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Objective: Hypofractionated radiotherapy has recently been applied to treat pulmonary metastases of hepatocellular carcinoma. However, there is no definite evidence on its safety and efficacy. We evaluate the clinical outcomes of hypofractionated radiotherapy for oligo pulmonary metastases of hepatocellular carcinoma in the multicenter and retrospective study., Methods: From March 2011 to February 2018, 58 patients with fewer than five pulmonary metastases of hepatocellular carcinoma who underwent hypofractionated radiotherapy in nine tertiary university hospitals were analyzed retrospectively. The primary endpoint was the local control rate. The secondary endpoints were overall survival, progression-free survival, prognostic factors affecting the treatment outcomes and treatment-related side effects., Results: The local tumor response rate including complete and partial response was 77.6% at 3 months after hypofractionated radiotherapy. The median survival and progression-free survival times were 20.9 and 5.3 months, respectively. The 1-year overall survival and progression-free survival rates were 65.5 and 22.4%, respectively. The good treatment response after hypofractionated radiotherapy (P = 0.001), the absence of intrahepatic tumor (P = 0.004) and Child-Pugh class A (P = 0.010) were revealed as significant prognostic factors for overall survival in the multivariate analysis. A progression-free interval of <6 months (P = 0.009) was a negative prognostic factor for overall survival in the multivariate analysis. Of 58 patients, five (8.6%) had grade 2 or higher radiation pneumonitis after hypofractionated radiotherapy., Conclusions: The favorable local control rate and acceptable toxicity indicate the clinical usefulness of hypofractionated radiotherapy for hepatocellular carcinoma patients who have less than five pulmonary metastases., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: There 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 Methods: We 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., Results: Initial 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., Conclusion: Fractionated 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.

Background: To report the results of a phase I/II study of helical IMRT-based stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC)., Methods: Eligibility included Child-Turcotte-Pugh class A or B, ≤3 lesions, and cumulative tumor diameter ≤6 cm. Dose was escalated from 36 Gy to 60 Gy delivered in 4 fractions. Grade ≥3 gastrointestinal toxicities (CTCAE v3.0) or radiation-induced liver disease defined dose-limiting toxicity (DLT)., Results: Thirty-two patients were enrolled: seven in dose levels 1-2 (36-44 Gy) and 25 in levels 3-4 (42-60 Gy). Failures included 1 local, 14 outfield intrahepatic, 2 distant, 1 concurrent local and outfield, 1 concurrent outfield and distant, and 1 concurrent local, outfield, and distant. Nine had grade 3 hematologic toxicities and 5 had grade 2 hepatic toxicities; no patient experienced DLT. Two-year local control (LFFS), outfield intrahepatic control (OutFFS), and overall survival (OS) rates were 80.9%, 46.7%, and 81.3%, respectively. Dose levels 3-4 and pre-radiotherapy multi-segment recurrence were independent prognostic factors for LFFS and OutFFS, respectively. Two-year LFFS, OutFFS, and OS were significantly higher for patients who were treated with dose-levels 3/4 for tumor(s) involving single segment compared with the rest of the patients., Conclusions: Helical IMRT-based SBRT was safe and effective, and patients with multi-segment recurrences prior to SBRT need to be closely followed., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Concurrent chemoradiation therapy (CCRT) followed by hepatic arterial infusional chemotherapy (HAIC) was reported to be effective for advanced hepatocellular carcinoma (HCC) with portal vein thrombosis. However, transarterial chemoembolization (TACE) is not preferred in this setting. The aim of this study was to assess the factors affecting survival after CCRT, including additional TACE during repeated HAIC., Methods: Thirty-eight patients who underwent CCRT as the initial treatment for Barcelona Clinic Liver Cancer stage C HCC with vascular invasion between 2009 and 2016 were reviewed retrospectively. During CCRT, 5-fluorouracil (5-FU) was infused via chemoport during the first and last five days of five weeks of external beam radiation therapy. After CCRT, repeated HAIC with cisplatin and 5-FU was performed monthly. Nineteen patients (50%) underwent additional TACE between repeated HAICs. Factors related to overall survival and progression free survival (PFS) were analyzed., Results: The mean age of patients was 55 years (male:female, 33:5). Underlying liver diseases were hepatitis B, hepatitis C and non-B/C in 29, 1 and 8 patients, respectively. The median radiation dose was 4500 cGy. The objective response (OR) rate at one months after CCRT was 36.8%. The median PFS was 7.4 (range, 1.8 - 32.1) months. The median overall survival was 11.6 (range 2.8-65.7) months. Achieving an OR after CCRT (hazard ratio [HR], 0.028; P < 0.001), additional TACE (HR, 0.134, P < 0.001), and further rounds of HAIC (HR, 0.742, P = 0.001) were independent significant factors related to overall survival. The overall survival duration of patients with an OR after CCRT (median 44.2 vs. 6.6 months, P < 0.001) and additional TACE (median 19.8 vs. 9.1 months, P = 0.001) were significantly greater than those without an OR after CCRT or additional TACE., Conclusion: Patients who achieved an OR after CCRT, underwent additional TACE, and were subjected to repeated rounds of HAIC following CCRT showed better survival after CCRT for advanced stage of HCC with vascular invasion. A further prospective study is needed to confirm the positive effect of additional TACE after CCRT.

