Pretreatment Child-Pugh Research Articles

Liver injury and recovery following radiation therapy for hepatocellular carcinoma: insights from functional liver imaging

Aim: A critical need for hepatocellular carcinoma (HCC) management is understanding how the liver recovers following radiotherapy (RT). We hypothesized that functional liver imaging with 99mTc-sulfur colloid (SC) SPECT/CT provides additional information on liver injury and recovery after RT compared to conventional imaging. Methods: The liver function of patients with HCC was assessed using 99mTc-SC SPECT/CT imaging before and after definitive RT. The anatomical liver volume (ALV) was segmented on CT imaging. Liver function was measured as the total liver function (TLF) encompassing 30% of maximum SC uptake. Changes in ALV and TLF were compared to clinical characteristics. Results: Of 31 patients with evaluable post-RT SC SPECT/CT scans (total of 32), 23 had pre-treatment Child-Pugh (CP)-A and 9 had CP-B/C scores. The median follow-up post-RT was 57 days. The median change in ALV was -1.7% with no significant difference between CP-A and CP-B/C patients (P = 0.26) or between short- (32-99 days) and long-term (271-1120 days) follow-up imaging groups (P = 0.28). The median change in TLF post-RT was -24% and was significantly different between short- and long-term groups (-39% vs. 2%, P = 0.001) and between CP-A and CP-B/C patients (-19% vs. -57%, P = 0.002). TLF significantly decreased following treatment at all radiation dose levels, with the decline correlating with the dose (P < 0.001). Conclusion: Functional imaging provides additional information regarding liver injury and recovery following RT that conventional imaging cannot reveal. Patients with CP-A liver status showed less decline following RT and most had liver function near or above pre-treatment levels.

Development and validation of a nomogram for radiation-induced hepatic toxicity after intensity modulated radiotherapy for hepatocellular carcinoma: a retrospective study.

This study aimed to construct a nomogram to predict radiation-induced hepatic toxicity in patients with hepatocellular carcinoma treated with intensity-modulated radiotherapy. This study reviewed the clinical characteristics and dose-volume parameters of 196 patients with hepatocellular carcinoma. Radiation-induced hepatic toxicity was defined as progression of the Child-Pugh score caused by intensity-modulated radiotherapy. Factors relevant to radiation-induced hepatic toxicity were selected using receiver operating characteristic and univariate logistic analysis. A risk assessment model was developed, and its discrimination was validated. Eighty-eight (44.90%) and 28 (14.29%) patients had radiation-induced hepatic toxicity ≥ 1 (Child-Pugh≥1) and radiation-induced hepatic toxicity ≥ 2 (Child-Pugh≥2). Pre-treatment Child-Pugh, body mass index and dose-volume parameters were correlated with radiation-induced hepatic toxicity ≥ 1 using univariate logistic analysis. V15 had the best predictive effectiveness among the dose-volume parameters in both the training (area under the curve: 0.763, 95% confidence interval: 0.683-0.842, P<0.001) and validation cohorts (area under the curve: 0.759, 95% confidence interval: 0.635-0.883, P<0.001). The area under the curve values of the model that was constructed by pre-treatment Child-Pugh, body mass index and V15 for radiation-induced hepatic toxicity ≥1 were 0.799 (95% confidence interval: 0.719-0.878, P<0.001) and 0.775 (95% confidence interval: 0.657-0.894, P<0.001) in the training and validation cohorts, respectively. Patients with a body mass index≤20.425, Barcelona clinic liver cancer=C, Hepatitis B Virus-positive, Eastern Cooperative Oncology Group=1-2 and hepatic fibrosis require lower V15 dose limits. Risk assessment model constructed from Pre-treatment Child-Pugh, V15 and body mass index can guide individualized patient selection of toxicity minimization strategies.

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.

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.

