Abstract
Background
This study compared long-term outcomes between patients with initial hepatocellular carcinoma (IHCC) and those with recurrent HCC (RHCC) treated with microwave ablation (MWA).
Methods
This retrospective study included 425 patients with HCCs (294 IHCCs and 131 RHCCs) within the Milan criteria who were treated with ultrasound-guided percutaneous MWA between January 2008 and November 2021. All patients with RHCC had previously undergone MWA for initial HCC. Overall survival (OS) and recurrence-free survival (RFS) rates were compared between the IHCC and RHCC groups before and after propensity score matching (PSM).
Results
Before matching, the 1-, 3-, 5-, and 10-year OS rates in the IHCC group were 95.9%, 78.5%, 60.2%, and 42.5%, respectively, which were significantly higher than those in the RHCC group (93.8%, 70.0%, 42.0%, and 6.6%, respectively). This difference remained significant after PSM. However, subgroup analyses suggested that there were no significant differences in OS rates between IHCC and RHCC in patients with solitary HCC ≤3.0 cm, AFP ≤200 ng/mL, ablative margins ≥0.5 cm, or Albumin-Bilirubin (ALBI) grade 1. RFS was significantly higher in IHCC than in RHCC before and after PSM, as well as in subgroup analyses. ALBI grade (hazard ratio (HR), 2.38; 95% CI: 1.46–3.86; p < 0.001), serum AFP level (HR, 2.07; 95% CI: 1.19–3.62; p = 0.010) and ablative margins (HR, 0.18; 95% CI: 0.06-0.59; p = 0.005) were independent prognostic factors for OS of RHCC. Serum AFP(HR, 1.29; 95% CI: 1.02–1.63, p = 0.036) level was the only factor associated with RFS in RHCC.
Conclusions
MWA yielded comparable OS in IHCC and RHCC patients with solitary HCC ≤3.0 cm, AFP ≤200 ng/mL, ablative margins ≥0.5 cm, or ALBI grade 1.
Introduction
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide [Citation1]. For early HCC, microwave ablations (MWA) and radiofrequency ablation (RFA) are recommended treatments in addition to surgery and liver transplantation [Citation2,Citation3]. In a recent study, MWA resulted in similar overall survival (OS) to laparoscopic resection when used as the first-line therapy for solitary 3–5 cm HCC [Citation4]. Studies have suggested that MWA and RFA have comparable efficacy and safety in the local control of HCC, and that MWA seems superior to RFA for larger HCC and reduces local recurrence [Citation5,Citation6]. Therefore, MWA may be used as a first-line therapy for early-stage HCC.
Although ablation is considered a potentially curative treatment for early HCC, it is only effective in 20–30% of patients with HCC treated with ablation [Citation7]. Tumor recurrence within the liver occurs in 60–80% within 5 years of local ablation [Citation8,Citation9]. Presently, the same algorithms are used to determine treatment strategies for primary and recurrent HCC. When HCC recurs, it is important to evaluate whether the patients are amenable to curative-intent therapy. Patients eligible for curative resection or ablation had superior long-term survival rates compared to those undergoing palliative transarterial chemoembolization or systemic therapy [Citation10]. Existing data suggest no differences in the outcomes of recurrent HCC following repeat resection versus ablation among patients within the Milan criteria or classified as having early-stage disease according to the Barcelona Clinic Liver Cancer classification. Ablation was associated with a lower incidence of complications than repeat resection [Citation11–17]. Hence, ablation remains an important treatment option for recurrent HCC, particularly in patients with early-stage HCC. The effectiveness of ablation for early primary HCC has been documented extensively. Nevertheless, its role in early-stage recurrent HCC has not been extensively studied. A recent study reported the outcomes of RFA for recurrent HCC and found that the efficacy of RFA for recurrent HCC was comparable to primary HCC for patients with solitary HCC of 5 cm or less [Citation18]. Few studies have reported the long-term (10-year) survival rates after MWA in patients with recurrent HCC. An earlier study reported the outcomes of recurrent HCC treated with MWA and suggested that MWA could be an effective therapeutic technique for initial recurrent HCC ≤5 cm in diameter after hepatectomy [Citation19]. Lee et al. analyzed the outcomes of recurrent HCC patients treated with RFA or MWA and found no differences between the two treatments [Citation20]. Several factors associated with the survival of recurrent HCC have been reported, including time to recurrence, extrahepatic spread, and the size and number of recurrent nodules [Citation21–24]. Zhang et al. compared MWA and repeat hepatectomy (RH) for recurrent HCC after stratification based on these risk factors. They found no differences between RH and MWA in patients with early recurrence. However, RH resulted in better outcomes in patients experiencing late recurrence [Citation25].
