Mean Liver Dose Research Articles

Investigate potential clinical benefits and linear energy transfer sparing utilizing proton arc therapy for hepatocellular carcinoma

PurposeTo investigate the potential clinical benefits and dose-averaged Linear Energy Transfer (LETd) sparing, utilizing proton arc plan for hepatocellular carcinoma (HCC) patients in comparison with Intensity Modulated Proton Therapy (IMPT). MethodsTen HCC patients have been retrospectively selected. Two planning groups were created: Proton Arc plans using Monaco ver. 6 and the clinical IMPT plan. Both planning groups used the same robustness parameters. The prescription dose is 67.5 Gy (RBE) in 15 fractions of the Clinical Target Volume (CTV). Robustness evaluations were performed to ensure dose coverage. Normal Tissue Complicated Probability (NTCP) model was utilized to predict the possibility of Radiation-Induced Liver Disease (RILD) and evaluate the potential benefit of proton arc therapy. LETd calculation and evaluation were performed as well. ResultsProton arc plan has shown better dosimetric improvements of most Organ-At-Risks (OARs). More specifically, the liver mean dose has been significantly reduced from 14.7 GyE to 10.62 GyE compared to the IMPT plan. The predicted possibility of RILD has also been significantly reduced for cases with a large and deep liver target where healthy liver tissue sparing is a challenge. Additionally, proton arc therapy could increase the average LETd in the target and reduce LETd in adjacent OARs. ConclusionsThe potential clinical benefit of utilizing proton arc therapy HCC varies depending on the patient-specific geometry. With more freedom, proton arc therapy can offer a better dosimetric plan quality in the challenge cases, which might not be feasible using the current IMPT technique.

Treatment Time and Dosimetric Advantage in Cone Beam Computed Tomography-Guided Online Adaptive Radiation Therapy Considering Interfractional and Intrafractional Changes in Patients With Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Radiation therapy is the standard treatment for localized gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The ETHOS system (Varian Medical System) has enabled us to perform cone beam computed tomography (CBCT)-guided online adaptive radiation therapy (oART). This study presents a retrospective dosimetric analysis for interfractional and intrafractional change and treatment time in oART for gastric MALT lymphoma. We included 3 male patients with gastric MALT lymphoma who underwent exhalation breath-hold fasting oART using the SpiroDynr'X system. Treatment details and plans (3 reference [REF] plans, 51 scheduled [SCH] plans, and adapted [ADP] plans) were retrospectively analyzed. Doses to the clinical target volume in planning CT (CTV_REF), CTV1, and CTV2 (representing the stomach in planning and preirradiation CBCT, respectively) and planning target volume (PTV) in the planning CBCT were estimated. D2%, D98%, D50%, and Dmean for these volumes, along with organ-at-risk doses, were examined across the 3 plans. The PTV dose coverage of CTV2 on preirradiation CBCT was calculated. CBCT-guided oART was completed within the scheduled period, using the ADP plans instead of the SCH plans on each treatment day in all cases. The average treatment time was approximately 45 minutes. CTV1 and CTV2 exhibited intrafractional and interfractional variations, fluctuating above and below CTV_REF. Some ADP plans resulted in incomplete PTV coverage of CTV2, but the unincluded volume was <1% of CTV2. D50%, D98%, and Dmean of CTV1, CTV2, and PTV were significantly improved in the ADP plans than in the SCH plans. Moreover, the Dmean to the liver and kidneys was reduced in the ADP plans. CBCT-guided oART in patients with gastric MALT lymphoma demonstrated that ADP plans improved CTV1, CTV2, and PTV doses and reduced the mean bilateral kidney and liver doses, suggesting that it may offer enhanced treatment precision for gastric MALT lymphoma.

Hypofractionated Radiotherapy-Related Lymphopenia Is Associated With Worse Survival in Unresectable Intrahepatic Cholangiocarcinoma.

