Radiotherapy For Hepatocellular Carcinoma Research Articles

Carbon-ion radiotherapy for hepatocellular carcinoma with major vascular invasion: a retrospective cohort study

BackgroundMacroscopic vascular invasion (MVI) significantly impacts survival in patients with hepatocellular carcinoma (HCC), warranting systemic therapy over locoregional therapy. Despite novel approaches, HCC with MVI has a poor prognosis compared to early-to intermediate-stage HCC. This study aimed to evaluate the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for HCC characterized by MVI.MethodsThis retrospective cohort study evaluated HCC patients with MVI treated using C-ion RT with a dose of 45.0–48.0 Gy/2 fractions or 52.8–60.0 Gy/4 fractions between 1995 and 2020 at our institution in Japan. We analyzed the prognostic factors and rates of local recurrence, survival, and adverse events. The local recurrence rate was determined using the cumulative incidence function, with death as a competing event. Survival rates were determined using the Kaplan–Meier method. The log-rank test for univariate analysis and the Cox proportional hazards model for multivariate analysis were used to compare subgroups.ResultsIn total, 76 patients with a median age of 71 years (range, 45–86 years) were evaluated. Among them, 68 had Child–Pugh grade A while eight had grade B disease. In 17 patients, the vascular tumor thrombus reached the inferior vena cava or main trunk of the portal vein. Over a median follow-up period of 27.9 months (range, 1.5–180.4 months), the 2-year overall survival, progression-free survival, and local recurrence rates were 70.0% (95% confidence interval [CI]: 57.7–79.4%), 32.7% (95% CI: 22.0–43.8%), and 8.9% (95% CI: 1.7–23.5%), respectively. A naïve tumor and a single lesion were significant prognostic factors for overall survival in the univariate analysis. Albumin-bilirubin grade 1 and a single lesion were independent prognostic factors in the multivariate analysis. Overall, four patients (5%) experienced grade 3 late adverse events, with no observed grade 4 or 5 acute or late adverse events.ConclusionsC-ion RT for HCC with MVI showed favorable local control and survival benefits with minimal toxicity.

CircNOP14 increases the radiosensitivity of hepatocellular carcinoma via inhibition of Ku70-dependent DNA damage repair

Circular RNAs (circRNAs) are profoundly affected in hepatocellular carcinoma (HCC) through various pathways. However, the role of circRNAs in the radiosensitivity of HCC cells is yet to be explored. In this study, we identified a circRNA—hsa_circ_0006737 (circNOP14) involved in the radiosensitivity of HCC. We found that circNOP14 increased the radiosensitivity of HCC cells both in vitro and in vivo. Notably, using a circRNA pulldown assay and RNA-binding protein immunoprecipitation, we identified Ku70 as a novel and robust interacting protein of circNOP14. Mechanistically, circNOP14 interacts with Ku70 and prevents its nuclear translocation, thereby increasing irradiation-induced DNA damage. Therefore, our findings may provide a predictive indicator and intervention option for 125I brachytherapy or external radiotherapy in HCC.

Nifuroxazide suppresses PD-L1 expression and enhances the efficacy of radiotherapy in hepatocellular carcinoma

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

Nifuroxazide suppresses PD-L1 expression and enhances the efficacy of radiotherapy in hepatocellular carcinoma.

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

Carbon ion radiotherapy of hepatocellular carcinoma provides excellent local control: The prospective phase I PROMETHEUS trial

Carbon ion radiotherapy of hepatocellular carcinoma provides excellent local control: The prospective phase I PROMETHEUS trial

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.

Applications of Yttrium-90 (90Y) in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, affecting millions of people worldwide. Due to the lack of systemic radiation therapy in hepatocellular carcinoma, researchers have been investigating the use of yttrium-90 (90Y) radioembolization for local-regional tumor control since the 1960s. With the development of glass and resin 90Y microspheres and the durable local control, good long-term efficacy, and equivalent tumor responsiveness and tolerability of 90Y-selective internal irradiation compared with alternative therapies such as transarterial chemoembolization (TACE) and sorafenib, 90Y radioembolization has gradually been applied in the treatment of hepatocellular carcinoma of all stages. In this article, we summarize the latest progress of 90Y in the treatment of hepatocellular carcinoma in terms of its principle, advantages, indications, contraindications, efficacy and adverse effects.

