Abstract
Introduction
This study aimed to compare the real-world effectiveness and safety of hepatic resection versus stereotactic body radiation therapy (SBRT) as initial local treatments for Barcelona Clinic Liver Cancer (BCLC) stage 0 hepatocellular carcinoma (HCC).
Methods
We retrospectively analyzed 537 treatment-naïve patients with single HCC measuring ≤2 cm who underwent hepatic resection (n = 450) or SBRT (n = 87) between January 2015 and December 2023. Inverse probability of treatment weighting (IPTW) was applied to balance baseline characteristics between treatment groups. Overall survival (OS) and disease-free survival (DFS) were evaluated using weighted Cox proportional hazards models, while competing-risk models estimated the cumulative incidence of overall and intrahepatic recurrence. Treatment-related adverse events (TRAEs) and longitudinal changes in liver function were also assessed.
Results
At baseline, patients in the SBRT group were significantly older, had a higher comorbidity burden, and exhibited poorer liver function compared to those in the resection group. Over a median follow-up of 56.8 months (range, 8.3–117.0), the unadjusted 3-year OS rates were 98.8% for resection versus 92.3% for SBRT (hazard ratio [HR] 3.15; p = 0.002), and 3-year DFS rates were 80.9% versus 64.9%, respectively (HR 1.58; p = 0.026). However, the IPTW-adjusted analysis demonstrated comparable outcomes between treatment groups, with 3-year rates of OS at 98.9% versus 96.2% (HR 1.15; p = 0.775), DFS at 79.1% versus 74.1% (HR 1.06; p = 0.851), and overall recurrence at 20.9% versus 20.2% (HR 0.96; p = 0.906) for resection and SBRT, respectively. Grade ≥3 TRAEs occurred in 31 patients (6.9%) in the resection group and none in the SBRT group. Liver function remained well preserved in both treatment groups.
Conclusion
After adjusting for baseline imbalances, SBRT achieved survival outcomes comparable to hepatic resection as initial local therapy, while maintaining an excellent safety profile. These findings suggest that SBRT may serve as a viable alternative for patients with BCLC stage 0 HCC who are suboptimal surgical candidates.
Keywords: Hepatocellular carcinoma, Very early stage, Stereotactic body radiation therapy, Hepatic resection, Inverse probability of treatment weighting
Introduction
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide and typically develops in the context of chronic liver disease [1]. The management of early-stage HCC represents an active area of multidisciplinary research as first-line curative treatments offer the best opportunity for long-term survival [2]. According to international guidelines, hepatic resection and radiofrequency ablation (RFA) are recommended as standard-of-care treatments for patients with very early or early-stage HCC [3–6].
Stereotactic body radiation therapy (SBRT) has emerged as a promising treatment modality, offering excellent local tumor control by delivering highly conformal and ablative radiation doses [7]. Over the past decade, SBRT has demonstrated superior local control and survival outcomes across various malignancies, leading to its widespread adoption as a definitive treatment comparable to surgical resection [8–10]. Consistent with these advancements, accumulating evidence from HCC studies has also revealed outstanding local control with SBRT, highlighted by a recent randomized controlled trial comparing SBRT and RFA, in which SBRT reduced local progression by more than half compared to RFA [11]. Despite these encouraging results, the long-established preference for conventional modalities such as hepatic resection and RFA has predominantly restricted the use of SBRT to patients who are heavily pretreated or ineligible for these standard treatments [12, 13]. Consequently, real-world data on upfront SBRT among treatment-naïve patients remain scarce, hindering robust assessment of its therapeutic efficacy and potential survival benefits in HCC management [12].
To address this critical evidence gap, we conducted a comparative cohort study of SBRT versus standard-of-care hepatic resection as initial local treatments in patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 HCC, using inverse probability of treatment weighting (IPTW) analysis. Building on extensive institutional experience with SBRT [14–17], this study evaluated long-term oncologic outcomes – including overall survival (OS), disease-free survival (DFS), treatment-related adverse events (TRAEs), and liver function preservation – to assess the viability of SBRT as a curative-intent alternative to hepatic resection in the management of BCLC stage 0 HCC.
Methods
Study Design and Population
This single-institution retrospective study was conducted at Asan Medical Center (Seoul, Republic of Korea). We identified patients with a single HCC measuring ≤2 cm (BCLC stage 0) who underwent either hepatic resection or SBRT as initial local treatment between January 2015 and December 2023. Eligibility criteria included Child-Pugh class A or B7 liver function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. Patients were excluded if they had vascular invasion; received prior or adjuvant treatments other than hepatic resection or SBRT; had a history of other primary malignancies; or had a follow-up duration of less than 6 months. This study was approved by the Institutional Review Board of Asan Medical Center (IRB No. 2024-0942).
HCC was diagnosed through histologic confirmation and/or typical findings on multiphase dynamic contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) using hepatocyte-specific contrast agents [6]. According to institutional protocol, hepatic resection was the primary treatment for patients with BCLC stage 0 HCC when curative resection was considered feasible. However, hepatic resection was not recommended for patients with insufficient future liver remnant volume, inability to achieve complete resection with adequate margins because of tumor location, clinically significant portal hypertension, impaired hepatic function, or high operative risk due to advanced age or substantial comorbidities. Although RFA was the preferred alternative, it was often not feasible for tumors that were poorly visualized on ultrasonography, located in technically challenging areas (e.g., adjacent to major vessels or bile ducts, subcapsular regions, or near the diaphragm or pericardium), or in patients with bleeding tendencies related to liver cirrhosis. For patients who declined or were deemed unsuitable for both hepatic resection and RFA, SBRT was considered an alternative curative-intent treatment. SBRT was considered feasible when the HCC lesion was located at a sufficient distance (>2 cm) from radiosensitive organs, including the stomach, duodenum, esophagus, and large bowel and when an adequate residual functional liver volume (>700 mL) was preserved. In contrast, SBRT was not performed in patients with uncontrolled ascites, hepatic encephalopathy, active gastric or duodenal ulcers, or poor general condition rendering them unsuitable for radiotherapy.
