Radiation-induced Liver Disease Research Articles

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

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

False Liver Metastasis by Positron Emission Tomography/Computed Tomography Scan after Chemoradiotherapy for Esophageal Cancer-Potential Overstaged Pitfalls of Treatment.

In patients with esophageal cancer undergoing neoadjuvant chemoradiotherapy (nCRT), subsequent restaging with F-18-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) can reveal the presence of interval metastases, such as liver metastases, in approximately 10% of cases. Nevertheless, it is not uncommon in clinical practice to observe focal FDG uptake in the liver that is not associated with liver metastases but rather with radiation-induced liver injury (RILI), which can result in the overstaging of the disease. Liver radiation damage is also a concern during distal esophageal cancer radiotherapy due to its proximity to the left liver lobe, typically included in the radiation field. Post-CRT, if FDG activity appears in the left or caudate liver lobes, a thorough investigation is needed to confirm or rule out distant metastases. The increased FDG uptake in liver lobes post-CRT often presents a diagnostic dilemma. Distinguishing between radiation-induced liver disease and metastasis is vital for appropriate patient management, necessitating a combination of imaging techniques and an understanding of the factors influencing the radiation response. Diagnosis involves identifying new foci of hepatic FDG avidity on PET/CT scans. Geographic regions of hypoattenuation on CT and well-demarcated regions with specific enhancement patterns on contrast-enhanced CT scans and MRI are characteristic of radiation-induced liver disease (RILD). Lack of mass effect on all three modalities (CT, MRI, PET) indicates RILD. Resolution of abnormalities on subsequent examinations also helps in diagnosing RILD. Moreover, it can also help to rule out occult metastases, thereby excluding those patients from further surgery who will not benefit from esophagectomy with curative intent.

Albumin-bilirubin score is a useful predictor of worsening liver reserve after stereotactic body radiation therapy in elderly Japanese patients with hepatocellular carcinoma.

The prognosis of patients with hepatocellular carcinoma (HCC) is closely related to their liver reserves. The Child-Pugh (CP) score has traditionally been used to evaluate this reserve, with CP Grade B (CP score ≥ 7) associated with a higher risk of radiation-induced liver disease after stereotactic body radiation therapy (SBRT). However, the CP score has limitations, as it does not accurately assess liver reserve capacity. The albumin-bilirubin (ALBI) score has been introduced as a meticulous indicator of liver reserve for the treatment of HCC. We retrospectively evaluated the role of the ALBI score in estimating the worsening liver reserve in 42 patients with HCC treated with SBRT using CyberKnife between 2015 and 2023. The median biologically effective dose (α/β = 10Gy) was 100Gy. For a median follow-up duration of 17.4months, the 1-year overall survival (OS), local control (LC) and progression-free survival (PFS) rates were 100, 98 and 62%, respectively. Worsening liver reserve was defined as an increase in the modified ALBI grade or CP score within 1year after SBRT. Univariate and multivariate analyses showed that the baseline ALBI score (≥-2.7 vs <-2.7) was the only significantly different predictor of worsening liver reserve. The OS and LC rates after SBRT for HCC were satisfactory. However, the PFS was poor, and recurrent HCC will require additional treatment. It is clinically important to predict the liver reserve capacity after SBRT, and the baseline ALBI score is a useful predictor.

High dose proton and photon-based radiation therapy for 213 liver lesions: a multi-institutional dosimetric comparison with a clinical perspective