Whether MWA is as effective in recurrent HCC as in primary HCC remains unclear, and the optimal candidates for MWA in recurrent HCC remain to be identified. In this study, we compared the outcomes following MWA for primary HCC with those of repeat MWA for recurrent HCC, analyzing the prognostic factors associated with long-term outcomes following repeat MWA for recurrent HCC.
Materials and methods
Patients
We conducted a retrospective study involving patients diagnosed with HCC who received ultrasound (US)-guided percutaneous MWA at the Department of Gastroenterology, XiJing Hospital, Xi’an, China. This study conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of XiJing Hospital (No.KY20221056-C-6). The requirement for patient consent was waived due to the retrospective nature of the study. Between January 2008 and December 2021, 519 patients who were ineligible for or refused surgical treatment underwent MWA for initial HCC. Out of these 519 patients, 150 received repeat MWA for recurrent HCC (). Only patients who met the Milan criteria were included. The following criteria were used for patient selection: (a) solitary HCC ≤5.0 cm in diameter, or two to three HCC tumors, each ≤3.0 cm in diameter according to the Milan criteria; (b) absence of extrahepatic metastasis or major vascular invasion; (c) Child-Pugh class A or B liver function. The exclusion criteria were as follows: (a) lost to follow-up within 1 month after MWA and (b) combined chemotherapy or tyrosine kinase inhibitors after MWA.
Figure 1. Flowchart shows patient selection. HCC: hepatocellular carcinoma; IHCC: initial HCC; RHCC: recurrent HCC; MWA: microwave ablation.
Finally, 425 patients were included, with 294 having initial HCC and 131 experiencing recurrent HCC (). Diagnosis of HCC within all groups was made either through imaging examination (initial HCC, n = 156; recurrent HCC, n = 121) or histological analysis (initial HCC, n = 138; recurrent HCC, n = 10) following the guidelines outlined by the European Association for the Study of the Liver (EASL) [Citation2].
Among 131 patients with recurrent HCC, 15 were diagnosed with local recurrence, and 116 with intrahepatic distant recurrence. The median time to recurrence was 19.0 (95% CI: 5.6–68.0) months, with 78 patients experiencing recurrence within the first 2 years and 53 recurring beyond 2 years.
MWA treatment
MWA was performed as previously reported [Citation26]. All MWA procedures were performed by experienced interventional radiologists. The MWA system consisted of a monopole microwave antenna and water-cooled microwave device (ECO-100, ECO Microwave Electronic Institute; KY-2000, Kangyou Medical Instrument) (14 G). A rational MWA scheme was designed based on the enhanced computed tomography (CT), magnetic resonance imaging (MRI), and contrast-enhanced ultrasonography findings. An ideal ablative margin was achieved to cover the tumor and surrounding tumor edge completely (≥0.5 cm), with the exception of margins situated at difficult locations—large vessels, gallbladder, or bile ducts—where individual MWA procedures were performed with the intention of minimizing potential damage [Citation5,Citation27,Citation28].
After the administration of local anesthesia, the MWA antenna was inserted under US guidance and introduced into the tumor to reach its deep margin. To achieve complete ablation, multiple overlapping ablation approaches were applied to the tumors. If the deep lesion site and every area of the targeted tumor were covered by hyperechoic regions on US, the procedure was terminated. The ablation area covering the tumor and its surrounding area measured at least 0.5–1.0 cm as the “safety margin.” This measurement was determined by comparing the diameter of hyperechoic regions post-procedure to the diameters of tumors before treatment [Citation29].
Follow-up and outcomes
One month after MWA treatment, all patients underwent contrast-enhanced CT or MRI to evaluate the technical success rate. After the initial CT/MRI scan, patients were followed up every 3–6 months until death or loss to follow-up. Each follow-up visit included a physical examination, liver function test, AFP test, and at least one imaging examination (abdominal US, contrast-enhanced CT, or MRI). Patients with elevated AFP levels or suspicious lesions on US screening underwent contrast-enhanced CT or MRI to confirm tumor recurrence. If the imaging findings were uncertain, the nodules were biopsied. Patients who did not visit our hospital as scheduled were telephoned for follow-up to obtain imaging examinations, treatment information, and living status. During follow-up, the number and size of recurrent tumors, recurrence patterns, and subsequent treatments were recorded. Recurrence-free survival (RFS) was calculated from the date of initial MWA for primary HCC or repeat MWA for recurrent HCC to the date of tumor recurrence or patient death from any cause. OS was defined as the interval between the initial or repeat MWA and all-cause death or last follow-up prior to 30 September 2022.
