Stereotactic body radiotherapy versus intensity-modulated radiotherapy for hepatocellular carcinoma with portal vein tumor thrombosis

It is unclear whether robotic stereotactic body radiotherapy (SBRT) is superior to intensity-modulated radiotherapy (IMRT) in advanced hepatocellular carcinoma (HCC). This study aimed to compare the long-term outcomes of SBRT with those of IMRT in HCCs with portal vein tumor thrombosis (PVTT). We retrospectively evaluated 287 HCC patients with PVTT who underwent radiotherapy between January 2000 and January 2017. Of them, 154 and 133 patients were treated with IMRT and SBRT, respectively. Overall survival (OS), progression-free survival (PFS), intrahepatic control (IC), and local control (LC) were evaluated in univariable and propensity-score matched analyses. After matching, 102 well-paired patients were selected. There was no significant difference in the 6-, 12-, 24-, and 60-month cumulative OS (73.5, 42.9, 23.6, 7.6% vs. 72.4, 45.1, 29.8, 13.2%, p = 0.151), PFS (53.9, 29.3, 21.8, 7.5% vs. 54.5, 19.3, 12.0, 9.6%, p = 0.744), IC (61.4, 45.7, 39.0, 26.8% vs. 75.1, 45.8, 35.9, 28.7%, p = 0.144), and LC (85.2, 56.5, 52.1, 47.4% vs. 87.4, 65.2, 62.1, 62.1%, p = 0.191) between the IMRT and SBRT groups. A biologically effective dose assumed at an a/b ratio of 10 (BED10) of ≥ 100 Gy was the optimal cutoff for predicting the OS, PFS, IC, and LC in the patients who received SBRT. When high-precision tracking technology is available, SBRT appears to be a safe and more time-efficient treatment, achieving comparable OS, PFS, IC and LC to IMRT for local advanced HCC with PVTT. A BED10 ≥ 100 Gy is recommended if tolerated by normal tissue.


Introduction
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide [1]. Approximately 10-40% of patients with HCC have portal vein tumor thrombosis (PVTT) at diagnosis, classified as Barcelona Clinic Liver Cancer (BCLC)-C stage. If left untreated, the median survival time of HCC patients with PVTT is only 2.7-4.0 months [2]. Over the past decade, sorafenib has been the recommended first-line treatment for advanced HCC patients with BCLC-C stage [3]. However, the outcomes of these patients treated with sorafenib remain poor, with an extended survival of only 1.5-4.0 months [4,5]. Radiotherapy, such as three-dimensional radiotherapy and intensity-modulated radiotherapy (IMRT), has been increasingly applied in advanced HCC management. A randomized clinical trial by Yoon et al. [6] showed superior efficacy of trans-arterial chemoembolization (TACE) plus RT to sorafenib in HCC patients with PVTT, with significantly extended overall survival (OS). Treatment guidelines in the Asian region, such as in Korea and China, recommend radiotherapy as treatment for PVTT [7,8].
Stereotactic body radiation therapy (SBRT) achieves encouraging outcomes comparable to those of liver resection, radiofrequency ablation, and TACE in early-stage HCC [9][10][11]. For advanced HCC, Bettinger et al. [12] reported a considerable survival benefit of SBRT compared to sorafenib, extending OS to a median of 9.3 months. However, it is unclear whether SBRT is also superior to IMRT in advanced HCC. Thus, this study aimed to compare the longterm outcomes of SBRT with those of IMRT in advanced HCC with PVTT.

Study design and patients
This was a retrospective study of advanced HCC patients with PVTT who underwent external radiation therapy in China. The patients who underwent IMRT in Cancer Hospital during January 2000-January 2017 and the patients who underwent SBRT in Rui Kang Hospital during January 2009-January 2017 were included. The eligibility criteria were as follows: (1) advanced HCC with PVTT diagnosed via histopathology or according to the clinical criteria for HCC diagnosis [8]; (2) Eastern Cooperative Oncology Group score 0-2; (3) Child-Pugh class A (CP-A) or B (CP-B), (4) no concurrent systemic treatments, and (5) For patients who underwent radiotherapy as a combination therapy to TACE, RT was started within 2 to 4 weeks after TACE, as long as the liver function was stable without increased CP score and hepatic enzyme levels.

