Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Meta-Analysis and International Stereotactic Radiosurgery Society Practice Guidelines.

This systematic review and meta-analysis reports on outcomes and hepatic toxicity rates after stereotactic body radiation therapy (SBRT) for liver-confined hepatocellular carcinoma (HCC) and presents consensus guidelines regarding appropriate patient management. Using the Preferred Reporting Items for Systemic Review and Meta-Analyses guidelines, a systematic review was performed from articles reporting outcomes at ≥5 years published before October 2022 from the Embase, MEDLINE, Cochrane, and Scopus databases with the following search terms: ("stereotactic body radiotherapy" OR "SBRT" OR "SABR" OR "stereotactic ablative radiotherapy") AND ("hepatocellular carcinoma" OR "HCC"). An aggregated data meta-analysis was conducted to assess overall survival (OS) and local control (LC) using weighted random effects models. In addition, individual patient data analyses incorporating data from 6 institutions were conducted as their own subgroup analyses. Seventeen observational studies, comprising 1889 patients with HCC treated with ≤9 SBRT fractions, between 2003 and 2019, were included in the aggregated data meta-analysis. The 3- and 5-year OS rates after SBRT were 57% (95% confidence interval [CI], 47%-66%) and 40% (95% CI, 29%-51%), respectively. The 3- and 5-year LC rates after SBRT were 84% (95% CI, 77%-90%) and 82% (95% CI, 74%-88%), respectively. Tumor size was the only prognostic factor for LC. Tumor size and region were significantly associated with OS. Five-year LC and OS rates of 79% (95% CI, 0.74-0.84) and 25% (95% CI, 0.20-0.30), respectively, were observed in the individual patient data analyses. Factors prognostic for improved OS were tumor size <3 cm, Eastern region, Child-Pugh score ≤B7, and the Barcelona Clinic Liver Cancer stage of 0 and A. The incidence of severe hepatic toxicity varied according to the criteria applied. SBRT is an effective treatment modality for patients with HCC with mature follow-up. Clinical practice guidelines were developed on behalf of the International Stereotactic Radiosurgery Society (ISRS).

Radiotherapy plus anti-PD1 versus radiotherapy for hepatic toxicity in patients with hepatocellular carcinoma.

PURPOSE: In this study, we aimed to compare the radiation-induced hepatic toxicity (RIHT) outcomes of radiotherapy (RT) plus antibodies against programmed cell death protein 1 (anti-PD1) versus RT alone in patients with hepatocellular carcinoma (HCC), evaluate prognostic factors of non-classic radiation-induced liver disease (ncRILD), and establish a nomogram for predicting the probability of ncRILD. PATIENTS AND METHODS: Patients with unresectable HCC treated with RT and anti-PD1 (RT + PD1, n = 30) or RT alone (n = 66) were enrolled retrospectively. Patients (n = 30) in each group were placed in a matched cohort using propensity score matching (PSM). Treatment-related hepatotoxicity was evaluated and analyzed before and after PSM. The prognostic factors affecting ncRILD were identified by univariable logistic analysis and Spearman's rank test in the matched cohort to generate a nomogram. RESULTS: There were no differences in RIHT except for increased aspartate aminotransferase (AST) ≥ grade 1 and increased total bilirubin ≥ grade 1 between the two groups before PSM. After PSM, AST ≥ grade 1 occurred more frequently in the RT + PD1 group (p = 0.020), and there were no significant differences in other hepatotoxicity metrics between the two groups. In the matched cohort, V25, tumor number, age, and prothrombin time (PT) were the optimal prognostic factors for ncRILD modeling. A nomogram revealed a good predictive performance (area under the curve = 0.82). CONCLUSIONS: The incidence of RIHT in patients with HCC treated with RT + PD1 was acceptable and similar to that of RT treatment. The nomogram based on V25, tumor number, age, and PT robustly predicted the probability of ncRILD.

New Staging Model for Radiation-based Hepatocellular Carcinoma Treatment: A National Multicenter Study.