Background & Aims: This nationwide, multicenter study investigated treatment outcomes as well as the optimal radiotherapeutic strategy in patients with hepatocellular carcinoma (HCC) and portal vein tumour thrombosis (PVTT)., Methods: We retrospectively reviewed the records of 985 patients who received radiotherapy (RT) for PVTT. The median equivalent RT dose was 48.75 Gy. Combined treatment, defined as liver-directed treatments performed within a month of RT, was administered to 657 patients (66.7%). The PVTT and primary tumour were irradiated in 413 patients (41.9%), and PVTT only was targeted in 572 patients (58.1%)., Results: The response rate of the PVTT was 51.8%, and RT responders had a significantly longer survival than non-responders (15.2 vs. 6.9 months). Equivalent RT dose and combined treatment predicted response of PVTT. The median overall survival (OS) was 10.2 months. Multivariate analysis revealed the equivalent RT dose ˃45 Gy and combined treatment as significant positive factors for OS. In the propensity score matching analysis, the combined treatment group had better OS than the no combined treatment group, whereas the OS of the PVTT + primary tumour group did not differ significantly from that of the PVTT only group., Conclusion: The equivalent RT dose ˃45 Gy, given in combination with other treatments, provided better PVTT control and OS. The optimal RT volume is suggested for either PVTT + primary or PVTT only. Taken together, multimodal treatment with equivalent RT dose higher than 45 Gy is recommended for patients with HCC and PVTT., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: The aim of this study was to examine patterns of radiotherapy (RT) in Korean patients with hepatocellular carcinoma (HCC) according to the evolving guideline for HCC established by the Korean Liver Cancer Study Group-National Cancer Center (KLCSG-NCC)., Materials and Methods: We reviewed 765 patients with HCC who were treated with RT between January 2011 and December 2012 in 12 institutions., Results: The median follow-up period was 13.3 months (range, 0.2 to 51.7 months). Compared with previous data between 2004 and 2005, the use of RT as a first treatment has increased (9.0% vs. 40.8%). Increased application of intensity-modulated RT resulted in an increase in radiation dose (fractional dose, 1.8 Gy vs. 2.5 Gy; biologically effective dose, 53.1 Gy 10 vs. 56.3 Gy 10 ). Median overall survival was 16.2 months, which is longer than that reported in previous data (12 months). In subgroup analysis, treatments were significantly different according to stage (p < 0.001). Stereotactic body RT was used in patients with early HCC, and most patients with advanced stage were treated with three-dimensional conformal RT., Conclusion: Based on the evolving KLCSG-NCC practice guideline for HCC, clinical practice patterns of RT have changed. Although RT is still used mainly in advanced HCC, the number of patients with good performance status who were treated with RT as a first treatment has increased. This change in practice patterns could result in improvement in overall survival., Competing Interests: relevant to this article was not reported.