Hepatic Resection
Hepatic resection was performed using either open or laparoscopic approaches, following standard oncologic principles. Intraoperative ultrasonography was routinely utilized to confirm tumor location, evaluate vascular anatomy, and determine the extent of resection. Parenchymal transection was conducted using a Cavitron Ultrasonic Surgical Aspirator (CUSA; Excel, Integra LifeSciences, Plainsboro, NJ, USA) combined with energy devices (Harmonic Scalpel or THUNDERBEAT). The Pringle maneuver was selectively applied in intermittent cycles to minimize intraoperative blood loss. Glissonean pedicles and major vascular branches were controlled using vascular staplers or surgical clips, and an abdominal drain was placed along the transection plane. Surgical margins and specimen integrity were verified both intraoperatively and through pathological assessment to ensure complete oncologic resection.
Stereotactic Body Radiation Therapy
The procedures for CT simulation, target volume delineation, and dose prescription for SBRT were described in detail in our previous studies [14–17]. Four-dimensional (4D) CT simulation was performed under free-breathing conditions using a GE LightSpeed RT 16 scanner (GE HealthCare, Chicago, IL, USA). Respiratory motion was monitored via the Real-time Position Management system (Varian Medical Systems, Palo Alto, CA, USA), and the acquired CT images were reconstructed into 10 respiratory phases using Advantage 4D software (GE HealthCare). Treatment planning was conducted on the three-dimensional radiotherapy planning system Eclipse (Varian Medical Systems). The gross tumor volume was defined as the contrast-enhanced lesion at the end-expiratory phase. The internal target volume was defined as the sum of the individual gross tumor volumes delineated within the gated phases. The planning target volume was generated by adding a 5 mm margin to the internal target volume to account for setup uncertainties. A total dose of 45 Gy was typically prescribed in three consecutive daily fractions, with adjustments made based on tumor extent, hepatic function, and organ-at-risk dose constraints. SBRT was delivered using respiratory-gated, image-guided techniques with an On-Board Imager (Varian Medical Systems). Cone-beam CT and gated fluoroscopy were employed for precise real-time image guidance, utilizing fiducial markers or the hepatic dome as surrogate markers for target localization.
Post-Treatment Evaluation
Patients underwent regular follow-up with laboratory tests and imaging studies (dynamic contrast-enhanced liver CT or MRI) every 3 months for the first 2 years and every 4–6 months thereafter. Disease recurrence was categorized as either intrahepatic or distant (extrahepatic). Tumor response after SBRT was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), with the best overall response observed during follow-up recorded [18]. TRAEs were retrospectively extracted from electronic medical records, including clinical notes, laboratory results, imaging findings, and procedure reports, and graded using modality-specific classification systems: the Clavien-Dindo classification for resection and the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) for SBRT [19, 20]. Acute TRAEs were defined as events occurring within 3 months of treatment and late TRAEs as events occurring beyond 3 months. Longitudinal liver function was evaluated using serial measurements of albumin, total bilirubin, platelet count, albumin-bilirubin (ALBI) grade, and Child-Pugh score. Clinically significant deterioration was defined as albumin ≤3.5 g/dL, total bilirubin >2.0 mg/dL, platelet count <100 × 103/μL, worsening of ALBI grade, or an increase of ≥2 points in the Child-Pugh score from baseline.
Statistical Analysis
To account for baseline differences between treatment groups, we employed an IPTW approach based on propensity scores. Propensity scores were estimated using a multivariable logistic regression model that included age, sex, Charlson Comorbidity Index (CCI), disease etiology, Child-Pugh score, liver cirrhosis, albumin, bilirubin, platelet count, aspartate aminotransferase (AST), alanine transaminase (ALT), tumor size, tumor location, alpha-fetoprotein (AFP), and protein induced by vitamin K absence-II (PIVKA-II). Covariate balance between the weighted groups was examined using standardized mean differences (SMDs), with an SMD of less than 0.1 indicating adequate balance.
Survival analyses were performed in both unadjusted and IPTW-adjusted cohorts. OS was defined as the time from diagnosis to death, and DFS was defined as the time from diagnosis to disease progression or death. Patients without events were censored at the date of last follow-up. The cumulative incidence of overall and intrahepatic recurrence was estimated using competing risk analysis, with death treated as a competing event. Kaplan-Meier methods and Cox proportional hazards models were used to compare OS and DFS, whereas Gray’s test and Fine-Gray subdistribution hazard models were employed for recurrence outcomes. A two-sided p value of less than 0.05 was considered statistically significant. All statistical analyses were performed using STATA (version 18.0; StataCorp LP, College Station, TX, USA) and R software (version 4.4.1; R Foundation for Statistical Computing, Vienna, Austria).
Results
Patient and Treatment Characteristics
Between January 2015 and December 2023, a total of 537 patients with BCLC stage 0 HCC were included, of whom 450 (83.8%) underwent hepatic resection and 87 (16.2%) received SBRT (Fig. 1). The reasons for selecting SBRT as the initial local treatment included ineligibility for hepatic resection or RFA, subcapsular tumors with parasitic blood supply that precluded effective transarterial chemoembolization (TACE), significant medical comorbidities, and preferences of the referring physicians or patients. The calendar-year distribution of treatment modalities demonstrated an increasing use of SBRT over the study period, whereas the number of hepatic resections remained stable or slightly decreased (online suppl. Fig. S1; for all online suppl. material, see https://doi.org/10.1159/000552740).
Fig. 1.
