Nonclassic Radiation-induced Liver Disease Research Articles

Recent update of proton beam therapy for hepatocellular carcinoma: A systematic review and meta-analysis.

Although access to proton beam therapy (PBT) is limited worldwide, its use for the treatment of hepatocellular carcinoma (HCC) is gradually increasing with the expansion of new facilities. Therefore, we conducted a systematic review and meta-analysis to investigate the updated evidence of PBT for HCC. The MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were systematically searched for studies that enrolled patients with liver-confined HCC that were treated with PBT for a cure up to February 2024. A total of 1858 HCC patients receiving PBT from 22 studies between 2004 and 2023 were selected for this meta-analysis. The median proportion of Child-Pugh class A was 86% (range: 41-100%), and the median tumor size was 3.6 cm (range: 1.2-9 cm). The median total dose ranged from 55 GyE to 76 GyE (median, 69 GyE). The pooled rates of 3- and 5-year local progression-free survival after PBT were 88% (95% confidence interval [CI], 85-91%) and 86% (95% CI, 82-90%), respectively. The pooled 3- and 5-year overall rates were 60% (95% CI, 54-66%) and 46% (95% CI, 38-54%), respectively. The pooled rates of grade 3 hepatic toxicity, classic radiation-induced liver disease (RILD), and non-classic RILD were 1%, 2%, and 1%, respectively. The current study supports PBT for HCC and demonstrates favorable long-term survival and low hepatic toxicities compared with other published studies on other radiotherapy modalities. However, further studies are needed to identify the subgroups that will benefit from PBT.

Co-relation of Portal Vein Tumour Thrombus Response With Survival Function Following Robotic Radiosurgery in Vascular Invasive Hepatocellular Carcinoma

Purpose or ObjectiveProspective evaluation of stereotactic body radiotherapy (SBRT) with Robotic Radiosurgery in hepatocellular carcinoma patients with macrovascular invasion (HCC-PVT). Materials and MethodsPatients with inoperable HCC-PVT, good performance score (PS0-1) and preserved liver function (up to Child Pugh B7) were accrued after ethical and scientific committee approval [CTRI: 2022/01/050234] for treatment on Robotic Radiosurgery (M6) and planned with Multiplan (iDMS V2.0). Triple-phase contrast computed tomography (CT) scan was done for contouring and gross tumor volume (GTV) included contrast enhancing mass within main portal vein and adjacent parenchymal disease. Dose prescription was as per risk stratification protocol (22- 50Gy in 5 fractions) while achieving the constraints of mean liver dose <15Gy, 800 cc liver <8Gy and the duodenum max of <24 Gy). Response assessment done at 2 months follow up for recanalization. Patient and treatment related factors evaluated for influence in survival function. ResultsBetween Jan 2017 till May 2022, 317 consecutive HCC with PVT patients were screened and 219 patients were accrued [male 92%, CP score 5-7 90%, mean age 63 years (38-85yrs), CLIP <3: 84 (40%), 3-6 117 (56%), infective etiology 9.5%, Performance status (PS) 0-37%; 1-56%]. Among 209 consecutive patients after accrual SBRT treatment done (10 patients were excluded after accrual due to ascites and decompensation), 139 were evaluable for response assessment (>2 mo follow up). At mean follow up of 10.2 months (SD 8.43), 88 (63%) patients expired and 51 (36%) were alive. 82 (59%) patients had recanalization of PVT (response), 57 (41%) pts did not recanalize, 28 (17%) had progressive disease had progressive/metastatic disease prior to response evaluation (<2 months). Mean overall survival in responders and non-responders were 18.4 (SE 2.52) and 9.34 month (SE 0.81) respectively (p<0.001). Mean survival in patients with PS0, PS1 and PS2 were 17, 11.7 and 9.7 months (p- 0.019) respectively. Overall survival (OS) in partial recanalization, bland thrombus and complete recanalization was 12.4, 14.1, 30.3 months respectively (p-0.002). Adjuvant sorafenib, Barcelona Clinic Liver Classification (BCLC) stage, gender, age, RT dose did not influence response to treatment. Recanalization rate was higher in good PS patients (p-0.019). OS in patients with response to treatment, no response to treatment, fit but not accrued and not suitable patients were 18.4, 9.34, 5.9, 2.6 months respectively (p-<0.001). 36/139 patients (24%) had RILD [10 (7.2%) had Classic Radiation induced liver disease (RILD) & 26 (19%) had non-classic RILD]. Derangement in Child Pugh Score (CP score change) by more than 2 was seen in 30 (24%) within 2-month period after Robotic Radiosurgery. 18 (13%) had unplanned admissions, two patients required embolization due to fiducial related bleeding, 20 (14%) had ascites of which 9 (6%) patients required abdominocentesis. ConclusionPVT response or recanalization after SBRT is a statistically significant prognostic factor for survival function in HCC-PVT.

