Radiotherapy For Hepatocellular Carcinoma Research Articles

Efficacy of Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma by Underlying Liver Disease Etiology

<h3>Purpose/Objective(s)</h3> The use of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) has been steadily increasing. Recently, it was reported that patients with HCC have a differential response to immune-checkpoint inhibitor based on the background liver disease etiology. Whether outcomes of SBRT are affected by underlying liver disease etiology is currently unknown. We therefore reviewed outcomes of SBRT with special focus on tumor size, BED, and underlying liver disease etiology. <h3>Materials/Methods</h3> This study is a retrospective review of HCC patients treated with SBRT at one institution between 2009 and 2021. Patients with tumor thrombus or extrahepatic disease were excluded. Kaplan-Meier curves and Cox regression models were used to describe freedom from local progression (FFLP) and overall survival (OS) rates and examine potential prognostic factors. <h3>Results</h3> One-hundred and sixty-four patients met study entry criteria. Median gross tumor volume (GTV) size was 9.3 cc (range 0.3 to 762.4 cc). 67% of patients had a history of hepatitis C, and 9% had a history of hepatitis B. 71% of patients received our institutional standard SBRT dose of 50 Gy in 5 fractions (biological effective dose [BED] 100 Gy). Other patients received lower doses ranging from 30 to 47.5 Gy in three to five fractions (BED range 48 to 93 Gy) if necessary to preserve normal liver tissue. Median follow-up time was 43 months (interquartile range [IQR] 36 to 52 months). Seventeen in-field failures and 67 deaths have occurred. 3- and 5-year FFLP rates were 84% and 75%, and 3- and 5-year OS rates were 65% and 48%, respectively. History of hepatitis C was associated with better FFLP (HR=0.36 (95% CI:0.14, 0.94), p=0.038). Treatment with 50 Gy was associated with better FFLP compared to treatment with lower doses for patients with hepatitis C (HR=0.15 (95%CI: 0.04, 0.63), p=0.01) but not for other patients (HR=3.1 (95%CI: 0.38, 24.7), p=0.29). <h3>Conclusion</h3> SBRT for HCC yields excellent local control, particularly for patients with hepatitis C. In hepatitis C patients, dose escalation beyond a BED of 100Gy may be more important for local control than in non-hepatitis C patients. More studies are necessary to better understand if HCC etiology should be considered when planning SBRT.

Outcomes for Salvage Abdominal Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma after Liver Transplantation

<h3>Purpose/Objective(s)</h3> While orthotopic liver transplantation (OLT) is considered curative for most hepatocellular carcinoma (HCC) patients, recurrence can occur in 10-20% of these patients. Data has shown stereotactic body radiation therapy (SBRT) to be safe and effective as treatment for primary HCC, however few studies have investigated the safety and efficacy of SBRT as treatment for HCC after OLT. The aim of this study is to evaluate the safety and efficacy of intra-abdominal salvage SBRT for HCC in patients who previously underwent OLT. <h3>Materials/Methods</h3> A retrospective chart review of a single, large institution was conducted to identify patients who received intra-abdominal SBRT as treatment for recurrent HCC after OLT from 1/1/2013 to 12/1/2021. Clinical safety was measured by the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v5.0 for grading adverse events, Child-Turcott-Pugh (CTP) score, and Albumin-Bilirubin (ALBI) grade for HCC. Dosimetric analysis was performed. Efficacy was measured by local control (LC) and objective response using modified Response Evaluation Criteria in Solid Tumors (mRECIST). The Kaplan-Meier method was used to evaluate overall survival (OS) and progression free survival (PFS). <h3>Results</h3> 18 lesions, treated among 15 patients were identified that received intra-abdominal SBRT for HCC recurrence after OLT. Nine patients were male, median age was 62 (interquartile range 52 to 80). The American Joint Committee on Cancer stage at diagnosis was most often T1N0M0 (n=8, 53%) or T2N0M0 (n=5, 33%). The most common etiology for HCC diagnosis was hepatitis C virus (n=9, 56%). Median CTP and ALBI scores at baseline were 5 (range 5 to 11) and -3.02 (range -3.36 to -1.35), respectively. Median change in CTP score from baseline to CTP at 3, 6, and 12 months was 0.00, 1.00, and 1.00. Median change in ALBI score from baseline to at 3, 6, and 12 months was 0.14, 0.40, and 0.42. The median treatment dose was 4750 cGy (interquartile range 500 cGy), all patients received 5 fractions. There was no grade 3 or above CTCAE toxicities. During 6 (33%) SBRT treatments, patient experienced grade 1 or 2 CTCAE toxicity with nausea, emesis, or fatigue. Local control was achieved in 94% of lesions (n=17). Local treatment response was: 11 (61.2%) complete response, 5 (27.8%) partial response, 1 (5.5%) stable disease, and 1 (5.5%) progressive disease. After median follow up of 19.2 months, 8 patients (53%) were deceased and 7 (47%) had no evidence of disease progression. OS was 100% at 6 months and 60.8% at 12 months. PFS was 92.9% at 6 months and 60.9% at 12 months. No dosimetric factor was found to predict for increased toxicity. <h3>Conclusion</h3> For patients with HCC after OLT, SBRT appears to be a safe and effective treatment modality, as no patients experienced significant toxicities and the majority had complete treatment response.