Subgroup analysis
Subgroup analyses were performed according to tumor number and size, AFP level, albumin–bilirubin (ALBI) grade [Citation30], and ablative margins [Citation31].
Statistical analysis
Continuous variables are presented as medians with interquartile ranges (IQR) and compared using the Mann − Whitney U test. Categorical variables are presented as counts and percentages and compared using Pearsons’s χ2 test or Fisher’s exact test.
We performed 1:1 propensity score matching (PSM) between initial HCC and recurrent HCC using a caliper of 0.1 with the following baseline characteristics as covariates: age, aspartate aminotransferase level (AST), total bilirubin level (TBIL), ALBI grade, and ablative margins.
Survival curves were constructed using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariate analyses for OS and RFS were conducted using the Cox proportional hazards model in the PSM recurrent cohort, and values lower than 0.1 were included in the final multivariable model. All tests were two-tailed, and p-values <0.05 were considered statistically significant. All statistical analyses were performed using R version 4.1.3 software (R Foundation for Statistical Computing, Vienna, Austria) and IBM SPSS Statistics 26.0 (IBM Corp., Armonk, NY).
Results
Patient characteristics
In total, 425 patients (294 with initial HCC and 131 with recurrent HCC) were included in the final analysis (). The mean age was 55.0 ± 10.5 years. The median follow-up time was 54 months (range: 1–136 months) for initial HCC and 65 months (range: 4–128 months) for recurrent HCC. A comparative analysis of the baseline demographics and clinical features between the initial HCC and recurrent HCC cohorts revealed a significantly younger age, higher AST and TBIL levels, and a higher proportion of ALBI grades 2 and 3 in the initial HCC group (all p < 0.05; ). Upon employing PSM (1:1 matching), two new cohorts, each comprising 124 patients, were generated, resulting in a balanced distribution of all variables across both groups (p > 0.05, ).
Table 1. Baseline characteristics of patients with initial and recurrent hepatocellular carcinoma (HCC) before and after propensity-score matching (PSM).
Three patients in the initial HCC group and two in the recurrent HCC group underwent a second MWA for residual lesions and achieved complete ablation. The primary technical success rates were comparable between the initial HCC group (291/294, 99.0%) and the recurrent HCC group (129/131, 98.5%) (p = 0.655).
Overall survival and recurrence-free survival
Of the entire cohort, 99 (99/294, 33.7%) patients in the initial HCC group and 77 (77/131, 58.8%) in the recurrent HCC group died. The median OS was 76.0 months for patients in the initial HCC group and 57.0 months in the recurrent HCC group (p < 0.001). The 1-, 3-, 5-, and 10-year OS rates after MWA were 95.9%, 78.5%, 60.2%, and 42.5%, respectively, in the initial HCC group, which were significantly higher than those in the recurrent HCC group (1-, 3-, 5-, and 10-year OS rates: 93.8%, 70.0%, 42.0%, and 6.6%, respectively) (p < 0.001; ). The differences in median OS and 1-, 3-, 5-, and 10-year OS rates between initial HCC and recurrent HCC remained significant after PSM (median OS: 67.0 months vs. 57.0 months; 1-, 3-, 5- and 10-year OS rates: 97.6%, 75.1%, 54.2% and 31.2% vs. 94.3%, 70.4%, 43.1% and 7.1%, respectively) (p = 0.045; ).
Figure 2. Overall and recurrence-free survival before and after propensity-score matching (PSM). (A,B) The overall survival was significantly better in patients with initial hepatocellular carcinoma (IHCC). (C,D) The recurrence-free survival was significantly better in patients with IHCC. RHCC: recurrent hepatocellular carcinoma.
During the follow-up period, the 1-, 3-, and 5-year RFS rates were 88.9%, 63.4%, and 47.9%, respectively, for patients in the initial HCC group, which were significantly higher than those in the recurrent HCC group (1-, 3-, and 5-year RFS rates: 63.6%, 25.7%, and 15.3%, respectively) (p < 0.001; ). The initial HCC group included 96 patients with intrahepatic distant recurrences and 30 patients with local recurrences. The median RFS was 60.0 (95% CI: 46.6–73.4) months. The recurrent HCC group included 75 patients with intrahepatic distant recurrences and 23 patients with local recurrences. The median RFS was 19.0 (95% CI: 15.2–22.8) months. After PSM, the 1-, 3-, and 5-year RFS rates in patients with initial HCC were significantly higher than those with recurrent HCC (87.8%, 55.4%, and 39.1% vs. 64.3%, 25.0%, and 15.7%, respectively) (p < 0.001; ).