Biochemical Safety of SBRT to Multiple Intrahepatic Lesions for Hepatocellular Carcinoma.

We aim to better characterize stereotactic body radiation therapy (SBRT)-related hepatic biochemical toxicity in patients with multiple intrahepatic lesions from hepatocellular carcinoma (HCC). We conducted a retrospective analysis of patients with HCC who underwent SBRT for 2 or more synchronous or metachronous liver lesions. We collected patient characteristics and dosimetric data (mean liver dose [MLD], cumulative effective volume [Veff], cumulative volume of liver receiving 15 Gy [V15Gy], and cumulative planning target volume [PTV]) along with liver-related toxicity (measured by albumin-bilirubin [ALBI] and Child-Pugh [CP] scores). A linear mixed-effects model was used to assess the effect of multi-target SBRT on changes in ALBI. There were 25 patients and 56 lesions with median follow-up of 29 months. Eleven patients had synchronous lesions, and 14 had recurrent lesions treated with separate SBRT courses. Among those receiving multiple SBRT courses, there were 7 lesions with overlap of V15Gy (median V15Gy overlap: 35 mL, range: 0.5-388 mL). There was no association between cumulative MLD, Veff, V15Gy, or PTV and change in ALBI. Four of 25 patients experienced non-classic radiation-induced liver disease (RILD), due to an increase of CP score by ≥2 points 3 to 6 months after SBRT. Sixteen of 25 patients experienced an increase in ALBI grade by 1 or more points 3 to 6 months after SBRT. Comparing the groups that received SBRT in a single course versus multiple courses revealed no statistically significant differences in liver toxicity. Liver SBRT for multiple lesions in a single or in separate courses is feasible and with acceptable risk of hepatotoxicity. Prospective studies with a larger cohort are needed to better characterize safety in this population.

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.

Non-classic radiation-induced liver disease after intensity-modulated radiotherapy for Child–Pugh grade B patients with locally advanced hepatocellular carcinoma

BackgroundThe incidence of classic radiation-induced liver disease (cRILD) has been significantly reduced. However, non-classic radiation-induced liver disease (ncRILD) remains a major concern following radiotherapy in patients with hepatocellular carcinoma (HCC). This study evaluated the incidence of ncRILD following intensity-modulated radiotherapy (IMRT) for Child–Pugh grade B (CP-B) patients with locally advanced HCC and established a nomogram for predicting ncRILD probability.MethodsSeventy-five CP-B patients with locally advanced HCC treated with IMRT between September 2014 and July 2021 were included. The max tumor size was 8.39 cm ± 5.06, and the median prescribed dose was 53.24 Gy ± 7.26. Treatment-related hepatotoxicity was evaluated within three months of completing IMRT. A nomogram model was formulated to predict the probability of ncRILD, using univariate and multivariate analysis.ResultsAmong CP-B patients with locally advanced HCC, ncRILD occurred in 17 (22.7%) patients. Two patients (2.7%) exhibited a transaminase elevation of ≥ G3, fourteen (18.7%) exhibited a Child–Pugh score increase of ≥ 2, and one (1.3%) demonstrated both a transaminase elevation of ≥ G3 and a Child–Pugh score increase of ≥ 2. No cRILD cases were observed. A mean dose to the normal liver of ≥ 15.1 Gy was used as the cutoff for ncRILD. Multivariate analysis revealed that the prothrombin time before IMRT, tumour number, and mean dose to the normal liver were independent risk factors for ncRILD. The nomogram established on the basis of these risk factors displayed exceptional predictive performance (AUC = 0.800, 95% CI 0.674–0.926).ConclusionsThe incidence of ncRILD following IMRT for CP-B patients with locally advanced HCC was acceptable. A nomogram based on prothrombin time before IMRT, tumour number, and mean dose to the normal liver accurately predicted the probability of ncRILD in these patients.

