.91 0.683 
NLR ≥2.6 1.44 0.65–3.22 0.371    
Tbil ≥34 μmol/L 0.57 0.03–4.63 0.632    
ALB ≥35 g/L 0.24 0.06–0.83 0.029 0.12 0.02–0.69 0.018 
ALT ≥40 IU/L 1.64 0.74–3.66 0.222    
AST ≥40 IU/L 1.49 0.66–3.45 0.343    
ALBI grade 2 1.28 0.56–2.87 0.556 1.02 0.30–3.38 0.969 
TACE sessions ≥2 0.84 0.37–1.87 0.672    
cCR 25.60 8.46–97.53 <0.001 30.32 9.19–128.00 <0.001 

OR, odds ratio; CI, confidence interval; HBV, hepatitis B virus; ECOG PS, Eastern Cooperative Oncology Group performance status; AFP, alpha-fetoprotein; PIVKA-II, protein induced by vitamin K absence-II; NLR, neutrophil-to-lymphocyte ratio; Tbil, total bilirubin; ALB, albumin; ALT, alanine aminotransferase; AST, aspartate transaminase; ALBI, albumin-bilirubin; TACE, transcatheter arterial chemoembolization; cCR, clinical complete response.

In this multicenter, retrospective study, we evaluated the long-term outcomes of patients with uHCC after triple therapy. The cCR rate was 17.4% in the entire cohort. Patients who achieved cCR had better OS and PFS than those who did not. Further, multivariate Cox regression analysis identified cCR as an independent predictor of OS and PFS. Notably, after successful conversion surgery following triple therapy, patients with cCR had a superior prognosis to those without cCR, and cCR was an independent predictor of OS and RFS. Additionally, cCR was significantly correlated with pCR and was an independent predictor of pCR. These results indicate that cCR can potentially serve as a surrogate maker for predicting the prognosis of patients with uHCC who undergo triple therapy. Our study further showed that AFP levels and extrahepatic metastasis could independently predict cCR. To the best of our knowledge, this is the first study to explore the prognostic value of cCR in patients with uHCC after triple therapy and to identify preoperative predictors for achieving cCR.

Remarkable progress has been made in the development of conversion therapies for uHCC in recent years [5‒13]. However, some challenges still need to be addressed. Among these, the prognostic prediction of uHCC after conversion therapy with triple therapy remains unknown. Predicting the prognosis of conversion therapy for uHCC is complex, as the prognosis is affected by multiple factors [23, 24]. Therefore, researchers are attempting to find more accurate methods for predicting the prognosis after conversion therapy for uHCC. Some studies have explored the use of pCR as a surrogate marker for predicting prognosis after conversion surgery [14‒17]. However, pCR can only be confirmed after surgical resection. The accurate selection of patients who are most likely to achieve pCR, which is crucial for guiding treatment decisions and prognostic assessment, remains an important issue. Therefore, noninvasive methods for predicting pCR are required. Recently, cCR has been found to exhibit a strong correlation with OS. In a meta-analysis, CR exhibited a strong correlation with OS, suggesting it may be an appropriate endpoint in future clinical studies involving immune checkpoint inhibitors in patients with uHCC [25]. In addition, many studies have shown that patients who achieve cCR may have a higher chance of achieving long-term OS, indicating that complete remission reflects a more comprehensive treatment response and tumor control [18‒21]. Kudo et al. [21] indicated that achieving CR and/or a drug-free status should be a therapeutic goal for patients with intermediate-stage HCC. In the present study, we found that patients who achieved cCR after triple therapy had better OS and PFS. In addition, after successful conversion surgery following triple therapy, patients with cCR had a superior prognosis compared to patients without cCR, and cCR was identified as an independent predictor of OS and RFS. These results indicate that cCR may be a new surrogate marker for predicting prognosis after conversion therapy.