Flowchart of patient selection. HCC, hepatocellular carcinoma; SBRT, stereotactic body radiation therapy.
Baseline characteristics are summarized in Table 1. Patients who underwent hepatic resection were significantly younger at diagnosis (median age: 58 vs. 64 years; p < 0.001), had fewer comorbidities (CCI ≥4: 8.2% vs. 32.2%; p < 0.001), and were more likely to have hepatitis B virus infection as the underlying etiology (87.8% vs. 52.9%; p < 0.001) compared to those treated with SBRT. Moreover, baseline liver function differed substantially between groups. Liver cirrhosis was more prevalent in the SBRT group than in the resection group (97.7% vs. 80.7%; p < 0.001). The SBRT group also had worse liver function parameters, including albumin, total bilirubin, platelet count, AST, and Child-Pugh score (all p < 0.001).
Table 1.
Baseline characteristics of the unadjusted and IPTW-adjusted cohorts
| Variable | Unadjusted cohort | IPTW-adjusted cohort | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Resection (n = 450) | SBRT (n = 87) | p value | SMD | Resection (n = 450) | SBRT (n = 87) | p value | SMD | |||||
| Age | | | | | <0.001 | 0.575 | | | | | 0.939 | 0.011 |
| ≤70 years | 420 | (93.3) | 63 | (72.4) | | | 395 | (87.8) | 76 | (87.5) | | |
| >70 years | 30 | (6.7) | 24 | (27.6) | | | 55 | (12.2) | 11 | (12.5) | | |
| Sex | | | | | 0.692 | 0.046 | | | | | 0.709 | 0.056 |
| Male | 335 | (74.4) | 63 | (72.4) | | | 337 | (74.8) | 63 | (72.4) | | |
| Female | 115 | (25.6) | 24 | (27.6) | | | 113 | (25.2) | 24 | (27.6) | | |
| Charlson Comorbidity Index | | | | | <0.001 | 0.642 | | | | | 0.949 | 0.044 |
| 0–1 | 194 | (43.1) | 20 | (23.0) | | | 180 | (40.0) | 33 | (38.5) | | |
| 2–3 | 219 | (48.7) | 39 | (44.8) | | | 216 | (48.1) | 43 | (49.5) | | |
| ≥4 | 37 | (8.2) | 28 | (32.2) | | | 54 | (11.9) | 10 | (12.0) | | |
| Etiology | | | | | <0.001 | 0.816 | | | | | 0.952 | 0.035 |
| Hepatitis B virus | 395 | (87.8) | 46 | (52.9) | | | 368 | (81.8) | 71 | (81.6) | | |
| Hepatitis C virus | 16 | (3.6) | 8 | (9.2) | | | 19 | (4.3) | 4 | (5.0) | | |
| Others | 39 | (8.7) | 33 | (37.9) | | | 62 | (13.8) | 12 | (13.4) | | |
| Child-Pugh score | | | | | <0.001 | 0.514 | | | | | 0.947 | 0.008 |
| 5 | 407 | (90.4) | 63 | (72.4) | | | 396 | (88.1) | 76 | (87.9) | | |
| 6 | 43 | (9.6) | 19 | (21.8) | | | 54 | (11.9) | 11 | (12.1) | | |
| 7 | 0 | (0.0) | 5 | (5.8) | | | 0 | (0.0) | 0 | (0.0) | | |
| Liver cirrhosis | | | | | <0.001 | 0.569 | | | | | 0.200 | 0.307 |
| No | 87 | (19.3) | 2 | (2.3) | | | 75 | (16.6) | 6 | (6.8) | | |
| Yes | 363 | (80.7) | 85 | (97.7) | | | 375 | (83.4) | 81 | (93.2) | | |
| Albumin | | | | | <0.001 | 0.494 | | | | | 0.818 | 0.028 |
| ≥3.5 g/dL | 429 | (95.3) | 69 | (79.3) | | | 421 | (93.5) | 81 | (92.8) | | |
| <3.5 g/dL | 21 | (4.7) | 18 | (20.7) | | | 29 | (6.5) | 6 | (7.2) | | |
| Total bilirubin | | | | | <0.001 | 0.585 | | | | | 0.718 | 0.046 |
| ≤1.2 mg/dL | 433 | (96.2) | 67 | (77.0) | | | 419 | (93.0) | 80 | (91.8) | | |
| >1.2 mg/dL | 17 | (3.8) | 20 | (23.0) | | | 32 | (7.0) | 7 | (8.2) | | |
| Platelet count | | | | | <0.001 | 0.776 | | | | | 0.689 | 0.051 |
| ≥100×103/μL | 413 | (91.8) | 53 | (60.9) | | | 392 | (87.2) | 74 | (85.4) | | |
| <100×103/μL | 37 | (8.2) | 34 | (39.1) | | | 58 | (12.8) | 13 | (14.6) | | |
| AST | | | | | <0.001 | 0.378 | | | | | 0.648 | 0.055 |
| ≤40 IU/L | 397 | (88.2) | 64 | (73.6) | | | 393 | (87.3) | 78 | (89.1) | | |
| >40 IU/L | 53 | (11.8) | 23 | (26.4) | | | 57 | (12.7) | 9 | (10.9) | | |
| ALT | | | | | 0.448 | 0.086 | | | | | 0.922 | 0.013 |
| ≤40 IU/L | 377 | (83.8) | 70 | (80.5) | | | 375 | (83.3) | 72 | (82.8) | | |
| >40 IU/L | 73 | (16.2) | 17 | (19.5) | | | 75 | (16.7) | 15 | (17.2) | | |
| Tumor size | | | | | 0.233 | 0.140 | | | | | 0.660 | 0.081 |
| ≤1.5 cm | 222 | (49.3) | 49 | (56.3) | | | 224 | (49.7) | 47 | (53.8) | | |
| >1.5 cm | 228 | (50.7) | 38 | (43.7) | | | 226 | (50.3) | 40 | (46.2) | | |
| Tumor locationa | | | | | 0.207 | 0.156 | | | | | 0.987 | 0.079 |
| Left lateral | 74 | (16.4) | 7 | (8.1) | | | 67 | (14.9) | 12 | (13.3) | | |
| Left medial | 58 | (12.9) | 13 | (14.9) | | | 58 | (12.8) | 10 | (11.7) | | |
| Right anterior | 166 | (36.9) | 38 | (43.7) | | | 179 | (39.8) | 35 | (40.3) | | |