BackgroundStereotactic radiotherapy (SRT) and Proton therapy (PT) are both options in the management of liver lesions. Limited clinical-dosimetric comparison are available. Moreover, dose-constraint routinely used in liver PT and SRT considers only the liver spared, while optimization strategies to limit the liver damaged are poorly reported.MethodsPrimary endpoint was to assess and compare liver sparing of four contemporary RT techniques. Secondary endpoints were freedom from local recurrence (FFLR), overall survival (OS), acute and late toxicity. We hypothesize that Focal Liver Reaction (FLR) is determined by a similar biologic dose. FLR was delineated on follow-up MRI. Mean C.I. was computed for all the schedules used. A so-called Fall-off Volume (FOV) was defined as the area of healthy liver (liver-PTV) receiving more than the isotoxic dose. Fall-off Volume Ratio (FOVR) was defined as ratio between FOV and PTV.Results213 lesions were identified. Mean best fitting isodose (isotoxic doses) for FLR were 18Gy, 21.5 Gy and 28.5 Gy for 3, 5 and 15 fractions. Among photons, an advantage in terms of healthy liver sparing was found for Vmat FFF with 5mm jaws (p = 0.013) and Cyberknife (p = 0.03). FOV and FOVR resulted lower for PT (p < 0.001). Three years FFLR resulted 83%. Classic Radiation induced liver disease (RILD, any grade) affected 2 patients.ConclusionsCyberknife and V-MAT FFF with 5mm jaws spare more liver than V-MAT FF with 10 mm jaws. PT spare more liver compared to photons. FOV and FOVR allows a quantitative analysis of healthy tissue sparing performance showing also the quality of plan in terms of dose fall-off.

Evaluating the safety and efficacy of the addition of liver radiation (RT) to atezolizumab and bevacizumab (A/B) in advanced hepatocellular carcinoma (HCC): A retrospective cohort analysis.

481 Background: Recently, the addition of stereotactic body RT to sorafenib in patients (pts) with advanced HCC demonstrated improved overall survival. However, A/B is the current standard of care for pts with advanced HCC based on IMBrave150. For these pts, RT may potentiate the antitumor immune response of A/B but carries the risk of bowel toxicity and impaired liver function. To date, there are limited data regarding safety and outcomes with the addition of liver RT to A/B in pts with advanced HCC. Here, we describe our single-center experience of adding RT to A/B for pts with advanced HCC. Methods: This single-center retrospective cohort study was conducted at the University of Pennsylvania. We identified all pts with HCC naïve to systemic therapy who received infusions of A/B and those who received RT to the liver within 30 days of starting A/B until discontinuation from 1/1/2020 until 2/2/2023. We assessed the real-world response rate (rwRR) determined from clinician impression after initiating A/B, safety outcomes, overall survival (OS), and time-to-progression (TTP) from initiation of A/B. Time-to-event outcomes were analyzed by the Kaplan-Meier method with log-rank test and Cox proportional hazards modeling. Results: We identified 49 pts (n=34 control, n=15 RT) with advanced HCC receiving first-line A/B. Those who received RT were more likely to have alcoholic liver disease (p=0.013) and were less likely to have ascites (p=0.04) but were otherwise balanced regarding demographics, prior locoregional therapies, presence of macrovascular invasion and extrahepatic spread, and baseline laboratories. The median RT dose was 63 Gy. The rwRR in the RT group was 73.3% (11/15) compared to 17.6% (6/34) in the control group (Risk Ratio (RR) 3.9, 95% CI 1.7-8.6, p&lt;0.001). Two pts in the control group (5.8%) and one patient in the RT group (6.7%) experienced clinically significant bleeding (RR=1.1 95% CI 0.1-11.6). In the RT group, three pts (20%) developed worsening liver dysfunction after completing RT, concerning for possible radiation-induced liver disease. Six pts in the control group and one patient in the RT group developed immune-related adverse events leading to discontinuation of A/B. The median OS in the RT group was 14.4 mos and 10.8 mos in the control group (Hazard Ratio (HR) death 0.49 (95% CI 0.20-1.22, p=0.12)). Median TTP was 6.4 months (mos) with RT compared to 5.8 mos in the control group (HR progression 0.72 (95%CI 0.35-1.46, p=0.36. Conclusions: In our retrospective cohort, the addition of liver RT to standard A/B resulted in increased responses and a non-significant improvement in outcomes without an increased risk of bleeding. An assessment of changes in liver dysfunction by Child-Pugh and ALBI score is ongoing. Overall, these data support prospective trials to evaluate the addition of RT to A/B.

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

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

Pencil Beam Scanning Carbon Ion Radiotherapy for Hepatocellular Carcinoma.

