Radiation-induced Liver Disease Research Articles

Radiomics-Based Predictive Model of Radiation-Induced Liver Disease in Hepatocellular Carcinoma Patients Receiving Stereo-Tactic Body Radiotherapy.

(1) Background: The application of stereotactic body radiation therapy (SBRT) in hepatocellular carcinoma (HCC) limited the risk of the radiation-induced liver disease (RILD) and we aimed to predict the occurrence of RILD more accurately. (2) Methods: 86 HCC patients were enrolled. We identified key predictive factors from clinical, radiomic, and dose-volumetric parameters using a multivariate analysis, sequential forward selection (SFS), and a K-nearest neighbor (KNN) algorithm. We developed a predictive model for RILD based on these factors, using the random forest or logistic regression algorithms. (3) Results: Five key predictive factors in the training set were identified, including the albumin–bilirubin grade, difference average, strength, V5, and V30. After model training, the F1 score, sensitivity, specificity, and accuracy of the final random forest model were 0.857, 100, 93.3, and 94.4% in the test set, respectively. Meanwhile, the logistic regression model yielded an F1 score, sensitivity, specificity, and accuracy of 0.8, 66.7, 100, and 94.4% in the test set, respectively. (4) Conclusions: Based on clinical, radiomic, and dose-volumetric factors, our models achieved satisfactory performance on the prediction of the occurrence of SBRT-related RILD in HCC patients. Before undergoing SBRT, the proposed models may detect patients at high risk of RILD, allowing to assist in treatment strategies accordingly.

Stereotactic Ablative Body Radiotherapy as a Bridge to Liver Transplant for Hepatocellular Carcinoma: Preliminary Results of Başkent University Experience.

Hepatocellular carcinoma is the most common primary liver tumor, with curative treatment options being liver transplant and resection. However, approximately 20% to 30% of patients have substantial disease progression while awaiting transplant. Here, we report our initial experience on stereotactic ablative body radiotherapy as a bridge to liver transplant for patients with hepatocellular carcinoma. Seven patients with 9 lesions received stereotactic ablative body radiotherapy as a bridge treatment to transplant. All patients underwent radiofrequency ablation, transcatheter arterial chemoembolization, or hepatic resection before stereotactic ablative body radiotherapy. Magnetic resonance imaging was used to evaluate radiographic responses 1 month later. Median age of patients was 65 years (range, 63-71 years), median stereotactic ablative body radiotherapy dose was 45 Gy (range, 30-54 Gy; delivered in 3-5 fractions), and median tumor diameter was 17 mm (range, 12-30 mm). Before stereotactic ablative body radiotherapy, all patients underwent liver-directed therapies, including transcatheter arterial chemoembolization for 3 lesions, transcatheter arterial chemoembolization and radiofrequency ablation for 4 lesions, surgical resection for 1 lesion, and surgical resection plus transcatheter arterial chemoembolization for the remaining lesion. Patients showed no evidence of gastrointestinal toxicity or radiation-induced liver disease. Acute toxicity was negligible; all patients completed the treatment course. One month after stereotactic ablative body radiotherapy administration, response rates were assessed with magnetic resonance imaging, with complete responses obtained in 5 lesions (55.5%), partial responses for 2 lesions, and stable disease for 2 lesions. No disease progression was shown following stereotactic ablative body radiotherapy application. Stereotactic ablative body radiotherapy is an effective, safe, and tolerable bridging therapy option. Although we observed an early response after treatment, exact response rates will not be known for at least 3 months following stereotactic ablative body radiotherapy. Thus, our findings should be confirmed through additional prospective studies with longer follow-up.

Effects of image-guided adaptive radiotherapy combined with hepatic artery chemoembolization in primary liver cancer patients

ObjectiveThe study aimed to explore the effects of image-guided adaptive radiotherapy combined with hepatic artery chemoembolization on the immune function of primary liver cancer patients. MethodsThe study included 84 primary liver cancer patients who received treatment at our hospital between April 2018 and January 2020. They were divided into the control group (n=42, hepatic artery chemoembolization) and the study group (n=42, image-guided adaptive radiotherapy combined with hepatic artery chemoembolization) using the random number table method. AFP, ALT, AST, CA724, CA242 and immune function before and after treatment were compared in the two groups and the short-term efficacy and adverse events (AEs) were statistically analyzed. The two groups were followed up. ResultsAfter treatment, the study group had a higher ORR and DCR compared to the control group, and the difference was statistically significant (P < 0.05). There was no statistical difference in the levels of AFP, ALT, AST, CA724 and CA242 between the two groups before treatment (P > 05). After treatment, the study group had lower levels of AFP, ALT, AST, CA724 and CA242 than the control group, and the difference was statistically significant (P < 0.05). There was no statistical difference in the levels of CD4+, CD8+, and CD4+/CD8+ before treatment in the two groups (P > 05). After treatment, the study group had higher levels of CD4+ and CD4+/CD8+ but lower levels of CD8+ compared to the control group, and the difference was statistically significant (P < 0.05). In the study group, 2 patients developed radiation-induced liver disease, and the incidence was 4.76% (2/42), which occurred at 4 and 6 weeks after the end of radiotherapy, respectively. The patients mainly had elevated transaminases, ascites, and liver enlargement and hepatoprotection and nutritional support were provided, and the patients gradually recovered after treatment. There was no statistical difference in the incidence of AEs between the two groups (p > 0.05). All patients in the study completed follow up and the follow up completion rate was 100%. The median duration of follow up was 22.5 months. In the study group, 12 of 42 patients (28.57%) died and 21 cases (50.00%) had recurrence. In the control group, 21 of 42 cases (50.00%) died and 27 cases (64.29%) recurred. At 1 year, there was no statistical difference in ORR and DCR between the two groups (P > 0.05) and at 2 years, the study group had a higher ORR and DCR than the control group, and the difference was statistically significant (P < 0.05). ConclusionImage-guided adaptive radiotherapy combined with hepatic artery chemoembolization may improve the immune function of primary liver cancer patients and is of important clinical application value.

