Increase In Child-Pugh Score Research Articles

Clinical characteristics of patients with advanced hepatocellular carcinoma who received long-term treatment with atezolizumab and bevacizumab for more than one year.

532 Background: Atezolizumab plus bevacizumab (Ate/Bev) has become the standard of care since 2020 as a first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). However, studies on patients receiving long-term treatment with Ate/Bev are still lacking. In this study, we evaluated the clinical characteristics and impacts on patients receiving Ate/Bev treatment for more than one year. Methods: We prospectively enrolled 246 patients with unresectable HCC who received Ate/Bev treatment at three tertiary cancer centers in Korea between May 2020 and April 2022. Comparative analyses were performed between patients treated with Ate/Bev for more than one year and those treated for less than one year. Additionally, treatment-related adverse events (AEs), and changes in liver function were evaluated. Results: Of the 246 patients, 69 (28.0%) were treated with Ate/Bev for more than one year. The long-term treatment group showed better Eastern Cooperative Oncology Group performance status, liver function, and lower residual hepatic tumor burden at baseline, compared to the group treated for less than one year. Furthermore, the long-term treatment group had a higher incidence of atezolizumab-related thyroid dysfunction (30.4% vs. 10.7%, p ‹ 0.001), dermatologic toxicity (30.4% vs. 14.1%, p = 0.006), and bevacizumab-related hypertension (43.5% vs. 22.6%, p = 0.002) and proteinuria (68.1% vs. 39.0%, p ‹ 0.001), compared to the less than one-year treatment group. The median time to onset of thyroid dysfunction and dermatologic toxicity after Ate/Bev treatment was 2.8 months and 3.3 months, respectively, while the median time to onset of hypertension and proteinuria was 4.2 months and 6.8 months, respectively. In the long-term treatment group, 30 patients (43.5%) showed an increase in Child-Pugh score, 20 (29.0%) had an increase in Child-Pugh grade during Ate/Bev treatment. Conclusions: The Ate/Bev long-term treatment group had better performance status, liver function, and a lower residual hepatic tumor burden at baseline. Atezolizumab-related immunologic adverse events occurred mostly early in the course of treatment, whereas bevacizumab-related adverse events occurred relatively later. In addition, a fraction of patients experienced deterioration of liver function during long-term Ate/Bev treatment.

Pre-Treatment Trends in Child-Pugh Score as an Indicator of Post-Treatment Survival in Patients Receiving Liver SBRT for HCC

We sought to understand the value of Child-Pugh (CP) score trends prior to undergoing stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma in patients with advanced cirrhosis, as an indicator of post-treatment morbidity and mortality. We hypothesize that an uptrend in CP score prior to RT increases risk of post-treatment cirrhosis progression, or death. We retrospectively reviewed all patients who underwent definitive SBRT for HCC between 2014-2022 in our health system. Most patients were referred for treatment in the 2nd or 3rd line setting, allowing us to determine CP score at multiple points before SBRT. Response to treatment was evaluated with RECIST or mRECIST criteria. Acute treatment toxicities were assessed by CTCAE v5. OS was assessed using the Kaplan-Meier method, and differences between groups were evaluated using log-rank test. A total of 61 patients were identified, 26 had an immediate pre-SBRT CP score of A5, 11 with A6, 10 with B7, 4 with B8, 4 with B9, 5 with C10, and 1 with C11. Median prescribed dose was 40Gy in 5fx. Median OS of all patients was 24 months. When stratified by CP category, median OS for CP A was not reached (NR) at time of analysis, CP B had a median OS of 14.8mo, and CP C with 1.9mo (p < 0.01). Local control rate at 6mo was 87.5%. 5 patients (8.3%) had CTCAE grade 2 acute toxicity. 10 patients had CP score progression of 2pts or more within 6mo after treatment, and 7 patients had a cause of death attributed to end stage liver disease. Median time interval between HCC diagnosis and start of RT was 338 days. In this time interval, patients with a CP score increase of 2 pts or more prior to starting RT had a median OS of 362 days, compared to NR for patients without increase (p = 0.02). When excluding the CP A group, patients with 2 pt increase had median OS of 362 days vs 445 days (p = 0.34). Again excluding the CP A group, patients with a 1 pt increase had median OS of 362 days vs NR (p = 0.23). Of 9 patients who had a pre-RT CP score increase of 2 pts or more, 7 experienced continued CP progression after treatment. In this multi-institutional retrospective analysis, we found 24 patients with advanced CP B/C cirrhosis who underwent SBRT, none of whom received orthotopic liver transplant. While CP C patients did relatively poorly, we find that some patients with CP B cirrhosis may tolerate SBRT well with good oncologic effect. When taking pre-treatment CP score increase into consideration, we saw a trend but no statistical significance indicating that a pre-SBRT increase in CP score may be associated with worse OS after treatment among CP B/C patients. We conclude that there may be a subset of patients with advanced cirrhosis who, if well selected, are appropriate candidates for SBRT. We suggest a novel use of the CP score and pre-RT trends as an additional clinical tool to aid in decision making when selecting patients. We also suggest that patients with marked up-trending scores pre-treatment have a high likelihood of continued cirrhosis progression after treatment.