The aim of this study was to evaluate the incidence of radiotherapy (RT)-related lymphopenia, its predictors, and association with survival in unresectable intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated-RT (HF-RT). Retrospective analysis of 96 patients with unresectable ICC who underwent HF-RT (median 58.05 Gy in 15 fractions) between 2009 and 2022 was performed. Absolute lymphocyte count (ALC) nadir within 12 weeks of RT was analyzed. Primary variable of interest was severe lymphopenia, defined as Grade 3+ (ALC <0.5 k/μL) per CTCAE v5.0. Primary outcome of interest was overall survival (OS) from RT. Median follow-up was 16 months. Fifty-two percent of patients had chemotherapy pre-RT, 23% during RT, and 40% post-RT. Pre-RT, median ALC was 1.1 k/μL and 5% had severe lymphopenia. Post-RT, 68% developed RT-related severe lymphopenia. Patients who developed severe lymphopenia had a significantly lower pre-RT ALC (median 1.1 vs. 1.5k/μL, P =0.01) and larger target tumor volume (median 125 vs. 62 cm 3 , P =0.02). In our multivariable Cox model, severe lymphopenia was associated with a 1.7-fold increased risk of death ( P =0.04); 1-year OS rates were 63% vs 77% ( P =0.03). Receipt of photon versus proton-based RT (OR=3.50, P =0.02), higher mean liver dose (OR=1.19, P <0.01), and longer RT duration (OR=1.49, P =0.02) predicted severe lymphopenia. HF-RT-related lymphopenia is an independent prognostic factor for survival in patients with unresectable ICC. Patients with lower baseline ALC and larger tumor volume may be at increased risk, and use of proton therapy, minimizing mean liver dose, and avoiding treatment breaks may reduce RT-related lymphopenia.

Valuation of advanced Dosimetry in Transarterial Radioembolization of Hepatocellular Carcinoma with 90Y microspheres

Objective : The aim of our study was to analyze the relationships between tumor (T) and normal tissue (N) absorbed dose in relation to the clinical outcomes in hepatocellular carcinoma (HCC) patients treated with 90Y microspheres. Materials and methods : After transarterial radioembolization of HCC with 90Y microspheres, 62 patients (10 females: 52 males, mean age 68.2±8.2 years) were imaged using a four-ring, time-of-flight (TOF), PET/CT system. Low dose, non-diagnostic CT images from PET/CT were utilized for localization of the 90Y microspheres and attenuation correction of PET images. Response assessment was conducted using mRECIST criteria on MRI one month post treatment and subsequently every three months after 90Y treatment. Results : Among 62 patients, mean liver, tumor, and normal tissue doses (mean ± SD) were 51.38±23.32 Gy, 682.60±785.19 Gy and 45.54±21.19 Gy, respectively. Out of these patients, 39 exhibited complete response (CR), 11 showed partial response (PR), 2 had stable disease (SD), and 10 showed progression of the disease (PD). For CR+PR patients the mean T was 824.63±833.10 Gy, whereas for PD patients, the mean T was significantly lower at 205.70±183.22 Gy. The mean liver and normal tissue doses were comparable; for CR+PR patients had liver and normal tissue doses of 51.01±22.55 Gy and 45.18±20.68 Gy, respectively, and for PD patients, these values were 54.34±26.73 Gy and 49.10±22.97 Gy, respectively. Conclusion : Despite not considering the partial volume effect and having a limited number of PD cases, our data indicates a statistically significant lower (P = 0.0001) tumor dose in patients with disease progression compared to those with complete and partial response. These results suggest that post-therapy personalized, and image-based dosimetry provides promising predictive outcomes in 90Y microsphere radiation therapy for liver cancers.

Managing hepatocellular carcinoma across the stages: efficacy and outcomes of stereotactic body radiotherapy

