Development and validation of a nomogram for radiation-induced hepatic toxicity after intensity modulated radiotherapy for hepatocellular carcinoma: a retrospective study.

OBJECTIVE: This study aimed to construct a nomogram to predict radiation-induced hepatic toxicity in patients with hepatocellular carcinoma treated with intensity-modulated radiotherapy. METHODS: This study reviewed the clinical characteristics and dose-volume parameters of 196 patients with hepatocellular carcinoma. Radiation-induced hepatic toxicity was defined as progression of the Child-Pugh score caused by intensity-modulated radiotherapy. Factors relevant to radiation-induced hepatic toxicity were selected using receiver operating characteristic and univariate logistic analysis. A risk assessment model was developed, and its discrimination was validated. RESULTS: Eighty-eight (44.90%) and 28 (14.29%) patients had radiation-induced hepatic toxicity ≥ 1 (Child-Pugh ≥ 1) and radiation-induced hepatic toxicity ≥ 2 (Child-Pugh ≥ 2). Pre-treatment Child-Pugh, body mass index and dose-volume parameters were correlated with radiation-induced hepatic toxicity ≥ 1 using univariate logistic analysis. V15 had the best predictive effectiveness among the dose-volume parameters in both the training (area under the curve: 0.763, 95% confidence interval: 0.683-0.842, P < 0.001) and validation cohorts (area under the curve: 0.759, 95% confidence interval: 0.635-0.883, P < 0.001). The area under the curve values of the model that was constructed by pre-treatment Child-Pugh, body mass index and V15 for radiation-induced hepatic toxicity ≥1 were 0.799 (95% confidence interval: 0.719-0.878, P < 0.001) and 0.775 (95% confidence interval: 0.657-0.894, P < 0.001) in the training and validation cohorts, respectively. Patients with a body mass index ≤ 20.425, Barcelona clinic liver cancer = C, Hepatitis B Virus-positive, Eastern Cooperative Oncology Group = 1-2 and hepatic fibrosis require lower V15 dose limits. CONCLUSIONS: Risk assessment model constructed from Pre-treatment Child-Pugh, V15 and body mass index can guide individualized patient selection of toxicity minimization strategies.

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.

The analgesic efficacy compared ultrasound-guided continuous transverse abdominis plane block with epidural analgesia following abdominal surgery: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: This review and meta-analysis aims to evaluate the analgesic efficacy of continuous transversus abdominis plane (TAP) block compared with epidural analgesia (EA) in adults after abdominal surgery. METHODS: The databases PubMed, Embase and Cochrane Central Register were searched from inception to June 2019 for all available randomized controlled trials (RCTs) that evaluated the analgesic efficacy of continuous TAP block compared with EA after abdominal surgery. The weighted mean differences (WMDs) were estimates for continuous variables with a 95% confidence interval (CI) and risk ratio (RR) for dichotomous data. The pre-specified primary outcome was the dynamic pain scores 24 h postoperatively. RESULTS: Eight trials including 453 patients (TAP block:224 patients; EA: 229 patients) ultimately met the inclusion criteria and seven trials were included in the meta-analysis. Dynamic pain scores after 24 h were equivalent between TAP block and EA groups (WMD:0.44; 95% CI: 0.1 to 0.99; I2 = 91%; p = 0.11). The analysis showed a significant difference between the subgroups according to regularly administering (4 trials; WMD:-0.11; 95% CI: - 0.32 to 0.09; I2 = 0%; p = 0.28) non-steroidal anti-inflammatory drugs (NSAIDs) or not (3 trials; WMD:1.02; 95% CI: 0.09 to 1.96; I2 = 94%; p = 0.03) for adjuvant analgesics postoperatively. The measured time of the urinary catheter removal in the TAP group was significantly shorter (3 trials, WMD:-18.95, 95% CI:-25.22 to - 12.71; I2 = 0%; p < 0.01), as was time to first ambulation postoperatively (4 trials, WMD:-6.61, 95% CI: - 13.03 to - 0.19; I2 = 67%; p < 0.05). CONCLUSION: Continuous TAP block, combined with NSAIDs, can provide non-inferior dynamic analgesia efficacy compared with EA in postoperative pain management after abdominal surgery. In addition, continuous TAP block is associated with fewer postoperative side effects.

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.