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.

Efficacy of a Second Course of Radiation for Patients With Metachronous Hepatocellular Carcinoma

Liver-directed radiation therapy is an effective treatment for hepatocellular carcinoma (HCC), but metachronous lesions develop outside the irradiated field in >50% of patients. We hypothesized that irradiation of these new lesions would produce an outcome like that of patients receiving a first course (C1) of treatment. We included patients with HCC who received a second course (C2) of radiation therapy >1 month after C1. Toxicity was defined as Child-Pugh score increase ≥2 within 6 months posttreatment (binary model) and as the change in albumin-bilirubin during the year after treatment (longitudinal model). Overall survival (OS) and local failure (LF) were captured at the patient and lesion level, respectively; both were summarized with Kaplan-Meier estimates. Predictors of toxicity and OS were assessed using generalized linear mixed and Cox regression models, respectively. Of 340 patients with HCC, 47 underwent irradiation for metachronous HCC, receiving similar prescription dose in C1/C2. Median follow-up was 17 months after C1 and 15 months after C2. Twenty-two percent of patients experienced toxicity after C1, and 25% experienced toxicity after C2. Worse baseline albumin-bilirubin predicted toxicity in both binary (odds ratio, 2.40; 95% CI, 1.46-3.94; P=.0005) and longitudinal models (P < .005). Two-year LF rate was 11.2% after C1 and 8.3% after C2; tumor dose (hazard ratio [HR], 0.982; 95% CI, 0.969-0.995; P=.007) and tumor size (HR, 1.135; 95% CI, 1.068-1.206; P < .005) predicted LF. Two-year OS was 46.0% after C1 and 42.6% after C2; tumor dose (HR, 0.986; 95% CI, 0.979-0.992; P < .005) and tumor size (HR, 1.049; 95% CI, 1.010-1.088; P=.0124) predicted OS. Reirradiation was not associated with toxicity (P > .7), LF (P=.79), or OS (P=.39). In this largest series in the Western hemisphere, we demonstrate that irradiation for metachronous HCC offers low rates of LF with acceptable toxicity and OS like that of patients receiving a C1. These findings support judicious selection of patients for reirradiation in metachronous HCC.

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.

Significant muscle loss after stereotactic body radiotherapy predicts worse survival in patients with hepatocellular carcinoma

The relationship between sarcopenia and treatment outcomes, especially in patients with hepatocellular carcinoma (HCC) undergoing stereotactic body radiotherapy (SBRT) has not been well-explored. This study aimed to investigate the effects of sarcopenia on the survival and toxicity after SBRT in patients with HCC. We included 137 patients with HCC treated with SBRT between 2008 and 2018. Sarcopenia was defined as a skeletal muscle index (SMI) of < 49 cm2/m2 for men and < 31 cm2/m2 for women using computed tomography images at the mid-level of the third lumbar vertebra. The SMI change was presented as the change per 90 days. The Kaplan–Meier method was used for survival estimation, and the Cox regression was used to determine prognosticators. Sarcopenia was present in 67 of 137 eligible patients. With the median follow-up of 14.1 months and 32.7 months in the entire cohort and in those alive, respectively, patients with pre-SBRT sarcopenia or SMI loss ≥ 7% after SBRT had worse overall survival than their counterparts. Significant survival predictors on multivariate analysis were SMI loss ≥ 7% after SBRT [hazard ratio (HR): 1.96, p = 0.013], presence of extrahepatic metastasis (HR: 3.47, p < 0.001), neutrophil-to-lymphocyte ratio (HR: 1.79, p = 0.027), and multiple tumors (HR: 2.19, p = 0.003). Separate Cox models according to the absence and presence of pre-SBRT sarcopenia showed that SMI loss ≥ 7% remained a significant survival predictor in patients with sarcopenia (HR: 3.06, p = 0.017) compared with those without sarcopenia. SMI loss ≥ 7% is also a predictor of the Child–Pugh score increase by ≥ 2 points after SBRT. SMI loss ≥ 7% after SBRT is a significant prognostic factor for worse survival and is associated with liver toxicity compared with pre-SBRT sarcopenia.