Benefit of perioperative radiotherapy for hepatocellular carcinoma: a quality-based systematic review and meta-analysis.

Although surgery is the standard curative modality for hepatocellular carcinoma, more than two-thirds experience intrahepatic recurrence. Since no standard perioperative treatment has been established, the authors performed a meta-analysis to evaluate the benefits of perioperative radiotherapy (RT). The PubMed, MEDLINE, EMBASE, and Cochrane Library were searched until May 2023. Randomized or propensity-matched studies evaluating at least five major clinical factors investigating benefit of perioperative RT, were included. The main effect measure were the pooled odds ratios (OR) regarding the benefit of perioperative RT using 2-year overall survival (OS) and 1-year disease-free survival (DFS) data. Seven studies (five randomized and two propensity-matched studies) involving 815 patients were included. The pooled ORs for 1-year DFS and 2-year OS were 0.359 (95% CI: 0.246-0.523) and 0.371 (95% CI: 0.293-0.576), respectively, favoring perioperative RT, with very low heterogeneity. In the subgroup analyses, the benefits of OS and DFS were consistent between the two subgroups [portal vein thrombosis (PVT) and narrow resection margin (RM) groups]. In the PVT subgroup, the pooled OS rates at both 1-year and 2-year (75.6 vs. 36.9%, P <0.001; 25.6 vs. 9.9%, P =0.004) and DFS rates at both 1-year and 2-year (25.2 vs. 10.3%, P =0.194; 11.9 vs. 3.0%, P =0.022) were higher in the perioperative RT group. In the narrow RM subgroup, the surgery and RT groups showed higher pooled OS rates for both 1-year and 2-year (97.3 vs. 91.9%, P =0.042; 90.4 vs. 78.7%, P =0.051) and DFS (88.1 vs. 72.6%, P <0.001; 70.1 vs. 51.7%, P <0.001). Grade 5 toxicity was not reported, and three studies reported grade ≥3 or higher liver function test abnormalities, ranging from 4.8-19.2%. The present study supports the oncological benefits of perioperative RT, for cases with high-risk of recurrence. Oncologic outcomes between subgroups differed according to clinical indications.

Comparing resection and stereotactic body radiation therapy for hepatocellular carcinoma with macrovascular invasion: A propensity score matched study.

521 Background: Macrovascular invasion (MVI) in hepatocellular carcinoma (HCC) patients is a poor prognostic factor. Current guidelines endorse systemic therapy for MVI. Local therapies present a potential for obliteration of MVI and improved survival. Surgery has been the standard local therapy at our institution, and stereotactic body radiotherapy (SBRT) has emerged as an alternative local therapy for this patient population. Methods: In this retrospective study, one-to-one optimal pair propensity score matching was used to compare outcomes of HCC patients with MVI who underwent surgery or received SBRT. Matching was done based on sex, age, ECOG, cirrhosis presence, Child-Pugh class, number of tumours, tumour volume, alpha-fetoprotein level, ALBI score, Japanese Classification of portal vein invasion, and hepatic vein invasion. Overall survival was estimated using the Kaplan-Meier method and between group differences determined using the log-rank test. The cumulative incidence of recurrence, accounting for the competing risk of death, was compared using Gray’s test. Results: Ninety of 193 patients were included after matching (45 patients in both the surgery and SBRT groups) (Table). The SBRT group had a median OS of 15 months (95% CI: 10-38), while in the surgery group it was 24 months (95% CI: 11-81). Comparing the 12-, 36-, and 60-month overall survival (OS) rates between the SBRT group (57%, 33%, 15%) and the surgery group (58%, 37%, 34%), there was no statistically significant differences (p=0.16); the 5-year OS was double in the surgical resection group. The 12-, 36-, and 60-month cumulative incidence of HCC recurrence in the SBRT group (47%, 73%, 75%) was comparable to the surgery group (69%, 69%, 69%) (p=0.89). Conclusions: Long term survival is possible in patients with HCC and MVI in a substantial minority of patients with HCC and MVI treated with local therapies. There was no statistical difference in outcomes; however, surgical resection resulted in numerically longer survival outcomes compared to SBRT after propensity score adjustment. There is rationale for investigating both local therapies with systemic therapies in future clinical trials. [Table: see text]

Concurrent nivolumab and external beam radiation therapy for hepatocellular carcinoma with macrovascular invasion: A phase II study

