Long-Term Prognostic Significance of TACE-Induced Complete Pathological Response in Patients with Hepatocellular Carcinoma Who Have Undergone Liver Transplantation

Introduction

Hepatocellular carcinoma (HCC) is among the most common and deadly cancers worldwide, particularly in patients with chronic liver disease or cirrhosis [1]. Concerning available treatment options, liver transplantation (LT) offers the most comprehensive approach because it addresses both the tumor and the underlying liver cirrhosis, making it a potentially curative therapy for appropriately selected patients.

Due to limitations in donor availability and strict transplant criteria, many patients undergo bridging or downstaging therapies while awaiting LT. These treatments include transcatheter arterial chemoembolization (TACE), which is frequently used to treat HCC, particularly in patients with liver cirrhosis, multifocal disease, or macrovascular invasion. TACE delivers chemotherapy directly to the tumor while blocking its blood supply, thus reducing tumor burden and controlling tumor progression [2,3]. Despite its widespread use, the prognostic value of tumor response to TACE before LT remains unclear. This uncertainty is largely due to the variable degree of tumor necrosis observed after treatment and the inconsistent criteria used to evaluate response [2–5]. Among potential indicators of favorable outcomes, complete pathological response (CPR) – defined as the total absence of viable tumor cells in the explanted liver – is increasingly recognized as a strong predictor of improved survival and reduced recurrence risk after LT [6–8].

The present study was designed to investigate long-term outcomes in LT recipients who achieved CPR after pretransplant TACE. By focusing on this specific group, we sought to clarify the prognostic implications of CPR and support better risk stratification for posttransplant HCC surveillance.

Material and Methods

STUDY DESIGN AND PATIENT SELECTION:

The LT database of our institution was retrospectively reviewed to identify patients who underwent primary LT for HCC between January 2006 and December 2020. Patients were excluded if they had not undergone preoperative TACE, had previously undergone hepatic resection followed by salvage transplantation, or had combined hepatocellular-cholangiocarcinoma. Patients were also excluded if they had undergone pretransplant radiofrequency ablation or received neoadjuvant chemotherapy.

The medical records of all enrolled patients were retrospectively reviewed. Patients were followed through April 2024 or until death, based on institutional medical records and data obtained from the National Health Insurance Service. The study protocol was approved by the Institutional Review Board of our institution (IRB No. 2025-0869), which waived the requirement for informed consent due to the retrospective study design. All procedures were performed in accordance with the ethical principles of the Declaration of Helsinki (2013 revision).

PREOPERATIVE DIAGNOSIS OF HCC:

Routine preoperative evaluations for HCC included abdominal and chest computed tomography, magnetic resonance imaging, 2-18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), and upper gastrointestinal endoscopy. The comprehensive protocol for these evaluations has been reported [8–10], as have the criteria for performing LT in patients with HCC [8,11,12].

PRETRANSPLANT TACE AND PATHOLOGICAL ASSESSMENT:

Pretransplant TACE serves multiple purposes, including curative treatment, palliative tumor reduction, tumor downstaging, and assessment of transplant eligibility, often in combination. Thus, most patients underwent multiple TACE sessions before LT. The procedures were conducted in accordance with Korean national guidelines [10].

CPR was defined as the presence of total tumor necrosis without viable cancer cells detected in any lesion. Because viable tumor cells were absent in these patients, the diagnosis of HCC was solely based on pretransplant imaging and tumor marker evaluations.

POSTTRANSPLANT SURVEILLANCE AND TREATMENTS FOR HCC RECURRENCE:

Following LT, patients underwent regular follow-up assessments every 1 to 2 months during the first posttransplant year and every 3 to 6 months thereafter. The follow-up protocol and immunosuppressive regimens have been comprehensively described [9,12–14]. Recurrent HCC was managed in accordance with general treatment guidelines.

STATISTICAL ANALYSIS:

Quantitative data are presented as medians with ranges or as means with standard deviations (SDs), as appropriate. Recurrence and survival outcomes were evaluated using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model, with results expressed as hazard ratios and corresponding 95% confidence intervals. P-values <0.05 were considered indicative of statistical significance. All statistical analyses were performed using SPSS (version 22; IBM Corp., Armonk, NY, USA) and MedCalc (version 23.2.1; MedCalc Software Ltd., Ostend, Belgium) softwares.