Carbon ion radiotherapy (CIRT) has emerged as a promising treatment modality for hepatocellular carcinoma (HCC). However, evidence of using the pencil beam scanning (PBS) technique to treat moving liver tumors remains lacking. The present study investigated the efficacy and toxicity of PBS CIRT in patients with HCC. Between January 2016 and October 2021, 90 consecutive HCC patients treated with definitive CIRT in our center were retrospectively analyzed. Fifty-eight patients received relative biological effectiveness-weighted doses of 50-70 Gy in 10 fractions, and 32 received 60-67.5 Gy in 15 fractions, which were determined by the tumor location and normal tissue constraints. Active motion-management techniques and necessary strategies were adopted to mitigate interplay effects efficiently. Oncologic outcomes and toxicities were evaluated. The median follow-up time was 28.6 months (range 5.7-74.6 months). The objective response rate was 75.0% for all 90 patients with 100 treated lesions. The overall survival rates at 1-, 2- and 3-years were 97.8%, 83.3% and 75.4%, respectively. The local control rates at 1-, 2- and 3-years were 96.4%, 96.4% and 93.1%, respectively. Radiation-induced liver disease was not documented, and 4 patients (4.4%) had their Child-Pugh score elevated by 1 point after CIRT. No grade 3 or higher acute non-hematological toxicities were observed. Six patients (6.7%) experienced grade 3 or higher late toxicities. The active scanning technique was clinically feasible to treat HCC by applying necessary mitigation measures for interplay effects. The desirable oncologic outcomes as well as favorable toxicity profiles presented in this study will be a valuable reference for other carbon-ion centers using the PBS technique and local effect model-based system, and add to a growing body of evidence about the role of CIRT in the management of HCC.

Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective.

It is estimated that 35-40% of hepatocellular carcinoma (HCC) patients present with multiple nodules at the time of diagnosis. Treating multifocal disease is difficult given patient population heterogeneity. Multiple interventional radiological (IR) options, including ablation, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE), are available, each with its own merits and limitations. Our aim is to explore the current state of the literature to identify where each of these options is best applied to multifocal HCC management. A narrative literature review of 107 papers was performed in PubMed. Articles from 2010 and newer were used for clinical data and for classification/scoring system details. The majority of the keywords for searches include the treatment modality name alongside terms such as "HCC", "multifocal", or "multinodular". Ablation is a curative option for Barcelona Clinic Liver Cancer (BCLC) A disease and is appropriate when liver transplantation (LT) is impractical. It is ideal in disease with ?3 nodules (each <3 cm) preferably confined to one segment. TACE [conventional TACE (cTACE), drug-eluting bead TACE (DEB-TACE), balloon-occluded TACE (B-TACE), and less so hepatic arterial infusion chemotherapy (HAIC)] is the major workhorse for multifocal BCLC B disease, in pre-transplant downstaging, and in advanced disease palliation. The Kinki BCLC B subclassification can guide TACE subtype selection. TACE response can be assessed over 2-3 sessions per modified Response Evaluation Criteria in Solid Tumors (mRECIST) and patient session tolerance. TARE is an option for BCLC C disease, with BCLC A/B applications limited by radiation induced liver disease (RILD). Pseudo-ablative techniques like sub-selective TARE (sTARE) are promising but are unproven and less useful in multinodular disease. Finally, combination therapies [TACE + ablation, liver resection (LR) + ablation/TACE] are an exciting option but warrant further study. Multifocal HCC remains challenging to manage. While BCLC is a useful starting point, the patient's tumor imaging characteristics and clinical circumstances must be considered when selecting the appropriate treatment modality.