Non-Classic Radiation-Induced Liver Disease after Intensity-Modulated Radiotherapy for Hepatocellular Carcinoma with Child–Pugh Grade B

<h3>Purpose/Objective(s)</h3> While the incidence of classic radiation-induced liver disease (cRILD) has been significantly reduced, non-classic radiation-induced liver disease (ncRILD) is still considered as the major limitation that affects the efficacy of radiotherapy (RT) for hepatocellular carcinoma (HCC) patients at present. The purpose of this study was to evaluate the incidence of ncRILD following intensity-modulated radiotherapy (IMRT) in HCC patients with Child–Pugh grade B and establish the nomogram for ncRILD predication. <h3>Materials/Methods</h3> Between September 2014 and July 2021, a total of 75 HCC patients with Child–Pugh grade B treated by IMRT were included. Treatment-related hepatotoxicity was evaluated within 3-month post to the completing RT. In this study, nomogram model was formulated to predict probability of ncRILD in univariate and multivariate analysis. <h3>Results</h3> ncRILD occurred in 17 patients (22.7%). Two of the patients (2.7%) had ≥ G3 transaminase elevation, 14 (18.7%) had a Child–Pugh score increase ≥ 2, and the remaining patient (1.3%) had ≥ G3 transaminase elevation and simultaneous Child–Pugh score increase ≥ 2. No cases of cRILD were observed. A mean dose ≥ 15.1 Gy to the normal liver for ncRILD was the cut-off. Multivariate analysis revealed that prothrombin time before IMRT, tumor number, and mean dose to the normal liver were independent risk factors for ncRILD. The nomogram based on these risk factors displayed exceptional prediction performance (AUC = 0.800, 95% CI, 0.674-0.926). <h3>Conclusion</h3> The incidence of ncRILD following IMRT for HCC patients with Child–Pugh grade B was acceptable. The nomogram based on prothrombin time before RT, tumor number and mean dose to the normal liver showed accurate prediction for the probability of ncRILD in these patients.

MRI-Guided Real-Time Online Adaptive Gated Stereotactic Body Radiation Therapy for Liver Tumors

<h3>Purpose/Objective(s)</h3> Liver tumors (primary or metastases) are commonly encountered in Oncology. Single breathing phase Magnetic resonance imaging (MRI)-guided gated and possible adaptive stereotactic body radiation therapy (SBRT) for liver tumors offer dosimetric advantages and facilitate safe dose escalation compared to non- MRI-guided SBRT (MRgSBRT). We aimed to evaluate the impact of MRgSBRT on treatment outcomes and report treatment related adverse events. <h3>Materials/Methods</h3> This IRB approved retrospective study included liver tumors patients treated consecutively with MRgSBRT between 2019 and 2021. All patients received Gadoxetate disodium contrast followed by single phase post-exhale CT and MRI simulations utilizing 0.35 T MRI-guided linear accelerator. MRI images (hybrid T1-T2 sequence) were used as the primary set of images for contouring and planning. Real-time online adaptive SBRT plans were generated to account for daily anatomical changes of nearby organs at risk (OARs) when indicated. Patients were followed up every 3 to 6 months with a brief history, physical examination and imaging as indicated. Patients' data were analyzed based on age, sex, histology, tumor volume and delivered biologically equivalent dose (BED <100 Gy vs BED > 100 Gy). Kaplan Meier curves were generated for freedom from local progression (FFLP) and overall survival (OS). <h3>Results</h3> The study included 35 eligible patients with 49 liver tumors (hepatocellular carcinoma 21 lesions, liver metastases 28 lesions). The median age was 69.5 years (range 25 - 95). The median planning target volume (PTV) was 43.5 cm³ (4.9 - 344.8 cm³). Most patients (80%) were prescribed 50 Gy in 5 fractions (median 50 Gy, range 35 - 50Gy) to PTV. A total of 255 fractions were delivered for patients who completed treatment, 22 of which were adapted (8.6%). The median follow up was 19.4 months (range 1-37 months). The median OS was 25.9 months with 95% confidence intervals (CI) (22.1 - 29.6). The 1-year OS rate was 77.7%, 3-year OS rate was 47.9%. Local control was a driver for OS with patients with durable local control having a median OS of 27.8 months [95%CI (23.8-31.6)] vs 13.5 months [95%CI (5.6-21.3), p=0.007] in patients with local progression. The median FFLP was 29.8 months [95%CI (27.2-32.3]. The estimated 1-year FFLP was 95.6 % and 3-year FFLP was 87.1%. The FFLP in patients with BED>100Gy was 30.9 months [95%CI (28.7-33.1)] vs 13.3 months [95%CI (5.3-21.3), p value=0.004] in patients who received <100Gy BED. Most patients tolerated treatment well, no acute grade 3 toxicity. Two patients developed late grade 3 toxicity (gastric ulcer and non-classic radiation induced liver disease). <h3>Conclusion</h3> In our study, Gated MRgSBRT with real-time online adaptive planning is feasible, provides durable local control and impacts overall survival in a heavily pretreated older group of liver tumor patients, with remarkably good safety profile. BED>100Gy improved local control. Improved local control seems to drive overall survival benefit in liver tumors.