PurposeHepatocellular carcinoma (HCC) poses a unique challenge due to its predilection for developing on compromised livers, often limiting surgical options. Stereotactic body radiotherapy (SBRT) has emerged as a promising local treatment modality for HCC. This study aims to assess the effectiveness of SBRT in HCC patients not suitable for surgery, focusing on local control, optimal radiation dosing, and prognostic factors.MethodsIn this retrospective analysis, 52 HCC patients treated with SBRT were examined. The study assessed local control, progression-free survival (PFS), and overall survival (OS) while conducting dosimetric analyses. The relationship between mean liver dose and Child–Pugh score (CPS) progression was also explored.ResultsSBRT demonstrated 93.4% freedom from local progression (FFLP) at 12 months. Notably, a near minimum dose (D98%) below 61 Gy as an equivalent dose in 2‑Gy fractions with α/β 10 Gy (EQD2α/β10) was associated with reduced FFLP (p-value 0.034). Logistic regression analysis revealed a dose–response relationship for FFLP and D98% with 95% and 98% probability of FFLP at a dose of 56.9 and 73.1 Gy, respectively. The study observed OS rates of 63.7% at 1 year and 34.3% at 3 years. Patients with portal vein tumor thrombus (PVTT) and larger tumors (≥ 37 cm3) experienced decreased PFS and OS. Multivariate analysis identified PVTT, larger tumor volume, and performance status as independent predictors of reduced OS. Notably, classical radiation-induced disease (cRILD) was absent, but nonclassical (nc) RILD occurred in 7.7% of patients. Regression analysis linked a mean EQD2α/β3–8 dose to the liver (12.8–12.6) with a 10% likelihood of ncRILD.ConclusionSBRT offers a compelling option for achieving high local control and promising survival outcomes in HCC. The study supports a radiation dose range of 61–73.1 Gy, coupled with a mean liver dose under 12.6–12.8 Gy as EQD2, to achieve favorable FFLP rates, with acceptable toxicity rates.

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.

Liver toxicity following reirradiation and multiple-target SBRT for primary hepatocellular carcinoma.

514 Background: Stereotactic body radiation therapy (SBRT) is increasingly used to treat hepatocellular carcinoma (HCC), but its safety in the treatment of multiple synchronous or recurrent lesions is underreported. We aim to better characterize SBRT-related hepatic toxicity in this population. Methods: We conducted a retrospective analysis of patients with primary HCC who underwent SBRT for 2 or more synchronous or recurrent liver lesions. We collected patient characteristics and dosimetric data (mean liver dose, cumulative effective volume [Veff], cumulative volume of liver receiving 15Gy [V15Gy], and cumulative planning target volume [PTV]) along with liver-related toxicity (measured by albumin-bilirubin [ALBI] and Child-Pugh [CP] scores). We employed a linear mixed-effects model to assess the effect of multi-target SBRT on changes in ALBI. Results: 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. Eight local failures occurred at a median of 8 months (range: 4 – 25 months) after SBRT. Among those receiving multiple SBRT courses, there were 7 lesions with overlap of V15Gy (median V15Gy overlap: 35mL, range: 0.5 – 388mL). There was no association between cumulative Veff, V15Gy, or PTV and change in ALBI. Four of 25 patients an increase of Child-Pugh (CP) score by ≥ 2 points, within 3 to 6 months after SBRT. Neither increase in CP nor ALBI were associated with cumulative Veff, V15Gy, and PTV. Comparing the groups that received SBRT in a single course versus multiple courses revealed no statistically significant differences in liver toxicity. Conclusions: LiverSBRT for multiple lesions in a single or in separate courses results in worsening of CP scores or ALBI in a small percentage of patients, suggesting a low risk of RILD. Prospective studies with a larger cohort are needed to better characterize safety in this population.

Combined Stereotactic Body Radiation Therapy and Immune Checkpoint Inhibition for Liver Metastases: Safety and Outcomes in a Pooled Analysis of 3 Phase 1 Trials