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.

MiR-302a-3p Promotes Radiotherapy Sensitivity of Hepatocellular Carcinoma by Regulating Cell Cycle via MCL1.

Background The relationship between tumor suppressor gene miR-302a-3p and radiotherapy for hepatocellular carcinoma (HCC) remains unclear. This study intended to illustrate the molecular mechanism how miR-302a-3p regulated radiotherapy sensitivity of HCC. Methods miR-302a-3p expression in HCC tissues and cells was examined by qRT-PCR. The effect of miR-302a-3p on HCC radiotherapy sensitivity were detected by CCK-8, colony formation, and flow cytometry assays. The expression levels of cell cycle-related proteins were detected by Western blot. The influence of miR-302a-3p on radiotherapy sensitivity of HCC was further investigated via cell cycle inhibitor (Caudatin) treatment. The target gene (MCL1) of miR-302a-3p was obtained by bioinformatics analysis, and their binding relationship was confirmed by RNA-binding protein immunoprecipitation assay. The mechanisms of miR-302a-3p regulating cell cycle and affecting radiotherapy sensitivity of HCC cells through MCL1 were further explored through the rescue experiments. Results miR-302a-3p expression was remarkably reduced in radiotherapy-resistant tissues and cells of HCC. miR-302a-3p overexpression restored sensitivity of radiotherapy-resistant HCC cells to radiotherapy. Treatment with cell cycle inhibitor Caudatin could reverse suppressive effect of miR-302a-3p downregulation on sensitivity of HCC to radiotherapy. Additionally, miR-302a-3p could restrain MCL1 expression. In vitro cell assays further revealed that miR-302a-3p/MCL1 axis could enhance radiotherapy sensitivity of HCC cells by inducing G0/G1 arrest. Conclusions miR-302a-3p facilitated radiotherapy sensitivity of HCC cells by regulating cell cycle via MCL1, which provided a new underlying target for radiotherapy resistance of HCC patients.

The inhibiting effect of alpha-based TARE on embolized vessels and neovascularization.

Transarterial embolization (TAE) is a personalized technology that offers precise delivery of chemotherapeutic drugs or selective internal radiation therapy for hepatocellular carcinoma (HCC). Beta-emitting radionuclide embolisms for TAE (β-based TARE) are commonly used in the clinic via inducing biochemical lethality on tumor cells, while alpha-emitting radionuclides-based embolisms for TAE (α-based TARE) are still under study. The feeding artery plays a key role in tumor growth, metastasis, and recurrence. In this research, the auricular central arteries (ACAs) of rabbits were embolized with silk fibroin-based microspheres (SFMs) or SFMs integrated with α (Ra-223) or β (I-131) radionuclides to investigate the influence on vessels. TARE-induced tissue necrosis and the following neovascularization were measured by pathological analysis and 68Ga-DOTA-RGD PET/CT. The results showed that, compared to I-131, Ra-223 enhanced the growth inhibition of human hepatoma cells Huh-7 and induced more DNA double-strand breaks in vascular smooth muscle cells. Unlike β-based TARE, which mainly led to extensive necrosis of surrounding tissues, α-based TARE induced irreversible necrosis of a limited area adjacent to the embolized vessels. RGD PET revealed the inhibition on neovascularization in α-based TARE (SUVmax = 0.053 ± 0.004) when compared with normal group (SUVmax = 0.099 ± 0.036), the SFMs-lipiodol group (SUVmax = 0.240 ± 0.040), and β-based TARE (SUVmax = 0.141 ± 0.026), owing to the avoidance of the embolism-induced neovascularization. In conclusion, α-based TARE provided a promising strategy for HCC treatments via destroying the embolized vessels and inhibiting neovascularization.

