Radiofrequency Ablation versus Transarterial Chemoembolization for Hepatocellular Carcinoma within Milan Criteria: Prognostic Role of Tumor Burden Score

Simple Summary Tumor burden score (TBS) has been recently introduced to assess the tumor burden in hepatocellular carcinoma (HCC), but its prognostic role in patients with early-stage HCC is unclear. We confirm that TBS is an independent prognostic predictor in HCC patients within the Milan criteria undergoing radiofrequency ablation (RFA) or transarterial chemoembolization (TACE). TACE may be an effective treatment alternative for these patients. Among patients with low TBS, RFA should be considered the priority treatment modality. Abstract Tumor burden score (TBS), estimated by the diameter and number of tumor nodules, was recently proposed to assess the tumor burden in hepatocellular carcinoma (HCC). We aimed to evaluate the prognostic impact of TBS on HCC patients within the Milan criteria undergoing radiofrequency ablation (RFA) or transarterial chemoembolization (TACE). A total of 883 patients undergoing RFA and TACE were included. The multivariate Cox proportional hazards model was used to determine independent prognostic predictors in different patient cohorts. The TACE group had significantly higher TBS compared with the RFA group. The RFA group had better long-term survival than the TACE group in patients within the Milan criteria in univariate survival analysis. In the Cox model, serum α-fetoprotein (AFP) > 20 ng/mL, performance status 1–2, medium and high TBS, albumin–bilirubin (ALBI) grade 2 and grade 3 were independent predictors linked with mortality (all p < 0.001). Overall, TACE was not an independent predictor; among patients with low TBS, TACE was independently associated with decreased survival compared with RFA (p = 0.034). Conclusions: TBS is a feasible prognostic marker for HCC patients within the Milan criteria. TACE may be an effective treatment alternative for these patients. Among patients with low TBS, RFA should be considered the priority treatment modality.


Introduction
Hepatocellular carcinoma (HCC) remains one of the difficult-to-treat cancers, with approximately 906,000 new cases in 2020 globally [1]. HCC ranks fifth in incidence and the second cause of morality in males. Known risk factors for HCC include chronic infection

Patients
Between the study period of 2002 and 2017, a total of 883 HCC patients within the Milan criteria undergoing RFA or TACE at Taipei Veterans General Hospital were prospectively enrolled and retrospectively analyzed. Their baseline characteristics, including age, sex, etiology of liver disease, performance status, tumor burden (tumor size, number, and TBS), liver functions, serum biochemistry, cancer stage and treatment, were investigated. Their survival status was inspected every 3-4 months until death or drop-out from the last follow-up. This study was approved by the institutional review board (IRB) of Taipei Veterans General Hospital (IRB protocol: 2022-01-23BC; approval date: 4 January 2022) and complies with current ethical guidelines in the Declaration of Helsinki. Waiver of patient consent was obtained and approved by the IRB due to the retrospective nature of this study.

Definition
HCC was diagnosed according to current clinical practice guidelines [3,16]. The performance status was defined by the Eastern Cooperative Oncology Group (ECOG) criteria [17]. Hepatitis B virus (HBV) infection was considered seropositive for hepatitis B surface antigen (HBsAg), seronegative for antibody for hepatitis C (anti-HCV), and as having no history of alcoholism. HCV-related HCC was denoted seropositive for anti-HCV, seronegative for HBsAg, and as having no history of alcoholism [18].

Definition of TBS
TBS was calculated as the distance from the origin of a Cartesian plane and comprised two variables: maximum tumor size (x-axis) and number of tumors (y-axis) [12,19]. TBS 2 = (maximum tumor diameter) 2 + (number of tumors) 2 According to this definition, TBS was classified as three groups: low TBS (<2.56), medium TBS (2.56 to 3.94), and high TBS (>3.94).

Treatments
Confirmed cases of HCC were discussed in the multidisciplinary cancer board for treatment recommendations. The inclusion criteria for patients with HCC are single tumor up to 5 cm or two to three nodules less than 3 cm, without vascular invasion or extrahepatic metastasis. The contraindications of RFA are (1) tumor location (close to the pericardium, diaphragm, gallbladder, caudate lobe of liver, central bile duct and inferior vena cava), and (2) presence of large amount of ascites. The details of the RFA procedure were described previously [23]. Briefly, under local anesthesia and ultrasound guidance, RFA was performed with a 17-gauge cooled-tip electrode and the Cool-Tip radiofrequency system (Radionics, Burlington, MA, USA). Post-RFA sonography was performed to confirm that there was no immediate complication. Patients who were unsuitable for RFA or resection were suggested to receive TACE for effective tumor control. TACE was delivered according to the Seldinger procedure as described previously [24]. After RFA or TACE, serum biochemistry, AFP level, and dynamic CT scan or MRI was performed every 3 months to evaluate the treatment efficacy. Repeated RFA or TACE to eradicate viable tumors was administered if clinically indicated.