Stereotactic body radiation therapy as a salvage treatment for single viable hepatocellular carcinoma at the site of incomplete transarterial chemoembolization: a retrospective analysis of 302 patients

BackgroundTo evaluate the clinical outcomes of patients who received stereotactic body radiation therapy (SBRT) for single viable hepatocellular carcinoma (HCC) at the site of incomplete transarterial chemoembolization (TACE).MethodsPatients treated with SBRT for single viable HCC after incomplete TACE between 2012 and 2017 at Asan Medical Center (Seoul, South Korea) were included. Incomplete TACE was defined as (1) evidence of viable HCC at the site of TACE on follow-up dynamic computed tomography (CT) or magnetic resonance imaging following one or more consecutive TACEs, (2) no definite tumor staining on superselective hepatic angiogram, or (3) no definite iodized oil uptake on post-embolization angiogram or CT. Doses of 10–15 Gy per fraction were given over 3–4 consecutive days. The primary outcome was local control rate at 3 years and secondary outcome included tumor response, overall survival rate, out-of-field intrahepatic recurrence-free survival, distant metastasis-free survival and treatment-related toxicities. Treatment-related adverse events were evaluated according to the common terminology criteria for adverse events, version 4.03.ResultsA total of 302 patients were analyzed. The median follow-up duration was 32.9 months (interquartile range [IQR], 23.6–41.7) and the median tumor size was 2.0 cm (range, 0.7–6.9). The local control (LC) and overall survival rates at 3 years were 91.2 and 72.7%, respectively. 95.4% of the tumors reached complete response (CR) during the entire follow-up period (anyCR). The median interval from SBRT to anyCR was 3.4 months (IQR, 1.9–4.7), and 39.9 and 83.3% of the lesions reached CR at 3- and 6-months after SBRT, respectively. Radiation-induced liver disease was observed in 8 (2.6%) patients. No patients experienced gastroduodenal bleeding within the radiation field.ConclusionSBRT could be considered a feasible salvage treatment option for HCC after incomplete TACE.

A Rare Case of Radiation-Induced Liver Disease in Treated Abdominal Lymphoma Showing High [18F]FDG Avidity and Low EOB Uptake Proportional to the Irradiation Dose.

A 44-year-old woman presented with high [18F]FDG uptake liver lesion after six courses of R-CHOP and radiotherapy for abdominal DLBCL, which was misdiagnosed as a hepatic invasion. EOB–MRI showed slight T2 hyperintensity, low-intensity DWI, and decreased EOB uptake in the hepatocellular phase. Compared with the pretreatment planning CT, the liver lesion coincided with the area of >40.5 Gy, resulting in the diagnosis of RILD. At the follow-up [18F]FDG PET/CT 7 months after irradiation, the abnormal liver uptake disappeared. Comparing [18F]FDG PET/CT, EOB–MRI, and planning CT can lead to the correct diagnosis of RILD and avoid unnecessary biopsies and treatment changes.

Leveraging Blood-Based Diagnostics to Predict Tumor Biology and Extend the Application and Personalization of Radiotherapy in Liver Cancers.

While the incidence of primary liver cancers has been increasing worldwide over the last few decades, the mortality has remained consistently high. Most patients present with underlying liver disease and have limited treatment options. In recent years, radiotherapy has emerged as a promising approach for some patients; however, the risk of radiation induced liver disease (RILD) remains a limiting factor for some patients. Thus, the discovery and validation of biomarkers to measure treatment response and toxicity is critical to make progress in personalizing radiotherapy for liver cancers. While tissue biomarkers are optimal, hepatocellular carcinoma (HCC) is typically diagnosed radiographically, making tumor tissue not readily available. Alternatively, blood-based diagnostics may be a more practical option as blood draws are minimally invasive, widely availability and may be performed serially during treatment. Possible blood-based diagnostics include indocyanine green test, plasma or serum levels of HGF or cytokines, circulating blood cells and genomic biomarkers. The albumin–bilirubin (ALBI) score incorporates albumin and bilirubin to subdivide patients with well-compensated underlying liver dysfunction (Child–Pugh score A) into two distinct groups. This review provides an overview of the current knowledge on circulating biomarkers and blood-based scores in patients with malignant liver disease undergoing radiotherapy and outlines potential future directions.