METTL3-Mediated STING Upregulation and Activation in Kupffer Cells Contribute to Radiation-Induced Liver Disease via Pyroptosis

Purpose: Radiation therapy is a vital adjuvant treatment for liver cancer, although the challenge of radiation-induced liver diseases (RILDs) limits its implementation. Kupffer cells (KCs) are a crucial cell population of the hepatic immune system and their biological function can be modulated by multiple epigenetic RNA modifications, including N6-methyladenosine (m6A) methylation. However, the mechanism for m6A methylation in KC-induced inflammatory response in RILD remains unclear. The present study investigated the function of m6A modification in KCs contributing to RILD. Methods and Materials: Methylated RNA-immunoprecipitation sequencing (MeRIP-seq) and RNA transcriptome sequencing were used to explore the m6A methylation profile of primary KCs isolated from mice after irradiation with 3 × 8 Gy. Western blotting and quantitative real-time polymerase chain reaction were used to evaluate gene expression. DNA pull-down and CHIP assays were performed to verify target gene binding and identify binding site. Results: MeRIP-seq revealed a significantly increased m6A modification level in human KCs after irradiation, suggesting the potential role of upregulated m6A in RILD. In addition, the study results corroborated that methyltransferase-like 3 (METTL3) acts as a main modulator to promote the methylation and gene expression of TEAD1, leading to STING-NLRP3 signaling activation. Importantly, it was shown that IGF2BP2 functions as an m6A “reader” to recognize methylated TEAD1 mRNA and promote its stability. METTL3/TEAD1 knockdown abolished the activation of STING-NLRP3 signaling and protected against RILD in addition to suppressing inflammatory cytokines and hepatocyte apoptosis. Moreover, clinically collected human normal liver tissue samples post-irradiation showed increased expression of STING and IL-1β in KCs compared to the non-irradiation group. Notably, STING pharmacological inhibition alleviated irradiation-induced liver injury in mice, indicating its potential therapeutic role in RILD. Conclusions: The results of our study reveal that TEAD1-STING-NLRP3 signaling activation contributes to RILD via METTL3-dependent m6A modification.

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.

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.

Whole Liver Radiotherapy for Multiple Liver Metastases in Thoracic Malignancies

Liver metastases (LM) are common in advanced thoracic cancer patients with dismal oncological outcomes. Even in the modern era of novel systemic therapy, LM led to a 21% increased mortality risk compared with those without. Options for progressive multiple LM after systemic therapy are limited. Therefore, a different treatment modality is urgently needed to overcome such a predicament. Herein, we renovate the classical whole liver radiotherapy (WLRT) and evaluate its efficacy and safety in treating thoracic cancer patients with progressive multiple LM. Patients with lung or thymic cancer who had multiple LM treated by WLRT between 2018 and 2022 were enrolled. Radiotherapy (RT) was delivered with a median dose of 24 Gy (range 8-25 Gy) in 8 fractions (range 1-16) at the discretion of treating physicians. Overall survival (OS) and cumulative incidence of intrahepatic progression were calculated from the completion of WLRT till death or progression by Kaplan-Meier and competing risk analyses, respectively. Twenty-four patients were enrolled in this retrospective study. Eleven patients (46%) had lung adenocarcinoma, of which nine patients had oncogenic mutations. Six patients (25%) had small cell lung cancer (SCLC), four patients (17%) had thymic squamous cell carcinoma (SqCC), two patients (8%) had lung SqCC, and one patient (4%) had mixed histology. Eighteen patients (75%) were under systemic therapy treatment before the diagnosis of LM, and fifteen (63%) received LM biopsy. The median time from the diagnosis of LM to WLRT was 7.5 months (range, 0.5-33.9 months). Eleven patients (46%) had concurrent RT and systemic therapy. With a median follow-up of 3.1 months, the 3-, 6- and 12-month OS were 57%, 38%, and 15%, respectively. After adjusting death as a competing risk, the cumulative incidence of LM progression at 3, 6, and 12 months were 10%, 19%, and 44%, respectively. Within three months after the completion of RT, one patient (4%) had grade 5 radiation-induced liver disease (RILD), one patient (4%) had grade 4 abnormal liver function test (LFT), three patients (13%) had grade 3 abnormal LFT, and twelve patients (50%) had ≤ grade 2 abnormal LFT. The patient who had Gr.5 RILD expired 51 days after the completion of RT with 24 Gy in 8 fractions concurrently with topotecan. He had primary SCLC with viral hepatitis B. His LFT was around the normal upper limit before WLRT. WLRT provided favorable intrahepatic control with acceptable radiation-related toxicities and could be considered a treatment option for patients with progressive LM under systemic therapy. Further investigation with a larger cohort is warranted to identify patients at a high risk of developing severe RILD.