Subgroup analyses
Subgroup analyses were performed in matched cohorts according to tumor status, AFP level, ALBI grade, and ablative margins. Patients in the initial HCC group with solitary tumor >3.0 cm or multiple nodules, AFP >200 ng/mL, or ALBI grade 2 and 3, had superior OS compared to those in the recurrent HCC group (, Supplementary Table 1). For patients with solitary tumor ≤3.0 cm, AFP ≤200 ng/mL, ALBI grade 1, and ablative margin ≥0.5 cm, no statistically significant differences were found in OS rates between the initial HCC and recurrent HCC groups (). Regardless of tumor status, AFP level, ablative margins, and ALBI grade, RFS rates in patients with initial HCC were significantly better than that in patients with recurrent HCC (, Supplementary Table 1).
Figure 3. Forest plot of overall survival in initial and recurrent hepatocellular carcinoma (HCC) patients after microwave ablation with different subgroups. IHCC: initial HCC; RHCC: recurrent HCC; AFP: a-fetoprotein; ALBI: albumin-bilirubin; mOS.mo: median overall survival (months).
Figure 4. Overall survival of patients with initial hepatocellular carcinoma (HCC) and recurrent HCC in these subgroups: (A) solitary HCC ≤3 cm, (B) AFP ≤ 200 ng/ml, (C) ablative margins ≥0.5 cm, (D) ALBI grade 1. AFP: a-fetoprotein; ALBI: albumin-bilirubin; IHCC: initial HCC; RHCC: recurrent HCC.
Figure 5. Forest plot of recurrence-free survival in initial and recurrent hepatocellular carcinoma (HCC) patients after microwave ablation with different subgroups. IHCC: initial HCC; RHCC: recurrent HCC; AFP: a-fetoprotein; ALBI: albumin-bilirubin; mRFS.mo: median recurrent-free survival (months).
Prognostic factors associated with overall survival and recurrence-free survival
Univariate and multivariate regression analyses were conducted to determine the factors associated with OS and RFS in patients with recurrent HCC who underwent repeat MWA. Multivariate Cox regression analysis identified ALBI grade (hazard ratio (HR), 2.38; 95% CI: 1.46–3.86; p < 0.001), serum AFP level (HR, 2.07; 95% CI: 1.19–3.62; p = 0.010) and ablative margins (HR, 0.18; 95% CI: 0.06–0.59; p = 0.005) as independent prognostic factors of OS in recurrent HCC (). No association with OS was observed concerning the location of recurrence (HR, 0.72; 95% CI: 0.38-1.37; p = 0.311), extent of recurrence (HR, 1.33; 95% CI: 0.75–2.33; p = 0.333) and time to recurrence (HR, 1.15; 95% CI: 0.70–1.88; p = 0.584) (). Serum AFP level (HR, 1.29; 95% CI: 1.02–1.63; p = 0.036) was the only factor associated with RFS in recurrent HCC patients ().
Table 2. Uni- And multivariable Cox analysis of factors affecting overall survival after repeat microwave ablation in patients with recurrent hepatocellular carcinoma (HCC).
Table 3. Uni- and multivariable Cox analysis of factors affecting recurrence-free survival after repeat microwave ablation in patients with recurrent hepatocellular carcinoma (HCC).
Discussion
Recurrence is common in HCC, even after initial curative treatment. The long-term prognosis of patients with recurrent HCC has not been extensively studied. A study involving 147 HCC patients treated with hepatic resection suggested that patients with recurrent HCC had a worse prognosis than those without recurrence [Citation32]. Zhang et al. reported that the 1-, 3-, 5- and 7-year OS rates for initial HCC recurrence after percutaneous MWA were 73.3%, 53.7%, 39.6%, and 17.3%, respectively [Citation19]. Another study using surgical microwave ablation for recurrent HCC demonstrated that the 5-year survival rate after MWA was 55.4% [Citation33]. Our study included 425 patients with HCC who met the Milan criteria and were treated with MWA for initial or recurrent tumors. Overall, patients with recurrent HCC had significantly worse outcomes (OS and RFS) than those with initial HCC, consistent with the findings of a previous study [Citation19,Citation33]. To our knowledge, this study included the largest population and presented the longest follow-up period reported to date.
