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To evaluate the effect and mechanism of radiotherapy (RT)-sorafenib pharmacokinetics (PK) in different regimens with conventional or high dose irradiation. Between February 2012 and December 2018, 43 patients with portal vein tumor thrombosis treated with sorafenib plus conventional RT (58%) or stereotactic body radiation therapy (SBRT, 42%) were retrospectively reviewed. In vivo and in vitro studies of concurrent and sequential RT with sorafenib were designed. SBRT resulted in a 3-fold increase in complete recanalization compared to conventional RT group (28% vs. 8%, p = 0.014). Compared to the control group, the area under the concentration vs. time curve (AUC) of sorafenib was increased in the concurrent RT 2Gy and RT 9Gy groups and the sequential RT 9Gy group by 132% (p = 0.046), 163% (p = 0.038) and 102% (p = 0.018), respectively; and was decreased by 59% in the sequential RT 2Gy group (p = 0.036). Sequential RT 2Gy and RT 9Gy increased CYP3A4 activity by 82% (p = 0.028) and 203% (p = 0.0004), respectively, compared to that with the corresponding concurrent regimen. SBRT produced better recanalization than conventional RT with sorafenib. The AUC of sorafenib was modulated by RT. P-gp expression was not influenced by RT. The sequential RT regimen increased CYP3A4 activity that may increase the RT-sorafenib synergy effect and overall sorafenib activity. The biodistribution of sorafenib was modulated by local RT with the different regimens.

Purpose: Portal vein thrombosis (PVT) is generally recognized as a prognostic factor in HCC. Our purpose is to assess and compare the survival of patients with PVT and without PVT, after Y-90 Trans-Arterial Radio-Embolization (TARE) of unresectable HCC, unresponsive to other loco-regional treatments., Materials and Methods: Between November 2005 and November 2012, Y-90 resin-based TARE was performed in an IRB-approved prospective protocol, on 89 patients with unresectable HCC. 33/89 patients had PVT, the remaining 56 were resistant-to-cTACE or underwent TARE as a downstaging therapy. All patients were studied with Multi-Detector Computed Tomography (MDCT), angiography, 99mTc-MAA-scintigraphy and liver biopsy. Gastro-duodenal artery was embolized in most cases. Proton-Pump Inhibitors were administered to prevent gastritis and ulcers. χ2 test with Yates correction and log rank test were used to compare the two proportions and Kaplan-Meier survival curves, respectively., Results: The average activity administered was 1.7 ± 0.4 GBq. After the treatment, CTCAE grade 2 adverse events occurred in 46% (41/89) patients: in particular, fever and abdominal pain were found in 25 and 16 patients, respectively. No major side-effect was observed. According to mRECIST criteria, partial response or complete response was found in 70% of patient three months after the treatment, and in 90.5% nine months after the treatment. No significant difference was found in survival of patients with PVT compared to those without PVT (p-value = 0.672). A complete regression of PVT was observed in almost half patients (13/27, 48.1%)., Conclusions: Portal vein invasion does not affect survival in advanced stage HCC-patients undergoing TARE using Y-90 resin-based microspheres. Y90 procedure is associated with regression of portal vein tumor thrombus., Competing Interests: The authors have declared that no competing interests exist.

Aim: Prognosis of hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) is extremely poor. However, proper therapeutic strategies have not been established yet. The purpose of this study is to identify the effects of external beam radiation therapy (EBRT) for MVI of HCC., Methods: We have analyzed and evaluated 80 consecutive patients with HCC with MVI who underwent EBRT, and factors associated with enhanced survival in EBRT were evaluated by univariate and multivariate analysis., Results: The local response rate of radiotherapy for the irradiated MVI was 66.2%. The time to progression of the irradiated MVI was 5.8 months. Univariate and multivariate analyses showed that the higher irradiation dose (over 45 Gy) and the irradiation location (hepatic vein tumor thrombus - HVTT) were significant factors associated with survival benefits of EBRT. The response of EBRT for HVTT was significantly superior to that for portal vein or bile duct tumor thrombus., Conclusion: We conclude that a multidisciplinary therapeutic strategy based on EBRT should be proactively selected in the treatment of advanced HCC with MVI., (© 2019 S. Karger AG, Basel.)