PurposeStereotactic body radiotherapy (SBRT) safely and effectively controls liver metastases, but its safety and efficacy when combined with immune checkpoint inhibitors (ICIs) are not well characterized. This analysis of three phase I trials of combination SBRT and ICI evaluates whether liver metastasis SBRT (LM-SBRT) increases the risk for hepatotoxicity when combined with ICI and explores efficacy endpoints. MethodsData were analyzed from three phase I trials of combination SBRT and ICI for patients with metastatic solid tumors conducted between 2016 and 2020. ICI was administered per trial protocol with LM-SBRT delivered to 45 Gy in 3 fractions with mean liver dose <16 Gy and ≥700cc of normal liver spared 17.1 Gy. Hepatic adverse events (HAEs) were defined as hepatic failure; autoimmune hepatitis; or elevation of AST, ALT, bilirubin or alkaline phosphatase using CTCAE 4.0. Cumulative incidence of HAE and local failure were modeled with death as a competing risk. Competing risks regression was performed using Fine-Gray modeling. Survival was estimated by the Kaplan-Meier method. Results200 patients were analyzed, including 81 patients with liver metastases, 57 of whom received LM-SBRT. The 12-month rate of any grade ≥2 HAE was 11% and 10% in LM-SBRT and non-LM-SBRT patients, respectively (NS). Radiographic evidence for liver disease and dual-agent ICI were significantly associated with HAEs on univariable and multivariable analysis while liver dose metrics were not. Patients with liver metastases had significantly worse progression-free and overall survival compared to those without and local failure of treated liver metastases was significantly higher than for treated extrahepatic metastases (28% vs 4% at 12 months, p < 0.001). ConclusionsCombination LM-SBRT and ICI did not significantly increase the risk for HAE compared to ICI without LM-SBRT, suggesting hepatotoxicity is largely driven by factors other than liver RT such as choice of ICI. Liver metastasis is associated with worse overall survival and local control outcomes.

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.

Dosimetric comparison of magnetic resonance-guided radiation therapy, intensity-modulated proton therapy and volumetric-modulated arc therapy for distal esophageal cancer

Advances in radiotherapy (RT) technologies permit significant decreases in the dose delivered to organs at risk (OARs) for patients with esophageal cancer (EC). Novel RT modalities such as proton beam therapy (PBT) and magnetic resonance-guided radiotherapy (MRgRT), as well as motion management techniques including breath hold (BH) are expected to further improve the therapeutic ratio. However, to our knowledge, the dosimetric benefits of PBT vs MRgRT vs volumetric-modulated arc therapy (VMAT) have not been directly compared for EC. We performed a retrospective in silico evaluation using the images and datasets of nine distal EC patients who were treated at our institution with a 0.35-Tesla MR linac to 50.4 Gy in 28 fractions in mid-inspiration BH (BH-MRgRT). Comparison free-breathing (FB) intensity-modulated PBT (FB-IMPT) and FB-VMAT plans were retrospectively created using the same prescription dose, target volume coverage goals, and OAR constraints. A 5 mm setup margin was used for all plans. BH-IMPT and BH-VMAT plans were not evaluated as they would not reflect our institutional practice. Planners were blinded to the results of the treatment plans created using different radiation modalities. The primary objective was to compare plan quality, target volume coverage, and OAR doses. All treatment plans met pre-defined target volume coverage and OAR constraints. The median conformity and homogeneity indices between FB-IMPT, BH-MRgRT and FB-VMAT were 1.13, 1.25, and 1.43 (PITV) and 1.04, 1.15, 1.04 (HI), respectively. For FB-IMPT, BH-MRgRT and FB-VMAT the median heart dose metrics were 52.8, 79.3, 146.8 (V30Gy, cc), 35.5, 43.8, 77.5 (V40Gy, cc), 16.9, 16.9, 32.5 (V50Gy, cc) and 6.5, 14.9, 17.3 (mean, Gy), respectively. Lung dose metrics were 8.6, 7.9, 18.5 (V20Gy, %), and 4.3, 6.3, 11.2 (mean, Gy), respectively. The mean liver dose (Gy) was 6.5, 19.6, 22.2 respectively. Both FB-IMPT and BH-MRgRT achieve substantial reductions in heart, lung, and liver dose compared to FB-VMAT. We plan to evaluate dosimetric outcomes across these RT modalities assuming consistent use of BH.

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.