Long-term Outcomes and Prognostic Factors of Stereotactic Body Radiotherapy for Hepatocellular Carcinoma.

This study was conducted to determine the prognosis and risk factors for survival in patients treated with stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC). This retrospective study analyzed 73 patients who underwent SBRT for HCC at Nagasaki University Hospital from December 2012 to July 2019 and examined the relationship between baseline information and prognosis. The Kaplan-Meier analysis and log-rank test were used to estimate the survival rate. Cox regression analysis was performed to determine the factors associated with overall survival (OS) after SBRT. The 1- and 2-year local control rates were 98.6% and 89.9%, respectively. Survival rates at 1, 3, and 5 years were 94.5%, 63.9%, and 45.5%, respectively. In the univariate analysis, baseline modified albumin-bilirubin grade (mALBI grade) [2b/3, hazard ratio (HR)=2.762, p=0.001], tumor size (≥2 cm, HR=2.479, p=0.003), and Barcelona Clinic Liver Cancer stage (BCLC) (B/C, HR=3.284, p<0.001) were significantly associated with poor prognosis. In multivariate analysis, baseline mALBI grade (2b/3, HR=2.283, p=0.009) and BCLC stage (B/C, HR=2.330, p=0.013) were significantly associated with poor prognosis. Only three patients (4.1%) developed grade 3 adverse events related to SBRT. SBRT is effective and safe in patients with HCC. The baseline mALBI grade is useful for predicting patient prognosis after SBRT. Patients with an mALBI grade of 1/2a are expected to have a better prognosis than patients with an mALBI grade of 2b/3.

SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma

Radioresistance is a principal culprit for the failure of radiotherapy in hepatocellular carcinoma (HCC). Insights on the regulation genes of radioresistance and underlying mechanisms in HCC are awaiting for profound investigation. In this study, the suppressor of cytokine signaling 2 (SOCS2) were screened out by RNA-seq and bioinformatics analyses as a potential prognosis predictor of HCC radiotherapy and then were determined to promote radiosensitivity in HCC both in vivo or in vitro. Meanwhile, the measurements of ferroptosis negative regulatory proteins of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), intracellular lipid peroxidation and Fe2+ concentration suggested that a high level of ferroptosis contributed to the radiosensitization of HCC. Moreover, SOCS2 and SLC7A11 were expressed oppositely in HCC clinical tissues and tumour xenografts with different radiosensitivities. Mechanistically, the N-terminal domain of SLC7A11 was specifically recognized by the SH2-structural domain of SOCS2. While the L162 and C166 of SOCS2-BOX region could bind elongin B/C compound to co-form a SOCS2/elongin B/C complex to recruit ubiquitin molecules. Herein, SOCS2 served as a bridge to transfer the attached ubiquitin to SLC7A11 and promoted K48-linked polyubiquitination degradation of SLC7A11, which ultimately led to the onset of ferroptosis and radiosensitization of HCC. In conclusion, it was demonstrated for the first time that high-expressed SOCS2 was one of the biomarkers predicting radiosensitivity of HCC by advancing the ubiquitination degradation of SLC7A11 and promoting ferroptosis, which indicates that targeting SOCS2 may enhance the efficiency of HCC radiotherapy and improve the prognosis of patients.

Does HCC Etiology Impact the Efficacy of Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma? An Asian Liver Radiation Therapy Group Study.