Hypofractionated intensity-modulated radiation therapy
All patients underwent plain and contrast-enhanced computed tomography (CT) scans in the supine position with both arms raised above the head for RT planning. Vacuum molds were used for patient immobilization. The CT images were acquired at 3-mm slice thickness in free quiet breathing mode. All target areas were sketched in the MIM 6.8 system (MIM, USA), and IMRT plans were generated using Pinnacle 3 system (Philips, Netherlands). The patients underwent hypofractionated IMRT using a linear accelerator with 6 MV X-rays (ELEKTA Synergy, Sweden).
Computerized tomography-magnetic resonance imaging (CT-MRI) fusion was performed to clearly show the intrahepatic lesion. The gross tumor volume (GTV) was defined by the hyperdense area of the intrahepatic primary tumor during the arterial phase and the hypodense filling defect area of the venous thrombus including PVTT during the venous phase. The clinical target volume (CTV) was 4-5 mm larger than the diameter of the tumor area and the distal end of the venous thrombus.
The planning target volume (PTV) was defined as the CTV plus an asymmetric 1-cm expansion in the cranialcaudal direction and 5-mm axially for setup uncertainty and respiratory motion. For both IMRT and SBRT, the PVTT was treated with the same dose as the primary tumor in the same patient. Hypofractionation was performed every other day (3-4 fractions a week). The final median radiation dose delivered to the isocenter was 51 Gy (range 30-60 Gy), with a median per dose of 4 Gy (range 2-7 Gy) and a median fraction of 12 (range 7-20). The median total irradiation time was 25 days (range 15-50 days).
The fraction doses were determined according to the following principles: 2-5 Gy/fraction for tumors larger than 5 cm in diameter and/or CP-B and more than 5-6 Gy/fraction for tumors less than 5 cm in diameter and/or CP-A. The dose is usually limited to 30-45 Gy for CP-B patients.

Stereotactic body radiation therapy
SBRT was delivered using the CyberKnife system (Accuray Inc., Sunnyvale, CA, USA) with tracking of liver motion using implanted fiducials. The simulation CT scan process and motion management were the same as those for IMRT. Seven days prior to the CT scan or MRI (slice thickness 3 mm), 3 to 4 fiducials (diameter 0.8 mm) were inserted into tumor tissue or into the surrounding area of the tumor under B-ultrasound or CT guidance. The definition of GTV was similar as that for the IMRT technique, and the CTV was equivalent to the gross tumor volume. GTV was expanded by 3-5 mm to establish the planning target volume (PTV), and this was usually decreased manually when the doselimiting organs overlapped.
SBRT was performed on consecutive days. The final median radiation dose delivered was 42 Gy (range 30-50 Gy), with a median per dose of 11 Gy (range 7-15 Gy) and a median fraction of 4 (range 3-5) with the median 66% (range 60-80%) isodose line, which covered > 97% PTV. The dose is usually limited to less than 30-40 Gy for CP-B patients. For all cases in both groups, the total dose was determined by the volume of the normal liver, CP-class, and the maximum dose to the stomach or duodenum. Treatment delivery and dose-volume constraints for organs at risk are shown in Table S1.