Bridge-to-transplant stereotactic body radiation therapy in patients with hepatocellular carcinoma and advanced cirrhosis.

TPS496 Background: Liver cancer is the third most common cause of cancer related death worldwide, and hepatocellular carcinoma (HCC) accounts for 90% of all primary liver cancers, with pre-existing cirrhosis being a very strong risk factor for HCC development. Liver transplantation (LTx) is the best treatment for patients with HCC and advanced cirrhosis as both conditions can be very effectively treated at once. As LTx wait-lists can be many months, liver-directed therapies (LDT), including stereotactic body radiation therapy (SBRT) to one or few lesions are essential as oncologic temporizing measures to bridge patients to LTx and prevent progression outside of LTx criteria. However, due to the fear of further hepatic decompensation, many patients with advanced cirrhosis are excluded from receiving LDT. Rather, recent studies suggest that SBRT be of safe and practical use in this fragile patient population with advanced cirrhosis and HCC, and thereby reduce the rate of transplantation drop-out. This pilot prospective study will assess the feasibility, safety and efficacy of bridge-to-transplantation SBRT for patients with advanced cirrhosis and HCC. Methods: Patients with non-metastatic and unresectable HCC and Child-Pugh (CP)-B8 or worse cirrhosis who are within Milan criteria (one tumor ≤ 5 cm in diameter or no more than 3 tumors each ≤ 3 cm in diameter) and have been listed or recommended to be listed for liver transplantation will be eligible for participation. Eligible participants will undergo SBRT consisting of 40 Gy to be given in 5 fractions every other day to the only or largest lesion, provided that criteria for normal organ constraints are met. In cases where normal organ constraints are not met, the dose will be iteratively de-escalated to two dose levels (35 Gy in 5 fractions, then 30 Gy in 5 fractions). If normal organ constraints are unable to be met at 30 Gy in 5 fractions, the participant will be considered ineligible for SBRT and considered a screen failure. The primary endpoint is the proportion of participants who are transplanted or with localized disease control that meets Milan criteria within a year of SBRT. Secondary endpoints will include localized control rate (mRECIST), incidence of intra- or extra-hepatic progressive disease (mRECIST), overall survival, incidence of liver toxicity per CTCAE v5.0, incidence of non-classical radiation-induced liver disease (defined as CTCAE grade 4 AST/ALT elevation or an increase in CP score of ≥ 2 within 3 months of SBRT) and quality of life scores per QLQ-C30 and FACT-Hep questionnaires. The study is open, aiming to enroll 15 patients with 8 patients enrolled at time of submission. Clinical trial information: NCT03812289.

Effects of Radiation Dose on Liver After Free-breathing Volumetric Modulated Arc Therapy for Breast Cancer.

To evaluate the early effect of radiation dose on liver function in breast cancer patients undergoing free-breathing volumetric modulated arc therapy (FB-VMAT). Medical records of 125 patients with breast cancer who underwent curative surgery followed by postoperative radiotherapy using FB-VMAT during 2018-2021 were reviewed. Results of the liver function test (LFT), performed within 1-week before and 6-months after radiotherapy, were collected and compared. The LFTs analyzed albumin, total and direct bilirubin, aspartate transaminase, alanine transferase, and alkaline phosphatase levels. The mean dose and relative liver volume receiving at least 10 Gy, 20 Gy, or 30 Gy were calculated. Median follow-up time was 21.4 months. One patient experienced locoregional and distant failures. The mean liver irradiation dose was 325.9 centigray (cGy) for all patients. The liver irradiation dose was higher in patients with right breast cancer than in those with left breast cancer (mean, 434.1 cGy vs. 260.6 cGy, p<0.001). Direct bilirubin and aspartate transaminase levels showed significant differences after FB-VMAT. LFT results outside normal limits were noted in 31 patients at follow-up, but nobody met the criteria of radiation-induced liver disease. Underlying liver disease, breast laterality, systemic treatment, or dose-volume histogram parameters were not associated with abnormal LFT results. FB-VMAT can deliver radiation doses safely without adversely affecting the liver. The mean dose ≤4 Gy could be a useful dose criterium of the liver for FB-VMAT plans.