Predictors of Hepatotoxicity in Patients with Metastatic Solid Tumors Treated with Immune Checkpoint Inhibition (ICI) and Liver-Directed SBRT

Liver-metastasis-directed SBRT (LM-SBRT) alone provides durable local control for liver metastases with low rates of toxicity when adhering to established dose constraints. Whether these constraints are sufficient in the context of concurrent ICI is not established. To determine whether LM-SBRT contributes to hepatotoxic adverse events (HAE) in patients receiving ICI, we analyzed potential predictors of HAE in a prospectively evaluated cohort of clinical trial patients treated with both SBRT and ICI. Patients with metastatic solid tumors were included from three trials of multi-site SBRT with ICI given concurrently or shortly after SBRT provided they received all study treatments and were monitored for adverse events. ICI agents included pembrolizumab alone or dual agent ICI with nivolumab and either cabiralizumab, urelumab, or ipilimumab. LM-SBRT was delivered to 45 Gy in 3 fr with mean liver dose (MLD) limited to 16 Gy and <700 cc of liver receiving 17.1 Gy. HAE were defined using CTCAE 4.0 as: elevation of AST, ALT, bilirubin or alkaline phosphatase; autoimmune hepatitis; hepatic failure; or cholecystitis. HAE were included if rated at least possibly related to treatment by the trial monitoring committee. Cumulative incidence (CI) of HAE was modeled with death as a competing risk. Competing risks regression was performed using Fine-Gray modeling. Two hundred thirteen patients were evaluable. Median follow-up was 10 months. Median age was 61, 90 had liver metastases at treatment, 65 received SBRT to a liver lesion, 15 had underlying liver disease (cirrhosis or hepatic steatosis) and 13 patients had a primary liver cancer. Dual agent ICI was given to 97 patients. Table 1 shows CI at 6 months of grades 1-4 HAE in all patients, LM-SBRT patients and non-liver SBRT patients (NL-SBRT). None experienced grade 5 HAE. There was no significant difference in CI of any grade of HAE between LM-SBRT and NL-SBRT patients. This was also true when comparing LM-SBRT patients to NL-SBRT patients with <0.1 Gy MLD. ICI dose reduction or cessation due to HAE occurred in 4 patients, none of whom received LM-SBRT. On univariate analysis, underlying liver disease and dual agent ICI were significantly associated with grade 2+ HAE while age, LM-SBRT, MLD, primary liver cancer and presence of liver metastases at treatment were not. On multivariate analysis, underlying liver disease and dual agent ICI remained significantly associated with grade 2+ HAE (HR: 6.7, 95% CI 2.3 - 19.1; 4.7, 95% CI 1.7 - 13.0). LM-SBRT and MLD were not significant on MVA. LM-SBRT did not significantly increase the risk for hepatotoxicity in patients receiving ICI when respecting the above dose constraints. Risk for hepatotoxicity appears to be driven by dual agent ICI and underlying liver disease.

Using kV Triggered Imaging and Liver Dome Position to Reduce the Dosimetric Error Caused by Breath Hold Variability for Liver Stereotactic Body Radiation Therapy

In a previous study, we demonstrated that manual gating using kV triggered imaging and liver dome position can reduce targeting errors caused by breath hold variability for liver stereotactic body radiation therapy (SBRT). In this study, we quantified the dosimetric error caused by breath hold variability and investigated the effect of liver dome gating on reducing dosimetric error. Twenty-five liver SBRT patients treated with deep inspiration breath-hold were included in this IRB approved study. Volumetric modulated arc therapy was used to deliver 30-60 Gy in 1-5 fractions. To verify the breath-hold reproducibility during treatment, a KV triggered image was acquired at the beginning of each breath-hold. The liver dome position was visually compared with the expected upper/lower liver boundaries created by expanding/contracting the liver contour 5mm in the superior-inferior direction. If the liver dome position was within the boundaries, delivery continued; otherwise, beam was held manually and the patient was instructed to take another breath hold until the liver dome position was within boundaries. To calculate delivered dose, for each fraction, the treatment plan was divided into sub-beams, each corresponding to one breath hold using delivery log files. The triggered images were registered to the planning CT to determine the liver position during each breath hold. Dose delivered during each breath hold was calculated by shifting the isocenter of the sub-beam according to the liver position. Breath holds discarded by gating were excluded since no dose was delivered during these breath holds. Delivered fractional doses were compared with planned fractional doses using GTV D99 and liver Dmean. To estimate delivered dose without gating, the first "corrective" breath hold taken after the discarded breath holds was replaced with the prior discarded breath hold and dose calculation was repeated. Seven hundred eleven triggered images from 91 treatment fractions were analyzed. Without gating, in 11 of the 91 fractions from 7 of the 25 patients, delivered GTV D99 reduced > 0.50 Gy from planned value (range 0.51-1.68 Gy, 3-10% of planned fractional GTV D99). Liver dome gating was able to detect/exclude irreproducible breath holds in 8 of the 11 fractions, increasing the delivered GTV D99 by 0.70 Gy per fraction on average (range 0.21-1.63 Gy). With liver dome gating, delivered fractional GTV D99 was comparable to planned value for all fractions (12.96 +/- 5.19 Gy vs 13.04 +/- 5.18 Gy, p > 0.05). Liver mean dose was not affected by breath hold variability or gating. Fractional liver Dmean was 2.26 +/- 1.19 Gy from plan, 2.27 +/- 1.21 Gy for delivery with gating and 2.27 +/- 1.20 Gy for delivery without gating. Breath hold variability may cause tumor underdose. Liver dome gating using kV triggered imaging reduces dosimetric error and ensures tumor coverage for liver SBRT.