Nivolumab was the first immune checkpoint inhibitor approved for hepatocellular carcinoma (HCC). External beam radiation therapy (EBRT) is locally effective and may enhance the effectiveness of immunotherapy. This study investigated the efficacy and safety of concurrent nivolumab and EBRT in HCC with macrovascular invasion. In this phase II multicenter trial, patients with HCC and macrovascular invasion were concurrently treated with intravenous nivolumab (3mg/kg every 2 weeks) and EBRT, followed by maintenance nivolumab until progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) and safety, and secondary endpoints were overall survival, time-to-progression, objective response rate, and disease control rate. Between January 2020 and June 2021, 50 patients (male 84%, median age 62.5) were enrolled; 47 (94.0%) and 13 (26.0%) with portal (Vp1/2, n= 21; Vp3, n= 23; Vp4, n= 3) and hepatic vein invasion, respectively. Patients received EBRT (median dose: 50 [IQR 43-50] Gy) after the first nivolumab dose. The median number of nivolumab doses was 8.5. Median PFS was 5.6 (90% CI 3.6-9.9) months. Median overall survival and time-to-progression were 15.2 (90% CI 10.8-19.6) and 5.6 (90% CI 3.6-9.9) months, respectively. The objective response rate and disease control rate were 36.0% and 74.0%, respectively. The median duration of response was 9.9 months. Of 35 patients with follow-up data, 23 received subsequent systemic treatment, including atezolizumab-bevacizumab, sorafenib, lenvatinib, and regorafenib. Treatment-related any grade adverse events (AEs) and grade 3/4 AEs occurred in 40 (80.0%) and 6 (12.0%) patients, respectively. Common treatment-related AEs included pruritus (38.0%) and rash (16.0%), with no treatment-related deaths. Concurrent nivolumab therapy and EBRT showed encouraging PFS with acceptable safety in patients with advanced HCC and macrovascular invasion. Immune checkpoint inhibitors, the standard care for advanced hepatocellular carcinoma (HCC), show relatively poor therapeutic effects in patients with advanced HCC and macrovascular invasion. In this investigator-initiated phase II study, we, for the first time, show that concurrent external beam radiation therapy with nivolumab, an immune checkpoint inhibitor, led to encouraging progression-free survival in patients with HCC and macrovascular invasion. The concurrent treatment was tolerable without significant safety concerns. Further randomized studies investigating the combination of immunotherapy and external beam radiation therapy are required. NCT04611165.

Portal-hypertension features are associated with ascites occurrence and survival in patients with hepatocellular carcinoma treated by external radiotherapy.

We studied the impact of Portal hypertension (PHT) on ascites occurrence and on radiotherapy outcome in cirrhotic patients with hepatocellular carcinoma (HCC). All cirrhotic patients that received radiotherapy for HCC between 2012 and 2022 were included. Portal hypertension-Score was built using univariate analysis with the presence of esophageal varices (EV), platelet count, history of acute variceal bleeding (AVB) and spleen size. Time-to-events data were estimated using Kaplan-Meier method with log-rank and Cox-models. 60 patients were included (female 27%, age 67 years-old, Child-Pugh A 82%, alcoholic/non-alcoholic steatohepatitis/hepatitis C virus 55/40/32%). 38% and 15% presented history of ascites and AVB respectively, 25% had large EV, 53.5% presented PHT score ≥ 5. 92% were BCLC-0/A, median tumor size was 30mm. At 6months, ascites incidence was 19% and precluded access to further HCC treatment for all patients with HCC recurrence. All PHT parameters included in the score and PHT score ≥ 5 (hazard ratio (HR)=14.07, p=0.01) were associated with ascites occurrence. Transplantation free survival and recurrence free survival at 1year were 56% and 47% respectively. Albi grade 3 (HR=3.01; p=0.04) was independently associated with Transplantation free survival. Radiotherapy should be cautiously performed in patients with PHT score ≥ 5 because of ascites occurrence risk precluding access to further HCC treatments.