Background and Aims: The study aimed to create a new staging model for radiotherapy-based treatment for prognostic hepatocellular carcinoma (HCC) classification. Methods: The training cohort comprised 658 patients receiving stereotactic body radiotherapy and external validation cohort comprised 533 patients receiving three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. We established a modified staging system as follows: stage I, solitary nodule without macrovascular invasion, or 2-3 nodules no more than 3.0 cm apart, and performance status (PS) 0-2 (Ia: ALBI-1 grade; Ib: ALBI-2 or 3 grade); stage II: 2-3 nodules with any one nodule more than 3.0-cm apart, or ≥4 nodules, and performance status 0-2 (IIa: ALBI-1 grade; IIb: ALBI-2 grade); stage III: macrovascular invasion, regional lymph node metastasis or distant metastasis, and performance status 0-2 (IIIa: ALBI-1 grade; IIIb: ALBI-2 grade); stage IV: performance status 3-4, or performance status 0-2 with ALBI-3 grade. We analyzed long-term overall survival based on different stages. Results: The staging model showed an excellent ability to discriminate patients according to four stages and seven substages with notably different curves in the training and validation cohort. The median survival decreased from stages I to IV with 63.0 months in stage I (not reached in Ia, and 53.0 months in Ib), 24.0 months in stage II (28.0 months in IIa, and 22.0 months in IIb), 11.0 months in stage III (18.0 months in IIIa, and 9.0 months in IIIb), and less than 9.0 months in stage IV in the training cohort. Conclusions: The modified staging model may provide an alternative for clinical radiation oncologists.

Combining stereotactic body radiotherapy with camrelizumab for unresectable hepatocellular carcinoma: a single-arm trial.

PURPOSE: Stereotactic body radiotherapy (SBRT) may have significant immunomodulatory effects that enhance tumor response to immune checkpoint inhibitors. This phase 2 clinical trial was conducted to evaluate the safety and efficacy of combining palliative SBRT with camrelizumab (an anti-PD1 monoclonal antibody) in patients with unresectable hepatocellular carcinoma (uHCC). METHODS: Patients with uHCC, Child-Pugh A/B liver function, and at least one measurable lesion were enrolled between April 2020 and August 2022. Patients were administered 200 mg camrelizumab intravenously from the first day of palliative SBRT and then every 3 weeks. Palliative SBRT was delivered daily over five fractions per week, with a dose range of 30-50 Gy. The primary endpoints were objective response rate (ORR) and safety. This trial was registered at ClinicalTrials.gov (NCT04193696). RESULTS: Twenty-one patients were enrolled; the median radiation dose was 40 Gy, and the median number of cycles of camrelizumab was five. The ORR was 52.4%. After a median follow-up of 19.7 months, the median progression-free and overall survival were 5.8 and 14.2 months, respectively. The overall survival probability was 85.7% at 6 months, 76.2% at 9 months, and 59.9% at 12 months. All grade 3 treatment-related adverse events (TRAEs) occurred in five patients (23.8%) and were manageable. No grade 4/5 TRAEs were observed. CONCLUSION: Palliative SBRT plus camrelizumab showed promising antitumor activity against uHCC. Toxicities were manageable with no unexpected safety issues. This study provides evidence of a new therapeutic method for the treatment of uHCC.

Prediction of the Mechanism of Sodium Butyrate against Radiation-Induced Lung Injury in Non-Small Cell Lung Cancer Based on Network Pharmacology and Molecular Dynamic Simulations and Molecular Dynamic Simulations.