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.

Dosimetric Comparison Study Between Free Breathing and Breath Hold Techniques in Patients Treated by Liver-Directed Stereotactic Body Radiation Therapy.

Background Breathing motion management is the key to delivering stereotactic body radiation therapy (SBRT) for liver lesions. This study aimed to compare the dosimetric parameters of liver SBRT using two different techniques: free breathing and breath hold. Method The study included 11 patients with liver metastases or hepatocellular carcinoma who underwent liver-directed SBRT. A dosimetric comparison was performed using dose-volume histogram analysis, evaluating parameters such as the maximum dose to 5 cc of bowel volume, mean liver dose (MLD), and liver V20and V30. Statistical analyses were performed to compare results. Results The findings revealed that the breath hold technique resulted in significantly lower doses to the bowel and smaller volumes of normal liver tissue receiving 20 Gy (V20) and 30 Gy (V30) than the free breathing. Although there was no statistically significant difference in the MLD between the two techniques, the breath hold technique resulted in a lower MLD. Conclusion This dosimetric comparison study suggests that the breath hold technique is associated with lower radiation exposure to the bowel and normal liver tissues. Although this may not be feasible for all patients, it may be an appropriate procedure for selected individuals. Further research is needed to validate these findings in different patient populations and explore their impact on clinical outcomes and patient-reported quality of life.

Feasibility and dosimetric evaluation of single- and multi-isocentre stereotactic body radiation therapy for multiple liver metastases.

Single-isocentre volumetric-modulated arc therapy (VMAT) stereotactic body radiation therapy (SBRT) improves treatment efficiency and patient compliance for patients with multiple liver metastases (MLM). However, the potential increase in dose spillage to normal liver tissue using a single-isocentre technique has not yet been studied. We comprehensively evaluated the quality of single- and multi-isocentre VMAT-SBRT for MLM and propose a RapidPlan-based automatic planning (AP) approach for MLM SBRT. A total of 30 patients with MLM (two or three lesions) were selected for this retrospective study. We manually replanned all patients treated with MLM SBRT by using the single-isocentre (MUS) and multi-isocentre (MUM) techniques. Then, we randomly selected 20 MUS and MUM plans for training to generate the single-isocentre RapidPlan model (RPS) and the multi-isocentre RapidPlan model (RPM). Finally, we used data from the remaining 10 patients to validate RPS and RPM. Compared with MUS, MUM reduced the mean dose delivered to the right kidney by 0.3 Gy. The mean liver dose (MLD) was 2.3 Gy higher for MUS compared with MUM. However, the monitor units, delivery time, and V20Gy of normal liver (liver-gross tumour volume) for MUM were significantly higher than for MUS. Based on validation, RPS and RPM slightly improved the MLD, V20Gy, normal tissue complications, and dose sparing to the right and left kidneys and spinal cord compared with manual plans (MUS vs RPS and MUM vs RPM), but RPS and RPM significantly increased monitor units and delivery time. The single-isocentre VMAT-SBRT approach could be used for MLM to reduce treatment time and patient comfort at the cost of a small increase in the MLD. Compared with the manual plans, RapidPlan-based plans, especially RPS, have slightly improved quality.