Results

PATIENT DEMOGRAPHICS:

Of the 2238 patients with HCC who underwent LT during the study period, 253 (11.3%) achieved CPR after TACE. These patients underwent an average of 2.2±2.3 TACE sessions (range, 1–12) prior to LT. The median interval between the first TACE session and LT was 18 months (range, 2–87 months). None of the patients with CPR demonstrated hypermetabolic activity on routine pretransplant FDG-PET. Median pretransplant serum concentrations of α-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) were 5.3 ng/mL (range, 0.2–3630 ng/mL) and 23 mAU/mL (range, 8–19 623 mAU/mL), respectively. Examination of explanted livers showed that the median number of non-viable tumors per patient was 1 (range, 1–12), and the median maximal tumor size was 1.6 cm (range, 0.3–6.8 cm). Detailed patient characteristics are provided in Table 1.

TUMOR RECURRENCE AND OVERALL PATIENT SURVIVAL OUTCOMES AFTER LT:

Patients were followed for a median of 79 months (range, 2–214 months) after LT. Of the 253 patients, 11 (4.3%) experienced HCC recurrence during post-LT follow-up. Initial sites of tumor recurrence included the liver graft (n=2), abdominal lymph nodes (n=2), adrenal glands (n=2), lungs (n=2), bone (n=1), peritoneum (n=1), and abdominal wall (n=1). In total, 29 patients (11.5%) died of various causes; 6 deaths were directly attributed to HCC recurrence. At 1, 3, 5, 10, and 15 years post-LT, cumulative tumor recurrence rates were 1.2%, 3.3%, 3.3%, 5.6%, and 5.6%, respectively (Figure 1A); overall patient survival rates were 96.0%, 93.7%, 92.4%, 91.3%, and 82.1%, respectively (Figure 1B).

PROGNOSTIC FACTOR ANALYSIS:

Univariate analysis identified 2 significant predictors of tumor recurrence: a maximal diameter of non-viable tumors greater than 2 cm (P=0.002; Figure 2A) and the presence of multiple non-viable tumors (P=0.004; Figure 3A). Multivariate analysis showed that both factors remained independent predictors of tumor recurrence risk (Table 2).

Similarly, univariate analysis of overall patient survival revealed that non-viable tumor size greater than 2 cm (P=0.016; Figure 2B) and the presence of multiple non-viable tumors (P=0.036; Figure 3B) were significantly associated with worse survival outcomes. Both variables also constituted predictors of patient survival on multivariate analysis (Table 2).

PROGNOSTIC STRATIFICATION OF LT RECIPIENTS SHOWING CPR:

The combination of non-viable tumor size greater than 2 cm and multiple non-viable tumors showed a clear prognostic distinction. Patients with multiple non-viable tumors larger than 2 cm exhibited significantly higher recurrence rates (P<0.001; Figure 4A) and tended to display reduced overall survival (P=0.058; Figure 4B) compared with the other 3 patient groups. Cluster analysis comparing the high-risk group (ie, patients with multiple non-viable tumors >2 cm) and the low-risk group (ie, all other patients) confirmed that tumor recurrence rates were significantly higher (P<0.001; Figure 4C) and overall survival rates were significantly lower (P=0.018; Figure 4D) in the high-risk group than in the low-risk group.

Discussion

CPR in response to TACE is widely recognized as a strong indicator of favorable prognosis in patients with HCC [9,10]. In the present study, patients who achieved TACE-induced CPR demonstrated exceptionally low recurrence rates and excellent long-term survival. These outcomes were comparable to those in LT recipients who satisfied highly stringent super-selection criteria [8,15].

The reported incidence of CPR after TACE for HCC considerably varies. Because responses to TACE differ among patients, many require multiple TACE sessions to achieve improved therapeutic outcomes and address newly developed lesions. Our previous study showed that 31.6% of patients achieved CPR after an average of 2.2±2.4 TACE procedures [8]. Another study involving 67 LT recipients with HCCs smaller than 5 cm found that 44 patients (65.7%) achieved complete radiologic responses across 71 nodules; CPR was confirmed in 53 of 95 nodules (55.8%) that had shown complete radiologic responses [16]. Although non-surgical treatments such as TACE and radiofrequency ablation can lead to complete radiologic response, many patients still require LT because of severe underlying liver cirrhosis. The achievement of complete radiologic response along with normalized tumor markers after initial or repeated TACE may delay LT in select patients with small tumors and well-preserved liver function [17,18].

The prevention of posttransplant tumor recurrence remains a critical challenge in patients who undergo LT for HCC, given that effective treatments for recurrence remain limited. Clinically, TACE is utilized for multiple purposes, including tumor downstaging and assessment of tumor biology to guide LT candidacy. TACE may also be used with curative intent in some patients. Although some reports suggest that the prognostic impact of pretransplant TACE is modest, primarily because it is performed for downstaging rather than as definitive therapy [19–22], the achievement of CPR in all tumor nodules may substantially modify this perspective. When CPR is achieved, TACE may serve as the final and most effective phase of downstaging by potentially eliminating viable tumor burden. CPR is widely regarded as a surrogate marker for substantial tumor cell eradication, which may reduce HCC recurrence risk after LT [6,7].