Background: Radiation-induced lung injury (RILI) is a severe side effect of radiotherapy for non-small cell lung cancer (NSCLC) ,and one of the major hindrances to improve the efficacy of radiotherapy. Previous studies have confirmed that sodium butyrate (NaB) has potential of anti-radiation toxicity. However, the mechanism of the protective effect of NaB against RILI has not yet been clarified. This study aimed to explore the underlying protective mechanisms of NaB against RILI in NSCLC through network pharmacology, molecular docking, molecular dynamic simulations and in vivo experiments. Methods: The predictive target genes of NaB were obtained from the PharmMapper database and the literature review. The involved genes of RILI and NSCLC were predicted using OMIM and GeneCards database. The intersectional genes of drug and disease were identified using the Venny tool and uploaded to the Cytoscape software to identify 5 core target genes of NaB associated with RILI. The correlations between the 5 core target genes and EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors were analyzed using TIMER 2.0, TIMER and TISIDB databases. We constructed the mechanism maps of the 3 key signaling pathways using the KEGG database based on the results of GO and KEGG analyses from Metascape database. The 5 core target genes and drug were docked using the AutoDock Vina tool and visualized using PyMOL software. GROMACS software was used to perform 100 ns molecular dynamics simulation. Irradiation-induced lung injury model in mice were established to assess the therapeutic effects of NaB. Results: A total of 51 intersectional genes involved in NaB against RILI in NSCLC were identified. The 5 core target genes were AKT1, TP53, NOTCH1, SIRT1, and PTEN. The expressions of the 5 core target genes were significantly associated with EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors, respectively. The results from GO analysis of the 51 intersectional genes revealed that the biological processes were focused on the regulation of smooth muscle cell proliferation, oxidative stress and cell death, while the three key KEGG pathways were enriched in PI3K-Akt signal pathway, p53 signal pathway, and FOXO signal pathway. The docking of NaB with the 5 core target genes showed affinity and stability, especially AKT1. In vivo experiments showed that NaB treatment significantly protected mice from RILI, with reduced lung histological damage. In addition, NaB treatment significantly inhibited the PI3K/Akt signaling pathway. Conclusions: NaB may protect patients from RILI in NSCLC through multiple target genes including AKT1, TP53, NOTCH1, SIRT1 and PTEN, with multiple signaling pathways involving, including PI3K-Akt pathway, p53 pathway, and FOXO pathways. Our findings effectively provide a feasible theoretical basis to further elucidate the mechanism of NaB in the treatment of RILI.

Efficacy and safety of radiotherapy plus anti-PD1 versus transcatheter arterial chemoembolization plus sorafenib for advanced hepatocellular carcinoma: a real-world study.

BACKGROUND: The combination of transcatheter arterial chemoembolization (TACE) plus sorafenib prolonged progression-free survival (PFS) and overall survival (OS) than sorafenib or TACE monotherapy for patients with hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of radiotherapy (RT) plus monoclonal antibody against programmed cell death 1 (anti-PD1) versus TACE plus sorafenib for patients with advanced HCC. METHODS: Patients with advanced HCC who treated with RT plus anti-PD1 and TACE plus sorafenib were enrolled. Objective response rate (ORR), PFS, disease control rate (DCR) and OS were calculated to assess the antitumor response and the treatment-related adverse events to the safety. RESULTS: Between January 2018 to March 2021, 37 patients underwent RT plus anti-PD1 and 41 patients underwent TACE plus sorafenib. The baseline characteristics between the two groups were comparable. The ORR and DCR were significantly higher in the RT + PD1 group than the TACE plus sorafenib group according to RECIST 1.1 (54.05% vs. 12.20%, P < 0.001; 70.27% vs. 46.37%, P = 0.041; respectively) and according to mRECIST (56.76% vs. 31.71%, P = 0.039; 70.27% vs. 46.37%, P = 0.041; respectively). RT plus anti-PD1 provided significantly better PFS (HR, 0.51; 95% CI 0.30-0.86; P = 0.017) than TACE plus sorafenib. Moreover, patients with RT plus anti-PD1 had significantly higher 3-, 6-, and 9-month OS rates than those with TACE plus sorafenib(97.3% vs. 92.30%, P < 0.001; 91.89% vs. 68.60%, P < 0.001; 75.5% vs. 60.60%, P < 0.001; respectively). The median OS was more favorable 17.4 months for the RT + PD1 group and 11.9 months for the TACE plus sorafenib group. No treatment-related death was observed. Grade 3 or more treatment-related adverse events (TRAEs) occurred significantly less in patients in the RT + PD1 group than the TACE plus sorafenib group (29.7% vs. 75.6%, P < 0.001), and all TRAEs were manageable. CONCLUSIONS: In this real-world study, RT plus anti-PD1 showed significantly promising efficacy and manageable safety than TACE plus sorafenib in patients with advanced HCC. Toxicities were manageable, with no unexpected safety signals. The study provides evidence on a new therapeutic method in the treatment of advanced HCC.

Effect of Body Composition on Outcomes in Patients with Hepatocellular Carcinoma Undergoing Radiotherapy: A Retrospective Study.