cCR was an independent predictor of pCR in this study. To date, no studies have explored the association between cCR and pCR in patients with uHCC receiving consolidation triple therapy. We found that cCR was significantly correlated with pCR in these patients. Most patients who achieved cCR also achieved pCR. However, there is still a gap between cCR and pCR that cannot be ignored. Some patients who achieve cCR after conversion therapy do not achieve pCR, as observed in our study. Therefore, a method for assessing tumor responses that may more accurately predict pCR is vital. Further, some patients who achieve pCR do not achieve cCR, which leads to an underestimation of the number of patients achieving pCR. In our study, 15 patients who did not achieve cCR before conversion surgery achieved pCR. This may be because tissue necrosis induced by triple therapy leads to inflammatory cell tissue infiltration and edema, which may appear as arterial phase enhancement on CT or MRI and be mistaken for viable tumor tissue. An established noninvasive radiographic marker to predict pCR following systemic therapy in HCC would provide guidance on the prognosis and optimal timing of resection, as well as help identify when systemic treatment should be continued. To date, cCR is the most relevant indicator for pCR; however, there is still a need for more methods of noninvasive and early identification of patients who achieve pCR and are most likely to benefit from triple therapy.

Given the powerful predictive value of cCR, we aimed to identify its predictors. We found that AFP levels and extrahepatic metastasis independently predicted cCR. AFP has long been recognized as an important predictor of HCC diagnosis and prognosis [26]. Yang et al. [27] revealed that AFP <100 ng/mL can predict pCR in patients with HCC after TACE. AFP levels can also predict pCR after locoregional therapy before liver transplantation [28]. Extrahepatic metastasis had a negative impact on prognosis, resulting in poor long-term survival, which has been observed in other studies [29, 30]. The median OS for patients with HCC with extrahepatic metastasis is reported to be between 4.9 and 10.3 months [29, 30]. A meta-analysis indicated that the presence of extrahepatic metastases in patients with HCC treated with immune checkpoint inhibitors may indicate an inferior ORR [25]. These data indicate that AFP levels and extrahepatic metastasis may be significant negative prognostic factors. Our data also suggest that AFP levels and extrahepatic metastasis play important roles in predicting cCR in patients with HCC after triple therapy.

Currently, there are no uniform criteria for determining cCR in patients with uHCC following conversion therapies. Li et al. [19] defined cCR as radiological CR with initially elevated AFP levels (>25 ng/mL, one time the upper limit of normal) returning to <25 ng/mL, the absence of distant metastases, and maintenance of these criteria across at least two consecutive follow-up assessments. Additionally, Kudo et al. [21] defined cCR as radiological CR accompanied by sustained normalization of tumor markers (AFP <10 ng/mL, PIVKA-II <40 mAU/mL, and AFP-L3 <10%) for at least 6 weeks. Zhao et al. [22] proposed a criterion for cCR involving radiological CR per mRECIST, normalization of baseline serum tumor markers, exclusion of distant metastases, and stability of this status for a period of time. These variations underscore the urgent need for further research to establish a standardized cCR definition in uHCC following conversion therapies, ensuring consistency and reliability in the clinical evaluation.

This study has a few limitations. First, this was a retrospective analysis with the potential for selection bias. Moreover, the median follow-up time was shorter than the median OS, which suggests that the median OS estimated may be biased. This highlights the need for a longer follow-up period to obtain a more stable median OS. Therefore, further studies are required to confirm our findings. However, to the best of our knowledge, this is the first study to confirm the prognostic value of cCR in patients with uHCC who underwent triple therapy and to identify the relationship between cCR and pCR. Second, most patients had HBV infections owing to the epidemiological characteristics of patients with HCC in China. Third, triple therapy is not currently a first-line treatment option for uHCC according to existing guidelines. However, an increasing number of studies have demonstrated its efficacy and safety, leading to its growing adoption as a first-line treatment for uHCC in China [9, 10, 13]. Further prospective randomized controlled trials with larger sample sizes are needed to validate our findings.

In conclusion, patients with uHCC who received triple therapy had an improved prognosis if they achieved cCR, and AFP levels and extrahepatic metastasis could predict cCR in these patients. cCR significantly correlated with pCR and was an independent predictor of pCR.