Comprehensive analysis of the role of Netrin G1 (NTNG1) in hepatocellular carcinoma cells.

Netrin G1 (NTNG1) is a member of the Netrin family and plays a crucial role in various human cancers. However, the molecular functions of NTNG1 in HCC and the underlying mechanisms remain unclear. HCC expression data was obtained from the GEO database and analyzed using various bioinformatics tools. The expression of NTNG1 in HCC tissues and liver cancer cells was evaluated through RT-qPCR and western blotting. Cells with stable NTNG1 overexpression and knockdown were established, and CCK-8, colony formation, and flow cytometry assays were conducted in vitro. The xenograft model was utilized to verify the tumorigenesis capacity of NTNG1 in vivo. IHC was employed to analyze the expression of NTNG1 and CD163 proteins. HCC-specific genes were screened, followed by functional enrichment and immune cell infiltration analysis. Finally, the Co-IP was used to detect the interaction between NTNG1 and N-cadherin. NTNG1 was highly expressed in HCC tissues and liver cancer cells, and associated with significantly poorer OS rates. In addition, NTNG1 overexpression in liver cancer cells significantly increased their proliferation, colony growth, invasion, migration, and EMT, while inhibiting apoptosis. Bioinformatics analyses indicated that NTNG1 was closely related to EMT and tumor infiltration. IHC staining revealed a positive correlation between NTNG1 expression and CD163 in HCC tissues. Additionally, an EMT inhibitor attenuated the expression levels of EMT-related markers and counteracted the effects of NTNG1 overexpression in liver cancer cells. This study is the first to identify NTNG1 as a potential therapeutic target in HCC, promoting tumor development and progression by regulating EMT.

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).

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.

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.

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.

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.

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.

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.

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.

Development and Validation of Multicenter Predictive Nomograms for Locally Advanced Pancreatic Cancer After Chemoradiotherapy.

OBJECTIVE: Due to common practice of hypofractionated radiotherapy in pancreatic cancer and heterogeneous chemotherapy regimens in previous studies, modified nomograms are required. Therefore, we aim to develop and validate prognostic nomograms for locally advanced pancreatic cancer (LAPC) after stereotactic body radiation therapy (SBRT) and chemotherapy. METHODS: The development cohort comprised 925 patients with LAPC receiving SBRT and gemcitabine-based chemotherapy in our center, while 297 patients from another two centers formed the validation cohort. Nomograms were created from COX models and internally validated by bootstrap. Model discriminations were evaluated by calibration plots and concordance index (C-index). A decision curve analysis (DCA) was performed to evaluate clinical benefits of nomograms. Additionally, recursive partitioning analysis (RPA) was used for stratifications of survival probability based on the total score of each patient calculated by nomograms. RESULTS: Weight loss, tumor diameter, radiation dose, CA19-9 kinetics after treatment and surgical resection were included in the nomogram for overall survival (OS), while the five factors plus performance status formed the nomogram for progression free survival (PFS). The corrected C-indexes for estimated 1-year and 2-year OS of the development cohort were 0.88 (95% CI: 0.85-0.91) and 0.86 (95% CI: 0.83-0.90). For those of the validation cohort, it was 0.88 (95% CI: 0.82-0.94) and 0.83 (95% CI: 0.74-0.91). Additionally, the corrected C-index for predicted 1-year PFS in the development and validation cohort was 0.83 (95% CI: 0.81-0.86) and 0.82 (95% CI: 0.78-0.87), respectively. The calibration plots showed good agreement of 1- and 2-year OS and 1-year PFS between the estimations and actual observations. Potential clinical benefits were demonstrated with DCA. Additionally, for 1- and 2-year OS and 1-year PFS, patients were stratified into four groups with different survival probability by RPA. CONCLUSION: The validated nomograms provided useful predictions of OS and PFS for LAPC with chemoradiotherapy.

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.

Development and Assessment of Novel Predictive Nomograms Based on APRI for Hepatitis B Virus-associated Small Solitary Hepatocellular Carcinoma with Stereotactic Body Radiotherapy.