Clinical Outcomes of Image-Guided Proton Therapy for Recurrent Hepatocellular Carcinoma after TACE and/or RFA Treatment

<h3>Purpose/Objective(s)</h3> Additional treatment options for recurrent hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE) and/or radiofrequency ablation (RFA) treatment are limited. Although proton therapy provides a more focused dose distribution on the tumor compared with X-ray therapy, the efficacy and safety of proton therapy for recurrent HCC remains unclear. The aim of this study was to evaluate the efficacy and safety of image-guided proton therapy (IGPT) for recurrent HCC after TACE and/or RFA. <h3>Materials/Methods</h3> Eligibility criteria were as follows: (1) histologically-confirmed or image-diagnosed recurrent HCC after TACE and/or RFA treatment; (2) intrahepatic recurrence cases other than treatment site recurrence are not included (3) no previous radiotherapy around the lesion and other HCC; (4) age > 20 and ≤ 80 years; (5) ECOG-PS ≤ 2; (6) Child-Pugh classification A5-B9; (7) dose constraints of the organs at risk achievable; (8) no portal vein or inferior vena cava tumor thrombus; and (9) written informed consent. Overall survival (OS), local control (LC), and progression-free survival rates were estimated using the Kaplan-Meier method. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events version 5.0. Quality of life (QOL) scores were evaluated with EORTC QLQ-C30 version 3.0, QLQ-HCC18, and SF-36. Prior to treatment planning, the fiducial marker was placed just adjacent to a recurrent tumor. IGPT was performed under respiratory gating. <h3>Results</h3> From June 2013 to December 2020, 80 patients were enrolled. Major underlying liver diseases were hepatitis B (n=19), hepatitis C (n=35), alcoholic hepatitis (n=9), and nonalcoholic fatty liver disease (n=17). The Child-Pugh score was A5 in 49 patients, A6 in 16, and B7-9 in 15. The number of Albumin-Bilirubin Grade 1, 2, and 3 were 40, 40, and 0, respectively. Nineteen patients had a history of hepatic resection for other HCC. Fifty-four patients with a peripherally-located tumor were given 66 GyE in 10 fractions and 26 with a central tumor received 72.6 GyE in 22 fractions. Maximum tumor diameter ranged from 10 to 174 mm (median, 31). The median follow-up period of surviving patients was 38.0 months (range: 12.0-96.0). The 3-year OS, LC and PFS were 81% (95% confidence interval: 71-90%), 92% (86-100%), and 38% (26-49%) respectively. In univariate analysis, Child classification, operability, and tumor diameter were associated with better survival, while only Child classification was associated in multivariate analysis. Clinical remission or sustained viral response were significant factors for OS in patients with HCC recurrence derived from hepatitis virus. Non-classic radiation-induced liver disease was observed in only 1 patient with decrease of Child-Pugh score (≥ 2 points). The QOL score did not change after 1 year. <h3>Conclusion</h3> IGPT is safe and effective for recurrent HCC after TACE and/or RFA treatment. IGPT may become one of standard treatments as a curative treatment for recurrent HCC.

Clinical outcome and pathologic correlation of stereotactic body radiation therapy as a bridge to transplantation for advanced hepatocellular carcinoma: a case series

BackgroundStereotactic body radiotherapy (SBRT) is an emerging modality for hepatocellular carcinoma (HCC). However, there is scant information about its safety and effectiveness in the neoadjuvant setting prior to liver transplantation (LT). We present the clinical outcome and pathologic assessment of SBRT followed by LT for patients with advanced HCC.MethodsThis retrospective study included HCC patients treated with neoadjuvant SBRT prior to LT between 2009 and 2018. Radiographic response and adverse effects, including radiation-induced liver disease (RILD), were evaluated. Pathologic response was assessed by the percentage of tumor necrosis relative to the total tumor volume. Overall survival (OS) and recurrence-free survival (RFS) were calculated using the Kaplan–Meier method.ResultsFourteen patients underwent SBRT for a total of 25 HCC lesions, followed by LT. The median tumor size was 4.45 cm in diameter, and the median prescribed dose was 45 Gy in 5 fractions. SBRT provided significant AFP reduction, 100% infield control, and a 62.5% response rate. The maximum detected toxicity included grade 3 thrombocytopenia and two grade 3–4 hyperbilirubinemia. One patient developed non-classic RILD. Patients were bridged to LT with a median time of 8.4 months after SBRT, and 23.1% of them achieved a complete pathologic response. The median OS and RFS were 37.8 and 18.3 months from the time of LT, respectively.ConclusionsSBRT provides favorable tumor control and acceptable adverse effects for patients awaiting LT. Further prospective studies to test SBRT as a bridging therapy for LT are feasible.

