Radiation-induced Hepatic Toxicity Research Articles

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

This study aimed to construct a nomogram to predict radiation-induced hepatic toxicity in patients with hepatocellular carcinoma treated with intensity-modulated radiotherapy. 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. 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. Risk assessment model constructed from Pre-treatment Child-Pugh, V15 and body mass index can guide individualized patient selection of toxicity minimization strategies.

The Current Evidence of Intensity-Modulated Radiotherapy for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Intensity-modulated radiotherapy (IMRT), an advanced RT technique, is a considerable treatment option for hepatocellular carcinoma (HCC). However, the distinguishing features of IMRT for HCC have not yet been clearly defined. A systematic review was performed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PubMed/MedLine, Embase, Cochrane Library, Web of Science, and KoreaMed were used to screen eligible studies focusing on treatment outcomes after IMRT for HCC until 18 April 2023. A total of 1755 HCC patients receiving IMRT among 29 studies from 2009 to 2023 were selected for the meta-analysis. The median proportion of Barcelona Clinic Liver Cancer stage C was 100% (range: 38-100%). Nineteen studies used combined treatment. Pooled rates of response and 1-year local control were 58% (95% confidence interval [CI], 50-65%) and 84% (95% CI, 70-94%), respectively. The median overall survival (OS) was 13 months (range: 5-45 months), and pooled 1- and 3-year OS rates were 59% (95% CI, 52-66%), and 23% (95% CI, 14-33%), respectively. Pooled rates of classic radiation-induced liver disease (RILD), nonclassic RILD, and hepatic toxicity ≥ grade 3 were 2%, 4%, and 4%, respectively. Although most patients had advanced-stage HCC and combined treatment was commonly used, IMRT for HCC showed similar survival to existing RT modalities and relatively low severe toxicity.

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

PurposeIn 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 methodsPatients 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.ResultsThere 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).ConclusionsThe 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.

Outcome of Postoperative Radiation Therapy for Cholangiocarcinoma and Analysis of Dose-Volume Histogram of Remnant Liver

There are few reports about tolerance dose of postoperative remnant liver. The aim of this study was to analysis dose-volume histogram (DVH) of the remnant liver for postoperative Cholangiocarcinoma (CCA) patients, to find toxicity rates, and to confirm the safety and efficacy of postoperative radiation therapy (RT). ALL thirty-two postoperative CCA patients received partial liver resection and postoperative RT with curative intent. The “liver reduction rate” was calculated by contouring liver volume at CT just before the surgery and at CT for planning the RT. To evaluate late toxicity, the radiation-induced hepatic toxicity (RIHT) was determined by CTCAE toxicity grade of bilirubin, AST, ALT, ALP, and albumin, and was defined from 3 months after RT until liver metastasis was revealed. The radiation-induced liver disease (RILD) was also evaluated. Tumor stages were distributed as follows: I: 1, II: 8, IIIA: 1, IIIB: 6, IIIC: 14, IVA: 2. Median prescribed total dose was 50 Gy. Median follow-up time was 27 months. Two-year overall survival (OS): 72.4%, disease-free survival: 47.7%, local control (LC): 65.3%, and the Median survival time was 40 months. The median “liver reduction rate” was 21%. The OS had statistically significant difference in nodal status (P=0.032) and “liver reduction rate” >30% (P=0.016). In the association between the ≥grade 2 RIHT and DVH, there were significantly differences in V30 and V40 (P=0.0041, P=0.0034), respectively. The grade ≥2 RIHT rates differ also significantly by sex (P=0.0084). Two patients (6.2%) were suspected RILD. This is the first report to analyze the tolerance dose or to report RILD and RIHT rates in the remnant liver after surgery for CCA. The postoperative RT showed good LC and acceptable intermediate-term tolerance. We suggest that RT for remnant liver should be considered the liver V30, V40 to prevent radiation-induced liver dysfunction.

Outcome of postoperative radiation therapy for cholangiocarcinoma and analysis of dose-volume histogram of remnant liver.