A new lightweight convolutional neural network for radiation-induced liver disease classification

Histopathological image analysis is used in the diagnosis of many diseases such as cancer, brain tumor, fatty liver and congenital heart diseases. In clinical practice, the time-consuming diagnostic process requires an expertise in the field, and disagreements can arise among pathologists at the decision stage. Machine learning methods can be used in diagnostic stage to overcome these issues. Especially, the use of deep learning systems in the analysis of histopathological images can reduce the workload of pathologists and can provide more objective results. Over traditional machine learning methods using handcrafted features, deep learning approaches that can automatically learn features stand out with their performance in the analysis of histopathology images. In this paper, we propose a patch-based lightweight convolution neural network for histopathological image classification for detecting radiation-induced liver damage. The proposed model was trained to classify the radiation-induced liver disease dataset comprising 555 histopathological images. An accuracy of 100% for binary classification and an accuracy of 87.57% for multi-class classification were achieved on the unseen test set. Our model outperforms state-of-the-art models, including ResNet-50, AlexNet, Vgg16, and GoogleNet. This paper is the first to classify radiation-induced liver disease data with deep learning, and it can be a promising tool for diagnosis purpose of pathologists. Since it is vital to detect a damage that leads to deteriorating liver function, this study is valuable in the field of medicine.

Clinical Values and Markers of Radiation-Induced Liver Disease for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus Treated With Stereotactic Body Radiotherapy.

BackgroundInformation about radiation-induced liver disease (RILD) in hepatocellular carcinoma (HCC) patients preexisting hepatitis B cirrhosis with portal vein tumor thrombus (PVTT) extended to the main portal vein treated with stereotactic body radiotherapy (SBRT) is still inadequate and the predictive markers for RILD have not been cleared in these patients. The aim of the study is to identify factors that can be used to predict RILD and to evaluate the influence of RILD in these patients.MethodsIn our study, 59 patients were analyzed and evaluated from December 2015 to June 2019, according to the entry criteria. After treatment, 59 patients were followed up within the first month and then every 3 months. Hematology test, tumor markers, three-phasic CT scan of the lungs, and CT or MRI scan of the liver were performed at each follow up.ResultsMedian overall survival time was 10.7 months (range, 5.8 to 14.9). RILD appeared in 17 of the 59 patients (28.8%) at the 3rd month after SBRT. In the univariate analysis, not only the CP score class (A or B) but also each different pretreatment CP score (p < 0.05) was a significant predictive factor of RILD. More RILD cases were detected with the increase of CP score. The recovery rate decreased as the baseline CP score increased (p < 0.05). It was found that the overall survival time was affected by only baseline CP score and RILD (p < 0.05).ConclusionsThe development of RILD has a dependency on the CP score in these patients. CP scores before treatment and RILD are significantly associated with overall survival. SBRT is an effective and safe method for patients with CP ≤ B7. For patients with CP-B8, liver function should be monitored more frequently. It is not safe enough for the SBRT treatment in CP-B9 patients.

Stereotactic body radiation therapy for primary liver tumors: An effective liver-directed therapy in the toolbox.

The use of radiation for primary liver cancers has historically been limited because of the risk of radiation-induced liver disease. Treatment fields have become more conformal because of several technical advances, and this has allowed for dose escalation. Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy, is now able to safely treat liver tumors to ablative doses while sparing functional liver parenchyma by using highly conformal therapy. Several retrospective and small prospective studies have examined the use of SBRT for liver cancers; however, there is a lack of well-powered randomized studies to definitively guide management in these settings. Recent advances in systemic therapy for primary liver cancers have improved outcomes; however, the optimal selection criteria for SBRT as a local therapy remain unclear among other liver-directed options such as radiofrequency ablation, transarterial chemoembolization, and radioembolization.

Granulocyte Colony-Stimulating Factor Treatment Before Radiotherapy Protects Against Radiation-Induced Liver Disease in Mice.

Radiation-induced liver disease (RILD) remains a major problem resulting from radiotherapy. In this scenario, immunotherapy with granulocyte colony-stimulating factor (G-CSF) arises as an attractive approach that might improve the injured liver. Here, we investigated G-CSF administration’s impact before and after liver irradiation exposure using an association of alcohol consumption and local irradiation to induce liver disease model in C57BL/6 mice. Male and female mice were submitted to a previous alcohol-induced liver injury protocol with water containing 5% alcohol for 90 days. Then, the animals were treated with G-CSF (100 μg/kg/d) for 3 days before or after liver irradiation (18 Gy). At days 7, 30, and 60 post-radiation, non-invasive liver images were acquired by ultrasonography, magnetic resonance, and computed tomography. Biochemical and histological evaluations were performed to verify whether G-CSF could prevent liver tissue damage or reverse the acute liver injury. Our data showed that the treatment with G-CSF before irradiation effectively improved morphofunctional parameters caused by RILD, restoring histological arrangement, promoting liver regeneration, preserving normal organelles distribution, and glycogen granules. The amount of OV-6 and F4/80-positive cells increased, and α-SMA positive cells’ presence was normalized. Additionally, prior G-CSF administration preserved serum biochemical parameters and increased the survival rates (100%). On the other hand, after irradiation, the treatment showed a slight improvement in survival rates (79%) and did not ameliorate RILD. Overall, our data suggest that G-CSF administration before radiation might be an immunotherapeutic alternative to radiotherapy planning to avoid RILD.