A prospective registry study of stereotactic magnetic resonance guided radiotherapy (MRgRT) for primary liver tumors

Background and PurposeStereotactic body radiation therapy (SBRT) has demonstrated safe and effective results for primary liver tumors. Magnetic Resonance guided Radiotherapy (MRgRT) is an innovative radiotherapy modality for abdominal tumors. The aim of this study is to report on acute and late toxicities and initial oncological results for primary liver tumors treated with MRgRT. Materials and MethodsWe prospectively included in our cohort all patients treated by MRgRT for a primary liver tumor at the Montpellier Cancer Institute. The primary endpoint was acute and late toxicities assessed according to CTCAE v 5.0. The mean prescribed dose was 50 Gy in 5 fractions. ResultsBetween October 2019 and April 2022, MRgRT treated 56 patients for 72 primary liver lesions. No acute or late toxicities of CTCAE grade greater than 2 attributable to radiotherapy were noted during follow-up. No cases of radiation-induced liver disease (RILD), either classical or non-classical, occurred. After a median follow-up of 13.2 months (95% CI [8.8; 15.7]), overall survival was 85.1% (95% CI: [70.8; 92.7]) at 1 year and 74.2% at 18 months (95% CI [52.6; 87.0]). Local control was 98.1% (95% CI: [87.4; 99.7]) and 94.7% (95% CI: [79.5; 98.7]) at 12 and 18 months, respectively. Among the HCC subgroup, no local recurrences were observed. ConclusionMRgRT for primary liver tumors is safe without severe adverse events and reach excellent local control. Numerous studies are underway to better assess the value of MRI guidance and adaptive process in these indications.

Comparing Predicted Toxicities between Hypofractionated Proton and Photon Radiotherapy of Liver Cancer Patients with Different Adaptive Schemes.

With the availability of MRI linacs, online adaptive intensity modulated radiotherapy (IMRT) has become a treatment option for liver cancer patients, often combined with hypofractionation. Intensity modulated proton therapy (IMPT) has the potential to reduce the dose to healthy tissue, but it is particularly sensitive to changes in the beam path and might therefore benefit from online adaptation. This study compares the normal tissue complication probabilities (NTCPs) for liver and duodenal toxicity for adaptive and non-adaptive IMRT and IMPT treatments of liver cancer patients. Adaptive and non-adaptive IMRT and IMPT plans were optimized to 50 Gy (RBE = 1.1 for IMPT) in five fractions for 10 liver cancer patients, using the original MRI linac images and physician-drawn structures. Three liver NTCP models were used to predict radiation-induced liver disease, an increase in albumin-bilirubin level, and a Child-Pugh score increase of more than 2. Additionally, three duodenal NTCP models were used to predict gastric bleeding, gastrointestinal (GI) toxicity with grades >3, and duodenal toxicity grades 2-4. NTCPs were calculated for adaptive and non-adaptive IMRT and IMPT treatments. In general, IMRT showed higher NTCP values than IMPT and the differences were often significant. However, the differences between adaptive and non-adaptive treatment schemes were not significant, indicating that the NTCP benefit of adaptive treatment regimens is expected to be smaller than the expected difference between IMRT and IMPT.

Radiotherapy plus anti-PD1 versus radiotherapy for hepatic toxicity in patients with hepatocellular carcinoma