| Right posterior | 148 | (32.9) | 27 | (31.0) | | | 143 | (31.7) | 30 | (34.0) | | |
| Caudate | 4 | (0.9) | 2 | (2.3) | | | 4 | (0.9) | 1 | (0.7) | | |
| Alpha-fetoprotein | | | | | 0.988 | 0.002 | | | | | 0.979 | 0.004 |
| ≤7.5 ng/mL | 259 | (57.6) | 50 | (57.5) | | | 262 | (58.3) | 51 | (58.5) | | |
| >7.5 ng/mL | 191 | (42.4) | 37 | (42.5) | | | 188 | (41.7) | 36 | (41.5) | | |
| PIVKA-II | | | | | 0.564 | 0.067 | | | | | 0.830 | 0.029 |
| ≤40 mAU/mL | 309 | (68.7) | 57 | (65.5) | | | 309 | (68.7) | 61 | (70.0) | | |
| >40 mAU/mL | 141 | (31.3) | 30 | (34.5) | | | 141 | (31.3) | 26 | (30.0) | | |
Data are presented as number of patients (%) for the unadjusted cohort and weighted number of patients (%) for the IPTW-adjusted cohort.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; IPTW, inverse probability of treatment weighting; SBRT, stereotactic body radiation therapy; SMD, standardized mean difference; PIVKA-II, protein induced by vitamin K absence-II.
aTumor location was categorized based on Couinaud classification of hepatic segments: left lateral (segments II and III), left medial (segment IV), right anterior (segments V and VIII), right posterior (segments VI and VII), and caudate lobe (segment I).
Regarding treatment details, the majority of patients in the resection group (n = 440, 97.8%) underwent anatomical resection, while 10 patients (2.2%) underwent nonanatomical resection. In the SBRT group, 83 patients (95.4%) received 45 Gy in 3 fractions and 4 patients (4.6%) received 36 Gy in 3 fractions. The best radiologic response after SBRT was complete response in 79 patients (90.8%), partial response in 7 patients (8.1%), and stable disease in 1 patient (1.1%), with a median time to best response of 5 months (range, 2–12 months). The median follow-up duration from the date of initial diagnosis was 59.1 months (range, 8.3–117.0 months) for the resection group and 41.2 months (range, 9.6–98.2 months) for the SBRT group (p < 0.001).
Unadjusted Analysis
Patterns of recurrence and salvage treatments are detailed in online supplementary Table S1. Intrahepatic recurrence was the predominant pattern in both groups, occurring in 123 patients (27.3%) after resection and 22 patients (25.2%) after SBRT. All intrahepatic recurrences in the resection group involved liver segments distinct from the primary site, whereas the SBRT group experienced recurrences in both different segments (n = 15, 17.2%) and the same segment (n = 7, 8.0%). Notably, only 1 patient (1.1%) developed in-field recurrence after SBRT, which was completely resolved with repeat SBRT. Upon initial recurrence, TACE was the most common salvage modality in the resection group (20.0%), while ablation was the most frequent initial salvage modality in the SBRT group (10.3%), followed by TACE (8.0%) (p = 0.002).
In the unadjusted cohort analysis, the resection group demonstrated significantly higher OS and DFS compared to the SBRT group. The 3- and 5-year OS rates were 98.8% (95% confidence interval [CI], 97.2%–99.5%) and 95.6% (95% CI, 92.8%–97.4%) in the resection group, compared to 92.3% (95% CI, 83.5%–96.5%) and 86.0% (95% CI, 73.9%–92.7%) in the SBRT group, respectively (hazard ratio [HR] 3.15; 95% CI, 1.51–6.58; p = 0.002) (Fig. 2a). Similarly, the 3- and 5-year DFS rates were 80.9% (95% CI, 76.7%–84.4%) and 68.2% (95% CI, 62.8%–72.9%) in the resection group, compared to 64.9% (95% CI, 52.2%–75.0%) and 60.6% (95% CI, 47.3%–71.5%) in the SBRT group, respectively (HR 1.58; 95% CI, 1.05–2.37; p = 0.026) (Fig. 2b). Multivariable analysis revealed that high CCI (HR 2.48; 95% CI, 1.08–5.68; p = 0.032) and non-hepatitis B virus etiology (HR 2.47; 95% CI, 1.13–5.43; p = 0.024) were independently associated with worse OS (Table 2). Conversely, treatment modality was no longer significantly associated with either OS (HR 1.19; 95% CI, 0.46–3.15; p = 0.713) or DFS (HR 1.20; 95% CI, 0.76–1.91; p = 0.427) in the multivariable model.
Fig. 2.
Unadjusted survival and recurrence outcomes between the resection and SBRT groups. Kaplan-Meier curves for (a) overall survival and (b) disease-free survival, and cumulative incidence curves for (c) overall recurrence and (d) intrahepatic recurrence in the unadjusted cohort. CI, confidence interval; HR, hazard ratio; SBRT, stereotactic body radiation therapy.
Table 2.