Purpose: There has been increasing use of external beam radiotherapy for localized treatment of hepatocellular carcinoma (HCC) with both palliative and curative intent. Quality control of target delineation in primary HCC is essential to deliver adequate doses of radiation to the primary tumor while preserving adjacent healthy organs. We analyzed interobserver variability in gross tumor volume (GTV) delineation for HCC., Patients and Methods: Twelve radiation oncologists specializing in liver malignancy participated in a multi-institutional contouring dummy-run study of nine HCC cases and independently delineated GTV on the same set of provided computed tomography images. Quantitative analysis was performed using an expectation maximization algorithm for simultaneous truth and performance level estimation (STAPLE) with kappa statistics calculating agreement between physicians. To quantify the interobserver variability of GTV delineations, the ratio of the actual delineated volume to the estimated consensus volume (STAPLE), the ratio of the common and encompassing volumes, and the coefficient of variation were calculated., Results: The median kappa agreement level was 0.71 (range 0.28-0.86). The ratio of the actual delineated volume to the estimated consensus volume ranged from 0.19 to 1.93 (median 0.94) for all cases. The ratio of the common and encompassing volumes ranged from 0.001 to 0.56 (median 0.25). The coefficient of variation for GTV delineation ranged from 8 to 57 % (median 26 %)., Conclusion: The interobserver variability in target delineation of HCC GTV in this study is noteworthy. Multi-institution studies involving radiotherapy for HCC require appropriate quality assurance programs for target delineation.

Background and Aims: Optimal response criteria and assessment timing were investigated through radiologic-pathologic correlation in hepatocellular carcinoma (HCC) treated with localized chemoradiotherapy (CRT)., Methods: We reviewed 19 consecutive HCC patients who underwent surgical resection after radiotherapy and concurrent hepatic arterial infusion chemotherapy. Patients who received transarterial chemoembolization before RT or surgery were excluded from evaluation. Tumor diameters and total and enhancing tumor volumes were measured from CT images obtained 1, 3, 6, and 9 months after CRT. Percent changes calculated using size (RECIST and WHO) and enhancement criteria (mRECIST and EASL) were correlated with percent changes in total and enhancing tumor volumes, and with percent viable tumor in surgical specimens., Results: Median time between CRT and resection was 4.1 months (range, 1.5-15.4 months). CR and PR rates were 0 and 68% by RECIST, 0 and 63% by WHO, 53% and 37% by mRECIST, and 53% and 42% by EASL. Pathologic CR (pCR) rate was 52.6%. Radiologic criteria showed strong correlation with tumor volumes at 1 and 3 months after CRT; at 6 months, however, size and enhancement criteria showed strong correlation only with total and enhancing tumor volumes, respectively. Enhancement criteria were better predictors of pathologic response at all times including preoperative evaluation (RECIST: R(2)  = 0.303, P = 0.015 and WHO: R(2)  = 0.366, P = 0.006 vs. mRECIST: R(2)  = 0.760, P < 0.0001 and EASL: R(2)  = 0.768, P < 0.0001). Time interval >6 months before resection showed significant correlation with pCR (P = 0.013)., Conclusions: We recommend using enhancement criteria in assessing tumor viability, especially if the tumor was to be resected <6 months after CRT., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Purpose: Pelvic bone metastases are difficult to treat because of complex pelvic bone anatomy and the proximity of normal organs. The adequacy of radiation dose and field coverage was evaluated., Patients and Methods: We analyzed 146 cases of pelvic bone metastases from HCC treated with radiotherapy (RT). Bone metastases were confirmed using CT/MRI. Subjective pain response was assessed using the visual analogue scale, and treatment-related toxicity with the Common Terminology Criteria for Adverse Events v3.0. Local failure free survival (LFFS) and overall survival were estimated using the Kaplan-Meier method., Results: The local control rate was 80.1% and the pain control rate was 68.5%. Compartmental target volume (CTV), encompassing the whole compartment of the involved bone, was found to be a significant factor (1-year LFFS, 78% vs. 50%; p=0.001). Sites of metastasis were categorized as either upper or lower pelvic bone; both categories showed improved local control with CTV. Metastatic lesions that received more than 50 Gy of EQD2 showed more partial response in pain after RT (58% vs. 79%; p=0.007). No patient showed toxicity higher than Grade IV., Conclusion: Compartmental RT targeted to the involved bone was associated with improved local control and LFFS. High-dose radiation was associated with an improved treatment response., Competing Interests: The authors have no conflicts of interest.