Dose-Effect Analysis of Radiation-Induced Liver Disease During Preoperative Chemoradiotherapy for Locally Advanced Gastric Cancer

PURPOSE/OBJECTIVE(S): to investigate the clinical and dose-volume factors of radiation-induced liver disease (RILD) during preoperative chemoradiotherapy for local advanced gastric adenocarcinoma, and provide a reference for optimization of the radiation plans.We retrospectively observed the clinical characteristics as well as dose-volume factors in a cohort of 190 patients with local advanced gastric adenocarcinoma in our hospital, including gender, age, treatment group, clinical TNM classification, primary tumor site, hepatitis, body mass index (BMI), alanine aminotransferase (ALT), alkaline phosphatase (ALP), serum albumin (ALB), total bilirubin (TBIL), activated partial thromboplastin time (APTT) from June 2013 to November 2020, based on an ongoing multicentric randomized phase III clinical trial (NCT01815853). There are 98 patients receiving chemotherapy (ChT, 3 cycles of XELOX regimen), and 99 patients receiving chemoradiation therapy (CRT, 1 cycle of induced XELOX regimen and 4500cGy/25f IMRT radiotherapy plus concurrent extenuated 2 cycles of XELOX regimen) before radical gastrectomy. The evaluation of RILD was performed based on clinical symptoms, Child-Pugh score system, Common Terminology Criteria of Adverse Event (CTCAE) 5.0 during preoperative treatment. ROC curves were used for appropriate cut-off values. Univariant and multivariant analysis were performed in dose-volume factors to find significant variables.In all of the patients, the incidence rate of RILD is 7.3%. With aid of supportive and symptom-eliminating treatments, all but one patient completed the assigned preoperative treatment. The RILD rate in the CRT group was higher than in ChT group (12.1% vs 2.2%, P = 0.009). As for the patients in CRT group, there were significant discrepancies in V3.5Gy (P = 0.017), V5Gy (P = 0.018), V10Gy (P = 0.033), V15Gy (P = 0.019), and borderline significance in the maximum dose (Dmax, P = 0.078) of liver between RILD patients and non-RILD patients in CRT group. Subsequent analysis showed that patients with the liver V3.5Gy (%) > 99.975%, liver V15Gy (%) > 66.470% had higher risk of RILD (OR: 5.797, P = 0.016; OR: 6.601, P = 0.023; respectively). However, V5Gy and V10Gy couldn't be considered as independent factors based on multivariant analysis (P = 0.757, P = 0.219, respectively), and the value of Dmax as independent prognostic factor was borderline significant (P = 0.050). There were no significant association between RILD and other clinical characteristics.Compared to chemotherapy, chemoradiation can increase the risk of RILD during preoperative treatment, but it's safe with regularly monitoring and appropriate treatment. Under the condition of the present liver-dose limitation, reduction of liver radiated volume in low dose (< = 15Gy) can eliminate the incidence rate of RILD. Besides, further studies are in need for the improvement for radiation plans of preoperative chemoradiation.

Prediction of Outcomes after Radiotherapy for Hepatocellular Carcinoma Independently Validated Using Multi-Institutional Data

Radiotherapy (RT) is increasingly used in advanced hepatocellular carcinoma (HCC), providing excellent local control. Regional and distant failures are common though, and radiation-induced liver disease (RILD) and post-RT lymphopenia have been shown to correlate with survival. In this study, we develop machine learning (ML) models to predict these endpoints and validate them using an independent dataset.We developed Cox regression and random survival forests to estimate survival, and both linear (logistic regression) and nonlinear discriminant ML models (support vector machines and gradient boosted trees) for four binary endpoints: 1-year survival, non-local failure within 1 year (NLF1y), RILD defined as 2+ increase in Child Pugh score and lymphopenia (count < 0.5 109/L). Metrics include c-index for survival analysis, area under the ROC curve (AUC) and accuracy in the 10/20% highest risk groups for discriminant analysis. The models training considered 21 clinical and dosimetric variables evaluated in a nested cross-validation approach for feature selection and hyperparameter tuning. After locking the models, we used an unseen independent dataset for external validation without any further calibration. A study analysis plan detailing methodology was published before access to the external validation set.207 HCC patients treated at a single institution between 2008 and 2019 were used for model training and 143 patients from a different institution for external validation. The survival models discriminated well between low- and high-risk groups (Harrell's c = 0.72), patients classified above median risk had a significantly higher risk of death (HR = 3.2 (95% CI [2.1-4.9]), P < 0.001) with 9.4 months observed median survival compared to 33.2 months for the low-risk group. Discriminatory power for top versus bottom survival quartile increased to HR = 6.1 [3.3-11], median survival 5.4 vs 42.5 months. Binary classification performance for all endpoints was consistent between training and validation with an external AUC of 0.79 for 1-year survival (internal 0.75), and 0.64-0.68 for the other endpoints (internal 0.53-0.71). The models predict NLF1y in high/very-high risk groups (87/100% accuracy) and lymphopenia in the very high-risk group (65-85% accuracy). Notably platelet count is selected by all generative classifiers of RILD, indicating interaction with known predictors.Independent validation of the models demonstrates the ability to accurately stratify patients by survival and discriminant endpoints with comparable performance on external validation, which underscores good generalizability. High prediction accuracy for sub-groups at high risk of non-local failure and lymphopenia could enable treatment modification in specific cases, while no approach reliably predicted RILD.