Analysis of treatment response based on 1.5T magnetic resonance imaging texture analysis in stereotactic body radiotherapy of hepatocellular carcinoma

PurposeMagnetic Resonance Image (MRI)-guided stereotactic body radiotherapy (MRgSBRT) is a promising technique in the treatment of hepatocellular carcinoma (HCC). However, treatment response varies among patients. The aim of this study was to evaluate the treatment response using radiomics features extracted from 1.5 T MRI in HCC patients treated with SBRT. Materials and methods19 patients with biopsy-proven HCC who were treated with SBRT by 1.5 T MRI-guided were enrolled, all of whom were treated with 8–10 fractions with biological effective dose (BED) range of 95.2–107.1 Gy. We acquired images of pretreatment, delivered BEDs of 35–40 Gy, and delivered BEDs of 55–60 Gy. We combined three classic feature selection methods: least absolute shrinkage and selection operator (LASSO), extreme gradient boosting (XGBoost), and random forest (RF) to extract the intersection of radiomics features from the gross tumor volume (GTV) and features were averaged over the three fractions. We used the receiver operating characteristic (ROC) area under curve (AUC) obtained using leave-one-out cross-validation (LOOCV) to assess the predictive capacity. ResultsSeven patients showed response to treatment based on post-treatment imaging studies. The optimum intersection of radiomics features selected by three methods was Neighborhood Grey Tone Difference Matrix (NGTDM) contrast and NGTDM strength. The logistic regression-based model achieved an AUC of 0.821 (95% confidence interval, 0.618–1). ConclusionsRadiomics features containing biological prognostic information extracted during MRgSBRT could predict tumor treatment response, facilitating stratification of high-risk patients and providing clinical application value for individualized care of patients with different response to treatment.

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.

Impact of radiation therapy and alpha-fetoprotein level on survival outcomes for patients with hepatocellular carcinoma: a population-based study.

The use of radiation therapy (RT) in hepatocellular carcinoma (HCC) remains a matter for debate. Recently published research indicate that advanced RT techniques may improve survival in patients with HCC. This study aimed to evaluate this hypothesis in a large-scale retrospective cohort. The effect of alpha-fetoprotein (AFP) was taken into account because of its important role in the prognosis of HCC. The Surveillance, Epidemiology, and End Results (SEER) database was queried for adults patients diagnosed 2010-2019 with HCC (≥ 18 years). The study population was divided into four groups: Non-radiation & AFP-positive (reference), Non-radiation & AF-negative, Radiation & AFP-positive, Radiation & AFP-negative. Distant metastasis (DM) was used as a stratification factor. Differences in 5-year overall survival (OS) of the four groups were assessed using the Kaplan-Meier method. Univariate and multivariable Cox proportional hazards model were used to estimate unadjusted and adjusted hazard ratios (HR). A total of 34,656 patients were eligible for this analysis, including 21,084 (60.8%), 8,449 (24.4%), 3,810 (11.0%) and 1,313 (3.8%) in the Non-radiation & AFP-positive, Non-radiation & AF-negative, Radiation & AFP-positive and Radiation & AFP-negative groups, respectively. Median OSs of the four groups were 3, 4, 5 and 11 months in the DM cohort, and 12, 28, 15, and 28 months in the Non-DM cohort. Patients in the Radiation & AFP - group had the best OS and patients in the Non-radiation & AFP + group had the worst OS (adjusted HR [95% confidence interval (CI)]: 0.497 [0.399-0.619] in the DM cohort, and 0.405 [0.372-0.441] in the Non-DM cohort). Radiation & AFP + also showed improved survival compared with the reference group (adjusted HR [95%CI]: 0.725 [0.657-0.801] in the DM cohort, and 0.630 [0.600-0.661] in the Non-DM cohort). This population-based cohort study confirmed a significant improvement in overall survival with radiation therapy in HCC. AFP-negative patients benefit the most from RT. Superior OS of radiation therapy and AFP-negative status persisted even in patients with complex metastasis patterns. Our data suggest that radiation may provide an alternative modality for unresectable HCC.