Response evaluation and follow-up
Patients were re-evaluated 1 month after treatment and subsequently every 3 or 6 months. Follow-up laboratory examinations included levels of alanine transaminase, aspartate transaminase, prothrombin time (PT), total bilirubin, albumin, and alpha-fetoprotein (AFP). Follow-up assessments also included CT or MRI at 1 month after the procedure and every 3-6 months thereafter.
Classic radiation-induced liver disease (c-RILD) was defined as an anicteric elevation in alkaline phosphatase levels of at least twofold the upper normal level and/or anicteric hepatomegaly and/or ascites within 2 weeks to 3 months after RT. Non-classic radiation-induced liver disease (nc-RILD) was defined as an elevation of liver transaminases more than 5 times the upper limit of normal or changes in CP class of ≥ 2 points within 3 months after RT. Patients with toxicity due to liver tumor progression were excluded.

Statistical analysis
Cumulative OS, progression-free survival (PFS), intrahepatic control (IC), and local control (LC) were calculated using the Kaplan-Meier method and compared using the log-rank test. OS was evaluated from the date of the first radiotherapy treatment to the date of any-cause death or the last follow-up. PFS was evaluated from the date of the first treatment to the date of any tumor recurrence, progression, or death or the date of censoring. IC was evaluated from the date of the first treatment to the date of intrahepatic failure (defined as the reappearance of radiologic hallmarks of HCC in the whole parenchyma of the liver including in-and out-field-treated lesions) or the date of censoring. LC was evaluated from the date of the first treatment to the date of infield recurrence. Categorical variables were compared using Pearson's chi-squared test, while continuous variables were compared using the Wilcoxon rank-sum test. Univariate and multivariate analyses were performed with the Cox proportional hazards model. The receiver operating characteristic (ROC) curve analysis was performed to determine the best cutoff value of BED 10 for the prediction of OS, PFS, LC, and IC.
To reduce potential selection bias and confounding effects of treatment, propensity score matching analysis (PSM) was applied. Patients in the SBRT and IMRT groups were matched in a 1:1 ratio using the nearest neighbor matching algorithm with a caliper of 0.2 without replacement. The propensity scores were calculated using a logistic regression model including the following variables: age, sex, bilirubinalbumin (ALBI) score, TACE, PT, alpha-fetoprotein level, and tumor size.

Patient characteristics
Overall, 287 patients were evaluated. Of them, 214 (74.6%) patients died, and 73 patients were right-censored. Table 1 shows the baseline characteristics of the SBRT group (n = 133) and the IMRT group (n = 154). Before propensity score matching, the proportion of patients with unfavorable baseline characteristics was higher in the SBRT group than that in the IMRT group, including combination TACE, older age, PT, albumin, ALBI score, and ALBI grade (all p < 0.05). After matching, 102 paired patients from the SBRT and IMRT groups were selected. The patient characteristics were well balanced between the two groups in the matched cohort.

Overall survival, progression-free survival, intrahepatic control, and local control
The median follow-up time was 31 months (range 3-84 months). Before propensity score matching, the median OS in the IMRT and SBRT groups was 10.0 vs. 10

Subgroup analysis by biologically effective dose
Univariable survival analysis showed that BED 10 was a prognostic factor for OS, PFS, IC, and LC. BED 10 was excluded from the multivariate analysis to avoid collinearity. Therefore, we further performed subgroup analyses by BED 10 . No optimal cutoff value was found in ROC analyses for the IMRT group. In ROC analyses of the matched cohort, the optimal cutoff for predicting OS, PFS, IC and LC of the SBRT group was 100 Gy (AUC = 0.601, Online Resource: Figure S1a In Kaplan-Meier analyses of the unmatched cohort, the 6-, 12-, 24-, and 60-month OS (87.5%, 61.5%, 46.2%, and 46.2% vs. 63%, 36.5%,22.6%, and 8.5%; p = 0.0078; Fig. 3a Fig. 3d) were significantly better in patients treated with a high BED 10 level (BED 10 ≥ 100 Gy) than in patients with a low BED 10 level (BED 10 < 100 Gy). The results of ROC analyses and Kaplan-Meier analyses with a BED 10 cutoff value of 100 Gy are shown in Online Resource: Table S3.