Disease Control and Hepatotoxicity Following Stereotactic Body Radiotherapy for Hepatocellular Carcinoma

<h3>Purpose/Objective(s)</h3> Stereotactic body radiotherapy (SBRT) is increasingly utilized in the definitive management of patients with hepatocellular carcinoma (HCC), but long-term data regarding treatment efficacy and hepatotoxicity are lacking. We present our experience with SBRT and analyze patient and tumor characteristics associated with local control (LC), overall survival (OS), worsening of Child-Pugh (CP) score, and albumin-bilirubin grade (ALBI). <h3>Materials/Methods</h3> Patients with HCC treated with SBRT at a large referral center were included in this IRB-approved retrospective institutional database. Baseline patient characteristics, SBRT dose and fractionation, and laboratory data were collected by chart review. LC and OS were calculated using the Kaplan-Meier method starting from the date of the cross-sectional imaging study diagnosing the HCC lesion treated with SBRT. LC (at lesion level) was computed with a cumulative incidence function censoring for death. Local progression was defined by the interpreting radiologist, interdisciplinary review, or any decision to intervene with salvage therapy. A mixed-effects multivariable analysis (MVA) using a Cox proportional hazards model was performed using patient age, performance status, gender, HCC diameter (maximum length per-lesion), biological effective dose (alpha/beta = 10), number of prior treatments to the target lesion, and pre-treatment CP score as regression variables. CP score and ALBI were used to quantify hepatotoxicity following SBRT. <h3>Results</h3> A total of 130 HCC lesions in 104 patients (69% male) were included and median follow up was 1.6 years (range 0.3 – 6.8). Hepatitis C was the most common etiology for underlying liver disease (n = 44, 42%). The medians for MVA variables were age = 65 years, ECOG performance status = 1, maximum lesion diameter = 2.4 cm, BED10 = 112.5 Gy, CP = A6, and ALBI = grade 1. LC and OS for the entire cohort were 92% and 80% at 1-year, and 89% and 46% at 3-years, respectively. On MVA, no variables were significantly associated with either LC or OS (all p-values > 0.05). At 3-months post-SBRT, the number of patients with a worsening in CP score of 2 and 3+ points were 7 (7%) and 4 (4%), respectively, while the number of patients with a decline in ALBI score of 1 and 2 grades was 27 (26%) and 2 (2%), respectively. Of 12 lesions with local progression following radiation, salvage therapy was delivered in 11 with the most common technique being thermal ablation (n = 7, 64%). There was one documented local failure after salvage treatment. <h3>Conclusion</h3> SBRT with an ablative dose is associated with excellent LC with little hepatotoxicity in well-selected patients. High rates of LC after SBRT appear maintained with longer follow up, but overall survival remains limited.

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.

Short-term Effects of Hepatic Arterial Buffer Responses Induced by Partial Splenic Embolization on the Hepatic Function of Patients with Cirrhosis According to the Child-Pugh Classification.

Objective This study primarily aimed to investigate the short-term effects of partial splenic embolization (PSE) on the Child-Pugh score and identify predictive factors for changes in the score caused by PSE. The secondary aim was to analyze changes in various parameters at one month postoperatively using these identified factors. Methods Between September 2007 and December 2019, 118 patients with cirrhosis and hypersplenism underwent PSE at our hospital. Testing was conducted preoperatively and at one month after PSE. Results Overall, the Child-Pugh score was not significantly changed postoperatively. The Child-Pugh score before PSE was identified as the strongest independent predictor of ameliorated and deteriorated Child-Pugh scores after PSE. Higher pretreatment Child-Pugh scores were correlated with higher posttreatment amelioration rates of the score. A significant decrease in the portal vein diameter and a significant increase in the common hepatic artery diameter were evident at the same level postoperatively in 64 patients with Child-Pugh class A (group A) and in 54 patients with Child-Pugh class B or C (group B/C) preoperatively. According to Murray's Law, PSE resulted in decreased portal venous flow and increased hepatic arterial flow, suggesting a hepatic arterial buffer response (HABR) induced by the procedure. Despite equivalent splenic infarction rates and similar posttreatment changes in hepatic hemodynamics, PSE significantly increased the Child-Pugh score of group A; however, the procedure significantly decreased the score of group B/C. Conclusion Considering original portal venous-hepatic arterial hemodynamics, PSE is expected to produce HABR-mediated hepatic functional improvements in cirrhosis patients with Child-Pugh class B/C.