Background/PurposeThe Asian Liver Radiation Therapy Study Group has formed a large and detailed multinational database of outcomes following stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC). Here, we explored the potential impact of HCC etiology on SBRT efficacy. Tumor control probability (TCP) models were established to estimate the likelihood of local control (LC).MethodsData from 415 patients who were treated with SBRT for HCC were reviewed. Cox proportional hazards models were used to identify key predictors of LC. TCP models accounting for biologic effective dose (BED) and tumor diameter were generated to quantify associations between etiology and LC.ResultsCox models demonstrated that hepatitis C virus (HCV) infection was associated with favorable LC following SBRT (HR=0.52, 95% CI 0.04–0.96, p=0.036). The 2-year LC rate for patients with HCV etiology was 88%, compared to 78% for other patients. Small tumor and high BED were also associated with favorable LC. TCP models demonstrated a 10–20% absolute increase in predicted LC across the range of SBRT doses and tumor sizes.ConclusionWe found a novel association between HCV status and LC after SBRT for HCC that warrants further exploration. If validated in other datasets, our findings could help clinicians tailor SBRT schedules.

Methyltransferase 1 is required for nonhomologous end-joining repair and renders hepatocellular carcinoma resistant to radiotherapy.

Radiotherapy is an increasingly essential therapeutic strategy in the management of hepatocellular carcinoma (HCC). Nevertheless, resistance to radiotherapy is one of the primary obstacles to successful treatment outcomes. Hence, we aim to elucidate the mechanisms underlying radioresistance and identify reliable biotargets that would be inhibited to enhance the efficacy of radiotherapy in HCC. From a label-free quantitative proteome screening, we identified transfer RNA (tRNA; guanine- N [7]-) methyltransferase 1 (METTL1), a key enzyme for N7-methylguanosine (m 7 G) tRNA modification, as an essential driver for HCC cells radioresistance. We reveal that METTL1 promotes DNA double-strand break (DSB) repair and renders HCC cells resistant to ionizing radiation (IR) using loss-of-function and gain-of-function assays in vitro and in vivo. Mechanistically, METTL1-mediated m 7 G tRNA modification selectively regulates the translation of DNA-dependent protein kinase catalytic subunit or DNA ligase IV with higher frequencies of m 7 G-related codons after IR treatment, thereby resulting in the enhancement of nonhomologous end-joining (NHEJ)-mediated DNA DSB repair efficiency. Clinically, high METTL1 expression in tumor tissue is significantly correlated with poor prognosis in radiotherapy-treated patients with HCC. Our findings show that METTL1 is a critical enhancer for HCC cell NHEJ-based DNA repair following IR therapy. These findings give insight into the role of tRNA modification in messenger RNA translation control in HCC radioresistance.

Role of rapid arc-image-guided radiotherapy in hepatocellular carcinoma with portal vein tumor thrombosis: A study from tertiary care center in Punjab, India.

Treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) is very challenging with poor outcome. In this situation, radiotherapy has become an alternative treatment modality, more precisely due to advances in radiation techniques. The goal of our study is to do analysis of these patients treated with rapid arc image-guided technology (RA-IGRT) at our institution. Thirteen patients were included in the study. As per intuition policy, patient set up, contouring, and treatment plans were generated. Radiological response assessment was done 1-month post-radiotherapy. Survival analysis curve along with Chi-square test for prognostic factors assessment was done using SPSS. With median dose of 45 Gy in 20 fractions, we were able to achieve 27.3% objective response rate with median survival of 5 months in eligible patients. One-year overall survival up to 30% can be achieved in HCC with PVTT, especially in patients with objective response to radiotherapy with Japan Integrated Staging score 2, provided it is precisely hit by RA-IGRT.

Outcomes and Toxicities of Modern Combined Modality Therapy with Atezolizumab Plus Bevacizumab and Radiation Therapy for Hepatocellular Carcinoma.