Computed tomography (CT)-assessed body composition is considered a novel prognostic factor for cancer patients. Owing to the need for new prognostic markers for hepatocellular carcinoma (HCC) patients undergoing radiotherapy, we investigated the impact of body composition on outcomes in this patient population. We retrospectively evaluated 109 HCC patients receiving radiotherapy. The skeletal muscle index, subcutaneous adipose tissue index (SATI), and visceral adipose tissue index within 1 mo, before radiotherapy were assessed based on a single CT image slice at the level of the third lumbar (L3) vertebra. The impact of body composition parameters on progression-free survival (PFS) and overall survival (OS) was assessed. Overall, 62 (56.9%) patients died, and 47 (43.1%) patients experienced recurrence during a median follow-up period of 20.5 mo. Multivariate analysis revealed that SATI was an independent prognostic factor for both PFS (hazard ratio [HR] 0.542, P = 0.025) and OS (HR 0.385, P = 0.005). Patients with high SATI (n = 43) had significantly better PFS (P = 0.0093) and OS (P = 0.032) than those with low SATI (n = 66). CT-assessed SATI is an independent prognostic factor in HCC patients receiving radiotherapy. Further validation is warranted to determine whether this finding can be translated into other study populations.

Chemoradiotherapy Versus Chemotherapy Alone for Advanced Esophageal Squamous Cell Carcinoma: The Role of Definitive Radiotherapy for Primary Tumor in the Metastatic Setting.

Introduction: The role of definitive radiotherapy in advanced esophageal squamous cell carcinoma (ESCC), especially in the metastatic setting, remains unclear. Therefore, we aimed to investigate the efficacy of chemoradiotherapy (CRT) versus chemotherapy (CT) alone in these selected patients. Methods: We retrospectively evaluated 194 newly diagnosed advanced ESCC who underwent definitive CRT or CT alone, including 97 patients with locally advanced and 97 patients with distant metastatic disease. Cumulative overall survival (OS) and progression-free survival (PFS) were evaluated with a log-rank test. Propensity score matching was used to simulate random allocation. In addition, we performed subgroup analysis in the locally advanced and metastatic disease. Results: After matching, 63 well-paired patients were selected. The adjusted median OS (12.5 vs. 7.6 months, p = 0.002) and PFS (9.0 vs. 4.8 months, p = 0.0025) in the CRT group were superior to that in the CT-alone group. Further subgroup analysis revealed that CRT conferred survival benefits to both locally advanced and metastatic cohorts. For patients with distant metastasis, median OS (12.9 vs. 9.3 months, p = 0.029) and PFS (9.9 vs. 4.0 months, p =0.0032) in the CRT group were superior to that in the CT-alone group. In a multivariate Cox regression analysis of the entire cohort, additional definitive radiotherapy was independently associated with better OS (p = 0.041) and PFS (p = 0.007). Conclusions: In both locally advanced and metastatic ESCC, additional definitive-dose radiotherapy was associated with improved clinical outcomes. Therefore, more consideration should be given to its application in the metastatic setting.

A Prospective Study of Liver Regeneration After Radiotherapy Based on a New (Su'S) Target Area Delineation.

BACKGROUND: In this study, we designed a new (Su'S) target area delineation to protect the normal liver during liver regeneration and prospectively evaluate liver regeneration after radiotherapy, as well as to explore the clinical factors of liver regeneration and established a model and nomogram. METHODS: Thirty patients treated with preoperative downstaging radiotherapy were prospectively included in the training cohort, and 21 patients treated with postoperative adjuvant radiotherapy were included in the validation cohort. The cut-off points of each optimal predictor were obtained using receiver-operating characteristic analysis. A model and nomogram for liver regeneration after radiotherapy were developed and validated. RESULTS: After radiotherapy, 12 (40%) and 13 (61.9%) patients in the training and validation cohorts experienced liver regeneration, respectively. The risk stratification model based on the cutoffs of standard residual liver volume spared from at least 20 Gy (SVs20 = 303.4 mL/m2) and alanine aminotransferase (ALT=43 u/L) was able to effectively discriminate the probability of liver regeneration. The model and nomogram of liver regeneration based on SVs20 and ALT showed good prediction performance (AUC=0.759) in the training cohort and performed well (AUC=0.808) in the validation cohort. CONCLUSIONS: SVs20 and ALT were optimal predictors of liver regeneration. This model may be beneficial to the constraints of the normal liver outside the radiotherapy-targeted areas.

Optimal stereotactic body radiotherapy dosage for hepatocellular carcinoma: a multicenter study.