A novel therapeutic strategy for esophageal varices using endoscopic treatment combined with splenic artery embolization according to the Child-Pugh classification.

Variceal hemorrhage may cause high rebleeding and mortality rates. Preventing the first episode of variceal bleeding is mandatory in patients with high-risk esophageal varices (EV). This study aimed to identify factors that predict the recurrence of EV after endoscopic treatment (ET), and to develop a reasonable therapeutic strategy for EV in cirrhosis. From January 2012 to December 2014, 45 patients with cirrhosis and high-risk EV underwent ET, including sclerotherapy and/or ligation. Statistical analyses identified factors associated with the recurrence of EV after ET, and the Kaplan-Meier method determined the cumulative variceal recurrence rates. The 1-, 2-, and 3-year cumulative posttreatment recurrence rates for EV were 13.3%, 29.5%, and 32.2%, respectively. No significant differences were evident between the patients with and without variceal recurrences at 1-year posttreatment. The multivariate regression analyses identified a history of partial splenic embolization (PSE) and the pretreatment Child-Pugh classification as independent predictors of variceal recurrences at 2 years (p < 0.05) and 3 years (p < 0.05) posttreatment. While EV did not recur after ET and splenic artery embolization in cases with Child-Pugh class A, the overall posttreatment variceal recurrence rates were 0% and 66.7% when PSE was performed before and after ET, respectively, in those with Child-Pugh class B or C. Splenic artery embolization significantly reduced the hepatic venous pressure gradient and markedly lowered the Child-Pugh score in 15 patients. Adjunctive PSE and pretreatment Child-Pugh class A could be independently associated with reduced cumulative recurrence rates of EV post-ET. From the perspectives of portal hemodynamics and hepatic function, splenic artery embolization before or after ET could prevent posttreatment variceal recurrence in patients with Child-Pugh class A, and PSE before ET could achieve the long-term eradication of EV following ET in those with Child-Pugh class B or C.

Predictors of Radiation-Induced Liver Disease in Patients with Hepatocellular Carcinoma Undergoing Proton Beam Therapy

To identify the dose-volumetric predictors for radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) who were treated with proton beam therapy (PBT). We retrospectively reviewed 102 HCC patients who underwent PBT between November 2015 and May 2017 in the absence of intrahepatic tumor progression within 4 months of treatment completion. The median cumulative dose was 72.6 GyE (range, 72.6-46.2 GyE), and pretreatment Child-Pugh class A and B were recorded in 90 and 12 patients, respectively. The RILD was defined as elevation of alkaline-phosphatase for more than twice the upper normal limit and non-malignant ascites, Grade ≥3 hepatic toxicity according to Common Terminology Criteria for Adverse Events, version 3.0, or Child-Pugh score worsening by ≥2 within 4 months of PBT completion. The radiation doses were converted to equivalent doses in 2 Gy per fraction (EQD2; α/β = 2 Gy). Possible correlations of clinical and dose-volumetric parameters with RILD were examined. Fifteen (15%) patients developed RILD (unrecoverable, N = 8; fatal, N = 3). Multivariate analysis identified gross tumor volume (GTV, P = 0.001), unirradiated-liver-volume (normal liver volume receiving <1 Gy; P = 0.003) and Child-Pugh classification (P = 0.007) as significantly independent predictors for RILD, and the mean liver dose (MLD) was not associated with RILD development. For the Child-Pugh class A patients with unirradiated-liver-volume ≥500, 499-400, 399-300 and <300 cm3, the incidence of RILD were 0%, 10%, 21% and 46% (P < 0.001), respectively. In the Child-Pugh class B group, RILD was recorded in 0%, 25% and 100% patients with unirradiated-liver-volume ≥700, 699-450 and <450 cm3 (P = 0.010), respectively. The unirradiated-liver-volume, not MLD, predicts RILD development in patients with HCC undergoing PBT. Our results suggested the relative and absolute limits of unirradiated-liver-volume being ≥500 and ≥300 cm3 for Child-Pugh class A patients and ≥700 and ≥450 cm3 for Child-Pugh class B patients, respectively.Abstract 275; TableChild-Pugh class AChild-Pugh class BUnirradiated-liver-volume (cm3)≥500 (N = 43)499-400 (N = 20)399-300 (N = 14)<300 (N = 13)P≥700 (N = 5)699-450 (N = 4)<450 (N = 3)POverall RILD, N (%)0 (0)2 (10)3 (21)6 (46)<0.0010 (0)1 (25)3 (100)0.010Non-recoverable RILD, N (%)0 (0)1 (5)1 (7)3 (23)0.0120 (0)0 (0)3 (100)0.005Fatal RILD, N (%)0 (0)0 (0)0 (0)1 (8)0.1140 (0)0 (0)2 (67)0.045 Open table in a new tab