Simple SummaryHepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide with slow progress in the development of effective therapies. The breakthrough IMbrave150 trial established atezolizumab plus bevacizumab as the standard of care first-line therapy for patients with unresectable/advanced HCC, demonstrating improved overall survival. Radiation therapy (RT) is a locoregional treatment that may prevent morbidity from tumor-related vascular compromise and associated liver failure. There is no documented evidence yet describing the safety and outcomes of combination RT and atezolizumab/bevacizumab. In the retrospective review of our experience, we identified 21 patients with advanced HCC who underwent liver-directed RT with atezolizumab/bevacizumab. From our findings, the treatment is well-tolerated, safe, and does not potentiate liver failure. There were uncommon autoimmune or GI bleeding events in some patients, mostly unrelated to RT. Post-RT absolute lymphocyte counts (ALC) improved more quickly with atezolizumab/bevacizumab than they did without, which may be a favorable treatment prognosticator.Atezolizumab plus bevacizumab has become frontline therapy for unresectable HCC. The compatibility of atezolizumab/bevacizumab with liver-directed RT has not been reported. Methods: HCC patients treated with liver-directed RT and atezolizumab/bevacizumab between 1/2020–11/2021 were included. Toxicity and outcomes were retrospectively recorded. For ALCs, we matched the analysis to a previously cohort of RT-treated HCC patients who did not receive atezolizumab/bevacizumab. Survival and time-to-liver-failure were analyzed using Kaplan–Meier. Results: Of 21 patients, with a median follow-up of 9.5 months, the median OS was 16.1 months. Post-RT, all patients had reduced tumors or treatment response. There were no ≥Grade 3 RT-related toxicities. Autoimmune complications occurred in two patients (9.5%), and GI bleeding in three patients (14.3%). Liver function remained stable post-RT. There was a marked decrease in ALCs immediately post-RT (post-RT/pre-RT ratio 47.3%, p < 0.0001), restored by 1 month to pre-treatment baseline (1-month post-RT/pre-RT ratio 95.1%, n.s.). Compared to HCC patients treated with RT alone, post-RT ALC recovery was faster with atezolizumab/bevacizumab (p = 0.009). Conclusion: In this first reported experience of RT with modern systemic therapy for HCC, combination therapy is safe and well-tolerated. As a favorable prognosticator, there appears to be faster recovery of ALC among patients who received RT with atezolizumab/bevacizumab.

Robust radiosensitization of hemoglobin-curcumin nanoparticles suppresses hypoxic hepatocellular carcinoma

BackgroundRadioresistance inducing by hypoxic microenvironment of hepatocellular carcinoma is a major obstacle to clinical radiotherapy. Advanced nanomedicine provides an alternative to alleviate the hypoxia extent of solid tumor, even to achieve effective synergistic treatment when combined with chemotherapy or radiotherapy.ResultsHerein, we developed a self-assembled nanoparticle based on hemoglobin and curcumin for photoacoustic imaging and radiotherapy of hypoxic hepatocellular carcinoma. The fabricated nanoparticles inhibited hepatoma migration and vascular mimics, and enhanced the radiosensitivity of hypoxic hepatoma cells in vitro via repressing cell proliferation and DNA damage repair, as well as inducing apoptosis. Benefit from oxygen-carrying hemoglobin combined with polyphenolic curcumin, the nanoparticles also effectively enhanced the photoacoustic contrast and the efficacy of radiotherapy for hepatocellular carcinoma in vivo.ConclusionsTogether, the current study offered a radiosensitization platform for optimizing the efficacy of nanomedicines on hypoxic radioresistant tumor.Graphical

A microenvironment-responsive FePt probes for imaging-guided Fenton-enhanced radiotherapy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) continues to be one of the most fatal malignancies with increasing morbidity, and potent therapeutics are urgently required given its insensitivity to traditional treatments. Here, we have developed a microenvironment-responsive FePt probes for the highly efficient Fenton-enhanced radiotherapy (FERT) of HCC. The selective release of Fe2+ in the acidic tumor microenvironment, but not in normal tissue, together with enhanced levels of hydrogen peroxide produced through the Pt radiosensitization effect, facilitates the generation of an enormous amount of hydroxyl radicals through the Fenton reaction, thereby extending the radiotherapeutic cascade and realizing a powerful therapeutic efficacy for HCC. Moreover, the “burst” release of Fe2+ contributes to the T2-to-T1 magnetic resonance imaging (MRI) switching effect, which informs the release of Fe2+, making imaging-guided cancer therapy feasible. This work not only breaks the bottleneck of traditional radiotherapy for HCC while minimally affecting normal tissues, but also provides a new strategy for FERT imaging guidance.Graphical

Evaluation of Multisource Adaptive MRI Fusion for Gross Tumor Volume Delineation of Hepatocellular Carcinoma.