Background: Phase I trial was conducted to determine feasibility and toxicity of helical intensity-modulated radiotherapy (IMRT)-based stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC)., Results: Eighteen patients (22 lesions) were enrolled. With no DLT at 52 Gy (13 Gy/fraction), protocol was amended for further escalation to 60 Gy (15 Gy/fraction). Radiologic complete response rate was 88.9%. Two outfield intrahepatic, 2 distant, 4 concurrent local and outfield, and 1 concurrent local, outfield and distant failures (no local failure at dose levels 3-4) occurred. The worst toxicity was grade 3 hematologic in five patients, with no gastrointestinal toxicity > grade 1. At median follow-up of 28 months for living patients, 2-year local control, progression-free (PFS), and overall survival rates were 71.3%, 49.4% and 69.3%, respectively. Multi-segmental recurrences prior to SBRT was independent prognostic factor for PFS (p = 0.033)., Materials and Methods: Eligible patients had Child-Pugh's class A or B, unresectable HCC, ≤ 3 lesions, and cumulative tumor diameter ≤ 6 cm. Starting at 36 Gy in four fractions, dose was escalated with 2 Gy/fraction per dose-level. CTCAE v 3.0 ≥ grade 3 gastrointestinal toxicity and radiation induced liver disease defined dose-limiting toxicity (DLT)., Conclusions: Helical IMRT-based SBRT was tolerable and showed encouraging results. Confirmatory phase II trial is underway., Competing Interests: Conflicts of interest relevant to this article was not reported.

Purpose: This study aimed to evaluate whether the deformable image registration (DIR) method is clinically applicable to the safe delivery of re-irradiation in hepatocellular carcinoma (HCC)., Materials and Methods: Between August 2010 and March 2012, 12 eligible HCC patients received re-irradiation using helical tomotherapy. The median total prescribed radiation doses at first irradiation and re-irradiation were 50 Gy (range, 36-60 Gy) and 50 Gy (range, 36-58.42 Gy), respectively. Most re-irradiation therapies (11 of 12) were administered to previously irradiated or marginal areas. Dose summation results were reproduced using DIR by rigid and deformable registration methods, and doses of organs-at-risk (OARs) were evaluated. Treatment outcomes were also assessed., Results: Thirty-six dose summation indices were obtained for three OARs (bowel, duodenum, and stomach doses in each patient). There was no statistical difference between the two different types of DIR methods (rigid and deformable) in terms of calculated summation ΣD (0.1 cc, 1 cc, 2 cc, and max) in each OAR. The median total mean remaining liver doses (M(RLD)) in rigid- and deformable-type registration were not statistically different for all cohorts (p=0.248), although a large difference in M(RLD) was observed when there was a significant difference in spatial liver volume change between radiation intervals. One duodenal ulcer perforation developed 20 months after re-irradiation., Conclusion: Although current dose summation algorithms and uncertainties do not warrant accurate dosimetric results, OARs-based DIR dose summation can be usefully utilized in the re-irradiation of HCC. Appropriate cohort selection, watchful interpretation, and selective use of DIR methods are crucial to enhance the radio-therapeutic ratio.

Purpose: For locally unresectable hepatocellular carcinoma (HCC) patients, concurrent chemoradiotherapy (CCRT) has been applied as a loco-regional treatment. After shrinkage of tumors in selected patients, surgical resection is performed. The aim of this study was to evaluate prognostic factors and long-term survivors in such patients., Materials and Methods: From January 2000 to January 2009, 264 patients with HCC were treated with CCRT (45 Gy with fractional dose of 1.8 Gy), and intra-arterial chemotherapy was administered during radiotherapy. Eighteen of these patients (6.8%) underwent hepatic resection after showing a response to CCRT. Cases were considered resectable when tumor-free margins and sufficient remnant volumes were obtained without extrahepatic metastasis. Prior to operation, there were six patients with complete remission, 11 with partial remission, and six with stable disease according to modified Response Evaluation Criteria in Solid Tumors., Results: In pathologic review, four patients (22.2%) showed total necrosis and seven patients (38.9%) showed 70-99% necrosis. A high level of necrosis (≥80%) was correlated with low risk for extrahepatic metastasis and long-term survival. In univariate analyses, vessel invasion and capsular infiltration were significantly correlated with disease free survival (DFS) (p=0.017 and 0.013, respectively), and vessel invasion was significantly correlated with overall survival (OS) (p=0.013). In multivariate analyses, capsule infiltration was a significant factor for DFS (p=0.016) and vessel invasion was significant for OS (p=0.015)., Conclusion: CCRT showed favorable responses and locally advanced HCC converted into resectable tumor after CCRT in selected patients. Long-term survivors showed the pathological features of near total necrosis, as well as negative capsule and vessel invasion.