Long-Term Clinical Outcome of Carbon Ion Radio Therapy for Hepatocellular Carcinoma in the Caudate Lobe

Surgical resection is the first-line treatment for hepatocellular carcinoma in the caudate lobe (caudate HCC), but it is often difficult due to the tumor's location. In addition, radiofrequency ablation and transcatheter arterial chemoembolization are also difficult for the same reason. This study aimed to evaluate the safety and efficacy of carbon-ion radiation therapy (C-ion RT) for caudate HCC. We performed a retrospective cohort study of patients with hepatocellular carcinoma treated by C-ion RT between April 2000 and March 2020 in our institution. The eligibility criteria for this study were: (1) located mainly in the caudate lobe (2) the treatment protocols of 45.0-48.0 Gy/2 fractions or 52.8-60.0 Gy/4 fractions, which proved the safety and efficacy in the past clinical trials; (3) N0M0 status; (4) an Eastern Cooperative Oncology Group performance status (PS) of 0 to 2; (5) controllable ascites. The prescribed dose (Gy) used in this study is relative biological effectiveness (RBE) weighted dose. Overall survival (OS), progression-free survival (PFS), and local control rate (LC) were calculated by the Kaplan-Meier method. Adverse events were evaluated by NCI-CTCAE ver. 5.0. SPSS software version 27.0 (IBM Inc.) was used for all analyses. We defined p-value < 0.05 as statistically significant. A total of 25 patients met the criteria and were evaluated. The median patient age was 73 years (range 58-89), and 21 of 25 patients were male. The number of patients with PS 0 was 22, PS 1 was 1, and PS 2 was 2. The number of HBV-related HCC cases was in 8, HCV-related HCC cases was in 11, and non-B and non-C cases was in 6. The median maximum tumor diameter was 3.0 cm (1.1-4.8 cm). In 6 patients, identification of vascular invasion to the main trunk of the portal vein and/or major hepatic vein was confirmed. The Child-Pugh (CP) grade was A in 21 patients and B in 4. The modified albumin-bilirubin (mALBI) grade 1 is in 17 patients, 2a in 4, 2b in 4. Prescribed doses were 45 Gy / 2 fr in 3 cases, 48 Gy / 2 fr in 12 cases, 52.8 Gy / 4 fr in 7 cases, and 60 Gy / 4 fr in 3 cases. With a median follow-up period of 43.6 months (range 0.3-85.0), 3-year OS, PFS, and LC were 74% (95% confidence interval [CI], 54.8-93.8%), 32% (95% CI, 11.8-51.4%), and 93% (95% CI, 79.4-106%), respectively. All patients had no Grade 2 or higher adverse events during the observation period. The safety and efficacy of C-ion RT for caudate HCC were demonstrated. These results suggested that C-ion RT may be a promising treatment option for patients with caudate HCC.

Efficacy and Safety of Image-Guided Hypofractionated Radiotherapy for Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis

To evaluate the efficacy and safety of image-guided 10-fraction hypofractionated radiotherapy (RT) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). Between 2016 and March 2022, 69 HCC with PVTT patients received RT (40-50Gy/10fx) in our institutions. The median prescribed dose of 50 Gy (range, 40-50 Gy, BED10; 56-75 Gy10) was delivered in 10 fractions in all patients. Follow-up imaging was performed at three-month intervals after the completion of RT. The extent of PVTT was described according to the Liver Cancer Study Group of Japan classification: Vp0 = no PVTT, Vp1 = segmental portal vein branch, Vp2 = right/left anterior/posterior portal vein, Vp3 = right/left portal vein and Vp4 = main portal vein. Response evaluation was performed using response evaluation criteria in solid tumors, version 1.1. Freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS) were calculated from the start date of RT. In this cohort, 4.3% of patients had Vp1 PVTT, 20.3% had Vp2, 37.7% had Vp3, and 37.7% had Vp4. The median PTV volume was 105.3 cc (interquartile range [IQR], 74.1-179.4 cc). Fifty-two (75.4%) patients received 50 Gy in 10 fractions. With a median follow-up of 10.2 months (IQR, 6-21 months), the median OS was 18.5 months, and 1-year FFLP, PFS, and OS rates were 84.8%, 26.9%, and 62.2% respectively. At 3 months after RT, 13.0% had a complete response, 36.2% had a partial response, 46.4% had a stable disease and 4.4% had a progressive disease. In the multivariate analysis, AFP ≥ 600 IU/ml (HR 2.06, p = 0.03), Child-Pugh Class B or C (HR 2.30, p = 0.02), and modified Union for International Cancer Control (mUICC) stage IVA or IVB (4.05, p = 0.02) were significantly related to OS. During the follow-up period, there were 2 (2.8%) cases of grade ≥3 toxicity: grade 3 AST/ALT elevation (n = 1), and acute cholangitis (n = 1). Hypofractionated RT demonstrated promising local PVTT control with acceptable toxicity. These data suggest that 10-fraction image-guided hypofractionated RT (BED10 = 56-75 Gy10) is a feasible treatment option for PVTT in HCC patients.