Univariable and multivariable analyses for OS and DFS
| Variable | Overall survival | Disease-free survival | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Univariable | Multivariable | Univariable | Multivariable | |||||||||
| HR | (95% CI) | p value | HR | (95% CI) | p value | HR | (95% CI) | p value | HR | (95% CI) | p value | |
| Treatment | ||||||||||||
| Resection | Reference | | Reference | | Reference | | Reference | | ||||
| SBRT | 3.15 | (1.51–6.58) | 0.002 | 1.19 | (0.46–3.15) | 0.713 | 1.58 | (1.05–2.37) | 0.026 | 1.20 | (0.76–1.91) | 0.427 |
| Age | ||||||||||||
| ≤70 years | Reference | | Reference | | Reference | | | | ||||
| >70 years | 3.12 | (1.47–6.63) | 0.003 | 1.19 | (0.44–3.23) | 0.733 | 1.24 | (0.77–2.01) | 0.372 | | | |
| Sex | ||||||||||||
| Male | Reference | | | | Reference | | Reference | | ||||
| Female | 0.97 | (0.48–1.95) | 0.931 | | | | 0.71 | (0.49–1.02) | 0.065 | 0.74 | (0.51–1.08) | 0.116 |
| Charlson Comorbidity Index | ||||||||||||
| 0–3 | Reference | | Reference | | Reference | | | | ||||
| ≥4 | 4.12 | (2.02–8.39) | <0.001 | 2.48 | (1.08–5.68) | 0.032 | 1.18 | (0.74–1.89) | 0.491 | | | |
| Etiology | ||||||||||||
| Hepatitis B virus | Reference | | Reference | | Reference | | Reference | | ||||
| Others | 4.46 | (2.31–8.62) | <0.001 | 2.47 | (1.13–5.43) | 0.024 | 1.41 | (0.98–2.04) | 0.070 | 1.15 | (0.77–1.72) | 0.482 |
| Child-Pugh score | ||||||||||||
| 5 | Reference | | Reference | | Reference | | Reference | | ||||
| 6–7 | 5.56 | (2.91–10.61) | <0.001 | 1.89 | (0.55–6.50) | 0.314 | 1.80 | (1.22–2.66) | 0.003 | 1.04 | (0.53–2.05) | 0.907 |
| Liver cirrhosis | ||||||||||||
| No | Reference | | | | | Reference | | | | | ||
| Yes | 2.14 | (0.66–6.95) | 0.207 | | | | 1.18 | (0.76–1.84) | 0.452 | | | |
| Albumin | ||||||||||||
| ≥3.5 g/dL | Reference | | Reference | | Reference | | Reference | | ||||
| <3.5 g/dL | 7.16 | (3.66–14.00) | <0.001 | 2.77 | (0.74–10.34) | 0.129 | 2.41 | (1.54–3.79) | <0.001 | 2.16 | (0.98–4.75) | 0.055 |
| Total bilirubin | ||||||||||||
| ≤1.2 mg/dL | Reference | | | | | Reference | | | | | ||
| >1.2 mg/dL | 1.37 | (0.42–4.47) | 0.597 | | | | 0.94 | (0.50–1.78) | 0.850 | | | |
| Platelet count | ||||||||||||
| ≥100×103/μL | Reference | | Reference | | Reference | | | | ||||
| <100×103/μL | 2.00 | (0.95–4.23) | 0.068 | 0.85 | (0.33–2.16) | 0.733 | 1.04 | (0.67–1.62) | 0.859 | | | |
| AST | ||||||||||||
| ≤40 IU/L | Reference | | | | Reference | | | | ||||
| >40 IU/L | 1.48 | (0.65–3.36) | 0.348 | | | | 1.09 | (0.71–1.68) | 0.695 | | | |
| ALT | ||||||||||||
| ≤40 IU/L | Reference | | | | Reference | | | | | |||
| >40 IU/L | 1.32 | (0.52–3.38) | 0.560 | | | | 1.27 | (0.93–1.72) | 0.127 | | | |
| Tumor size | ||||||||||||
| ≤1.5 cm | Reference | | | | | Reference | | | | | ||
| >1.5 cm | 0.77 | (0.41–1.45) | 0.420 | | | | 1.06 | (0.78–1.44) | 0.714 | | | |
| Tumor location | ||||||||||||
| Right lobe | Reference | | | | | Reference | | | | | ||
| Left lobe or caudate | 1.53 | (0.80–2.92) | 0.194 | | | | 1.02 | (0.73–1.42) | 0.908 | | | |
| Alpha-fetoprotein | ||||||||||||
| ≤7.5 ng/mL | Reference | | | | | Reference | | | | | ||
| >7.5 ng/mL | 1.03 | (0.55–1.94) | 0.919 | | | | 0.94 | (0.69–1.28) | 0.686 | | | |
| PIVKA-II | ||||||||||||
| ≤40 mAU/mL | Reference | | | | | Reference | | | | | ||
| >40 mAU/mL | 0.97 | (0.47–2.00) | 0.935 | | | | 1.31 | (0.94–1.82) | 0.113 | | | |
| Treatment year | ||||||||||||
| 2015–2019 | Reference | | | | | Reference | | | | | ||
| 2020–2023 | 1.06 | (0.43–2.67) | 0.892 | | | | 0.92 | (0.64–1.32) | 0.646 | | | |
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; HR, hazard ratio; PIVKA-II, protein induced by vitamin K absence or antagonist-II; SBRT, stereotactic body radiation therapy.