This study investigated the prognostic significance of portal vein tumor thrombosis (PVTT) response in hepatocellular carcinoma (HCC) patients treated with localized concurrent chemoradiotherapy (CCRT). We retrospectively analyzed 100 patients treated with CCRT for UICC Stage T2-4N0M0 HCC with PVTT between 2002 and 2011. The radiotherapy (RT) volume included both primary tumor and PVTT, and the median radiation dose was 45 Gy. Treatment response was evaluated for up to 6 months after RT. With respect to PVTT response to treatment, complete response (CR) and partial response (PR) were achieved in 14% and 48% of patients, respectively, yielding an objective response (OR) rate of 62%. PVTT size (≤3cm diameter) was associated with a higher rate of a CR (P = 0.001). The median overall survival (OS) was 11.6 months. Independent prognostic factors for OS were OR of the tumor to RT and a CR of the PVTT. Achieving an OR in both the tumor and the PVTT demonstrated a significant correlation with improved survival (P = 0.002). Progression of intrahepatic metastasis was affected not by CCRT but by the clinical features of the PVTT, particularly the initial PVTT site. PVTT response following CCRT seems prognostically significant. CR of the PVTT was associated with improved survival. Achieving an OR in both the tumor and PVTT was also associated with improved survival.

Purpose: Sorafenib is an effective systemic agent for advanced hepatocellular carcinoma. To increase its efficacy, we evaluated the feasibility and benefit of sorafenib combined with radiotherapy., Materials and Methods: From July 2007 to July 2011, 31 patients were treated with a daily dose of 800 mg of sorafenib and radiotherapy. Among them, 13 patients who received radiotherapy on the bone metastasis were excluded. Thirteen patients received 30-54 Gy of radiotherapy on the primary tumor (primary group) and 5 patients received 30-58.4 Gy on the measurable metastatic lesions (measurable metastasis group). Tumor responses at 1 month after the completion of radiotherapy and overall survival were evaluated., Results: The in-field response rate was 100% in the primary group and 60% in the measurable metastasis group. A decrease of more than 80% in the tumor marker α-fetoprotein was observed in 7 patients in the primary group (54%). Toxicities of grades 3-4 were hand-foot syndrome in 3 (17%) patients, duodenal bleeding in 1 (6%) patient, thrombocytopenia in 3 (17%) patients and elevation of aspartate transaminase in 1 (6%) patient. The median overall survival was 7.8 months (95% confidence interval, 3.0-12.6)., Conclusion: The combined treatment of sorafenib and radiotherapy was feasible and induced substantial tumor responses in the target lesions. The results of this study emphasize the importance of individualized approach in the management of advanced hepatocellular carcinoma and encourage the initiation of a controlled clinical trial.

Purpose: To assess the significance of the ratio between standardized uptake values (SUV) of tumor and normal liver tissue obtained from positron emission tomography with fluorine-18-fluorodeoxyglucose (FDG-PET) in predicting the response of hepatocellular carcinoma (HCC) patients treated with external beam radiotherapy (EBRT)., Methods and Materials: We retrospectively analyzed 35 HCC patients who were treated with EBRT between January 2004 and June 2007. All patients underwent FDG-PET in which SUV values were obtained from tumor and normal liver tissues and were used to calculate the ratios (SUV(Tumor)/SUV(Liver)). After FDG-PET, patients received liver treatment including concurrent chemoradiation, transarterial chemoembolization plus RT, or intraarterial chemotherapy plus RT. Using three-dimensional conformal RT, median dose of 45 Gy was delivered in conventional fractions. Patients underwent abdominal/pelvic CT 1 month after RT, and treatment responses were evaluated according to the Response Evaluation Criteria in Solid Tumors criteria., Results: Patients were divided into high-SUV ratio group (n = 20) and low-SUV ratio group (n = 15) according to SUV ratio at a cutoff value of 2.5. Objective responses consisting of either complete response (CR) or partial response (PR) were observed in 16 and 6 patients (46% vs. 17%, p = 0.015), respectively; median survivals after RT were 8 months and 5 months (p = 0.41) for the high-SUV ratio group and the low-SUV ratio group, respectively. Rates of intrahepatic metastases (9% vs. 11%, p = 0.39) and distant metastases (32% vs. 32%, p = 0.27) showed no significant difference between two groups., Conclusions: External beam RT for HCC patients with higher SUV ratios resulted in higher response rates than for patients with lower SUV ratios. Treatment of HCC with higher SUV ratios did not result in increased survival; high rates of intrahepatic and distant metastases in both SUV groups may have affected patient survival. SUV ratios from pre-RT FDG-PET may be beneficial for selecting patients who are likely to respond to EBRT for unresectable HCC., (Copyright © 2012 Elsevier Inc. All rights reserved.)