Clinical efficacy of external beam radiotherapy complementing incomplete transarterial chemoembolization for hepatocellular carcinoma

Purpose External beam radiotherapy (EBRT) has been commonly applied as salvage or a combination locoregional modality after transarterial chemoembolization (TACE) for hepatocellular carcinomas (HCCs). This study reports oncologic outcomes and feasibility after application of the two modalities in our center. Methods Forty consecutive patients who underwent EBRT due to incomplete responses of TACE were evaluated. Fourteen patients (35.0%) received stereotactic body radiotherapy (SBRT) and the remaining patients received conventionally fractionated radiotherapy (RT). A majority of patients who underwent SBRT received doses of 27 to 48 Gy in 3–4 fractions [median EQD2 (Equivalent dose in 2 Gy per fraction radiotherapy): 57.0 Gy]. Conventionally fractionated RT was performed with a median EQD2 of 47.8 Gy. Results The median follow-up duration was 14.4 months (range: 2.6–83.0 months). A majority (77.5%) of patients were regarded as having Child-Pugh grade A. The median tumor size was 3.4 cm (range: 0.8–20.1 cm). Ten patients (25.0%) had thrombosis at a main portal branch. The 1- and 2-year overall survival (OS) and progression-free survival (PFS) rates were 82.2% and 42.1% and 55.8% and 32.1%, respectively. The local control rates were 89.1% and 89.1% at 1 and 2 years, respectively. The albumin level was a significant factor affecting OS (p = .002), and the BCLC stage significantly affected PFS (p = .001). Intrahepatic, out-of-field recurrence was the main cause of disease progression (60.0%), and distant metastasis developed in 12 patients (30.0%) during follow-up. Non-classic radiation-induced liver disease was seen in five (12.5%) patients, and two (5%) patients experienced grade ≥3 hepatic toxicities. Conclusions EBRT after incomplete TACE was feasible and yielded favorable oncologic outcomes. However, disease progression related to intrahepatic failure remained a hindrance.

Clinical-dosimetric parameters predicting non-classic radiation-induced liver disease in hepatocellular carcinoma patients with Barcelona Clinic Liver Cancer (BCLC) stage A–B: a retrospective study

Clinical-dosimetric parameters predicting non-classic radiation-induced liver disease in hepatocellular carcinoma patients with Barcelona Clinic Liver Cancer (BCLC) stage A–B: a retrospective study

Helical IMRT-Based Stereotactic Body Radiation Therapy Using an Abdominal Compression Technique and Modified Fractionation Regimen for Small Hepatocellular Carcinoma.

Purpose:To assess the efficacy and safety of stereotactic body radiation therapy using an abdominal compression technique and modified fractionation regimen (5-10 fractions) in patients with small-sized hepatocellular carcinoma.Methods:A total of 101 patients with small-sized hepatocellular carcinoma treated with stereotactic body radiation therapy using an abdominal compression technique and modified fractionation regimen were registered between June 2011 and June 2019 in our hospital. A total dose of 48 to 60 Gy was applied over 5 to 14 consecutive days. Liver motion was controlled by abdominal compression, and a helical intensity-modified radiation therapy-based stereotactic body radiation therapy administrated in tomotherapy platform.Results:The median follow-up period was 23.2 months (range: 4.1-99.2 months). Complete response and partial response were observed in 63 (62.4%) patients and in 24 (23.8%) patients, respectively. At the time of our analysis, the 1-, 3-, and 5-year local control rates after stereotactic body radiation therapy were 96.1%, 89.0%, and 89.0%, respectively. However, logistic regression analysis revealed no correlation between the biologically effective dose and 3-year local control rates. The 1-, 3-, and 5-year overall survival rates were 96.9%, 69.0%, and 64.3%, respectively. For patients who were treatment-naive, the 1-, 3-, and 5-year overall survival were 96.3%, 82.0%, and 82.0%, respectively. No patients experienced classic radiation-induced liver disease or nonclassic radiation-induced liver disease after stereotactic body radiation therapy completion.Conclusions:When using an abdominal compression technique and modified fractionation regimen (5-10 fractions) based on helical intensity-modified radiation therapy, stereotactic body radiation therapy led to a lower toxicity and comparative rate of local control and overall survival for patients who with small-sized hepatocellular carcinoma.

Treatment Outcome after Fractionated Conformal Radiotherapy for Hepatocellular Carcinoma in Patients with Child-Pugh Classification B in Korea (KROG 16-05).