PurposeTumor delineation plays a critical role in radiotherapy for hepatocellular carcinoma (HCC) patients. The incorporation of MRI might improve the ability to correctly identify tumor boundaries and delineation consistency. In this study, we evaluated a novel Multisource Adaptive MRI Fusion (MAMF) method in HCC patients for tumor delineation.MethodsTen patients with HCC were included in this study retrospectively. Contrast-enhanced T1-weighted MRI at portal-venous phase (T1WPP), contrast-enhanced T1-weighted MRI at 19-min delayed phase (T1WDP), T2-weighted (T2W), and diffusion-weighted MRI (DWI) were acquired on a 3T MRI scanner and imported to in-house-developed MAMF software to generate synthetic MR fusion images. The original multi-contrast MR image sets were registered to planning CT by deformable image registration (DIR) using MIM. Four observers independently delineated gross tumor volumes (GTVs) on the planning CT, four original MR image sets, and the fused MRI for all patients. Tumor contrast-to-noise ratio (CNR) and Dice similarity coefficient (DSC) of the GTVs between each observer and a reference observer were measured on the six image sets. Inter-observer and inter-patient mean, SD, and coefficient of variation (CV) of the DSC were evaluated.ResultsFused MRI showed the highest tumor CNR compared to planning CT and original MR sets in the ten patients. The mean ± SD tumor CNR was 0.72 ± 0.73, 3.66 ± 2.96, 4.13 ± 3.98, 4.10 ± 3.17, 5.25 ± 2.44, and 9.82 ± 4.19 for CT, T1WPP, T2W, DWI, T1WDP, and fused MRI, respectively. Fused MRI has the minimum inter-observer and inter-patient variations as compared to original MR sets and planning CT sets. GTV delineation inter-observer mean DSC across the ten patients was 0.81 ± 0.09, 0.85 ± 0.08, 0.88 ± 0.04, 0.89 ± 0.08, 0.90 ± 0.04, and 0.95 ± 0.02 for planning CT, T1WPP, T2W, DWI, T1WDP, and fused MRI, respectively. The patient mean inter-observer CV of DSC was 3.3%, 3.2%, 1.7%, 2.6%, 1.5%, and 0.9% for planning CT, T1WPP, T2W, DWI, T1WDP, and fused MRI, respectively.ConclusionThe results demonstrated that the fused MRI generated using the MAMF method can enhance tumor CNR and improve inter-observer consistency of GTV delineation in HCC as compared to planning CT and four commonly used MR image sets (T1WPP, T1WDP, T2W, and DWI). The MAMF method holds great promise in MRI applications in HCC radiotherapy treatment planning.

Downstaging radiotherapy and surgical transformation for initially unresectable or borderline resectable hepatocellular carcinoma: A phase II study.

442 Background: Downstaging radiotherapy provide patients with initially unresectable or borderline resectable hepatocellular carcinoma (HCC) a chance to receive conversion curative resection. This study intended to prospectively evaluate the efficacy and toxicities of downstaging radiotherapy for HCC with macroscopic vascular invasion. Methods: From March 2018 to May 2020, 30 HCC patients with macroscopic vascular invasion were prospectively treated with transcatheter arterial chemoembolization combined with radiotherapy (n = 24) or radiotherapy alone (n = 6). The primary study endpoint was overall survival (OS). The secondary study endpoints were progression free survival (PFS), downstaging success rate, and surgical conversion rate. Adverse events were assessed. Results: The follow-up time of the entire cohort was 24 months. The median OS of the entire cohort was 22.0 months, 12-, and 24- months OS was 60.0% and 47.8%, respectively. The median PFS was 13.0 months, 12-, and 24-months PFS was 53.3% and 27.0%, respectively. During downstaging window phase within 3-6 months, 22 patients were evaluated as downstaging success by clinical imaging. Among them, 9 patients underwent R0 radical hepatectomy and 13 patients refused surgical treatment, yielding a downstaging success rate of 73.3% (22/30 patients) and a surgical conversion rate of 30.0% (9/30 patients). Of the patients who underwent surgery, 4 patients (44.4%) experienced ≥ grade 4 postoperative complications, including 2 (22.2%) with gastrointestinal bleeding and 2 (22.2%) with bile leakage. Conclusions: For unresectable or borderline resectable HCCs complicated with macroscopic vascular invasion, high-dose radiotherapy-based treatment provided favorable downstaging efficacy, surgical conversion rate, and survival outcomes. Clinical trial information: ChiCTR1800015350.