Analysis of the liver functional reserve of patients with advanced hepatocellular carcinoma undergoing sorafenib treatment: Prospects for regorafenib therapy.

This study aimed to investigate liver functional reserves during sorafenib treatment for advanced hepatocellular carcinoma (HCC), to identify predictive factors for maintaining them, and to analyze the proportion of candidates for regorafenib, which has been proven to improve patients' outcomes in the RESORCE trial. We retrospectively investigated Child-Pugh scores during and after sorafenib treatment and evaluated their effects on second-line treatment and outcomes of 125 patients with advanced HCC. Pretreatment Child-Pugh A was maintained in 59/90 (65.6%) patients and pretreatment Child-Pugh B was improved to Child-Pugh A in 10/35 (28.6%) patients when sorafenib ceased. A Child-Pugh score = 5 and aspartate amino transferase <40IU/L before treatment were contributing factors; vascular invasion and cessation of sorafenib due to gastrointestinal or liver-related adverse effects were reverse predictive factors for Child-Pugh A when sorafenib treatment ceased. Significantly more patients with Child-Pugh A when sorafenib treatment ceased received subsequent therapy and achieved better outcomes compared with patients with Child-Pugh B. When sorafenib treatment failed, 45/125 patients (36.0%) fulfilled key inclusion criteria of the RESORCE trial as follows: Child-Pugh A, Eastern Cooperative Oncology Group performance status 0 or 1, tumor progression revealed by imaging, and treatment with ≥400mg sorafenib for at least 20 of the last 28days before treatment failure in 56.8%, 84.8%, 73.6%, and 68.0% of patients, respectively. A comprehensive understanding and management of dynamic changes in liver functional reserve during sorafenib treatment contributed to the efficacy of subsequent therapy (e.g. regorafenib) and to better outcomes for patients with advanced HCC.

A case of the cirrhotic patient performed living donor liver transplantation after carbon-ion radiotherapy for hepatocellular carcinoma

The patient was a 50-year-old female with an initial diagnosis of a single hepatocellular carcinoma in liver cirrhosis. The tumor was located in the posterior liver segment (S7) and measured 5cm with a rapid growth rate and portal invasion. The pre-treatment Child-Pugh (C-P) was grade A (six points). The total prescribed dose of carbon-ion radiotherapy (C-ion RT) was 60Gy (relative biological effectiveness) given in 4 fractions. Thereafter, tumor shrinkage and rapid decrease of the serum alpha-fetoprotein level were observed. At 1-year follow-up a new lesion was diagnosed in the left lobe and the underlying liver failure had worsened to C-P grade B (eight points). Thus, she was recommended to undergo living-donor liver transplantation (LDLT). The postoperative course was uneventful. At pathological examination, no viable tumor cells in the region treated with C-ion RT were detected. At the time of the last follow-up, the patient was in overall good general condition with no signs of tumor recurrence.