Both overall and intrahepatic recurrence rates were numerically lower in the resection group, but the differences did not reach statistical significance. The 3- and 5-year cumulative incidences of overall recurrence were 19.8% (95% CI, 16.0%–23.6%) and 30.3% (95% CI, 24.9%–35.7%) in the resection group, compared to 24.5% (95% CI, 15.1%–33.9%) and 36.9% (95% CI, 22.8%–51.0%) in the SBRT group, respectively (subdistribution HR [sHR] 1.27; 95% CI, 0.81–2.00; p = 0.296) (Fig. 2c). For intrahepatic recurrence, the 3- and 5-year cumulative incidences were 19.3% (95% CI, 15.5%–23.0%) and 29.6% (95% CI, 24.2%–34.9%) in the resection group, compared to 22.3% (95% CI, 13.2%–31.5%) and 33.9% (95% CI, 20.1%–47.7%) in the SBRT group, respectively (sHR 1.18; 95% CI, 0.74–1.89; p = 0.486) (Fig. 2d).
IPTW-Adjusted Analysis
After IPTW adjustment, baseline balance was markedly improved, and all covariates except liver cirrhosis achieved an SMD <0.1 (online supplementary Fig. S2). Liver cirrhosis remained imbalanced after weighting (SMD = 0.307), reflecting the rarity of non-cirrhotic patients in the SBRT group (2/87, 2.3%) (Table 1). In contrast to the unadjusted cohort, IPTW-adjusted analysis demonstrated comparable outcomes between resection and SBRT across all assessed endpoints. The adjusted 3- and 5-year OS rates were 98.9% (95% CI, 97.4%–99.6%) and 93.9% (95% CI, 90.7%–96.0%) in the resection group, compared to 96.2% (95% CI, 86.9%–98.9%) and 95.5% (95% CI, 84.9%–98.7%) in the SBRT group, respectively (HR 1.15; 95% CI, 0.44–3.05; p = 0.775) (Fig. 3a). For DFS, the adjusted 3- and 5-year rates were 79.1% (95% CI, 74.8%–82.8%) and 66.2% (95% CI, 60.8%–71.0%) in the resection group, compared to 74.1% (95% CI, 59.6%–84.1%) and 73.4% (95% CI, 58.6%–83.7%) in the SBRT group, respectively (HR 1.06; 95% CI, 0.59–1.91; p = 0.851) (Fig. 3b).
Fig. 3.
IPTW-adjusted survival and recurrence outcomes between the resection and SBRT groups. Kaplan-Meier curves for (a) overall survival and (b) disease-free survival, and cumulative incidence curves for (c) overall recurrence and (d) intrahepatic recurrence in the IPTW-adjusted cohort. CI, confidence interval; HR, hazard ratio; IPTW, inverse probability of treatment weighting; SBRT, stereotactic body radiation therapy.
Recurrence outcomes also showed minimal differences in IPTW-adjusted analysis. The adjusted 3- and 5-year cumulative incidences of overall recurrence were 20.9% (95% CI, 16.8%–25.0%) and 31.5% (95% CI, 25.7%–37.2%) in the resection group, compared to 20.2% (95% CI, 9.6%–30.8%) and 30.5% (95% CI, 14.0%–47.0%) in the SBRT group, respectively (sHR 0.96; 95% CI, 0.52–1.79; p = 0.906) (Fig. 3c). The corresponding incidences of intrahepatic recurrence were 20.4% (95% CI, 16.4%–24.5%) and 30.7% (95% CI, 25.0%–36.4%) in the resection group, compared to 18.1% (95% CI, 7.9%–28.3%) and 27.4% (95% CI, 11.4%–43.4%) in the SBRT group, respectively (sHR 0.87; 95% CI, 0.46–1.65; p = 0.678) (Fig. 3d).
The results of sensitivity analyses stratified by age, CCI, Child-Pugh score, etiology, and AFP level are presented in online supplementary Table S2. The comparative effectiveness of SBRT versus hepatic resection remained consistent across all stratified analyses, with no significant effect modification observed (all p for interaction > 0.05), supporting the robustness of the IPTW-adjusted findings.
Treatment-Related Adverse Events
Acute and late TRAEs are summarized in Table 3. In the resection group, acute TRAEs occurred in 49 patients (10.9%), including 31 (6.9%) with grade ≥3 events, primarily consisting of abdominal fluid collection (n = 13), pleural effusion (n = 10), and bile leakage (n = 5). Late TRAEs were observed in 7 patients (1.6%), all of which were grade 3 events, consisting of chronic bile leakage/abscess (n = 4) and biliary stricture (n = 3). In contrast, no grade ≥3 TRAEs were observed in the SBRT group; two patients (2.2%) developed grade 2 acute events (transaminase elevation and thrombocytopenia), and 1 (1.1%) experienced a grade 2 late event (rib fracture).
Table 3.
Treatment-related adverse events
| Variable | Resection group (n = 450) | SBRT group (n = 87) | ||||
|---|---|---|---|---|---|---|
| grade 2 | grade 3 | grade 4 | grade 2 | grade 3 | grade 4 | |
| Acute TRAEs | ||||||
| Bile leakage | 10 (2.2) | 5 (1.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Abdominal fluid collection | 2 (0.4) | 13 (2.9) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Pleural effusion | 2 (0.4) | 9 (2.0) | 1 (0.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Postoperative hemorrhage | 0 (0.0) | 2 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Surgical site complications | 4 (0.9) | 1 (0.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| AST/ALT elevation | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (1.1) | 0 (0.0) | 0 (0.0) |
| Platelet count decrease | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (1.1) | 0 (0.0) | 0 (0.0) |
| Total | 18 (4.0) | 30 (6.7) | 1 (0.2) | 2 (2.2) | 0 (0.0) | 0 (0.0) |
| Late TRAEs | ||||||
| Chronic bile leakage/abscess | 0 (0.0) | 4 (0.9) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Biliary stricture | 0 (0.0) | 3 (0.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Rib fracture | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (1.1) | 0 (0.0) | 0 (0.0) |
| Total | 0 (0.0) | 7 (1.6) | 0 (0.0) | 1 (1.1) | 0 (0.0) | 0 (0.0) |
Data are presented as number of patients (%). Toxicity was graded using the Clavien-Dindo classification for the resection group and the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for the SBRT group.