The aim of this study was to analyze dose-volume histogram (DVH) of the remnant liver for postoperative cholangiocarcinoma (CCA) patients, to find toxicity rates, and to confirm efficacy of postoperative radiation therapy (RT).Thirty-two postoperative CCA patients received partial liver resection and postoperative RT with curative intent. The "liver reduction rate" was calculated by contouring liver volume at computed tomography (CT) just before the surgery and at CT for planning the RT. To evaluate late toxicity, the radiation-induced hepatic toxicity (RIHT) was determined by the common terminology criteria for adverse events toxicity grade of bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, and albumin, and was defined from 3 months after RT until liver metastasis was revealed. The radiation-induced liver disease (RILD) was also evaluated.Tumor stages were distributed as follows: I: 1, II: 8, IIIA: 1, IIIB: 6, IIIC: 14, IVA: 2. Median prescribed total dose was 50 Gy. Median follow-up time was 27 months. Two-year overall survival (OS): 72.4%, disease-free survival: 47.7%, local control: 65.3%, and the median survival time was 40 months. The median "liver reduction rate" was 21%. The OS had statistically significant difference in nodal status (P = .032) and "liver reduction rate" >30% (P = .016). In the association between the ≥grade 2 RIHT and DVH, there were significantly differences in V30 and V40 (P = .041, P = .034), respectively. The grade ≥2 RIHT rates differ also significantly by sex (P = .008). Two patients (6.2%) were suspected of RILD.We suggest that RT for remnant liver should be considered the liver V30, V40 to prevent radiation-induced liver dysfunction.

Radioembolization-Induced Chronic Hepatotoxicity: A Single-Center Cohort Analysis.

To identify and characterize the delayed effects of transarterial radioembolization (TARE) on the liver. A single-institution retrospective analysis was undertaken of all patients who received TARE between 2005 and 2014 and survived at least 1 year from the initial TARE (n= 106). Patients were evaluated for the presence or absence of radioembolization-induced chronic hepatotoxicity (RECHT) occurring at least 6 months after TARE. The mean age of patients was 63 years of age, and the malignancy most commonly treated was neuroendocrine tumor (54%). Adjudication of hepatic decompensation to RECHT versus alternative causes was performed by a multidisciplinary panel of specialists from hepatology, radiation oncology, and interventional radiology. Eight patients were excluded from analysis because of liver transplantation (2) or incomplete data (6). RECHT occurred in 13 of 98 patients (13%), and 5 deaths (5%) occurred from hepatic decompensation. There were a total of 69 toxicity events in patients developing RECHT. The most common events were elevation of alkaline phosphatase (10), decrease in serum albumin (10), and development of ascites (9). RECHT patients had a higher intrahepatic tumor volume (P= .021) and a higher number of hepatic comorbidities leading to cirrhosis (P= .015). Delayed radiation-induced hepatic toxicity occurred in 13% of patients following radioembolization, with 5 fatalities adjudicated to be a result of the treatment. Tumor involvement of greater than 50% of the liver and cirrhosis were predisposing factors for RECHT.

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

PurposeTo build and validate multivariate normal tissue complication probability (NTCP) models for radiation-induced hepatic toxicity (RIHT) after stereotactic body radiation therapy (SBRT). MethodsEighty-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. ResultsTwenty (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. ConclusionV15, 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 NumberChiCTR-IIC-16008233.

Defining Radiation-Induced Hepatic Toxicity in Hepatocellular Carcinoma Patients Treated with Stereotactic Body Radiotherapy.

The definition and criteria of radiation-induced hepatic toxicity (RIHT) in hepatocellular carcinoma patients vary among studies. Therefore, the reported rates of RIHT differ among studies, and this causes confusion. In this study, we evaluated RIHT using several laboratory and clinical parameters, and analyzed which criterion is more correlated with RT and survival. Forty-five HCC patients treated with stereotactic body radiotherapy were included for the analysis. All patients had unresectable HCC and Child-Pugh (CP) class A or B baseline liver function. A median total dose of 45 Gy was delivered by CyberKnife in 3 fractions. For individual laboratory parameter, ≥ grade 2 toxicity development of bilirubin, albumin, or prothrombin time by Common Terminology Criteria of Adverse Effects (CTCAE) was correlated with mean liver dose and survival. However, serum transaminases had no correlation with liver mean dose and survival, and were rather affected by other local treatments. Compared to the CTCAE, the increase in the CP score of 2 points or more was better correlated with liver failure and overall survival, and it was not affected by other local treatments or tumor progression. We concluded RIHT was better defined by the change in the CP score rather than the CTCAE in patients treated by stereotactic body radiotherapy for HCC.