BACKGROUND: The optimal dose and fractionation scheme of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) remains unclear due to different tolerated liver volumes and degrees of cirrhosis. In this study, we aimed to verify the dose-survival relationship to optimize dose selection for treatment of HCC. METHODS: This multicenter retrospective study included 602 patients with HCC, treated with SBRT between January 2011 and March 2017. The SBRT dosage was classified into high dose, moderate dose, and low dose levels: SaRT (BED10 ≥ 100 Gy), SbRT (EQD2 > 74 Gy to BED10 < 100 Gy), and ScRT (EQD2 < 74 Gy). Overall survival (OS), progression-free survival (PFS), local control (LC), and intrahepatic control (IC) were evaluated in univariable and multivariable analyses. RESULTS: The median tumor size was 5.6 cm (interquartile range [IQR] 1.1-21.0 cm). The median follow-up time was 50.0 months (IQR 6-100 months). High radiotherapy dose correlated with better outcomes. After classifying into the SaRT, SbRT, and ScRT groups, three notably different curves were obtained for long-term post-SBRT survival and intrahepatic control. On multivariate analysis, higher radiation dose was associated with improved OS, PFS, and intrahepatic control. CONCLUSIONS: If tolerated by normal tissue, we recommend SaRT (BED10 ≥ 100 Gy) as a first-line ablative dose or SbRT (EQD2 ≥ 74 Gy) as a second-line radical dose. Otherwise, ScRT (EQD2 < 74 Gy) is recommended as palliative irradiation.

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

BACKGROUND: 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). METHODS: 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. RESULTS: 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. 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 BED10 ≥ 100 Gy is recommended if tolerated by normal tissue.

Long-Term Survival Analysis of Transarterial Chemoembolization Plus Radiotherapy vs. Radiotherapy for Hepatocellular Carcinoma With Macroscopic Vascular Invasion.

Background: Macroscopic vascular invasion (MVI) is a terminal manifestation of hepatocellular carcinoma (HCC) and carries an extremely poor prognosis. In Chinese and Korean HCC guidelines, transarterial chemoembolization (TACE), or/and radiotherapy (RT) is adopted for treatment of MVI. In the current study, we aimed to compare the long-term outcome of TACE + RT to that of RT alone in patients with local advanced HCC with MVI. Methods: In this retrospective study, 148 treatment-naive patients of HCC with MVI were enrolled. Of the patients enrolled, 49 received TACE + RT treatment, whereas 99 patients received RT alone as a monotherapy. Overall survival (OS), progression-free survival (PFS), and intrahepatic control were evaluated using univariable and propensity score-matched analyses. Results: During follow-up, 126 patients (85.1%) died. The median follow-up time was 55.0 months in the RT group and 57.0 months in the TACE + RT group. The TACE + RT group showed better OS and PFS than the RT group, but intrahepatic control was comparable in these two groups. Of 41 cases well-pairs after propensity score matching, the associations between TACE + RT and better OS and PFS remained (15.0 vs. 8.0 months, and 8.0 vs. 4.0 months, all P < 0.05). The 1-, 2-, 3-, and 5-years OS rates in the TACE + RT group were 56.1, 28.6, 20.8, and 15.7 vs. 31.5%, 13.1%, 9.8%, and 6.7% in the RT group, respectively (P = 0.017). The 6-, 12-, and 24-months rates in the TACE + RT group were 51.2, 39.0, and 23.1% vs. 36.6%, 13.9%, and 11.1% in the RT group, respectively (P = 0.04). Two patients (4.1%) experienced radiation-induced liver disease (RILD), and one (2.0%) experienced RT-related gastrointestinal (GI) bleed in the TACE + RT groups. Nine patients (9.1%) experienced RILD, and two (2.0%) experienced RT-related GI bleed in the RT groups. Conclusion: Transarterial chemoembolization + RT had well-complementarity with no more complications than RT alone, providing a better PFS and OS compared with RT-alone treatment for HCC with MVI.

Stereotactic Body Radiation Therapy vs. Transarterial Chemoembolization in Inoperable Barcelona Clinic Liver Cancer Stage a Hepatocellular Carcinoma: A Retrospective, Propensity-Matched Analysis.