PurposeIn this study, we aimed to compare the radiation-induced hepatic toxicity (RIHT) outcomes of radiotherapy (RT) plus antibodies against programmed cell death protein 1 (anti-PD1) versus RT alone in patients with hepatocellular carcinoma (HCC), evaluate prognostic factors of non-classic radiation-induced liver disease (ncRILD), and establish a nomogram for predicting the probability of ncRILD.Patients and methodsPatients with unresectable HCC treated with RT and anti-PD1 (RT + PD1, n = 30) or RT alone (n = 66) were enrolled retrospectively. Patients (n = 30) in each group were placed in a matched cohort using propensity score matching (PSM). Treatment-related hepatotoxicity was evaluated and analyzed before and after PSM. The prognostic factors affecting ncRILD were identified by univariable logistic analysis and Spearman’s rank test in the matched cohort to generate a nomogram.ResultsThere were no differences in RIHT except for increased aspartate aminotransferase (AST) ≥ grade 1 and increased total bilirubin ≥ grade 1 between the two groups before PSM. After PSM, AST ≥ grade 1 occurred more frequently in the RT + PD1 group (p = 0.020), and there were no significant differences in other hepatotoxicity metrics between the two groups. In the matched cohort, V25, tumor number, age, and prothrombin time (PT) were the optimal prognostic factors for ncRILD modeling. A nomogram revealed a good predictive performance (area under the curve = 0.82).ConclusionsThe incidence of RIHT in patients with HCC treated with RT + PD1 was acceptable and similar to that of RT treatment. The nomogram based on V25, tumor number, age, and PT robustly predicted the probability of ncRILD.

Efficacy and safety of radiotherapy combined with regorafenib for advanced hepatocellular carcinoma: A real-world study from a single center.

e16142 Background: This study aimed to assess the efficacy and safety of radiotherapy (RT) combined with regorafenib as a second or further-line treatment for advanced hepatocellular carcinoma (HCC). Methods: Patients diagnosed with advanced HCC who had received RT combined with concurrent or sequential regorafenib treatment or regorafenib plus anti-PD-1 or anti-PD-L1 immune checkpoint inhibitors (ICIs) in our hospital from April 2018 to August 2022 were reviewed. Progression-free survival (PFS) was the primary endpoint. Overall survival (OS), objective response rate (ORR), disease control rate (DCR) and toxicity were the secondary endpoints. Results: Fifty-four patients were included with a median age of 56 (38-73). Forty-six patients (85.2%) were in Barcelona Clinic Liver Cancer (BCLC) stage C. Thirty-seven patients (68.5%) had portal vein tumor thrombosis and 15 (27.8%) had extrahepatic metastasis. All patients received intensity modulated radiation therapy, while 26 patients were concurrently treated with regorafenib and 28 patients were sequentially treated with regorafenib. The median dose of radiotherapy was 57.2Gy (30-69.8Gy). Anti-PD-1/anti-PD-L1 agents were applied to 31 patients at the use of regorafenib. The median PFS was 11.3 months. The 3-year PFS and OS were 23.8% and 51.9%, respectively. Treatment response after RT was shown. For tumor in in-field of RT, ORR was 75.9% and 92.6% according to RECIST and mRECIST criteria, respectively. No progression was found in in-field of RT. Out-field recurrence in liver and distance metastasis was the main failure pattern. For all lesions, the ORR was 40.7% and DCR was 55.6%, respectively. There was no significant difference of PFS and OS between patients with and without ICIs ( p &gt; 0.05). Univariate analysis showed that alpha-fetoprotein tumor marker level ≥ 1000 ng/ml ( p = 0.049), Albumin-Bilirubin grade ≥ 2 ( p = 0.012) and multiple intrahepatic tumors ( p = 0.031) were the risk factors of lower PFS. Patients were well tolerated to the treatments. The most common grade 3 toxicities were hand-foot syndrome (11.1%), fatigue (3.7%) and hypertension (1.9%). Classical or non-classical radiation-induced liver disease was not noted. Conclusions: Radiotherapy concurrently or sequentially with regorafinib treatment is an effective, well tolerated, and promising regimen in advanced HCC patients. [Table: see text]

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

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

Machine learning-based normal tissue complication probability model for predicting albumin-bilirubin (ALBI) grade increase in hepatocellular carcinoma patients