Effect of CyberKnife stereotactic body radiation therapy for hepatocellular carcinoma on hepatic toxicity.

ObjectiveTo evaluate the safety of CyberKnife stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) patients and identify the treatment-related risk factors of hepatic toxicity.Materials and methodsOne hundred and four HCC patients treated with CyberKnife SBRT were included in this study between August 2009 and December 2012. The average dose of prescribed radiation was 42.81±4.78 Gy (28–55 Gy) with the average fraction size of 8–16 Gy to the planning target volume. The average fractions were 3.31±0.81 (2–6 fractions). Response rates were determined, and the Child–Pugh (CP) score and class following CyberKnife SBRT were obtained to evaluate hepatic toxicity.ResultsSeventeen patients experienced progression in CP class and 24 patients experienced CTCAE V. 4.0 grade 2–3 hepatic toxicity during the five-month follow-up period, while no patient experienced grade 4 liver toxicity. Multivariate analysis indicated that only V25 was an independent factor in grade 2–3 hepatic toxicity (P=0.029, <0.05). Radiation-induced hepatic toxicity (RIHT), defined as an increase of at least two points within three months following CyberKnife SBRT, occurred in 13 of the 104 patients (13/104, 12.5%), and only the normal liver tissue was found to be associated with RIHT (P=0.008, <0.05).ConclusionCyberKnife SBRT is a feasible and safe treatment for HCC with regard to hepatic toxicity, while V25 and normal liver volume may be an independent factor of grade 2–3 hepatic toxicity and RIHT, respectively.

Defining the Radiation-Induced Hepatic Toxicity in Hepatocellular Carcinoma Patients Treated With Stereotactic Body Radiation Therapy

Defining the Radiation-Induced Hepatic Toxicity in Hepatocellular Carcinoma Patients Treated With Stereotactic Body Radiation Therapy

EP-1651: Reducing the probability of radiation-induced hepatic toxicity by changing the treatment modality

EP-1651: Reducing the probability of radiation-induced hepatic toxicity by changing the treatment modality

Identification of Biologically Effective Dose-Volumetric Parameters That Predict Radiation-Induced Hepatic Toxicity in Patients Treated With Helical Tomotherapy for Unresectable Locally Advanced Hepatocellular Carcinoma

The purpose of this study is to identify dose-volumetric parameters that predict radiation-induced hepatic toxicity (RIHT) by analyzing the relationship between the biologically effective dose (BED) delivered to the normal liver and RIHT.The clinical and dosimetric data from 123 patients with unresectable hepatocellular carcinoma (HCC) treated with helical tomotherapy were analyzed. The median radiation dose was a 50 Gy in 4.5 Gy fractions (range, 30–60 Gy in 1.8–5.0 Gy fractions) to 95% of the planning target volume. RIHT was defined as a Child-Pugh score increase of at least 2 points within 3 months of helical tomotherapy completion.RIHT developed in 60 patients (48.7%). Multivariate logistic regression analysis showed that VBED20 (percentage of nontarget normal liver volume that received more than a BED of 20 Gy) was a significant parameter (P < 0.001), and the cut-off value was 40.8% with a sensitivity and specificity of 0.833 and 0.698, respectively, according to the receiver operating characteristic curve (P < 0.001).Maintaining a VBED20 below 40.8% will reduce the risk of RIHT, and the proposed normal liver tolerance curve could be a useful guideline when treating unresectable HCC patients with various radiotherapy dose schedules.

Reducing the probability of radiation-induced hepatic toxicity by changing the treatment modality from helical tomotherapy to fixed-beam intensity-modulated radiotherapy.