Safety and Efficacy of Liver Stereotactic Radiation Therapy in Elderly Patients

<h3>Purpose/Objective(s)</h3> While radiation-related liver toxicity is a well-studied concern for patients with liver cancer who receive radiotherapy, few studies have specifically investigated the relationship between age and toxicity. We sought to examine treatment tolerance and efficacy in a cohort of elderly (≥ 70 years old) patients who received stereotactic radiation therapy (SBRT) for liver malignancies <h3>Materials/Methods</h3> A single-institution liver cancer database was queried for patients 70 years or older with follow-up imaging treated with radiation between 2/2005 and 1/2021. The database was further refined by patients with pre-treatment Child-Pugh scores recorded. Patients who were treated sequentially or concurrently for multiple tumors were considered to have had a single course of SBRT. Toxicity was defined as an increase in Child-Pugh score of ≥ 2 points within 6 months after a course of radiation. Freedom for local failure and overall survival were calculated using the Kaplan-Meier method. Local control was determined for each lesion treated. <h3>Results</h3> There were 108 individual patients with follow-up imaging who received at least one course of radiation. Patient characteristics are shown in Table 1. In total, there were 32 toxicity events over 126 radiation courses (25.4%). CPA patients had 22 toxicity events over 98 courses (22.4%), while CPB and CPC patients had 10 toxicity events over 28 courses (35.7%). Closer analysis of CPA patients based on those with a score of 5 (CPA5) vs. 6 (CPA6) results as CPA5 with 11 toxicities over 72 radiation courses (15.3%) and CPA6 with 11 toxicities over 28 courses (42.3%). Lesion local control rates were 90.2% at 1 year and 81.4% at 2 years. Overall survival was 69.1% at 1 year and 44.9% at 2 years. <h3>Conclusion</h3> In elderly patients with liver cancer and a baseline Child-Pugh score of 5, SBRT is relatively safe regarding liver toxicity and effective in terms of local control. However, the risk of toxicity greatly increases for those with a baseline Child-Pugh score ≥ 6. These results suggest further examination of baseline prognosis, treatment tolerance, and outcome is warranted among elderly patients with liver malignancies treated with SBRT.

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.

Radioembolization Followed by Transarterial Chemoembolization in Hepatocellular Carcinoma.

Background and objective: In recent years, combination therapies for hepatocellular carcinoma (HCC) have been increasingly used with superior treatment responses compared to monotherapies. However, the safety and efficacy of the transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) combinations for HCC patients have not been investigated in the literature. In this study, our aim was to evaluate the safety and outcomes of TACE after TARE in HCC patients.Materials and methods: All TARE procedures performed on HCC patients at a single institution between January 2008 and November 2016 were retrospectively reviewed. Seventy-three patients who did not receive any additional transarterial therapy in the areas targeted by TARE were assigned to the “TARE group,” while 27 patients who received TACE after TARE to the same target area were assigned to the “Combo group.” Post-procedural liver toxicity, tumor response, overall survival (OS), and time to progression (TTP) were evaluated.Results: Fewer patients in the Combo group had worsening liver function than the TARE group based on the change in bilirubin levels (19% vs. 40%; p=0.029) and Child-Pugh score increase (28% vs. 51%; p=0.056). The median OS time of all patients was 11.04 months. The Combo group had a significantly longer median OS of 36.8 months (vs. 10.6, p=0.003) and median TTP of 14.4 months (vs. 5.5, p=0.018). After accounting for selection bias, OS and TTP were still in favor of the Combo group, with hazard ratios of 0.651 (p<0.05) and 0.63 (p<0.05), respectively.Conclusion: The addition of TACE to TARE is a safe and effective treatment in unresectable HCC patients and can be considered in select patients with a lack of complete response or disease progression.

Bridge-to-transplant stereotactic body radiation therapy in patients with hepatocellular carcinoma and advanced cirrhosis.