Our previous studies revealed that the tumor recurrence rate was exceptionally low among LT recipients who met the super-selection criteria [8,12,15], a rate comparable to that observed in patients who achieved CPR. CPR indicates the complete elimination of viable HCC cells after locoregional treatments. Thus, the oncologic burden in very-early-stage HCCs may be equivalent to the burden in patients with CPR of more advanced HCCs. The present findings demonstrate that both the maximum diameter and number of non-viable HCC lesions are independent predictors of posttransplant tumor recurrence and overall patient survival. Notably, only 3 (2.0%) of 149 patients with a single non-viable tumor smaller than 2 cm experienced recurrence – at 6, 26, and 61 months post-LT – and all remained alive during follow-up. Furthermore, outcomes in patients with multiple non-viable tumors smaller than 2 cm or a single non-viable tumor larger than 2 cm were similar to those in patients with a single non-viable tumor smaller than 2 cm. Based on these findings, patients who achieve CPR can be stratified into 2 risk categories: high-risk (those with multiple non-viable tumors >2 cm) and low-risk (all others). High-risk patients require close posttransplant surveillance, whereas a less intensive follow-up protocol may be sufficient for low-risk patients.

Currently, the prognostic significance of CPR remains unclear because studies have shown conflicting results. For example, a single-center cohort study indicated that 32 (25.2%) of 127 patients achieved CPR after neoadjuvant therapy; CPR did not have a statistically significant impact on posttransplant tumor recurrence [23]. The 5-year tumor recurrence rates in propensity score–matched patients who did and did not achieve CPR were 14.0% and 15.9%, respectively (P=0.661), and corresponding overall survival rates were 73.2% and 67.4% (P=0.329). These findings suggest that CPR alone is not an independent predictor of long-term outcomes after LT for HCC [23]. However, a substantial proportion of patients in the present study who achieved CPR belonged to a high-risk subgroup, as indicated by a median maximum non-viable tumor diameter of 3 cm; this factor may have contributed to the high recurrence rates.

Another single-center cohort study evaluated long-term outcomes in patients with HCC who achieved either complete radiologic response or CPR [24]. Among 108 participants, 65 (60.2%) achieved complete radiologic response, and 36 (33.3%) achieved CPR. The 5-year overall survival (83.3% vs 65.2%, P=0.046) and recurrence-free survival (80.6% vs 62.5%, P=0.045) rates were marginally significantly higher in patients who achieved CPR than in those who did not. In contrast, overall survival (75.4% vs 65.1%, P=0.12) and recurrence-free survival (74.0% vs 62.8%, P=0.17) rates did not significantly differ between patients who did and did not achieve complete radiologic response. These findings highlight the weak correlation between radiologic responses and pathological outcomes, suggesting that radiologic assessments do not reliably predict CPR or long-term prognosis [24].

We previously evaluated pretransplant levels of HCC tumor markers in 166 LT recipients who achieved CPR [25]. Their median pretransplant serum AFP and PIVKA-II concentrations were 4.2 ng/mL and 20 mAU/mL, respectively, similar to levels observed in a control group without HCC and significantly lower than levels among patients with partial pathological responses (P<0.001). However, receiver operating characteristic curve analysis of AFP and PIVKA-II concentrations failed to establish definitive cutoff values distinguishing patients with HCC who achieved CPR from controls without HCC. These findings suggested that the normalization of AFP and PIVKA-II after locoregional therapy may serve as an indicator of CPR, although elevated concentrations of these markers were observed in a subset of patients who achieved CPR [25].

This study had some limitations. First, it was a retrospective analysis of patients at a single center in a region where hepatitis B virus infection is prevalent, which may limit the generalizability of the findings. The broader prognostic significance of CPR requires validation in diverse geographic and etiologic settings. Second, the study included only patients who achieved CPR and did not compare outcomes with patients who did not achieve CPR. Third, the cohort was limited to individuals with CPR specifically resulting from TACE; thus, it excluded patients who achieved CPR through other locoregional therapies such as radiofrequency ablation, microwave ablation, or radiotherapy, either alone or in combination with TACE. A notable strength of this study was the complete follow-up of all patients, ensuring robust survival outcome data.

Conclusions

The findings in this study suggest that CPR after TACE serves as a valuable surrogate marker for favorable posttransplant outcomes in patients with HCC. Patients who exhibit CPR with multiple non-viable tumors larger than 2 cm constitute a higher-risk subgroup and may require more intensive posttransplant surveillance. In contrast, patients in the low-risk CPR group may require less intensive follow-up due to their substantially lower recurrence risk.