Statistics
Chi-squared or Fisher's exact test was used for categorical data. The Mann-Whitney U test was used to compare continuous variables. Overall survival was assessed by the Kaplan-Meier analysis with the log-rank test. Factors that were significant in univariate survival analysis were entered into the multivariate Cox proportional hazards model to determine the independent predictors associated with survival. The IBM SPSS Statistics for Windows software, version 21.0 (IBM Corp., Armonk, NY, USA), was used for statistical analysis. A p value < 0.05 was considered statistically significant. Table 1 shows the comparison of baseline characteristics between two patient groups. The RFA group had significantly lower tumor burden (lower TBS and smaller tumors; Figure 1), better liver functional reserve, and better performance status than the TACE group (all p < 0.05). According to the Barcelona Clinic Liver Cancer (BCLC) stage, patients undergoing RFA more often belonged to stage 0 compared with those undergoing TACE (p < 0.001). No significant differences were noted in age, sex, etiology of chronic liver disease, serum α-fetoprotein (AFP), albumin, bilirubin level, and diabetes mellitus (all p > 0.05).

Kaplan-Meier Survival Analysis
The mean and median follow-up durations were 56 months and 43 months, respectively. During the follow-up, 167 (18%) patients dropped out from the study, and 627 (71%) patients died. Tumor progression and hepatic failure were the major causes of death, accounting for >95% cases.

Kaplan-Meier Survival Analysis
The mean and median follow-up durations were 56 months and 43 m tively. During the follow-up, 167 (18%) patients dropped out from the st (71%) patients died. Tumor progression and hepatic failure were the ma death, accounting for >95% cases.

Discussion
The Milan criteria are the major selection reference in liver transplantation for HCC. However, liver transplant in these patients is often limited by the shortage of donor organs. According to current practice guidelines, RFA is the recommended therapy for unresectable HCC within the Milan criteria. Notably, TACE is an effective treatment alternative for small HCC [25]. Very limited number of studies have specifically compared RFA vs. TACE as the primary therapeutic strategy for these patients. In this study, the long-term survival in a large patient cohort within the Milan criteria was investigated based on the distribution TBS. Our results show that although the RFA group had better long-term survival compared with the TACE group, the difference was not significant after adjustment in the multivariate Cox model, suggesting that other factors are more crucial predictors. Subgroup analysis showed that TBS is a feasible marker to discriminate long-term outcome, and we identify that TBS may provide differential impact in selecting RFA or TACE for these patients.
Tumor burden in HCC, including the diameter and number of tumor nodule as defined in the Milan criteria, is a major concern in treatment selection. Although using the categorical cut-offs is a simple and convenient way to assess disease burden, it does not appear to have clear statistical advantage, compared with continuous variables. Earlier studies proposed to use the total tumor diameter (TTD) and total tumor volume (TTV) which are also continuous scores, to assess the extent of tumor burden for HCC [26][27][28]. However, these two scores have apparent disadvantages because they require the information of size and number in all tumors during calculation. Alternatively, TBS is a more clinically feasible marker of disease burden to define the extent of tumor involvement in HCC. In our study, patients with medium and high TBS had 37% and 51% increased risk of death, respectively, compared with those of low TBS, suggesting that TBS is an important independent prognostic predictor in HCC. Consistent with previous studies [13][14][15]19,29,30], we confirm that TBS is a novel tool to discriminate survival difference patients with small HCC.
Clinically, RFA is usually recommended for patients with small HCC within the Milan criteria, and TACE is an alternative treatment option for patients unsuitable for RFA. However, the advantage of RFA over TACE in this regard is difficult to assess because the baseline characteristics are quite heterogeneous between two patient groups. In this study, we demonstrate that the survival advantage of RFA over TACE is not apparent after adjustment in the multivariate model. Notably, when the analysis was stratified according to TBS in the Cox model, we found that RFA is independently linked with increased survival compared with TACE in patients with low TBS, but not in the medium or high TBS groups. These results are consistent with previous studies [31,32], indicating that patients with low TBS are better candidates to receive RFA.
Liver functional reserve is known to play a critical role in the treatment selection for HCC. Consistently, our data indicate that patients with ALBI grade 2 and 3 had 1.6to 2.3-fold increased risk of mortality compared with ALBI grade 1 patients [20,33,34]. Performance status is another important outcome predictor in HCC. In this study, we show that patients with poor performance status are strongly linked with decreased survival. Alternatively, the serum AFP level was reported to intimately associate with aggressive cancer behavior in HCC. Consistent with previous studies [35,36], a high AFP level is also an independent factor in predicting an unfavorable outcome.
This study has a few limitations. Firstly, in this single center study, HBV is the predominant etiology of HCC. External validation is needed from Western countries, where other etiologies are more common. Secondly, the vast majority of our patients receiving RFA or TACE did not undergo subsequent liver transplantation due to an extreme organ shortage. Therefore, our results cannot be readily interpreted in centers with a large amount of liver transplants. Lastly, a potential drawback of TBS is in its mathematical rationale that the diameter and number of tumor nodules are weighted the same in statistics.

Conclusions
In conclusion, TBS is a feasible prognostic predictor in HCC patients within the Milan criteria. TACE may be an effective treatment alternative for these patients. Among patients with low TBS, RFA should be considered the priority treatment modality. Our findings require prospective studies for validation.  Informed Consent Statement: Waiver of patient consent was obtained and approved by the IRB due to the retrospective nature of this study.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.