PurposeThere is limited data on radiotherapy (RT) for hepatocellular carcinoma (HCC) in patients with Child-Pugh classification B (CP-B). This study aimed to evaluate the treatment outcomes of fractionated conformal RT in HCC patients with CP-B.Materials and MethodsWe retrospectively reviewed the data of HCC patients with CP-B treated with RT between 2009 and 2014 at 13 institutions in Korea. HCC was diagnosed by the Korea guideline of 2009, and modern RT techniques were applied. Fraction size was ≤ 5 Gy and the biologically effective dose (BED) ≥ 40 Gy10 (α/β = 10 Gy). A total of 184 patients were included in this study.ResultsInitial CP score was seven in 62.0% of patients, eight in 31.0%, and nine in 7.0%. Portal vein tumor thrombosis was present in 66.3% of patients. The BED ranged from 40.4 to 89.6 Gy10 (median, 56.0 Gy10). After RT completion, 48.4% of patients underwent additional treatment. The median overall survival (OS) was 9.4 months. The local progression-free survival and OS rates at 1 year were 58.9% and 39.8%, respectively. In the multivariate analysis, non-classic radiation-induced liver disease (RILD) (p < 0.001) and additional treatment (p < 0.001) were the most significant prognostic factors of OS. Among 132 evaluable patients without progressive disease, 19.7% experienced non-classic RILD. Normal liver volume was the most predictive dosimetric parameter of non-classic RILD.ConclusionFractionated conformal RT showed favorable OS with a moderate risk non-classic RILD. The individual radiotherapy for CP-B could be cautiously applied weighing the survival benefits and the RILD risks.

Protons versus Photons for Unresectable Hepatocellular Carcinoma: Liver Decompensation and Overall Survival

Ablative radiation therapy is increasingly being used for hepatocellular carcinoma (HCC) resulting in excellent local control rates; however, patients without evidence of disease progression often die from liver failure. The clinical benefit of proton- over photon-based radiation therapy is unclear. We therefore sought to compare clinical outcomes of proton versus photon ablative radiation therapy in patients with unresectable HCC. This is a single-institution retrospective study of patients treated during 2008 to 2017 with nonmetastatic, unresectable HCC not previously treated with liver-directed radiation therapy and who did not receive further liver-directed radiation therapy within 12months after completion of index treatment. The primary outcome, overall survival (OS), was assessed using Cox regression. Secondary endpoints included incidence of non-classic radiation-induced liver disease (defined as increase in baseline Child-Pugh score by ≥2 points at 3months posttreatment), assessed using logistic regression, and locoregional recurrence, assessed using Fine-Gray regression for competing risks. All outcomes were measured from radiation start date. The median follow-up was 14months. Of 133 patients with median age 68years and 75% male, 49 (37%) were treated with proton radiation therapy. Proton radiation therapy was associated with improved OS (adjusted hazard ratio, 0.47; P=.008; 95% confidence interval [CI], 0.27-0.82). The median OS for proton and photon patients was 31 and 14months, respectively, and the 24-month OS for proton and photon patients was 59.1% and 28.6%, respectively. Proton radiation therapy was also associated with a decreased risk of non-classic radiation-induced liver disease (odds ratio, 0.26; P=.03; 95% CI, 0.08-0.86). Development of nonclassic RILD at 3months was associated with worse OS (adjusted hazard ratio, 3.83; P<.001; 95% CI, 2.12-6.92). There was no difference in locoregional recurrence, including local failure, between protons and photons. Proton radiation therapy was associated with improved survival, which may be driven by decreased incidence of posttreatment liver decompensation. Our findings support prospective investigations comparing proton versus photon ablative radiation therapy for HCC.

Effectiveness of stereotactic ablative radiotherapy in patients with advanced hepatocellular carcinoma unsuitable for transarterial chemoembolization.