AST, aspartate aminotransferase; ALT, alanine aminotransferase; SBRT, stereotactic body radiation therapy; TRAEs, treatment-related adverse events.
Longitudinal changes in liver function are illustrated in online supplementary Figure S3. Both groups maintained well-preserved liver function at near-baseline levels throughout the follow-up period, except for transient postoperative fluctuations that resolved within 3 months. No patients in either group experienced clinically significant deterioration in Child-Pugh scores or other liver function parameters.
Discussion
This propensity score-weighted study provides essential real-world evidence comparing SBRT with hepatic resection, focusing on a treatment-naïve, very early-stage HCC cohort – a clinically relevant population for establishing SBRT efficacy that has been largely unexplored. Our crude analyses indicated superior survival outcomes with hepatic resection; however, these differences disappeared after adjusting for significant baseline imbalances that disadvantaged the SBRT group, including older age, higher comorbidity burden, and compromised liver function. Notably, these findings align with prior comparative studies of SBRT and hepatic resection, as summarized in Table 4. Despite wide variability in study designs and reported clinical outcomes, most investigations have shown initial survival advantages favoring hepatic resection, which were subsequently attenuated or eliminated after baseline adjustments [21–26]. By leveraging a clearly defined patient cohort and rigorous IPTW methodology, our study demonstrated comparable outcomes between SBRT and hepatic resection across all measured clinical endpoints, suggesting that the observed survival differences may largely reflect patient selection biases inherent in HCC practice. Additionally, our analysis showed that the SBRT group experienced minimal adverse events and maintained stable liver function, further supporting the clinical utility of SBRT for treatment-naïve patients with very early-stage HCC who are not candidates for standard treatments.
Table 4.
Summary of studies comparing hepatic resection and SBRT as first-line treatments for hepatocellular carcinoma
| Author (year) | Treatment | No. of patients | Child-Pugh A (%) | Solitary tumor (%) | Tumor ≤3 cm (%) | Median follow-up, months | Overall survival (%) | Disease-free survival (%) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Unadjusted | Adjusted | Unadjusted | Adjusted | |||||||||||
| 3-year | 5-year | 3-year | 5-year | 3-year | 5-year | 3-year | 5-year | |||||||
| Su et al. [21] (2017) | Resection | 35 | 100 | 70 | 56 | 40.0 | 83.1 | 64.4 | 89.3 | 69.2 | 58.3 | 40.3 | 62.4 | 35.9 |
| SBRT | 82 | 100 | 64 | 43 | 33.0 | 81.8 | 70.0 | 91.8 | 74.3 | 50.2 | 40.7 | 59.2 | 43.9 | |
| Nakano et al. [22] (2018) | Resection | 254 | 94 | 71 | 100 | 41.7 | 89.5 | 81.2 | NR | 75.2 | 58.9 | 48.0 | NR | 33.8 |
| SBRT | 27 | 85 | 96 | 100 | 28.0 | 71.6 | 47.8 | NR | 47.8 | 32.9 | 16.4 | NR | 16.4 | |
| Sun et al. [23] (2020) | Resection | 195 | 99 | 100 | 54 | 60.0 | 85.6 | 73.0 | 85.5 | 70.7 | 55.5 | 46.1 | 56.4 | 47.3 |
| SBRT | 122 | 91 | 100 | 66 | 60.0 | 77.0 | 63.0 | 83.7 | 71.0 | 55.7 | 46.0 | 58.9 | 49.0 | |
| Maher et al. [24] (2024) | Resection | 25 | 100 | 100 | 100 | 23.1 | 100.0 | NR | NR | NR | 85.0 | NR | NR | NR |
| SBRT | 36 | 78 | 100 | 100 | 23.1 | 69.0 | NR | NR | NR | 67.0 | NR | NR | NR | |
| Lee et al. (present study) | Resection | 450 | 100 | 100 | 100 | 59.1 | 98.8 | 95.6 | 98.9 | 93.9 | 80.9 | 68.2 | 79.1 | 66.2 |
| SBRT | 87 | 94 | 100 | 100 | 41.2 | 92.3 | 86.0 | 96.2 | 95.5 | 64.9 | 60.6 | 74.1 | 73.4 | |
All included studies were retrospective cohort studies directly comparing hepatic resection and SBRT as first-line treatment. Unadjusted and propensity score-adjusted outcomes are presented where available.
NR, not reported; SBRT, stereotactic body radiation therapy.
Based on compelling evidence of robust local control across various malignancies, SBRT has gained growing recognition in the management of HCC, supported by several pivotal comparative studies with RFA [27–29]. In an international multicenter study of 2,064 patients with unresectable HCC, SBRT demonstrated significantly better local control compared to RFA (HR 0.45; p < 0.001), despite the SBRT cohort having larger tumors, poorer liver function, and more frequent prior liver-directed treatments [30]. More recently, the first phase III randomized controlled trial comparing SBRT and RFA for recurrent single HCC reported 2-year local progression-free survival rates of 92.7% with SBRT and 75.8% with RFA, yielding an absolute difference of 17% at 2 years (HR 0.45; p = 0.014) [11]. Similarly, comparative data between SBRT and TACE underscore the superior local control achieved with SBRT. A multicenter phase II randomized trial showed 2-year local control rates of 100% with SBRT versus 43.6% with drug-eluting bead TACE (p = 0.019) [31], corroborated by a recent meta-analysis reporting a pooled HR for local control of 0.25 (95% CI, 0.09–0.67; p = 0.006), favoring SBRT over TACE [32]. Importantly, SBRT has consistently demonstrated favorable toxicity profiles across contemporary studies, with grade ≥3 TRAEs occurring in fewer than 5% of patients, alleviating historical concerns regarding radiation-induced hepatic decompensation [33].