Abstract CT151: A phase II study of optimized individualized adaptive radiation therapy for hepatocellular carcinoma

Abstract Introduction: Stereotactic body radiation therapy (SBRT) for the treatment of hepatocellular carcinoma (HCC) remains a challenge due to high rates of toxicity in patients with impaired liver function or tumors not amenable to thermal ablation. We performed a single-arm prospective phase II clinical trial utilizing a novel treatment paradigm optimizing the utility of SBRT based on the individual patient’s probability for tumor control traded off against the risk of liver injury. We hypothesized that maximizing the utility of treatment would decrease toxicity while achieving the same tumor control rate as standard therapy. Methods: Patients with Child-Pugh (CP) A to B7 disease with tumors &amp;gt;3.5 cm, or CP ≥ B8 with any size tumor were prospectively enrolled on an IRB approved clinical trial to undergo SBRT with baseline dose optimization and mid-treatment response adaptation. Optimization and adaptation were based on the expected utility of treatment, calculated as a weighted average of the probability of 4 combinations of toxicity and efficacy outcomes. These calculations were based on the individual patient’s baseline indocyanine green retention at 15 minutes or albumin-bilirubin score (ALBI), CP score, intended dose and fractionation, and mean liver dose with the goal of maximizing the difference between the probability of local control compared to the probability of treatment-related toxicity. Primary endpoints were rate of liver decompensation as measured by ≥2 point change in CP score within 6 months, and lesion-specific local control. Overlap weighting was used to compare patients treated on protocol with patients receiving conventional SBRT at another high-volume cancer center. Results: 56 patients with 80 tumors met inclusion criteria and had a median follow-up of 11.2 months. 44 tumors with a median size of 3.8 cm were treated in CP-A to B7 patients, while 36 tumors with a median size of 2.1 cm were treated in CP ≥ B8 patients. Optimization resulted modification of initial dose for 38% of patients. Sixty-eight percent of patients underwent mid-treatment adaptation with either omission or dose reduction of the final two treatments based on change in expected utility. The 1 year freedom from local progression was 94%. A total of 21% of patients experienced a ≥ 2 point change in CP score within 6 months. Overlap weighted analysis revealed similar local control (HR 0.69, 95% CI [0.25-1.91], p = 0.48), and overall survival (HR 1.45, 95% CI [0.69-3.0], p = 0.33), with decreased toxicity (OR 0.26, 95% CI [0.07 - 0.99], p = 0.048) compared to conventional SBRT. Conclusion: SBRT for HCC patients with large tumors or poor liver function can be optimized via an individualized, utility-based treatment paradigm which may decrease treatment-related toxicity while maintaining tumor control. Citation Format: Daniel J. Herr, Chang Wang, Mishal Mendiratta-Lala, Martha Matuszak, Charles S. Mayo, Yue Cao, Neehar Parikh, Randy Ten Hanken, Dawn Owen, Teodor Stanescu, Michael Yan, Laura A. Dawson, Matthew Schipper, Theodore S. Lawrence, Kyle C. Cuneo. A phase II study of optimized individualized adaptive radiation therapy for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT151.

Long-term characterization of MRI-morphologic alterations after active motion-compensated liver SBRT: a multi-institutional pooled analysis