This study was performed in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of Fujian Provincial Hospital (Approval No. K2024-04-021). All the patients in this study provided written informed consent.

The authors declare no conflicts of interest.

This study was funded by the Natural Science Foundation of Fujian Province (Grant No. 2022J011021), the Medical Innovation Project of Health and Family Planning Commission of Fujian Province (Grant No. 2022CXA002), and the Project of Young and Middle-aged Backbone Talents Cultivation of Fujian Provincial Health Commission (Grant No. 2023GGA006). Funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Jun-Yi Wu, Zhen-Xin Zeng, and Yi-Nan Li contributed equally to this work. Jun-Yi Wu, Zhen-Xin Zeng, and Yi-Nan Li: conceptualization and writing – original draft preparation; Jia-Yi Wu and Zhi-Bo Zhang: methodology and visualization; Shao-Wu Zhuang and Bin Li: formal analysis and validation; Jian-Yin Zhou and Shu-Qun Li: investigation and supervision; Jia-Yi Wu and Mao-Lin Yan: resources and writing – review and editing; De-Yi Liu, Han Li, and Xiang-Ye Ou: project administration. All authors have read and agreed to the published version of this manuscript.

Additional Information

Jun-Yi Wu, Zhen-Xin Zeng and Yi-Nan Li equally contributed to this study as co-first authors.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author (Mao-Lin Yan).