TPS496 Background: Liver cancer is the third most common cause of cancer related death worldwide, and hepatocellular carcinoma (HCC) accounts for 90% of all primary liver cancers, with pre-existing cirrhosis being a very strong risk factor for HCC development. Liver transplantation (LTx) is the best treatment for patients with HCC and advanced cirrhosis as both conditions can be very effectively treated at once. As LTx wait-lists can be many months, liver-directed therapies (LDT), including stereotactic body radiation therapy (SBRT) to one or few lesions are essential as oncologic temporizing measures to bridge patients to LTx and prevent progression outside of LTx criteria. However, due to the fear of further hepatic decompensation, many patients with advanced cirrhosis are excluded from receiving LDT. Rather, recent studies suggest that SBRT be of safe and practical use in this fragile patient population with advanced cirrhosis and HCC, and thereby reduce the rate of transplantation drop-out. This pilot prospective study will assess the feasibility, safety and efficacy of bridge-to-transplantation SBRT for patients with advanced cirrhosis and HCC. Methods: Patients with non-metastatic and unresectable HCC and Child-Pugh (CP)-B8 or worse cirrhosis who are within Milan criteria (one tumor ≤ 5 cm in diameter or no more than 3 tumors each ≤ 3 cm in diameter) and have been listed or recommended to be listed for liver transplantation will be eligible for participation. Eligible participants will undergo SBRT consisting of 40 Gy to be given in 5 fractions every other day to the only or largest lesion, provided that criteria for normal organ constraints are met. In cases where normal organ constraints are not met, the dose will be iteratively de-escalated to two dose levels (35 Gy in 5 fractions, then 30 Gy in 5 fractions). If normal organ constraints are unable to be met at 30 Gy in 5 fractions, the participant will be considered ineligible for SBRT and considered a screen failure. The primary endpoint is the proportion of participants who are transplanted or with localized disease control that meets Milan criteria within a year of SBRT. Secondary endpoints will include localized control rate (mRECIST), incidence of intra- or extra-hepatic progressive disease (mRECIST), overall survival, incidence of liver toxicity per CTCAE v5.0, incidence of non-classical radiation-induced liver disease (defined as CTCAE grade 4 AST/ALT elevation or an increase in CP score of ≥ 2 within 3 months of SBRT) and quality of life scores per QLQ-C30 and FACT-Hep questionnaires. The study is open, aiming to enroll 15 patients with 8 patients enrolled at time of submission. Clinical trial information: NCT03812289.

Prediction of Outcomes after Radiotherapy for Hepatocellular Carcinoma Independently Validated Using Multi-Institutional Data

Radiotherapy (RT) is increasingly used in advanced hepatocellular carcinoma (HCC), providing excellent local control. Regional and distant failures are common though, and radiation-induced liver disease (RILD) and post-RT lymphopenia have been shown to correlate with survival. In this study, we develop machine learning (ML) models to predict these endpoints and validate them using an independent dataset.We developed Cox regression and random survival forests to estimate survival, and both linear (logistic regression) and nonlinear discriminant ML models (support vector machines and gradient boosted trees) for four binary endpoints: 1-year survival, non-local failure within 1 year (NLF1y), RILD defined as 2+ increase in Child Pugh score and lymphopenia (count < 0.5 109/L). Metrics include c-index for survival analysis, area under the ROC curve (AUC) and accuracy in the 10/20% highest risk groups for discriminant analysis. The models training considered 21 clinical and dosimetric variables evaluated in a nested cross-validation approach for feature selection and hyperparameter tuning. After locking the models, we used an unseen independent dataset for external validation without any further calibration. A study analysis plan detailing methodology was published before access to the external validation set.207 HCC patients treated at a single institution between 2008 and 2019 were used for model training and 143 patients from a different institution for external validation. The survival models discriminated well between low- and high-risk groups (Harrell's c = 0.72), patients classified above median risk had a significantly higher risk of death (HR = 3.2 (95% CI [2.1-4.9]), P < 0.001) with 9.4 months observed median survival compared to 33.2 months for the low-risk group. Discriminatory power for top versus bottom survival quartile increased to HR = 6.1 [3.3-11], median survival 5.4 vs 42.5 months. Binary classification performance for all endpoints was consistent between training and validation with an external AUC of 0.79 for 1-year survival (internal 0.75), and 0.64-0.68 for the other endpoints (internal 0.53-0.71). The models predict NLF1y in high/very-high risk groups (87/100% accuracy) and lymphopenia in the very high-risk group (65-85% accuracy). Notably platelet count is selected by all generative classifiers of RILD, indicating interaction with known predictors.Independent validation of the models demonstrates the ability to accurately stratify patients by survival and discriminant endpoints with comparable performance on external validation, which underscores good generalizability. High prediction accuracy for sub-groups at high risk of non-local failure and lymphopenia could enable treatment modification in specific cases, while no approach reliably predicted RILD.

Adaptation of lenvatinib treatment in patients with hepatocellular carcinoma and portal vein tumor thrombosis.

The aim of this study was to clarify the adaptation of lenvatinib treatment in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). Fifty-three patients with HCC were treated with lenvatinib. Before and after treatment blood sampling, patients were examined by computed tomography and ultrasonography. In patients with portal trunk invasion (Vp4), the analysis focused on the degree of occlusion due to the tumor in the portal trunk. In patients without major PVTT {ie, invasion of the primary branch of the portal vein [Vp3] or Vp4}, portal blood flow volume was measured by Doppler analysis; however, Doppler analysis is difficult to perform in patients with major PVTT, so the time from administration of the contrast agent to when it reached the primary branch of the portal vein (portal vein arrival time) was evaluated with the contrast agent Sonazoid. Patients with Vp4 had a significantly worse prognosis than patients with Vp3 and a significant increase in Child-Pugh score at 2months. Patients with major PVTT had a poor prognosis if the degree of occlusion of the portal trunk was 70% or more. In patients without major PVTT, portal blood flow was significantly decreased after administration of lenvatinib; and in patients with major PVTT, the hepatic artery and portal vein arrival times were significantly increased. Lenvatinib treatment should be avoided in patients with Vp4 with a high degree of portal trunk occlusion because of concerns about decreased portal blood flow.