Intratumoral Dose Escalation Using Lattice Radiotherapy for Hepatocellular Carcinoma with Unfavorable Size and Location

Stereotactic body radiation therapy (SBRT) is a standard of care for unresectable hepatocellular carcinoma (HCC). However, its safe delivery is limited by tumor size and adjacent organs-at-risk (OARs). RTOG 1112 showed a survival benefit with local control in advanced HCC, but median dose was limited to 35 Gy in 5 fractions due to OARs. Here, we demonstrate the dosimetric feasibility of lattice radiation therapy (LRT) for dose escalation in advanced HCC. Five-fraction volumetric arc-based (VMAT) LRT plans were generated using a customized Python v3.6 script. For each combination of peak/valley doses and sphere size and spacing, a bounding box was generated around the gross tumor volume (GTV) and divided into equal segments in the x, y, and z planes. Individual spheres were constructed for a given parameter set and those fully encompassed within the target contracted by 2 cm were used to create peak dose targets with values of 30, 40, or 50 Gy. Valley dose target volumes over a range of 2 to 45 Gy were generated by subtracting an 8 mm expansion of the peak dose spheres from the overall target volume. Multi-criteria optimization (MCO) was applied to generate a final plan. The planning target volume (PTV) was a 5-mm uniform expansion from the GTV. All plans were generated at maximum inspiration on 4D-CT. OAR parameters were compared against a standard 5-fraction SBRT plan using Wilcoxon signed-rank testing. GTV and PTV measured 593 (23%) and 804 (32%) cm3, respectively, of a total liver volume of 2525 cm3. The minimum distance of GTV from stomach and duodenum was 6 mm and 2 mm, respectively. Plans were evaluated as per RTOG 1112 with stepwise reduction from a maximum PTV dose of 50 Gy based upon ability to meet mean liver dose (MLD, defined as liver-GTV) constraints; the 30 Gy threshold was the highest achievable. Of 7 eligible LRT plans, 5 with ablative 50 Gy peak doses were analyzed. Associated valley doses were 15 or 20 Gy. Median values of mean GTV and PTV doses for these plans were 36.2 (IQR, 34.6 - 37.8) and 32.9 (IQR, 31.3 - 33.4) Gy, respectively. A median of 12.4% (IQR, 7.4 - 28.4) of the GTV received a dose of 50 Gy. Median doses to 0.5 cc of stomach and duodenum were 16.7 Gy (range, 15.6 - 19.6) and 14.4 Gy (range, 12.3 - 23.9), respectively. The median value for MLD was 13.9 Gy (range, 13.6 to 14.8) and the median volume of normal liver spared 15 Gy was 1114 cm3 (range, 969 to 1154). These hepatic parameters were significantly decreased compared to a standard 30 Gy SBRT plan (18.1 Gy and 611.3 cc spared, p = 0.043 for both) which did not meet constraints. Dose escalation of advanced HCC using LRT is dosimetrically feasible. Though mean target doses remained limited by MLD, LRT allowed delivery of ablative dose to 12.4% of the GTV while meeting critical OAR constraints. Intratumoral dose-escalation may improve local control in advanced HCC patients.

Clinical and Dosimetric Results of Proton or Photon Radiation Therapy for Large (>5 cm) Hepatocellular Carcinoma: A Retrospective Analysis