Enhancement of Radiation Response Associated With Metformin in Hepatocellular Carcinoma: Preclinical Animal and Clinical Cohort Study.

This study examined whether metformin can enhance the radiation response in a hepatocellular carcinoma (HCC) xenograft mice model and patient population. Huh-7 human HCC-bearing xenograft mice were treated with gamma-ray, metformin, neutron therapy, and their combinations. Tumour growth and lung colonies were assessed. Overall, 145 patients who underwent radiotherapy for HCC were retrospectively analysed. The combinations of gamma-ray and metformin and neutron radiation and metformin inhibited tumour growth and metastatic lung nodule formation when compared to the monotherapy and gamma-ray groups, respectively. In patients who received radiotherapy for HCC, the overall survival rate was higher in the metformin-treated group than in the non-metformin group. Metformin inhibited tumour growth and metastasis in HCC by enhancing the radiation response in animal experiments. Additionally, metformin was also found to be associated with a higher survival outcome in patients with HCC.

NEAT1 Confers Radioresistance to Hepatocellular Carcinoma Cells by Inducing Autophagy through GABARAP.

A long noncoding RNA (lncRNA), nuclear enriched abundant transcript 1 (NEAT1) variant 1 (NEAT1v1), is involved in the maintenance of cancer stem cells (CSCs) in hepatocellular carcinoma (HCC). CSCs are suggested to play important roles in therapeutic resistance. Therefore, we investigated whether NEAT1v1 is involved in the sensitivity to radiation therapy in HCC. Gene knockdown was performed using short hairpin RNAs, and NEAT1v1-overexpressing HCC cell lines were generated by stable transfection with a NEAT1v1-expressing plasmid DNA. Cells were irradiated using an X-ray generator. We found that NEAT1 knockdown enhanced the radiosensitivity of HCC cell lines and concomitantly inhibited autophagy. NEAT1v1 overexpression enhanced autophagy in the irradiated cells and conferred radioresistance. Gamma-aminobutyric acid receptor-associated protein (GABARAP) expression was downregulated by NEAT1 knockdown, whereas it was upregulated in NEAT1v1-overexpressing cells. Moreover, GABARAP was required for NEAT1v1-induced autophagy and radioresistance as its knockdown significantly inhibited autophagy and sensitized the cells to radiation. Since GABARAP is a crucial protein for the autophagosome-lysosome fusion, our results suggest that NEAT1v1 confers radioresistance to HCC by promoting autophagy through GABARAP.

Dosimetric Evaluation of CyberKnife Synchrony System for Liver Tumors With Respiratory Phase Shifts.

This study evaluated the effects of the respiratory phase shifts between liver tumor and chest wall motions on the dose distribution for the CyberKnife Synchrony respiratory tracking system (SRTS). Eight patients who received stereotactic body radiotherapy for hepatocellular carcinoma or liver metastases were analyzed. Three-dimensional (3D) motion of the implanted fiducial markers and vertical motion of the sternal bone were derived from the four-dimensional computed tomography (4D-CT) images acquired with a 320-row area detector CT. For each patient, Gaussian random numbers were generated for the standard deviation of the tracking error calculated from the phase shift and a literature. For each voxel of the target, the dose delivered from each beam was calculated 100 times with the random 3D offsets representing the tracking error. The median respiratory phase shifts were 6.0% and 4.6% for the anterior-posterior (AP) and superior-inferior (SI) directions, respectively. The median motion tracking errors influenced by respiratory phase shifts were 1.21 mm and 0.96 mm for the AP and SI directions, respectively. The change in the dose covering 90% of the target (D90%) was within 1.1% when median phase shifts were considered. When evaluating the 90th percentile of the phase shifts, the D90% decreased up to 6.6%. We have developed a technique to estimate the impact of the respiratory phase shifts on the dose distribution of a liver tumor treated with the SRTS. The calculation of the respiratory phase shifts from the area-detector 4D-CT will be valuable to improve the tracking accuracy of the SRTS.