Toward MR-integrated proton therapy: modeling the potential benefits for liver tumors

Magnetic resonance imaging (MRI)-integrated proton therapy (MRiPT) is envisioned to improve treatment quality for many cancer patients. However, given the availability of alternative image-guided strategies, its clinical need is yet to be justified. This study aims to compare the expected clinical outcomes of MRiPT with standard of practice cone-beam CT (CBCT)-guided PT, and other MR-guided methods, i.e. offline MR-guided PT and MR-linac, for treatment of liver tumors. Clinical outcomes were assessed by quantifying the dosimetric and biological impact of target margin reduction enabled by each image-guided approach. Planning target volume (PTV) margins were calculated using random and systematic setup, delineation and motion uncertainties, which were quantified by analyzing longitudinal MRI data for 10 patients with liver tumors. Proton treatment plans were created using appropriate PTV margins for each image-guided PT method. Photon plans with margins equivalent to MRiPT were generated to represent MR-linac. Normal tissue complication probabilities (NTCP) of the uninvolved liver were compared. We found that PTV margin can be reduced by 20% and 40% for offline MR-guided PT and MRiPT, respectively, compared with CBCT-guided PT. Furthermore, clinical target volume expansion could be largely alleviated when delineating on MRI rather than CT. Dosimetric implications included decreased equivalent mean dose of the uninvolved liver, i.e. up to 24.4 Gy and 27.3 Gy for offline MR-guided PT and MRiPT compared to CBCT-guided PT, respectively. Considering Child–Pugh score increase as endpoint, NTCP of the uninvolved liver was significantly decreased for MRiPT compared to CBCT-guided PT (up to 48.4%, p < 0.01), offline MR-guided PT (up to 12.9%, p < 0.01) and MR-linac (up to 30.8%, p < 0.05). Target underdose was possible in the absence of MRI-guidance (D90 reduction up to 4.2 Gy in 20% of cases). In conclusion, MRiPT has the potential to significantly reduce healthy liver toxicities in patients with liver tumors. It is superior to other image-guided techniques currently available.

Intensity Modulated Proton Therapy for Hepatocellular Carcinoma: Initial Clinical Experience

PurposeOur purpose was to assess the safety and efficacy of intensity modulated proton therapy (IMPT) for the treatment of hepatocellular carcinoma (HCC). Methods and MaterialsA retrospective review was conducted on all patients who were treated with IMPT for HCC with curative intent from June 2015 to December 2018. All patients had fiducials placed before treatment. Inverse treatment planning used robust optimization with 2 to 3 beams. The majority of patients were treated in 15 fractions (n = 30, 81%, 52.5-67.5 Gy, relative biological effectiveness), whereas the remainder were treated in 5 fractions (n = 7, 19%, 37.5-50 Gy, relative biological effectiveness). Daily image guidance consisted of orthogonal kilovoltage x-rays and use of a 6° of freedom robotic couch. Outcomes (local control, progression free survival, and overall survival) were determined using Kaplan-Meier methods. ResultsThirty-seven patients were included. The median follow-up for living patients was 21 months (Q1-Q3, 17-30 months). Pretreatment Child-Pugh score was A5-6 in 70% of patients and B7-9 in 30% of patients. Nineteen patients had prior liver directed therapy for HCC before IMPT. Eight patients (22%) required a replan during treatment, most commonly due to inadequate clinical target volume coverage. One patient (3%) experienced a grade 3 acute toxicity (pain) with no recorded grade 4 or 5 toxicities. An increase in Child-Pugh score by ≥ 2 within 3 months of treatment was observed in 6 patients (16%). At 1 year, local control was 94%, intrahepatic control was 54%, progression free survival was 35%, and overall survival was 78%. ConclusionsIMPT is safe and feasible for treatment of HCC.

Impact of Prior Y90 Dosimetry on Toxicity and Outcomes Following SBRT for Hepatocellular Carcinoma