Purpose: To evaluate the safety and efficacy of iodine-125 ( 125 I) seed strand implantation in combination with transarterial chemoembolization for the treatment of hepatitis B-related unresectable hepatocellular carcinoma (HCC) with portal vein invasion., Materials and Methods: From January 2013 to June 2016, 76 HCC patients with type II tumor thrombus were included in this single-center retrospective study. Twenty patients underwent 125 I seed strand implantation combined with transarterial chemoembolization (group A; n = 20), while 56 patients underwent transarterial chemoembolization alone (group B; n = 56). The procedure-related and radiation complications were assessed. Overall survivals were compared by propensity-score analysis., Results: The technique was successfully performed in all patients. The mean intended dose (r = 10 mm; z = 0; 240 days) was 62.6 ± 1.8 Gy. No grade 3 or 4 adverse events related to the procedure occurred in either group. After propensity-score-matching analysis, 19 patients were selected into each group, respectively. In the propensity-matching cohort, the median overall survival time was significantly longer in group A than in the group B (19 pairs; 28.0 ± 2.4 vs 8.7 ± 0.4 mo; P = .001). Treatment strategy, arterioportal shunt, and number of transarterial chemoembolization sessions were significant predictors of favorable overall survival time., Conclusions: 125 I seed strand implantation combined with transarterial chemoembolization is a safe and effective treatment for HCC patients with portal vein invasion., (Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.)

Background: To determine the effect of Yttrium-90 (Y90) radioembolization on health-related quality of life (HRQOL) and its effect on overall survival advanced, unresectable infiltrative hepatocellular carcinoma (HCC) patients with concurrent portal vein thrombosis (PVT)., Methods: Consecutive patients with unresectable infiltrative HCC and PVT were recruited. The Short-Form 36 (SF-36) questionnaire was used to assess HRQOL for consecutive patients treated with glass-based Y90 based on a prospective phase II trial. MR imaging was used to determine tumor progression every 3 months post-treatment. Overall survival (OS) from treatment and time to progression (TTP) was analyzed using Kaplan-Meier estimation and log-rank test., Results: Thirty patients were treated and followed for 17.4 months; physical and mental component summary scores (PCS & MCS) remained unchanged at one, three, and six months. While no difference was observed in baseline SF-36 scores for patients with prolonged TTP (≥4 months) and OS (≥ 6 months), corresponding 1-month PCS were significantly higher than those with TTP < 4 months and OS < 6 months. At 1 month, patients with normalized Physical Function (PF), Role Physical (RP) and PCS within 2 standard deviations (SD) of US normalized baseline scores had a significantly prolonged median OS (15.7 vs. 3.7 months; p < 0.001) and TTP (12.4 vs. 1.8 mo; p < 0.001) compared those with physical component scores greater than 2SD below normalized US population values., Conclusion: Y90 radioembolization for HCC demonstrated long-term preservation of HRQOL. Lower baseline HRQOL scores were predictive of poorer OS. Early (1 month post-treatment) significant decreases in PCS were independent predictors of poorer OS and TTP., Trial Registration: ClinicalTrials.gov identifier NCT01556282 , registered March 16, 2012.

Sorafenib has improved the median overall survival of unresectable or otherwise untreatable hepatocellular carcinoma (HCC) of ∼3 months, compared to supportive cares. Complete response, although rare, has been reported. The authors reported herein a case of complete biochemical and radiological remission of advanced unresectable HCC with lymph node metastasis and tumoral portal vein thrombosis treated by 5 months therapy with sorafenib followed by adjuvant Yttrium-90 radioembolization. At 12 months follow-up, there is no evidence of HCC recurrence.

The aim of the study is to evaluate the practicability and therapeutic efficacy of (125)iodine seeds implantation percutaneously for portal vein tumor thrombosis (PVTT) in patients with hepatocellular carcinoma (HCC). Nineteen patients with HCC accompanied with PVTT received ultrasound-guided implantation of 8-30 (125)iodine seeds, 8 mm apart within the portal vein tumor thrombi. The patients were followed up postoperatively for a period of 3-22 months. The successful rates of the procedure, postoperative changes of liver and renal function, hemogram, complications and therapeutic response were monitored. (125)I seeds were successfully implanted in the portal veins in all patients without serious complications. During the follow-up period, the portal vein tumor thrombi all shrunk obviously. Percutaneous implantation of (125)iodine seeds into the portal vein is an effective and safe treatment for PVTT accompanying HCC.