The rarity of in-field recurrence after SBRT in our cohort (1.1%) underscores its potent tumor-ablative efficacy, which is driven by unique radiobiological mechanisms that eradicate tumor cells through multiple direct and indirect pathways. High-dose radiation induces severe DNA damage, resulting in catastrophic mitotic failure and direct tumor cell death, while simultaneously causing endothelial apoptosis that disrupts tumor vasculature, triggers hypoxia, and leads to indirect cell death [34]. SBRT also promotes immunogenic cell death by releasing tumor-associated antigens and damage-associated molecular patterns, thereby enhancing antigen presentation, pro-inflammatory cytokine signaling, and the activation of cytotoxic CD8+ T cells [35]. These effects are particularly relevant in HCC, which typically develops in a chronically inflamed and cirrhotic liver characterized by an immunosuppressive microenvironment. Furthermore, this mechanism provides a biological rationale for combining SBRT with immune checkpoint inhibitors [36, 37]. Beyond these radiobiological effects, continuous technological advances have markedly refined SBRT delivery, incorporating 4D-CT simulation, sophisticated planning algorithms, real-time tumor tracking, and advanced motion-management techniques [38, 39]. Modern SBRT platforms now achieve highly conformal three-dimensional dose distributions with sub-centimeter precision, ensuring comprehensive tumor coverage while minimizing irradiation of surrounding normal tissues. Furthermore, the noninvasive nature and anatomical versatility of SBRT expand treatment eligibility to lesions in technically challenging locations for surgery or RFA and facilitate retreatment in cases of intrahepatic recurrence [40]. Collectively, these strengths suggest a potential role for SBRT in addressing therapeutic gray zones in current HCC guidelines. Although hepatic resection and RFA have long been the mainstays of treatment for very early-stage HCC, a substantial proportion of patients remain unsuitable for either modality, for whom SBRT may serve as a compelling alternative option [12]. Given the historical paucity of data in this setting, our findings have important clinical implications, highlighting the need to reposition SBRT within HCC treatment algorithms.
This study has several limitations. First, the retrospective design and the clinical practice of prioritizing hepatic resection and RFA inherently introduced selection bias. SBRT was generally reserved for patients who were ineligible for these modalities and often had less favorable baseline characteristics. Although IPTW adjustment was applied to mitigate measured baseline differences, liver cirrhosis remained imbalanced after weighting, and unmeasured confounding cannot be excluded. Second, institutional practices evolved over the study period, with SBRT being adopted more frequently in recent years. This temporal shift resulted in significant differences in follow-up duration and post-recurrence salvage patterns between groups. Third, all patients in the resection group had histologic confirmation of HCC, whereas only 2 patients (2.3%) in the SBRT group underwent tissue diagnosis, with the majority diagnosed based on characteristic findings on multiphase CT or MRI. Although this diagnostic approach aligns with guidelines, the possibility of overdiagnosis or misclassification in the SBRT group may have influenced recurrence estimates. Finally, direct comparison of safety profiles was limited by the use of different grading systems across treatment modalities and the potential under-reporting of minor events. Collectively, despite our statistical efforts including IPTW adjustment, these inherent limitations may have confounded the comparative outcomes, warranting cautious interpretation of these findings. Nonetheless, this study provides clinically meaningful evidence for SBRT, derived from a homogeneous cohort of treatment-naïve, very early-stage HCC patients. Our findings may inform clinical decision-making and guide the design of future prospective trials in this challenging patient population.
In conclusion, SBRT demonstrated robust oncologic outcomes comparable to hepatic resection in treatment-naïve patients with very early-stage HCC. After balancing baseline characteristics using IPTW adjustment, both modalities achieved similar OS, DFS, and recurrence rates with minimal adverse events. Given its noninvasive nature and anatomical versatility, SBRT may be considered a viable initial curative-intent alternative for carefully selected patients with very early-stage HCC, particularly those who are unsuitable for standard curative options.
Acknowledgement
We thank Dr. Joon Seo Lim from the Scientific Publications Team at Asan Medical Center for his editorial assistance in preparing this manuscript.
Statement of Ethics
This study protocol was reviewed and approved by the Institutional Review Board of Asan Medical Center, Seoul, Republic of Korea (IRB No. 2024-0942). The requirement for informed consent was waived by the Institutional Review Board due to the retrospective nature of the study.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
All authors had access to the study data and had reviewed and approved the final manuscript. Study design and conceptualization and supervision and administrative support: Sang Min Yoon and Gi-Won Song. Data acquisition: Hye In Lee, Jinhong Jung, Gil-Chun Park, Dong-Hwan Jung, Tae-Yong Ha, Deok-Bog Moon, Ki-Hun Kim, Chul-Soo Ahn, Shin Hwang, Ju Hyun Shim, Jin-hong Park, Gi-Won Song, Sang Min Yoon, and Sung-Gyu Lee. Data analysis and drafting of the manuscript: Hye In Lee. Critical revision of the manuscript for important intellectual content: Jinhong Jung, Gil-Chun Park, Dong-Hwan Jung, Tae-Yong Ha, Deok-Bog Moon, Ki-Hun Kim, Chul-Soo Ahn, Shin Hwang, Ju Hyun Shim, Jin-hong Park, Gi-Won Song, Sang Min Yoon, and Sung-Gyu Lee.
Funding Statement
This study was not supported by any sponsor or funder.
Data Availability Statement
The data that support the findings of this study are not publicly available because they contain information that could compromise the privacy of participants but are available from the corresponding authors upon reasonable request.
Supplementary Material.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are not publicly available because they contain information that could compromise the privacy of participants but are available from the corresponding authors upon reasonable request.