Toxicity and Dosimetric Parameters of Ablative Radiation Therapy in the Management of Patients with Child-Pugh B/C Liver Function and Unresectable Hepatocellular Carcinoma (HCC)

To date there is no clear standard non-surgical therapeutic option for HCC patients. Ablative radiation therapy (SBRT/HIGRT) is an emerging non-invasive treatment for patients with HCC. However, there is concern about the risk for radiation-induced liver toxicity following radiation in patients with decompensated liver function (Child-Pugh B/C).We retrospectively identified all patients with unresectable, non-metastatic HCC treated with SBRT/HIGRT and underlying Child-Pugh B or C liver function prior to radiation therapy at our University and Veterans Affairs (VA) radiation oncology departments from 2014 to 2019. Primary endpoints included treatment-related toxicity, as well as, evaluation of dosimetric parameters for OAR.38 patients (39 treatment courses) were included. Most patients (97%) had Child-Pugh B7-B9 (62% CP B7, 21% CP B8, 15% CP B9) or ALBI grade 2-3 (69% ALBI grade 2, 31% ALBI grade 3) liver disease prior to radiation therapy. A single patient had Child-Pugh C10 liver function. The most commonly utilized regimens include 50 Gy in either 5 or 10 fractions. The median delivered dose was 50 Gy (range 30-50) in an average of 7.5 fractions (range 5-10). Most patients had a single lesion (63%) with a median lesion size of 3.2 cm (range 1.10-7.40 cm). The mean liver dose was 9.40 Gy (range 3.38-23.94) with a liver D800cc of 4.14 Gy (range 0.35-17.31). All patients completed their intended treatment course with a median follow up of 43 months. Four (10.3%) treatment courses resulted in non-classical radiation-induced liver disease (RILD) (defined as an increase of 2 or more points in Child-Pugh score), compared to 8.3% for patients with Child-Pugh A liver function treated during a similar time period. Otherwise, one patient (2.6%) experienced acute grade 3+ (non-RILD) hepatobiliary toxicity (transient transaminitis). Two-year freedom from local progression was 73% (95% CI 37-90%), median overall survival 12 months (95% CI 5-25 months), and median progression free-survival was not reached.Ablative radiation therapy as definitive management for patients with unresectable, non-metastatic HCC appears to be reasonably well tolerated in patients with decompensated liver function at baseline (Child-Pugh B7-B9), with low rates of RILD and encouraging local control. With careful selection, these patients appear to be reasonable candidates for consideration of SBRT/HIGRT. Our analysis did not include enough patients with Child-Pugh C10+ disease to draw meaningful conclusions.

The Role of Hypofractionated Radiation Therapy in the Management of Unresectable Hepatocellular Carcinoma (HCC)

Management of HCC without surgical resection or transplantation is poorly defined with no standard. Stereotactic body radiation therapy (SBRT) or hypofractionated image-guided radiotherapy (HIGRT), is an evolving, non-invasive, therapeutic option for patients with HCC delivering ablative doses with modest toxicity.We retrospectively identified all patients with unresectable, non-metastatic HCC treated with SBRT/HIGRT who presented to our University and Veterans Affairs (VA) radiation oncology departments from 2013 to 2019. Primary study endpoints included freedom from local progression, progression free survival, overall survival, and treatment-related toxicity.149 patients were included in our analysis with median delivered radiation dose of 50 Gy in 5 fractions. This included a total of 172 treatment courses, as 21 patients received more than one course (19 patients received 2 courses; 2 patients received 3 courses). Twenty-two of the re-treatment courses were to previously unirradiated lesions, while one course was delivered to a previously treated lesion exhibiting local progression. Sixty-nine percent (69%) of patients were Child-Pugh A and 89% had a baseline ALBI grade of 1-2 prior to treatment. A majority of patients (59%) had a single lesion with a median size of 2.70 cm (Q1 2.00, Q3 3.95). Fifty-seven percent (57%) of patients received a biologically effective dose (BEDα/β = 10) of at least 75 Gy and 48% of patients had undergone prior liver-directed therapy. All patients completed their intended treatment course with 1 patient (0.7%) experiencing Grade 3+ acute and 4 patients (2.6%) experiencing Grade 3+ late toxicities. Fifteen treatment courses (8.7%) resulted in non-classical radiation-induced liver disease (RILD), defined as an increase of 2 or more points in Child-Pugh score following radiation. With median follow up of 40 months, median overall survival was 25 months (95% CI 18-30 months). The 2-year freedom from local progression was 75% (95% CI 65-83%) overall, 64% (95% CI 48-77%) among patients who received BED ≤75 Gy and 86% (95% CI 72-93%) among those who received BED > 75 Gy. Median progression free survival was not reached. During the study period, 8.1% of patients developed regional nodal progression and 18.8% developed distant metastatic disease (42.9% osseous, 50.0% lung, 46.4% soft tissue/peritoneal/other involvement; multiple patients with more than one site of metastatic involvement).SBRT/HIGRT results in high rates of local control with minimal treatment related toxicities. Randomized, prospective trials should seek to establish SBRT/HIGRT as a standard local therapeutic option for patients with unresectable, non-metastatic HCC.