Discussion
With the improvement of precision radiotherapy techniques, robotic SBRT was widely used in the treatment of HCC. In the current study, SBRT achieved higher BED within fewer fractions and a shorter duration of treatment than IMRT but obtained comparable OS, PFS, IC, and LC. To the best of our knowledge, this is the first study to directly compare the efficacy of SBRT with that of hypofractionated IMRT in the treatment of HCC. Our results in both groups compared favorably to the published literatures [12][13][14][15][16][17][18][19][20][21] ( Table 2). The comparability of PFS and OS in our study may be because the therapeutic effect is actually the same, and not the artificial result of particularly poor or excellent IMRT and SBRT procedures. Similarly, Rim et al. [22] reported a comparable 1-year OS between 3-dimensional conformal RT and SBRT (48.5% vs 46.5%). Yang et al. [18] also showed a considerable survival benefit in SBRT compared to RT (1-and 2-year OS: 33.1% and 16.5% vs. 17.3% and 5.2%) in 140 patients with advanced HCC with PVTT. Consequently, it is plausible that SBRT is feasible for patients with PVTT, with acceptable toxicity and survival outcomes.
In the current study, the SBRT group received significantly higher BED 10 than did the IMRT group (median: 89.7 Gy vs. 72.8 Gy after matching, p < 0.001). Further, BED 10 ≥ 100 Gy was a favorable predicator of OS, PFS, IC, and LC for patients who underwent SBRT, while no optimal BED cutoff was identified for the IMRT group. After propensity score matching, 41 (40.2%) patients in the SBRT group experienced intrahepatic progression. The patients receiving BED 10 ≥ 100 Gy achieved better intrahepatic control and local control, along with better OS, PFS in the SBRT group, while the incidence of RILD in the BED ≥ 100 Gy group had no significant difference from that in the BED < 100 Gy group (4/25 vs. 8/108, p = 0.228). BED 10 ≥ 100 Gy was used to be considered as radiation "ablation" and associated with improved outcomes in multiple prior studies of HCC < 5 cm [23]. Our previous results also showed that an escalated dose (BED 10 ≥ 100 Gy) was a significant prognostic factor for HCC > 5 cm [24]. Scorsetti et al. [25] also reported that the 2-year in-field local control (100% vs 87%) and PFS (52.5% vs 17.3%) was higher for BED ≥ 100 Gy than for < 100 Gy. In a large-scale study of 456 patients by Robbins et al. [26], the median and 1year OS were 15.3 months and 56.6% for BED ≤ 75 Gy, 18.3 months and 67.5% for BED > 75 Gy and ≤ 100 Gy, and 37.2 months and 81.4% for BED > 100 Gy. In summary, our results may provide the rationale for using high BED (BED 10 ≥ 100 Gy) SBRT to treat HCC patients with PVTT if tolerated by normal tissue.
The toxicities were tolerable in both groups, and there was no difference in the rate of RILD (15/102 [14.7%] vs. 12/102 [11.8%], Chi-square p = 0.5). Our previous studies show V15 ≤ 21.5% and/or the absolute liver volume spared from at less 10 Gy (Vs10) ≥ 621.8 mL could improve the safety of SBRT in the treatment of HCC [27]. For hypofractionated treatment, mean normal liver doses of < 23 Gy and/or V20 < 48.5% were crucial for reducing the risk of RILD [28,29]. According to our previous experience, patients with CP-B class are at higher risk of RILD than those with CP-A; consistent findings were obtained in this study ( We have to acknowledge some limitations of our study. First, this was a retrospective and non-randomized study. Second, selection bias might have increased given the long study duration of 17 years (2000-2017). Third, we cannot account for the unknown differences between the two groups, such as the institutional experience, and the patient's

Conclusions
When high-precision tracking technology is available, SBRT appears to be a safe and more time-efficient treatment, achieving comparable OS, PFS, IC and LC to IMRT for local advanced HCC with PVTT. A BED 10 ≥ 100 Gy is recommended if tolerated by normal tissue.