To estimate and compare the risk of radiation-induced hepatic toxicity (RIHT) in helical tomotherapy and fixed-beam intensity-modulated radiotherapy (IMRT) for the treatment of hepatocellular carcinoma (HCC). Twenty patients with unresectable HCC treated with tomotherapy were selected. We performed tomotherapy re-planning to reduce the non-target normal liver volume receiving a dose of more than 15 Gy (NTNL-V15Gy), and we created a fixed-beam IMRT plan (FB-P). We compared the dosimetric results as well as the estimated probability of RIHT among the tomotherapy initial plan (T-IP), the tomotherapy re-plan (T-RP), and the FB-P. Comparing the T-RP and FB-P, the homogeneity index was 0.11 better with the T-RP. However, the mean NTNL-V15Gy was 6.3% lower with the FB-P. These differences result in a decline in the probability of RIHT from 0.216 in the T-RP to 0.115 in the FB-P. In patients whose NTNL-V15Gy was higher than 43.2% with the T-RP, the probability of RIHT markedly reduced from 0.533 to 0.274. By changing the treatment modality from tomotherapy to fixed-beam IMRT, we could reduce the liver dose and the probability of RIHT without scarifying the target coverage, especially in patients whose liver dose is high.

Significance of an increase in the Child-Pugh score after radiotherapy in patients with unresectable hepatocellular carcinoma.

BackgroundWe attempted to analyze the effects of an increase in the Child-Pugh (CP) score on the overall survival of patients with unresectable hepatocellular carcinoma (HCC) after radiotherapy (RT).MethodsFrom March 2006 to February 2012, 103 patients received RT using the TomoTherapy Hi-Art at Incheon St. Mary’s Hospital and Seoul St. Mary’s Hospital. The dose per fraction was 1.8–5 Gy, and the total dose was 40–60 Gy (median, 50 Gy). We considered an increase of at least 2 points in the CP score within 3 months after RT to be clinically important radiation-induced hepatic toxicity and analyzed the effects of an increased CP score on overall survival.ResultsThe median follow-up duration was 11.6 months (range, 3.5–85.3 months). The median survival time was 11.6 months. In multivariate analysis, planning target volume and an increase in the CP score after RT were found to be a statistically significant factors (p = 0.010 and 0.015, respectively). In a comparison of cases with and without an increase in the CP score, there was an 11.0-month difference in the median survival time (6.9 vs. 17.9 months), and the relative risk of mortality was 1.8.ConclusionAn increase of at least 2 points in the CP score within 3 months of RT completion is an important on-treatment factor that affects overall survival. To minimize such increases, careful patient selection and a more sophisticated radiation treatment plan are imperative.

Determination of the α/β ratio for the normal liver on the basis of radiation-induced hepatic toxicities in patients with hepatocellular carcinoma

BackgroundThe purpose of this study was to determine the α/β ratio for normal liver with hepatitis by analyzing the toxicity data from patients with unresectable hepatocellular carcinoma treated with helical tomotherapy.MethodsBetween March 2006 and February 2012, 98 patients were eligible for this study. 66 patients received 45–50 Gy in 4.5-5 Gy fractions (Group A) and 32 patients received 36–60 Gy in 2.5-3 Gy fractions (Group B). Radiation-induced hepatic toxicity was defined as an increase of at least 2 points in the Child-Pugh score within 4 months of completing helical tomotherapy. We attempted to find the statistically significant parameters in the 2 groups using α/β ratios of 2, 4, 6, 8, or 10, and compared the estimated probability curves of each significant parameter. We hypothesized that the α/β ratio associated with the best matches for the curves between the 2 groups would be equivalent to the α/β ratio for the normal liver.ResultsWhen using an α/β ratio of 2 or 4, different parameters were found to be statistically significant in a multivariate analysis (Group A: VBED30 for α/β ratio = 2 and VBED25 for α/β ratio = 4, Group B: VBED25 for α/β ratio = 2 and VBED20 for α/β ratio = 4). When using an α/β ratio of 6, 8, or 10, VBED20 was found to be a statistically significant parameter in both groups. Comparison of the estimated probability curve of each significant parameter between the groups revealed that an α/β ratio of 8 resulted in the best matches.ConclusionsWe suggest that the α/β ratio of the normal liver with hepatitis is 8. We hope that previously reported parameters and their values can be effectively used in different fractionation schemes by calculating the biologically effective dose using an α/β ratio of 8.