Phase II Study of Concurrent Sorafenib and Radiotherapy for Advanced Hepatocellular Carcinoma With Portal Vein and/or Hepatic Vein Tumor Thrombosis

<h3>Purpose/Objective(s)</h3> Portal vein or hepatic vein tumor thrombosis is a leading predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). We conduct this phase II clinical trial to investigate the efficacy and safety of concurrent sorafenib and radiotherapy for advanced HCC with portal vein and/or hepatic vein tumor thrombosis. <h3>Materials/Methods</h3> We designed a single-arm, prospective phase II trial to evaluate median survival time (MST), overall response rate (ORR), time to progression (TTP) and toxicities in patients of HCC with portal vein and/or hepatic vein tumor thrombosis receiving concurrent sorafenib and radiotherapy. Eligibility criteria included the following: clinical or histologic diagnosis of HCC with portal vein or hepatic vein tumor thrombosis; liver-GTV > 700ml; and ECOG performance status score of 0 or 1 <b>etc</b>. Eligibility patients would receive radiotherapy to hepatic primary tumor and vein tumor thrombosis with concurrently sorafenib with a dose of 400mg twice daily. Prescription of radiotherapy would be a conventional fraction dose of 2-2.6Gy to a total dose of 40 to 65Gy to tumor. Sorafenib will be maintained with a dose of 400mg twice daily after radiotherapy until disease progression, or unacceptable adverse events. <h3>Results</h3> Between April 2018 and January 2020, a total of 86 eligible patients were enrolled. Seventy patients were with portal vein thrombosis, 5 patients were with hepatic vein tumor thrombosis, and 11 patients were with portal vein and hepatic vein tumor thrombosis. For portal vein thrombosis, 87.5% patients involved main trunk or first branches of portal vein. For hepatic vein tumor thrombosis, 43.8% patients involved inferior vena cava, and 2 patients involved right atrium. The median dose of radiotherapy was 54Gy (40-65Gy). ORR was 53.4% and disease control rate (DCR) was 76.6%. With a median follow-up of 24 months for living patients, MST and TTP was 16.8 months and 7.1 months, respectively. The 2-year local control rate for hepatic primary tumor and tumor thrombosis were 83.0% and 90.7%, respectively. Out-field recurrence in liver and distance metastasis were the main failure pattern. The 2-year out-field recurrence rate in liver and distance metastasis rate were 43.6% and 45.7%. Concurrent sorafenib and radiotherapy was well tolerated by patients. All patients were able to complete radiotherapy as planned. And 87.2% patients could complete concurrent sorafenib as a dose of 400mg twice daily. The most common grade 3 toxicities were thrombocytopenia (23.3%), leukopenia (14.0%), dermatitis (4.7%), anemia (3.5%), hand-foot syndrome (2.3%) and elevated alanine aminotransferase (2.3%). Classical or non-classical radiation-induced liver disease was not noted. <h3>Conclusion</h3> Concurrent sorafenib and radiotherapy is an effective, well tolerated and promising treatment in HCC patients with portal vein and/or hepatic vein tumor thrombosis. This trial was registered at ClinicalTrials.gov (number NCT03535259).

Uniform versus non-uniform dose prescription for proton stereotactic body radiotherapy of liver tumors investigated by extensive motion-including treatment simulations