Background and Objective: It is unclear if stereotactic body radiation therapy (SBRT) or transarterial chemoembolization (TACE) is better for the treatment of inoperable early-stage hepatocellular carcinoma (HCC). This study aimed to retrospectively compare the efficacy of SBRT to TACE in patients with inoperable Barcelona Clinic Liver Cancer (BCLC)-A stage HCC. Materials and Methods: In this multi-institutional retrospective study, a total of 326 patients with inoperable BCLC-A stage HCC were enrolled. Totally, 167 patients initially received SBRT and 159 initially received TACE. Overall survival (OS), local control (LC), intrahepatic control (IC), and progression-free survival (PFS) were evaluated in univariable and propensity-score matched analyses. Results: There was a smaller median tumor size in the SBRT group than in the TACE group (3.4 cm vs. 7.2 cm, P < 0.001). After propensity score matching in the selection of 95 patient pairs, SBRT had better LC, IC, and PFS than TACE but showed comparable OS. The accumulative 1-, 3-, and 5-year OS rates were 85.7, 65.1, and 62.8% in the SBRT group and 83.6, 61.0, and 50.4% in the TACE group, respectively (P = 0.29). The accumulative 1-, 3-, and 5-year PFS were 63.4, 35.9, and 27.5% in the SBRT group and 53.5, 27.4, and 14.2% in the TACE group, respectively (P = 0.049). The accumulative 1-, 3-, and 5-year LC were 86.8, 62.5, and 56.9% in the SBRT group and 69.3, 53.3, and 36.6% in the TACE group, respectively (P = 0.0047). The accumulative 1-, 3-, and 5-year IC were 77.3, 45.9, and 42.4% in the SBRT group and 57.3, 34.1, and 17.7% in the TACE group, respectively (P = 0.003). On multivariate analysis, treatment (SBRT vs. TACE) was a significant covariate associated with local and intrahepatic control (HR = 1.59; 95% CI: 1.03-2.47; P = 0.04; HR = 1.61; 95% CI: 1.13-2.29; P = 0.009). Conclusions: SBRT was an alternative to TACE for inoperable BCLC-A stage HCC with better local and intrahepatic control. Controlled clinical trials are recommended to evaluate the actual effects of this novel regimen adequately.

Albumin - bilirubin (ALBI) versus Child-Turcotte-Pugh (CTP) in prognosis of HCC after stereotactic body radiation therapy.

BACKGROUND: Child-Turcotte-Pugh (CTP) score extensively used to assess hepatic function, predicting postoperative outcome of hepatocellular carcinoma (HCC) patients. Lately, the albumin-bilirubin (ALBI) grade has been identified to be a predictor of overall survival of HCC patients. In this investigation, we compared the pre-SBRT ALBI and CTP scores with the prognosis of patients with HCC. METHODS: This cohort study included 594 HCC patients who treated with SBRT. Overall survival (OS) rates were measured from treatment date to death date or last follow-up. We compared ALBI score with the CTP score in predicting long-term survival. RESULTS: The average follow-up time was 21 months (1 to 82 months). The CTP and ALBI ratings have discriminatory for long-term survival across the groups. CTP class was significantly related to OS, with a median OS of 29.9 months in CTP-A, 11.5 in CTP-B (P < 0.0001). ALBI grade is also significantly related to OS, with a median OS of 53.0 months in ALBI-1, 19.5 months in ALBI-2, and 6.5 months in ALBI-3(P < 0.0001). Within CTP-A class, CTP score-A5/A6 and ALBI grade has a similar predictive power (all P < 0.001). However, both CTP score and ALBI grade have no predictive power in CTP ≥ B7 class (all P>0.05). CONCLUSIONS: To assess liver dysfunction in HCC patients before SBRT, traditional CTP classification is a necessary but imperfect tool for assessing HCC liver injury. The ALBI score is a more objective, discriminatory and evidence-based approach in CTP-A groups, and need to be validated in CTP ≥ B7 class.

A prospective cohort study of hepatic toxicity after stereotactic body radiation therapy for hepatocellular carcinoma.