Dosimetric parameter predicting the deterioration of hepatic function after helical tomotherapy in patients with unresectable locally advanced hepatocellular carcinoma

BackgroundThe purpose of this study was to identify parameters capable of predicting the deterioration of hepatic function after helical tomotherapy in patients with unresectable locally advanced hepatocellular carcinoma.MethodsBetween March 2006 and February 2012, 72 patients were eligible for this study. All patients received hypofractionated radiotherapy using the TomoTherapy Hi-Art (TomoTherapy, Madison, WI, USA) at Seoul St. Mary's Hospital and Incheon St. Mary's Hospital, the Catholic University of Korea. The radiation dose was a median 50 Gy (range: 40–50 Gy) in 10 fractions to 95% of the planning target volume. Radiation-induced hepatic toxicity was defined as an increase of at least 2 points in the Child-Pugh (CP) score within 3 months after completion of helical tomotherapy.ResultsAn increase of at least 2 points in the CP score occurred in 32 of the 72 patients (44.4%). Multivariate logistic regression analysis revealed that pretreatment CP class and V15Gy were significant parameters associated with an increase in CP score (p = 0.009 and p < 0.001, respectively). The area under receiver operating characteristic curve was 0.863 for V15Gy (p < 0.001). For V15Gy, with a cutoff value of 43.2%, the accuracy was 0.806 (58/72) with a sensitivity of 0.938 and a specificity of 0.725.ConclusionsAn increase of at least 2 points in the CP score is a radiation dose-limiting factor, and the non-target normal liver receiving a dose more than 15 Gy (V15Gy) should be <43.2% to reduce the risk of the deterioration of hepatic function.

Protective Effect of Lycopene against Radiation-Induced Hepatic Toxicity in Rats

The radioprotective effect of lycopene against liver damage was investigated in 80 female Sprague Dawley rats (10 per group). Early-group rats included: controls (group 1), lycopene (group 2), radiotherapy alone (group 3), and lycopene + radiotherapy (group 4). Lycopene (5 mg/kg per day) was administered orally for 7 days; single-fraction 8 Gy abdominopelvic radiotherapy was administered on day 8. Early-group rats were sacrificed on day 10. Late-group rats (groups 5-8) underwent treatment with the same regimens but, in groups 6 and 8, lycopene was administered until all rats were sacrificed, 60 days postradiotherapy. Liver malondialdehyde levels increased significantly and glutathione (GSH) levels, GSH-peroxidase (GSH-Px) and superoxide dismutase (SOD) activity decreased significantly in radiotherapy versus control groups. In lycopene + radiotherapy groups, malondialdehyde levels decreased significantly and GSH levels, GSH-Px and SOD activity increased significantly compared with radiotherapy groups. No significant between-group histo pathological differences were observed in early groups; in late groups, histopathological changes increased significantly in the radiotherapy group versus control group. A significant decrease in histopathological changes occurred in the lycopene + radiotherapy group compared with the radiotherapy group. Lycopene supplementation significantly reduced radiotherapy-induced oxidative liver injury.

Stereotactic Body Radiotherapy for Patients With Unresectable Primary Hepatocellular Carcinoma: Dose-Volumetric Parameters Predicting the Hepatic Complication