Background: The correlation between serum inflammatory marker before treatment and the survival of patients with hepatitis B virus (HBV)-associated small solitary hepatocellular carcinoma (HCC) after stereotactic body radiotherapy (SBRT) remains unclear. The objective of our study is to estimate survival in such patients using multivariable prediction models and investigate the prognostic value of aspartate aminotransferase-to-platelet index (APRI), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) for HBV-associated small solitary HCC patients treated with SBRT. Patients and methods: Patients with HBV-associated small solitary HCC who were newly treated with SBRT were retrospectively analysed in our hospital from 2009 to 2016. We counted the APRI, NLR, PLR, and LMR before treatment and calculated their cut-off values for predicting overall survival (OS) and progression-free survival (PFS) by receiver operating characteristic (ROC) analysis. The random forest model combined with least absolute shrinkage and selection operator (LASSO) regression model for OS and PFS were used to screen potentially prognostic factors from serum inflammatory markers, demographic data, and clinical characteristics. Predictive models for OS and PFS were developed by multivariable COX regression and nomograms were constructed. Discrimination was assessed using the C-index. Internal validation was assessed using the Bootstrap method. Survival analysis was carried out to assess the prognostic value of serum inflammatory markers, and OS and PFS curves were compared by Kaplan-Meier analysis and Log-Rank test, respectively. Results: A total of 72 patients with HBV-associated small solitary HCC were recruited for the study. The median follow-up time was 2015 days (range, 232-3823 days). Age, tumor size, NLR, PLR, and APRI were used to construct nomogram for OS, while gender, age, TNM stage, portal hypertension, AFP, APRI were for PFS. The two models displayed good discriminations with C-indexes of 0.738 (95% CI: 0.632-0.844) and 0.657 (95% CI: 0.538-0.777), and their C-indexes in the internal validation cohort reached 0.790 (95% CI: 0.684-0.896) and 0.739 (95% CI: 0.619-0.859). The multivariable cox analysis indicated that APRI<0.47 was favourable independent prognostic factors for OS and PFS. Compared to APRI≥0.47, APRI<0.47 predicts better OS (p=0.003) and PFS (p=0.003). Conclusions: Nomograms based on APRI are superior in predicting OS and PFS in HBV-associated small solitary HCC patients who have received SBRT. APRI before treatment is a feasible and convenient prognostic indicator for OS and PFS, which helpfully determines the beneficial population of SBRT for HBV-associated small solitary HCC.

Failure patterns and outcomes of dose escalation of stereotactic body radiotherapy for locally advanced pancreatic cancer: a multicenter cohort study.

OBJECTIVE: This study aims to compare recurrence patterns and outcomes of biologically effective dose (BED10, α/ß = 10) of 60-70 Gy with those of a BED10 >70 Gy for locally advanced pancreatic cancer (LAPC). METHODS: Patients from three centers with a biopsy and a radiographically proven LAPC were retrospectively included and data were prospectively collected from June 2012 to June 2019. Radiotherapy was delivered by stereotactic body radiation therapy. Recurrences were categorized as in-field, marginal, and outside-the-field recurrence. Patients in two groups were required to receive abdominal enhanced contrast CT or MRI every 2-3 months and CA19-9 examinations every month during follow-up. Treatment-related toxicities were evaluated every month. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. RESULTS: After propensity score matching, there were 486 patients in each group. The median prescription dose of the two groups was 37 Gy/5-8 f (range: 36-40.8 Gy/5-8 f) and 42 Gy/5-8 f (range: 40-49.6 Gy/5-8 f), respectively. The median OS of patients with a BED10 >70 Gy and a BED10 60-70 Gy was 20.3 months (95% CI: 19.1-21.5 months) and 18.2 months (95% CI: 17.8-18.6 months) respectively (p < 0.001). The median PFS of the two cohorts was 15.4 months (95% CI: 14.2-16.6 months) and 13.3 months (95% CI: 12.9-13.7 months) respectively (p < 0.001). A higher incidence of in-field and marginal recurrence was found in patients with BED10 of 60-70 Gy (in-field: 97/486 versus 72/486, p = 0.034; marginal: 109/486 versus 84/486, p = 0.044). However, more patients with BED10 >70 Gy had grade 2 or 3 acute (87/486 versus 64/486, p = 0.042) and late gastrointestinal toxicities (77/486 versus 55/486, p = 0.039) than those with BED10 of 60-70 Gy. CONCLUSION: BED10 >70 Gy was found to have the best survival benefits along with a higher incidence of acute and late gastrointestinal toxicities. Therefore, a higher dose may be required in the case of patients' good tolerance.