Purpose:The aim of this study was to develop a normal tissue complication probability model using a machine learning approach (ML-based NTCP) to predict the risk of radiation-induced liver disease in hepatocellular carcinoma (HCC) patients.Materials and methods:The study population included 201 HCC patients treated with radiotherapy. The patients’ medical records were retrospectively reviewed to obtain the clinical and radiotherapy data. Toxicity was defined by albumin-bilirubin (ALBI) grade increase. The normal liver dose-volume histogram was reduced to mean liver dose (MLD) based on the fraction size-adjusted equivalent uniform dose (2 Gy/fraction and α/β = 2). Three types of ML-based classification models were used, a penalized logistic regression (PLR), random forest (RF), and gradient-boosted tree (GBT) model. Model performance was compared using the area under the receiver operating characteristic curve (AUROC). Internal validation was performed by 5-fold cross validation and external validation was done in 44 new patients.Results:Liver toxicity occurred in 87 patients (43.1%). The best individual model was the GBT model using baseline liver function, liver volume, and MLD as inputs and the best overall model was an ensemble of the PLR and GBT models. An AUROC of 0.82 with a standard deviation of 0.06 was achieved for the internal validation. An AUROC of 0.78 with a standard deviation of 0.03 was achieved for the external validation. The behaviors of the best GBT model were also in good agreement with the domain knowledge on NTCP.Conclusion:We propose the methodology to develop an ML-based NTCP model to estimate the risk of ALBI grade increase.

Radiotherapy with Multimodality Therapy for Hepatocellular Carcinoma with Hepatic Vein and/or Inferior Vena Cava Tumor Thrombus

<h3>Purpose/Objective(s)</h3> Liver cancer is the seventh most common malignancy and second leading cause of cancer-related death worldwide. Hepatic vein and/or inferior vena cava (IVC) tumor thrombus are less common. Improvement in techniques allowed the increasing use of radiotherapy in treating tumor thrombus in hepatocellular carcinoma (HCC). Hence, the present study evaluated the treatment response and survival outcomes of HCC with hepatic vein tumor thrombus (HVTT) and/or IVC involvement receiving radiotherapy in modern RT technique combined with other multimodality therapies. <h3>Materials/Methods</h3> HCC patients with HVTT and/or IVC tumor thrombus receiving radiotherapy were identified at our institution. All patients were treated with VMAT or IMRT technique and 4D-CT was used in simulation. All thrombus and primary tumor in liver were included in the GTV unless they were far from gross primary tumor. The prescription dose to 95% of the PTV was planned at 50-65Gy in 22-28 fractions over 5-6 weeks. After the completion of RT, chest-abdominal CT and liver MRI were performed at 1, 3, 6, 12 months and then 3 to 6 months thereafter. Treatment response was defined as the best response evaluation in 3 months after RT. Overall survival (OS), progression free survival (PFS) and in-field PFS were recorded during follow-up. <h3>Results</h3> Between April 2010 and September 2021, 30 men and 4 women with a median age of 53.5 years (range 30-71 years) were retrospectively included in the cohort. 7 (20.6%) patients had lymph node metastasis and 10 (29.4%) patients had distant metastasis before radiotherapy (RT). In addition to hepatic vein/inferior vena cava (IVC) tumor thrombus, portal vein and right atrium involvement were present in 17 (50.0%) and 6 (17.6%) patients. Half of the patients received TACE and 14 (41.2%) patients received systemic treatment including target therapy and immune therapy before radiotherapy. Most patients received target therapy concurrent with (70.6%) and/or post RT (79.4%). During follow-up (median 13.0 months), the median PFS and median in-field PFS were 4.2 months and not reached, respectively. The PFS and in-field PFS rate were 24.6% and 79.2% at 1 year, 19.7% and 72.0% at 2 years. The OS rate was 77.6% at 1 year and 36.3% at 2 years with a median OS of 15.8 months. PFS and OS were not associated with portal vein involvement, IVC involvement and distant metastasis before RT. The most common first failure site was lung (13/34 patients, 38.2%), followed by liver (7/34 patients, 20.6%). Only 5 (14.7%) patients had progression in the RT field of liver during follow-up. No patients had radiation-induced liver disease or pulmonary embolism during follow-up. <h3>Conclusion</h3> Our study proved that HCC lesions and tumor thrombus were sensitive to RT even after other local therapies. Combination of RT and systemic therapy in treating HCC patients with HVTT and IVC tumor thrombus was safe and effective.

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.