Background:Stereotactic ablative radiotherapy (SABR) can deliver tumoricidal doses and achieve long-term control in early hepatocellular carcinoma (HCC). However, limited studies have investigated the safety and effectiveness of SABR in patients with advanced diseases that is unsuitable for transarterial chemoembolization (TACE).Methods:In this observational study, we reviewed the medical records of patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease treated with linear accelerator-based SABR between 2008 and 2016. Their tumors were either refractory to TACE or TACE was contraindicated. Overall survival (OS), in-field progression-free survival (IFPFS), and out-field progression-free survival were calculated using Kaplan–Meier analysis. The Cox regression model was used to examine the effects of variables. Treatment-related toxicities were scored according to the Common Terminology Criteria for Adverse Events (version 4.03) and whether patients developed radiation-induced liver disease (RILD) after SABR.Results:This study included 32 patients. The mean maximal tumor diameter and tumor volumes were 4.7 cm and 135.9 ml, respectively. Patients received linear accelerator-based SABR with a median prescribed dose of 48 Gy (30–60 Gy) in three to six fractions. Based on the assessment of treatment response by using the Response Evaluation Criteria in Solid Tumors (version 1.1), 19% of patients achieved a complete response and 53% achieved a partial response. After a median follow-up of 18.1 months (4.0–65.9 months), 10, 19, and 9 patients experienced in-field failure, out-field hepatic recurrence, and extrahepatic metastases, respectively. The estimated 2-year OS and IFPFS rates were 54.4% and 62.7%, respectively. In a multivariate analysis, a pretreatment Cancer of the Liver Italian Program (CLIP) score of ⩾2 (p = 0.01) was a prognostic factor for shorter OS, and a biologically effective dose (BED) of < 85 Gy10 (p = 0.011) and a Child–Pugh score of ⩾6 (p = 0.014) were prognostic factors for inferior IFPFS. In this study five and eight patients developed classic and nonclassic RILD, respectively.Conclusions:SABR can serve as a salvage treatment for patients with HCC with BCLC stage C disease unsuitable for TACE, in particular, in those with a baseline CLIP score of ⩽1. A BED10 of ⩾85 Gy is an appropriate prescribed dose for tumor control. Because out-field relapse is the major cause of treatment failure, SABR in combination with novel systemic modalities should be investigated in future studies.

How small is TOO small? New liver constraint is needed- Proton therapy of hepatocellular carcinoma patients with small normal liver.

PurposeThis study evaluated the outcomes of hepatocellular carcinoma (HCC) patients with small normal liver volume (NLV) treated with proton beam therapy (PBT) and introduced estimated standard liver volume (eSLV) as a new constraint.Materials and methodsHCC patients with NLV < 800 cm3 and no distant metastasis who received treatment in our proton center were included. The doses of PBT were mainly 72.6 Gray equivalents (GyE) in 22 fractions and 66 GyE in 10 fractions according to tumor locations. The Urata equation was used to calculate eSLV.ResultsTwenty-two patients were treated between November 2015 and December 2016. The 1-year progression-free and overall survival rates were 40.4% and 81.8%, respectively. The 1-year in-field failure-free rate was 95.5%. NLV ranged from 483.9 to 795.8 cm3 (median = 673.8 cm3), eSLV ranged from 889.3 to 1290.0 cm3 (median = 1104.5 cm3), and the resulting NLV/eSLV ratio ranged from 44.3 to 81.2% (median = 57.7%). Non-irradiated liver volume (NILV) ranged from 232.9 to 531.6 cm3 (median = 391.2 cm3). The NILV/eSLV ratio ranged from 21.2 to 48.0% (median = 33.3%). NLV in the patients who received <30 GyE (rV30) ranged from 319.1 to 633.3 cm3 (median = 488.2 cm3), and their rV30/eSLV ratio ranged from 30.7 to 58.0%. None of our patients developed liver failure. One patient with initial abnormal liver enzyme levels developed non-classic radiation-induced liver disease (RILD).ConclusionFrom the viewpoint of minimal liver toxicity occurring in our patients with NLV < 800 cm3, conventional liver constraints involving the use of absolute volume could not accurately predict the risk of RILD. It is reasonable to start using individualized constraints with eSLV for HCC patients undergoing PBT. According to the study results, an NILV/eSLV ratio of >20% and an rV30/eSLV ratio of >30% are acceptable.

Liver reirradiation for patients with hepatocellular carcinoma and liver metastasis

PurposeThis study aimed to assess the safety and efficacy of administering liver reirradiation to patients with primary liver tumors or liver metastasis. Methods and materialsA total of 49 patients (with 64 individual tumors) who received liver reirradiation at our institution between June 2008 and December 2016 were identified for retrospective review. Patients were treated to the same, different, or a combination of previously treated liver tumors for recurrent primary (53%) or metastatic (47%) disease using photons or protons. Clinical and treatment-related factors were compiled and patients were monitored for toxicity and evidence of classic or nonclassic radiation-induced liver disease. Survival was estimated with the Kaplan-Meier method and cumulative incidence of local failure (LF) was used to estimate LF using the Response Evaluation Criteria in Solid Tumors version 1.1. ResultsThe median age at the time of reirradiation was 72 years and the median interval between radiation courses was 9 months. At a median follow-up of 10.5 months, 36 patients (73%) had died, 9 patients (18%) were alive, and 4 patients (8%) were lost to follow-up. The median survival for the cohort was 14 months. The overall 1-year estimate of LF was 46.4%. The 1-year estimates of LF for liver metastases and hepatocellular carcinoma were 61.0% and 32.5%, respectively. The average prescription dose was similar between the reirradiation and initial courses (equivalent dose in 2 Gy fractions EQD2: 65.0 vs 64.3 Gyα/β = 10, respectively) but the average dose to the untreated liver was lower at the time of reirradiation (EQD2: 10.5 vs 13.9 Gyα/β = 3, respectively, P = .01). Among patients with hepatocellular carcinoma, the average normal liver dose was significantly larger for patients who exhibited a worsening of Child-Pugh score after reirradiation compared with those who did not (1210 cGy vs 759 cGy, P = .04). With regard to toxicity, 85.7% of patients experienced grade 1 to 2 toxicity, 4.1% developed grade 3, and only 2 patients (4.1%) met the criteria for radiation-induced liver disease after reirradiation. ConclusionsLiver reirradiation may be an effective and safe option for select patients; however, further prospective study is necessary to establish treatment guidelines and recommended dosing.