Compared to x-ray-based stereotactic body radiotherapy (SBRT) of liver cancer, proton SBRT may reduce the normal liver tissue dose. For an optimal trade-off between target and liver dose, a non-uniform dose prescription is often applied in x-ray SBRT, but lacks investigation for proton SBRT. Also, proton SBRT is prone to breathing-induced motion-uncertainties causing target mishit or dose alterations by interplay with the proton delivery. This study investigated non-uniform and uniform dose prescription in proton-based liver SBRT, including effects of rigid target motion observed during planning-4DCT and treatment. The study was based on 42 x-ray SBRT fractions delivered to 14 patients under electromagnetic motion-monitoring. For each patient, a non-uniform and uniform proton plan were made. The uniform plan was renormalized to be iso-toxic with the non-uniform plan using a NTCP model for radiation-induced liver disease. The motion data were used in treatment simulations to estimate the delivered target dose with rigid motion. Treatment simulations were performed with and without a repainting scheme designed to mitigate interplay effects. Including rigid motion, the achieved CTV mean dose after three fractions delivered without repainting was on average (±SD) 24.8 ± 8.4% higher and the D98% was 16.2 ± 11.3% higher for non-uniform plans than for uniform plans. The interplay-induced increase in D2% relative to the static plans was reduced from 3.2 ± 4.1% without repainting to −0.5 ± 1.7% with repainting for non-uniform plans and from 1.5 ± 2.0% to 0.1 ± 1.3% for uniform plans. Considerable differences were observed between estimated CTV doses based on 4DCT motion and intra-treatment motion. In conclusion, non-uniform dose prescription in proton SBRT may provide considerably higher tumor doses than uniform prescription for the same complication risk. Due to motion variability, target doses estimated from 4DCT motion may not accurately reflect the delivered dose. Future studies including modelling of deformations and associated range uncertainties are warranted to confirm the findings.

Indications of IMRT, PRT and CIRT for HCC from comparisons of dosimetry and normal tissue complication possibility.

To identify the indications for hepatocellular carcinoma (HCC) irradiated by intensity-modulated photon radiotherapy (IMRT), proton radiotherapy (PRT) or carbon-ion radiotherapy (CIRT) by comparing of dosimetric parameters and incidences of classic radiation-induced liver disease (RILD). In all, 40HCCs were divided into groupA (tumors located > 1 cm away from gastrointestinal [GI] tract), and groupB (tumors located < 1 cm away from GI tract). The prescribed curative doses were 60 Gy (relative biological effectiveness [RBE]) in 10fractions for groupA, and 67.5 Gy (RBE) in 15fractions for groupB. IMRT, PRT and CIRT plans were separately generated to reach the curative doses and coverage. Dosimetric parameters evaluated were mean dose to normal liver (MDTNL) and the volume of normal liver receiving more than 1 Gy (RBE) (V1). Lyman-Kutcher-Burman model was used to determine the incidences of classic RILD, and Power model of non-linear regression, to estimate the tumor volume that could be irradiated with the curative doses within dose constraint of MDTNL. With comparable target doses, the MDTNL (Gy [RBE]) were 18.8 ± 3.7, 13.5 ± 3.1 and 12.8 ± 2.7 in groupA and 24.9 ± 7.1, 18.2 ± 3.7 and 17.5 ± 3.7 in groupB, respectively, for IMRT, PRT and CIRT. The classic RILD incidences (%) were 22.3 ± 30.0 in IMRT, 2.3 ± 4.9 in PRT and 1.2 ± 2.4 in CIRT. V1 (%) were 89.9 ± 8.8, 43.0 ± 10.2 and 45.9 ± 8.8, respectively, for IMRT, PRT and CIRT. PRT and CIRT could spare the liver more than IMRT. IMRT could deliver the curative doses to HCC up to adiameter of 7.9 cm; PRT, up to 13.2 cm; and CIRT, up to 14.8 cm.

ALKBH5-Modified HMGB1-STING Activation Contributes to Radiation Induced Liver Disease via Innate Immune Response.

Radiation therapy, which is vital for the treatment of primary liver cancer, comes with unavoidable liver injury, which limits its implementation. N6-methyladenosine (m6A) methylation is involved in many molecular functions. However, its role in radiation-induced liver diseases (RILD) remains unknown. Herein, we investigate the role of m6A methylation in RILD. Methylated RNA-immunoprecipitation sequencing and RNA transcriptome sequencing were used to reveal the methylation pattern of human hepatic stellate cells (HSCs) exposed to irradiation. C3H/HeN mice and stimulator of interferon genes (STING)-deficient mice underwent x-ray irradiation of 24 Gy in 3 fractions. The m6A methylation of the high-mobility group box 1 (HMGB1) transcript was validated using methylated RNA immunoprecipitation, RNA immunoprecipitation, luciferase assays, and a messenger RNA decay assay. Human hepatic stellate cells showed significant differences in methylation patterns after 8 Gy of x-ray irradiation. Irradiation recruited AlkB homolog 5 (ALKBH5) to demethylate m6A residues in the 3' untranslated region of HMGB1, which resulted in the activation of STING-interferon regulatory factor 3 signaling. Changes in the transcription of the 3' untranslated region of HMGB1 occurred after the knockdown of ALKBH5, which were eliminated after m6A residue mutation. Strikingly, ALKBH5 deficiency or HMGB1 silencing both attenuated type I interferon production and decreased hepatocyte apoptosis. In vivo depletion of ALKBH5 abolished the upregulation of HMGB1-mediated STING signaling and decreased liver inflammation, which was consistent with STING-/- mice treated with irradiation. Notably, YTHDF2 (m6A reader protein) directly bound to HMGB1 m6A-modified sites and promoted its degradation. ALKBH5-dependent HMGB1 expression mediates STING-interferon regulatory factor 3 innate immune response in RILD.