PURPOSE: To build and validate multivariate normal tissue complication probability (NTCP) models for radiation-induced hepatic toxicity (RIHT) after stereotactic body radiation therapy (SBRT). METHODS: Eighty-five patients with hepatocellular carcinoma (HCC) in a phase II clinical trial were enroled. A progression of at least 1 or 2 points in the Child-Pugh (CP) score post-SBRT was classified as RIHT (≥1 or ≥2). NTCP models for RIHT (≥1 or ≥2) were developed using logistic regression. Nomograms for each model were formulated. The cut-off point of each independent dosimetric risk factor was obtained using receiver-operating characteristic (ROC) analysis. We used an independent cohort (101 patients) for model validation. RESULTS: Twenty (23.5%) and 12 (14.2%) patients experienced RIHT (≥1) and RIHT (≥2), respectively. V15, VS10, and pretreatment CP (pre-CP) were the optimal predictors for RIHT (≥1 and ≥2) modelling. V15 ≤33.1% and VS10 ≥416.2 mL for RIHT (≥1), and V15 ≤21.5% and VS10 ≥621.8 mL for RIHT (≥2), were the cut-off points. Four NTCP models and their nomograms were generated. These models and nomograms showed good prediction performance (area under the curve (AUC), 0.83-0.89). Our NTCP model (RIHT ≥2) based on V15 plus pre-CP performed well (AUC = 0.78) in a validation cohort. CONCLUSION: V15, VS10, and pre-CP are crucial predictors for RIHT (≥1 and ≥2). Our NTCP models and nomograms were conducive to obtain individual constraints for patients with HCC. REGISTRATION NUMBER: ChiCTR-IIC-16008233.

Long-Term Survival Analysis of Stereotactic Ablative Radiotherapy Versus Liver Resection for Small Hepatocellular Carcinoma.

PURPOSE: To compare the efficacy of stereotactic ablative radiation therapy (SABR) versus liver resection for small hepatocellular carcinoma (HCC) ≤5 cm with Child-Pugh A cirrhosis. METHODS AND MATERIALS: This retrospective study included 117 patients with small HCCs with 1 or 2 nodules. Eighty-two patients received SABR (SABR group), and 35 patients underwent liver resection (resection group). Overall survival (OS) and progression-free survival (PFS) were analyzed. One-to-one matched pairs between the 2 groups were created using propensity score matching to reduce the potential confounding effect of treatment and selection bias. RESULTS: There was no between-group difference in OS and PFS. Before propensity score matching, the 1-, 3-, and 5-year OS was 96.3%, 81.8%, and 70.0% in the SABR group and 93.9%, 83.1%, and 64.4% in the resection group, respectively (P=.558). The 1-, 3- and 5-year PFS was 81.4%, 50.2%, and 40.7% in the SABR group and 68.0%, 58.3%, and 40.3% in the resection group, respectively (P=.932). After propensity score matching, 33 paired patients were selected from the SABR and resection groups. The 1-, 3-, and 5-year OS was 100%, 91.8%, and 74.3% in the SABR group and 96.7%, 89.3%, and 69.2% in the resection group, respectively (P=.405). The 1-, 3-, and 5-year PFS was 84.4%, 59.2%, and 43.9% in the SABR group and 69.0%, 62.4%, and 35.9% in the resection group, respectively (P=.945). There was a similarity of hepatotoxicity between the 2 groups. The SABR group showed fewer complications, such as hepatic hemorrhage, hepatic pain, and weight loss. Acute nausea was significantly more frequent in the SABR group than in the resection group. CONCLUSION: For patients with small primary HCC with 1 or 2 nodules and Child-Pugh A cirrhosis, SABR has local effects that are similar to those with liver resection. Stereotactic ablative radiation therapy has an advantage over resection in being less invasive.

Long-term survival analysis in combined transarterial embolization and stereotactic body radiation therapy versus stereotactic body radiation monotherapy for unresectable hepatocellular carcinoma >5 cm.