Stereotactic body radiation therapy (SBRT) is the only non-invasive local therapy for the treatment of hepatocellular carcinoma (HCC) and is often utilized following transarterial embolization. There is a paucity of data reporting safety and outcomes of patients (pts) receiving SBRT after yttrium-90 (Y90). We evaluated the impact of Y90 and SBRT composite plan dosimetry on toxicity and outcomes of HCC pts. An IRB-approved registry of 260 liver SBRT pts was used. Pts included in analysis received Y90 prior to SBRT and had post-90Y PET imaging (measuring Bremsstrahlung component of Y90). Volume of ablated liver was estimated using the sharp edge of PET gradient and the SBRT volume receiving at least 30 Gy (V30). Characteristics between groups were compared using Chi-square and independent t-test. Clinical, imaging, and laboratory follow up are reported. Twenty eights pts with median follow up of 14 m (4.6-49.6) were included. Pts received 1 (N = 15), 2 (N = 10), or 3 (N = 3) prior Y90 treatments, to a median volume of 286 cm3 (21-1512) a median 4.4 m (1.1-82.9) prior to SBRT. SBRT dose ranged from 24-50 Gy in 3-5 fractions with a median PTV of 117 cm3 (26-857). Y90 and V30 overlap ranged from 0-577 cm3 with a median of 80 cm3. Treatment intent was definitive in 23 pts, to downstage within transplant criteria in 4 pts, and as a bridge to transplant in 1 pt. Baseline Child-Pugh (CP) score was A, B, and C in 23, 3, 2 pts, respectively. At a median 9 m (1.5-46.4) after SBRT local control was 93%. Liver, nodal, and distant failure had an incidence of 11%, 3.6%, and 11%, respectively. Change in CP score was analyzed at 1-2 m and 3 m post SBRT. Twenty-six patients had at least one calculable time point. Change in CP class from A to B was seen in 6 pts (26%), of which two recovered back to CP A by 3 m. The 3 CP B pts did not change class, and the 2 CP C pts received successful liver transplants 2-3 m after SBRT downstaging. Factors associated with an increase in CP score within 3 m of SBRT include SBRT mean liver dose (P = 0.001), SBRT V30 (P = 0.049), and <1200 cm3 of un-ablated liver (P = 0.003). Volume of liver treated by Y90 and time between Y90 and SBRT was not associated with an increase in CP score within 3 m of SBRT. Non-hematologic toxicity includes 2 acute biliary stricture (grade 2-3), 1 late biliary stricture (grade 2), 1 late chest wall pain (grade 1), and 1 late grade 2 radiographic myonecrosis. One CP A pt died 4 weeks after SBRT of cardiopulmonary comorbidities. Time between Y90 and SBRT, volume of liver exposed to prior Y90, and overlap between V30 and Y90 volumes do not appear to adversely impact CP score within 3 m of SBRT. In addition to known dosimetric properties including mean liver dose, and V30, we found that un-ablated liver volume <1200 cm3 was associated with an increase in CP score within 3 m of SBRT in this cohort of pts. Pts with HCC previously treated with Y90 appear to tolerate SBRT well with no clinically significant change in CP score, minimal toxicity, and excellent local control.

Impact of Prior Y90 Dosimetry on Toxicity and Outcomes Following SBRT for Hepatocellular Carcinoma

Stereotactic body radiation therapy (SBRT) is the only non-invasive local therapy for the treatment of hepatocellular carcinoma (HCC) and is often utilized following transarterial embolization. There is a paucity of data reporting safety and outcomes of patients (pts) receiving SBRT after yttrium-90 (Y90). We evaluated the impact of Y90 and SBRT composite plan dosimetry on toxicity and outcomes of HCC pts. An IRB-approved registry of 260 liver SBRT pts was used. Pts included in analysis received Y90 prior to SBRT and had post-Y90 PET imaging (measuring Bremsstrahlung component of Y90). Volume of ablated liver was the sum of Y90 ablation region (using the sharp edge of PET gradient) and the SBRT volume receiving at least 30 Gy (V30). Characteristics between groups were compared using Chi-square and independent t-test. Clinical, imaging, and laboratory follow up are reported. Twenty eights pts with median follow up of 14 m (4.6-49.6) were included. Pts received 1 (N=15), 2 (N=10), or 3 (N=3) prior Y90 treatments, to a median volume of 286 cm3 (21-1512) a median 4.4 m (1.1-82.9) prior to SBRT. SBRT dose ranged from 24-50 Gy in 3-5 fractions with a median PTV of 117 cm3 (26-857). Y90 and V30 overlap ranged from 0-577 cm3 with a median of 80 cm3. Treatment intent was definitive in 23 pts, to downstage within transplant criteria in 3 pts, and as a bridge to transplant in 1 pt. Baseline Child-Pugh (CP) score was A, B, and C in 23, 3, 2 pts, respectively. At a median 9 m (1.5-46.4) after SBRT local control was 93%. Liver, nodal, and distant failure had an incidence of 11%, 3.6%, and 11%, respectively. Change in CP score was analyzed at 1-2 m and 3 m post SBRT. Twenty six patients had at least one calculable time point. Change in CP class from A to B was seen in 6 pts (26%), of which two recovered back to CP A by 3 m. The 3 CP B pts did not change class, and the 2 CP C pts received successful liver transplants 2-3 m after SBRT downstaging. Factors associated with an increase in CP score within 3 m of SBRT include SBRT mean liver dose (P=0.001), SBRT V30 (P=0.049), and <1200 cm3 of un-ablated liver (P=0.003). Volume of liver treated by Y90 and time between Y90 and SBRT was not associated with an increase in CP score within 3 m of SBRT. Non-hematologic toxicity include 2 acute biliary strictures (grade 2-3), 1 late biliary stricture (grade 2), 1 late chest wall pain (grade 1), and 1 late grade 2 radiographic myonecrosis. One CP A pt died 4 weeks after SBRT of cardiopulmonary comorbidities. Time between Y90 and SBRT, volume of liver exposed to prior Y90, and overlap between V30 and Y90 volumes do not appear to adversely impact CP score within 3 m of SBRT. As expected, dosimetric properties including mean liver dose, V30, and un-ablated liver volume <1200 cm3 are associated with an increase in CP score within 3 m of SBRT. Pts with HCC previously treated with Y90 appear to tolerate SBRT well with no clinically significant change in CP score, minimal toxicity, and excellent local control.