To identify the parameters that predict hepatic toxicity and deterioration of hepatic function. A total of 47 patients with small unresectable primary hepatocellular carcinoma received hypofractionated stereotactic body radiotherapy (SBRT) using the CyberKnife. Of those, 36 patients received no other local treatments that could influence hepatic toxicity at least for 3 months after the completion of SBRT. The gross tumor volume (GTV) was 18.3 ± 15.9 cm(3) (range, 3.0-81.3 cm(3)), and the total dose administered was 30-39 Gy (median, 36 Gy). To assess the deterioration of hepatic function, we evaluated the presence or absence of the progression of Child-Pugh class (CP class). To identify the parameters of predicting the radiation-induced hepatic toxicity and deterioration of the hepatic function, several clinical and dose-volumetric parameters were evaluated. Of 36 patients, 12 (33%) developed Grade 2 or higher hepatic toxicity and 4 (11%) developed progression of CP class. The multivariate analysis showed that the only significant parameter associated with the progression of CP class was the total liver volume receiving a dose less than 18 Gy (<18 Gy). The progression of CP class after SBRT limits other additional local treatments and also reflects the deterioration of hepatic function. Therefore, it would be important to note that the presence or absence of the progression of CP class is a dose-limiting factor. The total liver volume receiving <18 Gy should be greater than 800 cm(3) to reduce the risk of the deterioration of hepatic function.

Identification of Proteins Indicating Radiation-induced Hepatic Toxicity in Cirrhotic Rats

Radiation therapy (RT) has been emerging as one of the palliative treatments for locally advanced hepatocellular carcinoma (HCC). However, hepatic toxicity is a major obstacle in radiotherapy for HCC. The purpose of this study is to identify proteins indicating radiation-induced hepatic toxicity in cirrhotic rats, which can be used as possible biomarkers. Liver cirrhosis was induced in Wistar rats with thioacetamide (TAA) 0.3 g/L in drinking water for 9 weeks. The development of liver cirrhosis was observed histologically. Radiation hepatic injury was induced by treating 1/3 of the liver with 10 Gy single dose radiation. To find out commonly expressed proteins, liver tissue and serum were analyzed using two-dimensional electrophoresis and quadrupole time of flight mass spectrometry. Identified proteins were validated using western blotting. Histological examination showed that the degree of hepatic fibrosis increased by radiation in liver cirrhosis. It was associated with a decrease in the proliferation of cell nuclear antigen and an increase of apoptosis. The proteomic analysis of liver tissue and serum identified 60 proteins which showed significant change in expression between the TAA-alone and TAA-plus-radiation groups. Among these, an increase of heparanase precursor and decrease of hepatocyte growth factor were shown commonly in liver tissue and serum following radiation. Hepatic fibrosis increased following radiation in cirrhotic rats. These proteins might be useful in detecting and monitoring radiation-induced hepatic injury.

Dose–volumetric parameters predicting radiation-induced hepatic toxicity in unresectable hepatocellular carcinoma patients treated with three-dimensional conformal radiotherapy

To identify the dose-volumetric parameters associated with the risk of radiation-induced hepatic toxicity (RIHT) in hepatocellular carcinoma patients treated with three-dimensional conformal radiotherapy. A total of 105 hepatocellular carcinoma patients underwent three-dimensional conformal radiotherapy (total dose range, 44-58.5 Gy; median, 54). RIHT was scored within 4 months of completing three-dimensional conformal radiotherapy. The dose-volume parameters analyzed were the gross tumor volume; normal liver volume; total liver volume; radiation dose; mean dose to the normal liver; percentage of the normal liver volume receiving > or =20, > or =25, > or =30, > or =35, and > or =40 Gy; percentage of the total liver volume receiving > or =20, > or =25, > or =30, > or =35, and > or =40 Gy; and the normal tissue complication probability. Of the 105 patients, Grade 1 RIHT was observed in 21 (20.0%), Grade 2 in 7 (6.7%), Grade 3 in 5 (4.8%), and Grade 4 in 1 (1.0%) patient. No fatal Grade 5 RIHT developed. On multivariate analysis for predicting Grade 2 or worse RIHT, the total liver volume receiving > or =30 Gy was the only significant parameter (p < 0.001). Grade 2 or worse RIHT was observed in only 2 (2.4%) of 85 patients with a total liver volume receiving 30 Gy of < or =60% and in 11 (55.0%) of 20 patients with >60% (p < 0.001). The total liver volume receiving > or =30 Gy appears to be a useful dose-volumetric parameter for predicting the risk of RIHT. This volume should be limited to < or =60% whenever possible to minimize the risk of Grade 2 or worse RIHT.