BackgroundStereotactic body radiotherapy (SBRT) is an effective therapeutic approach in patients with liver metastases. However, long-term changes in hepatic normal tissue have to be taken into account in multimodal treatment regimes. Magnetic-resonance-imaging (MRI) based morphologic liver alterations (MMA) after liver SBRT have been analyzed longitudinally.Material and methods57 patients treated with gantry-based or robotic-based SBRT of 69 treatment volumes of liver metastases, who had long-term follow-up (FU) ≥6 months were included in this retrospective analysis. Post-SBRT MMAs were contoured on each contrast-enhanced-T1-weighted (T1w) MRI-sequence. Morphologic/volumetric data of the liver and MMAs were evaluated longitudinally, including the dependency on treatment-related factors of the planning target volume (PTV) and liver.ResultsThe median FU time was 1 year [6–48 months]. 66 of 69 treatment volumes developed MMAs (mean 143.8 ± 135.1 ccm at first appearance). 31.8% of MMAs resolved completely during FU. Of the persisting MMAs 82.2%/13.3% decreased/increased in size until last available FU. Morphological characterization of the MMAs at first appearance included 75% hypointense and 25% hyperintense T1w-MRI-based appearances. Hypointense as compared to hyperintense appearance was significantly associated with a higher mean liver dose EQD2α/β=3 Gy (p = 0.0212) and non-significantly greater MMA size. Variance analysis demonstrated a significant reduction of MMA and total liver volume after SBRT (p < 0.0001). The volume reduction decelerated longitudinally for both MMA (p < 0.0001) and liver size (p = 0.0033). Radiation doses (PTV-BEDα/β=3 Gy and 10 Gy) were not significantly associated with MMA volume reduction. SBRT of liver metastases with mean liver dose EQD2α/β=3 Gy > 18 Gy were characterized by greater MMA volumes (p = 0.0826) and steeper MMA reduction gradients during FU than those with EQD2α/β=3 Gy ≤ 18 Gy (p < 0.0001).ConclusionRadiogenic MMAs either completely resolve or usually decrease in volume with pronounced reduction during short-term FU. This course was independent of the MMA’s morphological appearance. Further, increased mean liver dose was associated with greater MMA size and a greater gradient of MMA size reduction during FU.

Dosimetric evaluation of the benefit of deep inspiration breath hold (DIBH) for locoregional irradiation of right breast cancer with volumetric modulated arctherapy (VMAT)

Introduction Right-lateralized cardiac substructures can be substantially exposed during right breast cancer (R-BC) radiotherapy. The cardiac benefit of deep inspiration breath hold (DIBH) is established in combination with volumetric modulated arctherapy (VMAT) for left breast cancer with regional node irradiation but is unknown for R-BC. This study evaluated the dosimetric benefit of DIBH for locoregional irradiation of R-BC with VMAT. Material and Methods All patients treated for R-BC with adjuvant locoregional DIBH-VMAT in the Department of Radiation Oncology of the Institut Curie (Paris, France) until December 2022 were included, corresponding to 15 patients. FB- and DIBH-VMAT plans were compared both for a normofractionated regimen (50 Gy/25fx) used for treatment and a replanned hypofractionated regimen (40 Gy/15fx). Dose to the heart, cardiac substructures (sinoatrial node (SAN), atrio-ventricular node (AVN), right coronary artery, left anterior descending coronary artery, left ventricle), ipsilateral lung and liver were retrieved and compared. Results Mean heart dose (MHD) was 3.33 Gy with FB vs. 3.10 Gy with DIBH on normofractionated plans (p = 0.489), and 2.58 Gy with FB vs. 2.41 Gy with DIBH on hypofractionated plan (p = 0.489). The benefit of DIBH was not significant for any cardiac substructure. The most exposed cardiac substructure were the SAN (mean dose of 6.62 Gy for FB- and 5.64 Gy for DIBH-VMAT on normofractionated plans) and the RCA (mean dose of 4.21 Gy for FB- and 4.06 Gy for DIBH-VMAT on normofractionated plans). The maximum benefit was observed for the RCA with a median individual dose reduction of 0.84 Gy on normofractionated plans (p = 0.599). No significant dosimetric difference were observed for right lung. Liver mean dose was significantly lower with DIBH with median values decreasing from 2.54 Gy to 0.87 Gy (p = 0.01). Conclusion Adding DIBH to efficient cardiac-sparing radiotherapy techniques, such as VMAT, is not justified in the general case for locoregional R-BC irradiation. Specific R-BC patient subpopulations who could benefit from additional DIBH combination with locoregional VMAT are yet to be identified.

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.