Outcomes with Proton and Photon Radiotherapy for Unresectable Hepatocellular Carcinoma

Emerging data suggest improved outcomes for hepatocellular carcinoma (HCC) with proton radiotherapy (RT), but the data nonetheless remain limited. Based on prior observations, we hypothesized that protons may better mitigate lymphocyte depletion and preserve liver function as compared to photon RT. We retrospectively examined liver function, lymphocyte counts, and survival outcomes for proton or photon RT for patients with HCC. We reviewed the records of 143 patients (111 male, 32 female) treated with RT for unresectable HCC from 2006-2016 at our institution. Serial absolute lymphocyte counts were graded according to CTCAE 4.0. Child-Pugh score (CPS) was calculated at RT start and at peak value within 9 months of RT completion. Univariate and multivariate logistic regressions were used to identify factors associated with change in CPS. Comparisons of distant metastasis-free survival (DMFS) and overall survival (OS) were assessed using the log-rank test and predictors of OS were evaluated using Cox proportional-hazards models. Median age at treatment was 66 years (range, 19-90 years). Portal vein thrombus (PVT) was present in 55%. Treatment modality used was 72% photon and 28% proton; baseline characteristics between these groups were similar. The mean pre-treatment CPS for both groups was 5.8. Median biologically equivalent dose (BED) was 84Gy (range, 44-180Gy) and 97GyE (range, 39-140GyE) for patients treated with photons and protons, respectively. The mean change in CPS was +1.8 (95% confidence interval [CI], 1.3-2.2) for photon patients vs. +0.8 (95% CI, 0.3-1.2) for proton patients (p=0.0058). Grade 3+ (G3+) lymphopenia in patients treated with photons vs. protons was 76% vs. 55% (p=0.015). On univariate analysis, stage 3+, G3+ lymphopenia, pre-treatment CP Class B, and presence of PVT were associated with increased likelihood of worsening CPS. Multivariate analysis revealed that age (odds ratio [OR], 1.069, p=0.03), pre-treatment liver function (CP Class B vs. A, OR, 6.72, p=0.03) and treatment modality (proton vs. photon, OR, 0.26, p=0.03) were associated with liver decompensation. For clinical outcomes, median follow-up was 10 months (range, 1-70 months). For photon-treated patients, median DMFS was 9 months (95% CI, 6-13 months) and median OS was 13 months (95% CI, 10-24 months). For proton-treated patients, median DMFS was 22 months (95% CI, 13-28 months) and median OS was 30 months (95% CI, 15-60 months). Multivariate analysis revealed an increased risk of mortality associated independently with increase in CPS (hazard ratio [HR] 1.79, p<0.001), G3+ lymphopenia (HR 5.44, p=0.04), higher volume of PTV (HR 1.0007, p=0.04), and PVT (HR 4.35, p=0.03). Post-RT liver decompensation and G3+ lymphopenia are independently associated with reduced survival, and proton therapy may mitigate these toxicities compared to photons, especially in patients with advanced cirrhosis. Further investigation is warranted to clarify the role of protons for HCC.