BACKGROUND: The survival following transarterial chemoembolization (TACE) alone is still low in unresectable hepatocellular carcinoma (HCC) with almost patients developing disease progression after treatment. There is need to investigate additional therapeutic options that would intensify the initial response to TACE. The present study was to retrospectively compare the outcome and evaluate the prognostic factors of stereotactic body radiation therapy (SBRT) alone or as an adjunct to transarterial embolization (TAE) or TACE in the treatment of HCC >5 cm. METHODS: From January 2011 to April 2015, 77 patients received SBRT followed by TAE or TACE (TAE/TACE + SBRT group) and 50 patients received SBRT alone (SBRT group). The dose of SBRT was 30-50 Gy which was prescribed in 3-5 fractions. Eligibility criteria were: a longest tumor diameter >5.0 cm and Child-Turcotte-Pugh (CTP) Class A or B. Exclusion criteria included tumor thrombus, lymph node involvement and extrahepatic metastasis. RESULTS: The median follow-up period was 20.5 months. Median tumor size was 8.5 cm (range, 5.1-21.0 cm). Median overall survival (OS) in the TAE/TACE + SBRT group was 42.0 months versus 21.0 months in the SBRT group. The 1-, 3- and 5-year OS was 75.5, 50.8, and 46.9 % in the TAE/TACE + SBRT group and was 62.4, 32.9, and 32.9 % in the SBRT group, respectively (P = 0.047). The 1-, 3- and 5-year distant metastasis-free survival (DMFS) was 66.3, 44.3, and 40.6 % in the TAE/TACE + SBRT group and was 56.8, 26.1, and 17.4 % in the SBRT group, respectively (P = 0.049). The progression-free survival (PFS) and local relapse-free survival (LRFS) were not significantly different between the two groups. In the entire patient population, a biologically effective dose (BED10) ≥100 Gy and an equivalent dose in 2 Gy fractions (EQD2) ≥74 Gy were significant prognostic factors for OS, PFS, LRFS and DMFS. CONCLUSIONS: SBRT combined with TAE/TACE may be an effective complementary treatment approach for HCC >5 cm in diameter. BED10 ≥100 Gy and EQD2 ≥74 Gy should receive more attention when the SBRT plan is designed.

Stereotactic body radiation therapy for small primary or recurrent hepatocellular carcinoma in 132 Chinese patients.

AIM: To evaluate the efficacy of stereotactic body radiation therapy (SBRT) in small hepatocellular carcinoma (HCC) patients. METHODS: From March 2009 to April 2015, we treated 132 small HCC patients with SBRT. Eligibility criteria included longest tumor diameter ≤5.0 cm; Child-Turcotte-Pugh (CTP) Class A or B; unfeasible, difficult or refusal to undergo other surgery or percutaneous ablative therapies; and tumor recurrence after other local treatment. The dose of 42-46 Gy in 3-5 fractions and 28-30 Gy in 1 fraction was prescribed. RESULTS: Of the treated patients, 114 were classified as CTP A and 18 as CTP B. Median tumor size was range 1.1-5.0 cm. The local control rate at 1 years was 90.9%. OS at 1, 3, and 5 years was 94.1%, 73.5%, and 64.3%, respectively. PFS at 1, 3, and 5 years was 82.7%, 58.3%, and 36.4%, respectively. Hepatic toxicity grade ≥3 was observed in 11 patients. Multivariate analysis revealed that CTP B was associated with worse OS (P < 0.001) and multiple nodules were associated with worse PFS (P = 0.001). CONCLUSIONS: SBRT is a promising alternative treatment for patients with primary or recurrent small HCC who are unsuitable for surgical resection or local ablative therapy.

Stereotactic body radiotherapy using CyberKnife for locally advanced unresectable and metastatic pancreatic cancer.

AIM: To evaluate the efficacy and toxicity of stereotactic body radiotherapy using CyberKnife for locally advanced unresectable and metastatic pancreatic cancer. METHODS: From June 2010 to May 2014, 25 patients with locally advanced unresectable and metastatic pancreatic cancer underwent stereotactic body radiotherapy. Nine patients presented with unresectable locally advanced disease and 16 had metastatic disease. Primary end-points of this study were overall survival, relief of abdominal pain, and toxicity. RESULTS: Fourteen patients were treated with a total dose of 30-36 Gy in three fractions and the remainder with 40-48 Gy in four fractions. Median follow-up was 11 mo (range: 2-25 mo). The median survival duration calculated from the time of stereotactic body radiotherapy for the entire group, the locally advanced group, and the metastatic group was 9.0 mo, 13.5 mo, and 8.5 mo, respectively. Overall survival was 37% and 18% at one and two years, respectively. Abdominal pain relief was achieved within 2 wk of completing radiotherapy in the patients who received successful palliation (13 of 20 patients had significant pain). Five patients (20%) had grade 1 nausea, and one (4%) had grade 2 nausea. No acute grade 3+ toxicity was seen. CONCLUSION: Stereotactic body radiotherapy using the CyberKnife system is a promising, noninvasive, palliative treatment with acceptable toxicity for locally advanced unresectable and metastatic pancreatic cancer.