Efficacy and Safety of 4 Fractions of Carbon-Ion Radiation Therapy for Hepatocellular Carcinoma: A Prospective Study

Introduction: Prospective evidence supporting the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for hepatocellular carcinoma (HCC) remains lacking. This prospective study aimed to evaluate the safety and efficacy of hypofractionated C-ion RT in patients with HCC. Methods: The inclusion criteria were as follows: (1) pathologically or clinically diagnosed HCC; (2) measurable tumor and tumor size ≤10 cm; (3) absence of major vascular invasion; (4) no extrahepatic metastasis; (5) the alimentary tract was not adjacent to the target lesion (>1 cm); (6) not suitable for or refusal to undergo surgery or local ablative therapies; (7) an interval ≥4 weeks from previous therapy; (8) no other intrahepatic lesion or at least 2 years after the previous curative therapy; (9) performance status score, 0–2; and (10) Child-Pugh score, 5–9. The prescribed C-ion RT dose was 52.8 Gy (relative biological effectiveness [RBE]) or 60.0 Gy (RBE) in 4 fractions. Results: In total, 35 patients with HCC were enrolled between October 2010 and May 2016. The median follow-up durations in the survivor group (n = 23) and in the whole cohort were 55.1 and 49.0 months, respectively. The 2-, 3-, and 4-year overall survival rates were 82.8%, 76.7%, and 69.4%, respectively. The 2-, 3-, and 4-year local control (LC) rates were 92.6%, 76.5%, and 76.5%, respectively. The median time-to-progression was 25.6 months (95% confidence interval, 13.7–37.5 months). Grade 4 or 5 toxicities were not observed. Grade 3 acute and late toxicities were observed in 2 patients. There was no significant deterioration in serum albumin, bilirubin, prothrombin time-international normalized ratio, platelet count, or Child-Pugh score after C-ion RT. Conclusion: Four fractions of C-ion RT for HCC did not yield serious adverse events and showed promising LC, thus making it a safe and effective modality for this type of malignancy.

Integration of glucose and cardiolipin anabolism confers radiation resistance of HCC.

Background and AimsPoor response to ionizing radiation (IR) due to resistance remains a clinical challenge. Altered metabolism represents a defining characteristic of nearly all types of cancers. However, how radioresistance is linked to metabolic reprogramming remains elusive in hepatocellular carcinoma (HCC).Approach and ResultsBaseline radiation responsiveness of different HCC cells were identified and cells with acquired radio‐resistance were generated. By performing proteomics, metabolomics, metabolic flux, and other functional studies, we depicted a metabolic phenotype that mediates radiation resistance in HCC, whereby increased glucose flux leads to glucose addiction in radioresistant HCC cells and a corresponding increase in glycerophospholipids biosynthesis to enhance the levels of cardiolipin. Accumulation of cardiolipin dampens the effectiveness of IR by inhibiting cytochrome c release to initiate apoptosis. Mechanistically, mammalian target of rapamycin complex 1 (mTORC1) signaling‐mediated translational control of hypoxia inducible factor‐1α (HIF‐1α) and sterol regulatory element‐binding protein‐1 (SREBP1) remodels such metabolic cascade. Targeting mTORC1 or glucose to cardiolipin synthesis, in combination with IR, strongly diminishes tumor burden. Finally, activation of glucose metabolism predicts poor response to radiotherapy in cancer patients.ConclusionsWe demonstrate a link between radiation resistance and metabolic integration and suggest that metabolically dismantling the radioresistant features of tumors may provide potential combination approaches for radiotherapy in HCC.