No consensus has been reached regarding the optimal treatment for recurrent HCC after initial curative treatment. Currently, recurrent HCC is treated according to the same principles as primary HCC, and RH, RFA, and MWA are treatment options for early-stage recurrences. The reported 5-year survival rates after RH and RFA for recurrent HCC are 28 − 72% and 29 − 83%, respectively, with no significant differences between these two treatment modalities [Citation34]. A matched cohort study analyzed the 5-year OS after MWA for recurrent HCC and found it to be 36.7%, which is equivalent to that after RH and RFA [Citation33]. In our study, the outcomes of patients with recurrent HCC were significantly worse than those of patients with initial HCC. Whether other treatment strategies, such as TACE/SIRT or systemic therapy, can achieve comparable or superior results to repeat MWA remains unclear. Therefore, further comparative studies are required to address this issue.
Several factors have been reported to predict long-term outcomes of MWA, including tumor size, AFP level, and whether sufficient ablation can be achieved [Citation5,Citation31,Citation35]. In addition, the ALBI grade, a simple model developed in 2015, has been proven to be a more objective measure of liver function reserve in HCC than the Child-Turcotte-Pugh score, which shows a reproducible predictive value for HCC [Citation36,Citation37]. We grouped the patients according to these factors. Our findings showed that MWA resulted in comparable OS for patients in the recurrent HCC and initial HCC groups, specifically those with solitary tumor ≤3 cm, AFP ≤ 200 ng/mL, ablative margins ≥0.5 cm, or ALBI grade 1. A study conducted by Zhang TT et al. [Citation19] indicated the efficacy of percutaneous MWA for initial recurrent HCC ≤5 cm in diameter post-hepatectomy. In our study, all the patients underwent MWA as the initial therapy, and comparable OS was only evident in cases of initial HCC and recurrent HCC with solitary tumors ≤3 cm. We hypothesized that MWA could be effective for treating recurrent HCC since it is used for initial HCC in patients with single small tumors, low AFP serum concentrations, safe ablative margins, and well-preserved liver function. However, RFS post-MWA demonstrated a more adverse outcome for recurrent HCC across all subgroups than for initial HCC, indicating that close surveillance is paramount following MWA for recurrent HCC.
Numerous factors are associated with the prognosis of recurrent HCC, including tumor status, liver function reserve, BCLC stage, duration until recurrence post-initial therapy, and modalities used for recurrent treatment [Citation38,Citation39]. ALBI grade, comorbid disease, tumor size or numbers, and time to recurrence had been reported to be associated with OS after MWA for HCC recurrence [,Citation40]. In our study, ALBI grade, ablative margins, and serum AFP level emerged as independent risk factors influencing the long-term OS of patients with recurrent HCC post-repeat MWA. Specifically, serum AFP level was the only prognostic factor for RFS. The duration until recurrence after MWA did not significantly affect either OS or RFS in our study. The variance between the outcomes of our study and those of previous studies may be due to the differences in the study populations (such as hepatectomy vs. MWA for initial HCC, surgical ablation vs. percutaneous MWA/TACE/HAIC vs. MWA only as the treatment method for recurrence) [Citation32,Citation33]. Notwithstanding, our findings suggest that repeat MWA should be considered as the treatment of choice for recurrent HCC in selected patients previously treated with MWA for initial HCC.
This study has some limitations. Firstly, it was a retrospective study, and the findings need to be confirmed by a prospective study. Secondly, we only included patients treated with MWA for initial HCC. Caution should be taken to apply the conclusions from this study to patients undergoing other forms of initial treatment. Thirdly, this study was limited by the lack of CT and 3D software assessments of the ablation zone, which have been shown to be more accurate to evaluate treatment success of MWA [Citation41–43]. Finally, we aimed to assess the efficacy of MWA in both primary and recurrent HCC; therefore, we did not compare MWA to other treatments for recurrent HCC.
In conclusion, in patients with solitary HCC ≤3 cm, AFP ≤200 ng/mL, ablative margins ≥0.5 cm, or ALBI grade 1, MWA provided comparable long-term survival for initial HCC and recurrent HCC. Repeated MWA can be considered for these patients. Further research is required to compare other treatment options with repeated MWA for the management of recurrent HCC.
Date availability statement
The data that support the findings of this study are available from the Department of Gastroenterology, XiJing Hospital. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the corresponding authors with the permission of XiJing hospital.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
References
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