The aim of this study was to evaluate the role of radiotherapy in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVT) and to determine the prognostic factors for overall survival. Altogether, 106 patients with HCC and PVT referred for radiotherapy between 2004 and 2009 were retrospectively reviewed. A total of 60 Gy in 30 daily fractions was delivered with intensity-modulated radiotherapy techniques. Patient-related and treatment-related factors were analyzed to evaluate their prognostic significance for the overall survival rate. Complete response was noted in 10 patients and partial response in 55 patients. The liver lesions had become resectable after the completion of radiotherapy in 12 patients, and surgery was subsequently performed. One or two courses of transarterial chemoembolization (TACE) were administered to 19 patients following radiotherapy. The 1-year and 2-year overall survival rates were 34.7% and 11%, respectively, and the median survival was 7 months for the entire cohort of patients. Post-radiotherapy treatment modality, response to radiotherapy and JIS score were demonstrated as independent prognostic factors for overall survival (P = 0.003, P < 0.001, P < 0.001, respectively). For patients who received surgical intervention after radiotherapy, the median survival was 30 months and the 2-year overall survival rate was 67%. Radiotherapy achieved a 61.5% objective response rate and prolonged survival in patients with PVT. The liver tumors had become resectable after radiotherapy in 11% of patients. Our results suggested that radiotherapy could offer survival benefits and should be considered as a treatment option for patients with PVT. Radiotherapy could also be considered as a preoperative treatment modality in patients with HCC and PVT., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: To compare positron emission tomography/computed tomography (PET/CT) imaging with bremsstrahlung single photon emission computed tomography (SPECT) in patients after yttrium-90 ((90)Y) microsphere radioembolization to assess particle uptake., Materials and Methods: This prospective study comprised patients with large (> 5 cm) hepatocellular carcinoma (HCC) or tumor-associated portal vein thrombus (PVT), or both. After radioembolization for HCC, patients underwent bremsstrahlung SPECT/CT and time-of-flight PET/CT imaging of (90)Y without additional tracer administration. Follow-up imaging and toxicity was analyzed. Imaging analyses of PET/CT and bremsstrahlung SPECT/CT were independently performed., Results: There were 13 patients enrolled in the study, including 7 with PVT. Median tumor diameter was 7 cm. PET/CT demonstrated precise localization of (90)Y particles in the liver, with specific patterns of uptake in large tumors. In cases of PVT, PET/CT showed activity within the PVT. When correlated to short-term follow-up imaging, areas of necrosis correlated with regions of uptake seen on PET/CT. Compared with bremsstrahlung imaging, PET/CT demonstrated at least comparable spatial resolution with less scatter. Quantitative uptake in nontreated regions of interest showed significantly reduced scatter with PET/CT versus SPECT/CT (1% vs 14%, P < .001)., Conclusions: Evaluation of (90)Y particle uptake with PET/CT potentially demonstrates high spatial resolution and low scatter compared with bremsstrahlung SPECT/CT. Confirmation of particles within PVT on PET/CT correlates with response on follow-up imaging and may account for the efficacy of radioembolization in patients with PVT., (Copyright © 2013 SIR. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: To compare the efficacy and toxicity of short-course carbon ion radiotherapy (C-ion RT) for patients with hepatocellular carcinoma (HCC) in terms of tumor location: adjacent to the porta hepatis or not., Materials and Methods: The study consisted of 64 patients undergoing C-ion RT of 52.8 GyE in four fractions between April 2000 and March 2003. Of these patients, 18 had HCC located within 2 cm of the main portal vein (porta hepatis group) and 46 patients had HCC far from the porta hepatis (non-porta hepatis group). We compared local control, survival, and adverse events between the two groups., Results: The 5-year overall survival and local control rates were 22.2% and 87.8% in the porta hepatis group and 34.8% and 95.7% in the non-porta hepatis group, respectively. There were no significant differences (P=0.252, P=0.306, respectively). Further, there were no significant differences in toxicities. Biliary stricture associated with C-ion RT did not occur., Conclusions: Excellent local control was obtained independent of tumor location. The short-course C-ion RT of 52.8 GyE in four fractions appears to be an effective and safe treatment modality in the porta hepatis group just as in the non-porta hepatis group., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: To compare the differences in dose-volume data among coplanar intensity modulated radiotherapy (IMRT), noncoplanar IMRT, and helical tomotherapy (HT) among patients with hepatocellular carcinoma (HCC) and portal vein thrombosis (PVT)., Methods: Nine patients with unresectable HCC and PVT underwent step and shoot coplanar IMRT with intent to deliver 46-54 Gy to the tumor and portal vein. The volume of liver received 30Gy was set to keep less than 30% of whole normal liver (V30<30%). The mean dose to at least one side of kidney was kept below 23 Gy, and 50 Gy as for stomach. The maximum dose was kept below 47 Gy for spinal cord. Several parameters including mean hepatic dose, percent volume of normal liver with radiation dose at X Gy (Vx), uniformity index, conformal index, and doses to organs at risk were evaluated from the dose-volume histogram., Results: HT provided better uniformity for the planning-target volume dose coverage than both IMRT techniques. The noncoplanar IMRT technique reduces the V10 to normal liver with a statistically significant level as compared to HT. The constraints for the liver in the V30 for coplanar IMRT vs. noncoplanar IMRT vs. HT could be reconsidered as 21% vs. 17% vs. 17%, respectively. When delivering 50 Gy and 60-66 Gy to the tumor bed, the constraints of mean dose to the normal liver could be less than 20 Gy and 25 Gy, respectively., Conclusion: Noncoplanar IMRT and HT are potential techniques of radiation therapy for HCC patients with PVT. Constraints for the liver in IMRT and HT could be stricter than for 3DCRT.