1.
Vogel
A
,
Meyer
T
,
Sapisochin
G
,
Salem
R
,
Saborowski
A
.
Hepatocellular carcinoma
.
Lancet
.
2022
;
400
(
10360
):
1345
62
.
2.
Bray
F
,
Laversanne
M
,
Sung
H
,
Ferlay
J
,
Siegel
RL
,
Soerjomataram
I
, et al
.
Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
.
CA Cancer J Clin
.
2024
;
74
(
3
):
229
63
.
3.
Roayaie
S
,
Jibara
G
,
Tabrizian
P
,
Park
J-W
,
Yang
J
,
Yan
L
, et al
.
The role of hepatic resection in the treatment of hepatocellular cancer
.
Hepatology
.
2015
;
62
(
2
):
440
51
.
4.
Reig
M
,
Forner
A
,
Rimola
J
,
Ferrer-Fàbrega
J
,
Burrel
M
,
Garcia-Criado
Á
, et al
.
BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update
.
J Hepatol
.
2022
;
76
(
3
):
681
93
.
5.
Finn
RS
,
Qin
S
,
Ikeda
M
,
Galle
PR
,
Ducreux
M
,
Kim
T-Y
, et al
.
Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma
.
N Engl J Med
.
2020
;
382
(
20
):
1894
905
.
6.
Yuan
Y
,
He
W
,
Yang
Z
,
Qiu
J
,
Huang
Z
,
Shi
Y
, et al
.
TACE-HAIC combined with targeted therapy and immunotherapy versus TACE alone for hepatocellular carcinoma with portal vein tumour thrombus: a propensity score matching study
.
Int J Surg
.
2023
;
109
(
5
):
1222
30
.
7.
Yau
T
,
Kang
YK
,
Kim
TY
,
El-Khoueiry
AB
,
Santoro
A
,
Sangro
B
, et al
.
Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the checkmate 040 randomized clinical trial
.
JAMA Oncol
.
2020
;
6
(
11
):
e204564
.
8.
Kudo
M
.
A novel treatment strategy for patients with intermediate-stage HCC who are not suitable for TACE: upfront systemic therapy followed by curative conversion
.
Liver Cancer
.
2021
;
10
(
6
):
539
44
.
9.
Zhu
H-D
,
Li
H-L
,
Huang
M-S
,
Yang
W-Z
,
Yin
G-W
,
Zhong
B-Y
, et al
.
Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001)
.
Signal Transduct Tar
.
2023
;
8
(
1
):
58
.
10.
Jin
Z-C
,
Chen
J-J
,
Zhu
X-L
,
Duan
X-H
,
Xin
Y-J
,
Zhong
B-Y
, et al
.
Immune checkpoint inhibitors and anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors with or without transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma (CHANCE2201): a target trial emulation study
.
eClinicalMedicine
.
2024
;
72
:
102622
.
11.
Wu
J-Y
,
Yin
Z-Y
,
Bai
Y-N
,
Chen
Y-F
,
Zhou
S-Q
,
Wang
S-J
, et al
.
Lenvatinib combined with anti-PD-1 antibodies plus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: a multicenter retrospective study
.
JHC
.
2021
;
8
:
1233
40
.
12.
Wu
J-Y
,
Zhang
Z-B
,
Zhou
J-Y
,
Ke
J-P
,
Bai
Y-N
,
Chen
Y-F
, et al
.
Outcomes of salvage surgery for initially unresectable hepatocellular carcinoma converted by transcatheter arterial chemoembolization combined with lenvatinib plus anti-PD-1 antibodies: a multicenter retrospective study
.
Liver Cancer
.
2023
;
12
(
3
):
229
37
.
13.
Wu
J
,
Wu
J
,
Li
S
,
Luo
M
,
Zeng
Z
,
Li
Y
, et al
.
Effect of transcatheter arterial chemoembolization combined with lenvatinib plus anti–PD-1 antibodies in patients with unresectable hepatocellular carcinoma: a treatment with Chinese characteristics
.
BST
.
2024
;
18
(
1
):
42
8
.
14.
Allard
M-A
,
Sebagh
M
,
Ruiz
A
,
Guettier
C
,
Paule
B
,
Vibert
E
, et al
.
Does pathological response after transarterial chemoembolization for hepatocellular carcinoma in cirrhotic patients with cirrhosis predict outcome after liver resection or transplantation
.
J Hepatol
.
2015
;
63
(
1
):
83
92
.
15.
Zeng
Z-X
,
Wu
J-Y
,
Wu
J-Y
,
Zhang
Z-B
,
Wang
K
,
Zhuang
S-W
, et al
.
Prognostic value of pathological response for patients with unresectable hepatocellular carcinoma undergoing conversion surgery
.
Liver Cancer
.
2024
;
13
(
5
):
498
508
.
16.
Zhu
X-D
,
Huang
C
,
Shen
Y-H
,
Xu
B
,
Ge
N-L
,
Ji
Y
, et al
.
Hepatectomy after conversion therapy using tyrosine kinase inhibitors plus anti-PD-1 antibody therapy for patients with unresectable hepatocellular carcinoma
.
Ann Surg Oncol
.
2023
;
30
(
5
):
2782
90
.
17.
Yi
Y
,
Sun
B-Y
,
Weng
J-L
,
Zhou
C
,
Zhou
C-H
,
Cai
M-H
, et al
.
Lenvatinib plus anti-PD-1 therapy represents a feasible conversion resection strategy for patients with initially unresectable hepatocellular carcinoma: a retrospective study