Dosimetric Analysis and Normal-Tissue Complication Probability Modeling of Child-Pugh Score and Albumin-Bilirubin Grade Increase After Hepatic Irradiation

This study aimed to develop robust normal-tissue complication probability (NTCP) models for patients with hepatocellular carcinoma treated with radiation therapy (RT) using Child-Pugh (CP) score and albumin-bilirubin (ALBI) grade increase as endpoints for hepatic toxicity. Data from 108 patients with hepatocellular carcinoma treated with RT between 2008 and 2017 were evaluated, of which 47 patients (44%) were treated with proton RT. Of these patients, 29 received stereotactic body RT and 79 moderately hypofractionated RT to median physical tumor doses of 43 Gy in 5 fractions and 59 Gy in 15 fractions, respectively. A generalized Lyman-Kutcher-Berman (LKB) model was used to model the NTCP using 2 clinical endpoints, both evaluated at 3 months after RT: CP score increase of ≥2 and ALBI grade increase of ≥1 from the pre-RT baseline. Confidence intervals on LKB fit parameters were determined using bootstrap resampling. Compared with previous NTCP models, this study found a stronger correlation between normal liver volume receiving low doses of radiation (5-10 Gy) and a CP score or ALBI grade increase. A CP score increase exhibited a stronger correlation to normal liver volumes irradiated than an ALBI grade increase. LKB models for CP increase found values for the volume-effect parameter of a = 0.06 for all patients, and a = 0.02/0.09 when fit to photon/proton patients separately. Subset analyses for patients with superior initial liver functions showed consistent dose-volume effects (a = 0.1) and consistent dose-response relationships. This study presents an update of liver NTCP models in the era of modern RT techniques using relevant endpoints of hepatic toxicity, CP score and ALBI grade increase. The results show a stronger influence of low-dose bath on hepatic toxicity than those found in previous studies, indicating that RT techniques that minimize the low-dose bath may be beneficial for patients.

Iatrogenic Arterioportal Fistula Caused by Radiofrequency Ablation of Hepatocellular Carcinoma: Clinical Course and Treatment Outcomes

PurposeTo analyze the clinical course and treatment outcomes of patients with iatrogenic arterioportal fistula (APF) caused by radiofrequency (RF) ablation of hepatocellular carcinoma (HCC). Materials and MethodsAmong the 1,620 hepatocellular carcinoma patients treated by RF ablation between January 2012 and August 2017, 99 who developed APF after RF ablation were included in this retrospective study. Depending on the extent of portal vein enhancement on arterial phase images, APF was classified as massive or nonmassive. The patients’ clinical course was investigated and statistically evaluated by univariable and multivariable analyses. ResultsThrombocytopenia (odds ratio [OR] = 3.939; 95% confidence interval [CI], 1.141–13.598) was the only risk factor for developing massive APF. Eleven patients underwent embolotherapy (technical success rate, 90.9%) and no patients experienced serious adverse events within 30 days of the procedure. Patients with massive APF (66.7%) had a significantly higher chance of a Child-Pugh score increase than did the patients with nonmassive APF (13.6%) (P < .001). Massive APF had a significantly lower chance of natural regression than did nonmassive APF (P < .001). Child-Pugh B (OR = 17.739; 95% confidence interval, 2.361–133.279) and massive APF without treatment (OR = 11.061; 95% confidence interval, 1.257−97.341) were independent risk factors for liver failure that led to death of liver transplant within 1 year after RF ablation. ConclusionsMassive APF caused by RF ablation is mostly irreversible and significantly worsens patients’ outcomes, but may be effectively treated with embolotherapy.

Stereotactic Body Radiotherapy for Large Unresectable Hepatocellular Carcinomas – A Single Institution Phase II Study

AimsTo evaluate the safety and efficacy of liver stereotactic body radiotherapy (SBRT) in the treatment of unresectable hepatocellular carcinomas (HCC) measuring >5 cm. Materials and methodsBetween November 2013 and February 2016, 13 patients with unresectable HCC (>5 cm), ineligible for other local treatments, with a Child-Pugh score (CPS) ≤ B7, were enrolled into a single-institution phase II study. SBRT was delivered by volumetric-modulated arc radiotherapy. Radiological response was reported using modified Response Evaluation Criteria in Solid Tumours criteria and toxicities graded by Common Terminology Criteria for Adverse Events v4 criteria. ResultsSixteen hepatomas (median size 7.5 cm, range 5.1–9.7 cm) were treated in 13 patients. The baseline CPS was A5/6 in nine patients (69%) and B7 in four patients (31%). Five patients (38%) received previous liver-directed treatment. The median prescribed dose was 45 Gy (range 40–45 Gy) in five fractions. The median follow-up was 17.7 months. The 1-year local control rate was 92%. The median overall survival was 17.7 months and the 1-year overall survival was 62%. The median time to local progression was not reached. Five patients (39%) had an increase in CPS by two or more points at 3 months. Overall, there were 10 grade 3 acute toxicities occurring in seven patients, of which six were haematological. Quality of life remained clinically stable or improved at 3 months in 61.5% and 53.8% of patients based on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 Global Health Score and Functional Assessment of Cancer Therapy – Hepatobiliary version 4 score, respectively. ConclusionsIn our cohort, SBRT to unresectable large HCC tumours provided excellent local control with acceptable toxicities. Regional recurrence remained the major cause of failure. Further studies are warranted to examine the role for SBRT in combination with other modalities to maximise disease control in the liver.