Purpose: To report the clinical and dosimetric attributes of patients with large unresectable hepatocellular carcinoma (HCC) undergoing proton or photon radiotherapy. Methods: We retrospectively analyzed the outcomes and dosimetric indices of 159 patients with >5 cm non-metastatic HCC who underwent definitive radiotherapy using either protons (N=105) or photons (N=54) between 2014 and 2018. Additional photon plans were performed in the 105 proton-treated patients using the same dose prescription criteria for intragroup dosimetric comparison. Results: After a median follow-up of 47 months, patients with biologically effective dose (BED10) ≥75 Gy exhibited significantly better local control (LC, 2-year: 85.6% vs. 20.5%, P<0.001), progression-free survival (PFS, median 7.4 vs. 3.2 months, P<0.001), and overall survival (OS, median 18.1 vs. 7.3 months, P<0.001) compared to those with BED10 <75 Gy. Notably, proton-treated patients had a significantly higher BED10 (96 vs. 67 Gy, P<0.001) and improved LC (2-year: 88.5% vs. 33.8%, P<0.001), PFS (median 7.4 vs. 3.3 months, P=0.001), and OS (median 18.9 vs. 8.3 months, P<0.001) than those undergoing photon radiotherapy. Furthermore, patients treated with protons had significantly lower V1 of the liver (P<0.001), mean upper gastrointestinal (UGI) tract dose (P<0.001), and mean splenic dose (P<0.001), with significantly decreased incidences of radiation-induced liver disease (P=0.007), grade ≥3 UGI bleeding (P=0.001), and grade ≥3 lymphopenia (P=0.003). On multivariate analysis, proton radiotherapy consistently correlated with superior LC (P<0.001), PFS (P<0.001), and OS (P<0.001). In intragroup dosimetric comparison, photon plans demonstrated significantly higher mean liver dose (MLD, P<0.001) compared with actually delivered proton treatments, and 72 (69%) of them had MLD exceeding 28 Gy which necessitated target dose de-escalation. Conclusions: In the context of large HCC radiotherapy, a higher target BED10 was associated with improved outcomes. Notably, proton therapy has demonstrated the capability to deliver ablative doses while also being accompanied by fewer instances of severe toxicity.

Liver parenchymal changes detected by MR elastography and diffusion-weighted imaging after stereotactic body radiotherapy for hepatocellular carcinoma.

Stereotactic body radiotherapy (SBRT) is a local treatment option for hepatocellular carcinoma (HCC). SBRT-induced focal reactions on the liver parenchyma have not been thoroughly evaluated using quantitative magnetic resonance imaging (MRI). To quantitatively evaluate liver parenchymal changes caused by SBRT for HCC using magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI). We retrospectively evaluated 22 adult patients who received SBRT for HCC and 27 who received locoregional therapy other than SBRT (controls). Liver stiffness by MRE and apparent diffusion coefficient (ADC) values by DWI of the liver parenchyma were measured before and after SBRT. Regions of interest (ROIs) were drawn on the two areas of radiation dose distribution levels, > 30 Gy and ≤ 30 Gy; a ROI was drawn in the control group. The two indices were compared before and after SBRT using a Wilcoxon matched-pairs signed-rank test. Liver stiffness and ADC values were significantly increased after SBRT in the dose areas of > 30 Gy compared with those before SBRT (4.05 vs 4.85 kPa; p < 0.05 in liver stiffness, and 1.10 vs 1.40 ×10-3 s/mm2; p < 0.05 in ADC values). In the dose area of ≦ 30 Gy, liver stiffness showed a significant increase in one reader (p = 0.033) but not in another reader (p = 0.085); ADC value showed no significant difference before and after SBRT as per both readers (p > 0.05). The control group demonstrated no significant differences before and after treatment (p > 0.05). MRE and DWI can be used to detect SBRT-induced liver parenchymal changes.

Predictive Power of the Albumin-Bilirubin Score for Hepatotoxicity in Stereotactic Ablative Radiation Therapy for Hepatocellular Carcinoma.

Assessment of liver function is crucial in predicting treatment outcomes for hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic performance of the albumin-bilirubin (ALBI) score for predicting hepatotoxicity following stereotactic body radiation therapy (SBRT) in HCC patients. A retrospective analysis was conducted on 123 HCC cases treated between 2018 and 2020. ALBI and Child-Turcotte-Pugh (CTP) scores were calculated, and hepatotoxicity was defined as a post-SBRT CTP score increase ≥2. Receiver operating characteristic (ROC) curves were used for comparison. The optimal cutoff value of the ALBI score was determined. Among the 121 patients analyzed, hepatotoxicity occurred in 5%. The ALBI score showed better predictive accuracy (area under the ROC curve: 0.77) than the CTP score. The optimal cutoff value of the ALBI score was -2.47, with a sensitivity of 85.7% and a specificity of 71.1%. Multivariable analysis revealed that ALBI score and PTV were significant factors for hepatotoxicity. In conclusion, the ALBI score demonstrated prognostic value for hepatotoxicity prediction after SBRT in HCC patients. Considering the ALBI score and PTV provides valuable insights for assessing hepatotoxicity risk during SBRT treatment for HCC.