.
Front Oncol
.
2022
;
12
:
1046584
.
18.
Wu
J-Y
,
Wu
J-Y
,
Fu
Y-K
,
Ou
X-Y
,
Li
S-Q
,
Zhang
Z-B
, et al
.
Outcomes of salvage surgery versus non-salvage surgery for initially unresectable hepatocellular carcinoma after conversion therapy with transcatheter arterial chemoembolization combined with lenvatinib plus anti-PD-1 antibody: a multicenter retrospective study
.
Ann Surg Oncol
.
2024
;
31
(
5
):
3073
83
.
19.
Li
B
,
Wang
C
,
He
W
,
Qiu
J
,
Zheng
Y
,
Zou
R
, et al
.
Watch-and-Wait strategy vs. resection in patients with radiologic complete response after conversion therapy for initially unresectable hepatocellular carcinoma:a propensity score-matching comparative study
.
Int J Surg
.
2024
;
110
(
5
):
2545
55
.
20.
Wu
J-Y
,
Wu
J-Y
,
Liu
D-Y
,
Li
H
,
Zhuang
S-W
,
Li
B
, et al
.
Clinical complete response after conversion therapy for unresectable hepatocellular carcinoma: is salvage hepatectomy necessary? JHC
.
J Hepatocell Carcinoma
.
2023
;
10
:
2161
71
.
21.
Kudo
M
,
Aoki
T
,
Ueshima
K
,
Tsuchiya
K
,
Morita
M
,
Chishina
H
, et al
.
Achievement of complete response and drug-free status by atezolizumab plus bevacizumab combined with or without curative conversion in patients with transarterial chemoembolization-unsuitable, intermediate-stage hepatocellular carcinoma: a multicenter proof-of-concept study
.
Liver Cancer
.
2023
;
12
(
4
):
321
38
.
22.
Zhao
L
,
Zhao
H
,
Sun
H
.
It’s time to propose a uniform criteria for determining “clinical complete response” in hepatocellular carcinoma
.
Hepatobiliary Surg Nutr
.
2022
;
11
(
4
):
620
2
.
23.
Deng
M
,
Zhao
R
,
Guan
R
,
Li
S
,
Zuo
Z
,
Lin
W
, et al
.
Development of nomograms to predict recurrence after conversion hepatectomy for hepatocellular carcinoma previously treated with transarterial interventional therapy
.
Eur J Med Res
.
2023
;
28
(
1
):
328
.
24.
Zhang
L
,
Sun
JH
,
Hou
ZH
,
Zhong
BY
,
Yang
MJ
,
Zhou
GH
, et al
.
Prognosis nomogram for hepatocellular carcinoma patients with portal vein invasion undergoing transarterial chemoembolization plus sorafenib treatment: a retrospective multicentre study
.
Cardiovasc Intervent Radiol
.
2021
;
44
(
1
):
63
72
.
25.
Han
CL
,
Tian
BW
,
Yan
LJ
,
Ding
ZN
,
Liu
H
,
Mao
XC
, et al
.
Efficacy and safety of immune checkpoint inhibitors for hepatocellular carcinoma patients with macrovascular invasion or extrahepatic spread: a systematic review and meta-analysis of 54 studies with 6187 hepatocellular carcinoma patients
.
Cancer Immunol Immunother
.
2023
;
72
(
7
):
1957
69
.
26.
Wang
MD
,
Sun
LY
,
Qian
GJ
,
Li
C
,
Gu
LH
,
Yao
LQ
, et al
.
Prothrombin induced by vitamin K Absence-II versus alpha-fetoprotein in detection of both resectable hepatocellular carcinoma and early recurrence after curative liver resection: a retrospective cohort study
.
Int J Surg
.
2022
;
105
:
106843
.
27.
Yang
Y
,
Dang
Z
,
Lu
P
,
Qian
Y
,
Lin
K
,
Pan
Z
, et al
.
Impact of pathological response after preoperative transcatheter arterial chemoembolization (TACE) on incidences of microvascular invasion and early tumor recurrence in hepatocellular carcinoma: a multicenter propensity score matching analysis
.
Hepatobiliary Surg Nutr
.
2022
;
11
(
3
):
386
99
.
28.
DiNorcia
J
,
Florman
SS
,
Haydel
B
,
Tabrizian
P
,
Ruiz
RM
,
Klintmalm
GB
, et al
.
Pathologic response to pretransplant locoregional therapy is predictive of patient outcome after liver transplantation for hepatocellular carcinoma: analysis from the US multicenter HCC transplant consortium
.
Ann Surg
.
2020
;
271
(
4
):
616
24
.
29.
Aino
H
,
Sumie
S
,
Niizeki
T
,
Kuromatsu
R
,
Tajiri
N
,
Nakano
M
, et al
.
The systemic inflammatory response as a prognostic factor for advanced hepatocellular carcinoma with extrahepatic metastasis
.
Mol Clin Oncol
.
2016
;
5
(
1
):
83
8
.
30.
Uchino
K
,
Tateishi
R
,
Shiina
S
,
Kanda
M
,
Masuzaki
R
,
Kondo
Y
, et al
.
Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors
.
Cancer
.
2011
;
117
(
19
):
4475
83
.