Toward consensus reporting of radiation-induced liver toxicity in the treatment of primary liver malignancies: Defining clinically relevant endpoints

BackgroundOur purpose was to define the most clinically relevant “nonclassic” radiation-induced liver disease (RILD) endpoints in cirrhotic patients receiving stereotactic body radiation therapy or proton beam therapy for primary liver cancer. Methods and materialsWe retrospectively collected pretreatment, detailed toxicity (≤6 months posttreatment), and outcomes data from 48 patients. Deaths were examined for association with RILD. Univariate and multivariate Cox models defined significant predictors of overall survival (OS)/RILD-specific survival (RILD-SS). ResultsWith median follow-up of 13 months, 23 patients (48%) had an increase in Child-Pugh (CP) score (≥2, 25%) and 3 (6%) had ≥G3 transaminase elevation. Of 18 deaths, 6 were potentially ascribed to RILD. Univariate analysis showed that CP score increases of ≥1 and ≥2 and CP class change predicted OS, as did ≥G3 aspartate transaminase (AST) elevation and ≥1 Common Terminology Criteria for Adverse Events (CTCAE) AST toxicity grade change. On multivariate analysis, CP score increase of ≥2 and ≥1 CTCAE AST toxicity grade change were the strongest independent nonclassic RILD predictors of OS. For RILD-SS, CP score increases of ≥2, ≥grade 3 CTCAE alanine transaminase, and ≥grade 2 bilirubin elevations were predictive. ConclusionsIncreased CP score ≥2 strongly predicts for both OS and RILD-SS and should be reported in future studies along with transaminase elevations, which are also predictive of outcomes.

Dosimetric analysis of liver toxicity after liver metastasis stereotactic body radiation therapy

PurposeThe aim of this study is to describe the incidence and type of liver toxicity seen following liver metastases stereotactic body radiation therapy (SBRT) and the corresponding clinical and dosimetric factors associated with toxicity. Methods and materialsBetween 2002 and 2009, 81 evaluable patients with liver metastases were treated on 2 prospective studies assessing SBRT, with prescription doses based on the effective liver volume irradiated evaluated. Toxicity was defined as grade ≥2 classic or nonclassic radiation induced liver disease (RILD). Specific toxicity endpoints evaluated were worsening transaminases and albumin levels within 3 months of SBRT. ResultsSeventy percent of patients had colorectal carcinoma, 55% had extrahepatic disease, 1 patient had hepatitis B, and 54% had received prior chemotherapy. Baseline transaminases were elevated at Common Terminology Criteria for Adverse Effects, V4.0, grade 1, 2, and 3 levels in 33 (41%), 2 (2%), and 0 (0%) patients. The mean prescription dose was 43 Gy (27.7-60 Gy) in 6 fractions. The mean liver (minus gross tumor volume) dose (MLD) was 16 Gy (3-25.6 Gy) in 6 fractions. No classic or nonclassical ≥grade 2 RILD was observed. Within 3 months of SBRT, 49 (61%) patients had worsening of grade of transaminase and 23 (28%) patients had a reduction in albumin, all transient (majority grade ≤2 toxicity) without subsequent clinical toxicity. Seventeen patients exceeded Quantitative Analysis of Normal Tissue Effects in the Clinic MLD guidelines (≤20 Gy), 13 (76%) of whom had worsening of transaminase grade. On multivariate analysis, worsening of liver enzymes was more likely in patients with higher doses to the spared 700 mL of liver (P = .026), and reduction of albumin was more likely with higher effective liver volume (odds ratio, 1.53 [range, 1.08-2.16]) P = .016). ConclusionsLiver metastases SBRT is safe with a low risk of transient biochemical liver toxicity, more likely in patients with a higher effective liver volume and higher doses to the spared uninvolved liver volume.