Background and Purpose: The prognosis of patients with advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is extremely poor, as effective treatment options are limited. The authors performed a retrospective review to evaluate the efficacy of proton-beam therapy (PBT) for patients presenting with PVTT in the setting of HCC., Patients and Methods: Between February 1991 and September 2005, 35 patients with HCC and tumor thrombi in the main trunk or major branches of the portal vein presented for consideration of PBT. Their tumor sizes ranged from 25 mm to 130 mm (median, 60 mm). A median total dose of 72.6 GyE in 22 fractions was delivered over 31 days to a target volume that encompassed both the primary hepatic lesion and the PVTT., Results: 32 patients were progression-free during a median follow-up period of 21 months (range, 2-88 months) and three patients experienced disease progression. Local progression-free survival rates were 46% at 2 years and 20% at 5 years, and the median local progression-free survival was 21 months. Acute toxicity > or = grade 3 was observed in three patients, and no patient experienced late toxicity > or = grade 3. None of the patients had to discontinue treatment as a result of toxicity., Conclusion: PBT improved local control and significantly prolonged survival in HCC patients with PVTT.

Background/aims: The purpose of this study is to evaluate the effect of radiation therapy (RT) for tumor thrombosis (TT) in the major portal vein (PV) or inferior vena cava (IVC) from unresectable hepatocellular carcinoma., Methodology: Fifteen HCC patients with main PVTT (n = 10) and IVCTT (n 5) were treated with three-dimensional conformal RT between 2001 and 2004. The mean dose was 38.5 Gy (range 28 to 54Gy). The concurrent therapies to intrahepatic tumor included transcatheter arterial chemoembolization (TACE) in 7, TACE + hepatic arterial infusion in 2 and systemic chemotherapy in 1 patient. The therapeutic effect was assessed by tumor regression for TT., Results: An objective response was observed in 3 of 15 patients (20%). There were no patients with progressive disease. The median survival time was 10 months. In 12 cases with stable disease, time to progression (TTP) estimated above 6 months were 42% (5/12 cases). In univariate analysis, therapeutic effect and TTP were affected to survival time. All patients did not have severe deterioration of liver function., Conclusions: In the current study, we concluded that RT was superior treatment in terms of local control capability and was useful to continue further treatment because RT did not make liver function worse.