A prospective cohort study of hepatic toxicity after stereotactic body radiation therapy for hepatocellular carcinoma

PurposeTo build and validate multivariate normal tissue complication probability (NTCP) models for radiation-induced hepatic toxicity (RIHT) after stereotactic body radiation therapy (SBRT). MethodsEighty-five patients with hepatocellular carcinoma (HCC) in a phase II clinical trial were enroled. A progression of at least 1 or 2 points in the Child–Pugh (CP) score post-SBRT was classified as RIHT (≥1 or ≥2). NTCP models for RIHT (≥1 or ≥2) were developed using logistic regression. Nomograms for each model were formulated. The cut-off point of each independent dosimetric risk factor was obtained using receiver-operating characteristic (ROC) analysis. We used an independent cohort (101 patients) for model validation. ResultsTwenty (23.5%) and 12 (14.2%) patients experienced RIHT (≥1) and RIHT (≥2), respectively. V15, VS10, and pretreatment CP (pre-CP) were the optimal predictors for RIHT (≥1 and ≥2) modelling. V15 ≤33.1% and VS10 ≥416.2 mL for RIHT (≥1), and V15 ≤21.5% and VS10 ≥621.8 mL for RIHT (≥2), were the cut-off points. Four NTCP models and their nomograms were generated. These models and nomograms showed good prediction performance (area under the curve (AUC), 0.83–0.89). Our NTCP model (RIHT ≥2) based on V15 plus pre-CP performed well (AUC = 0.78) in a validation cohort. ConclusionV15, VS10, and pre-CP are crucial predictors for RIHT (≥1 and ≥2). Our NTCP models and nomograms were conducive to obtain individual constraints for patients with HCC. Registration NumberChiCTR-IIC-16008233.

Predictive factors for Child-Pugh score elevation in hepatocellular carcinoma patients treated with conformal radiation therapy: dose-volume histogram analysis.

We designed the study to identify the clinical and dose-volumetric parameters associated with the risk of Child-Pugh score elevation in hepatocellular carcinoma patients treated with conformal radiation therapy. All 161 hepatocellular carcinoma patients in the study underwent 4D-computed tomography simulation, and a dose-volume histogram was generated after radiotherapy planning. Patients who had an elevated Child-Pugh (e-CP) score of 2 or more without progressive disease within 3 months were defined as e-CP positive. Twenty-six of 142 patients without progressive disease were e-CP positive. Pretreatment Child-Pugh class, further treatment within 30 days of radiotherapy, lymph node metastasis, mean liver dose, V(20 Gy), V(25 Gy), and V(30 Gy) were significantly correlated with e-CP positivity. The e-CP developed in 13 of 106 patients (12.3%) with V(30 Gy) of ≤28.1% and in 13 of 36 patients (36.1%) with V(30 Gy) >28.1% (P = 0.001). Our data demonstrate that mean liver dose, V(10 Gy), V(20 Gy), V(25 Gy), and V(30 Gy) are independent dose-volumetric predictors for e-CP positivity in hepatocellular carcinoma patients treated with conformal radiation therapy. V(30 Gy) should be limited to less than 28.1% to minimize the risk of e-CP.

Clinical significance of radiation-induced liver disease after stereotactic body radiation therapy for hepatocellular carcinoma.

Background/AimsThe aim of this study was to investigate parameters that predict radiation-induced liver disease (RILD) following stereotactic body radiotherapy (SBRT) in patients with hepatocellular carcinoma (HCC) and to identify the clinical significance of RILD.MethodsWe retrospectively reviewed the medical records of 117 HCC patients who were treated by SBRT from March 2011 to February 2015. RILD was defined as elevated liver transaminases more than five times the upper normal limit or a worsening of Child-Pugh (CP) score by 2 within 3 months after SBRT. All patients were assessed at 1 month and every 3 months after SBRT.ResultsMedian follow-up was 22.5 months (range, 3 to 56) after SBRT. RILD was developed in 29 of the 117 patients (24.7%). On univariate analysis, significant predictive factors of RILD were pretreatment CP score (p < 0.001) and normal liver volume (p = 0.002). Multivariate analysis showed that CP score was a significant predictor of RILD (p < 0.001). The incidence of RILD increased above a CP score of 6 remarkably. The rate of recovery from RILD decreased significantly above a CP score of 8. Survival analysis showed that CP score was an independent prognostic factor of overall survival (p = 0.001).ConclusionsCP score is a significant factor to predict RILD in patients with chronic liver disease. RILD can be tolerated by patients with a CP score ≤ 7. However, careful monitoring of liver function is needed for patients with a CP score 7 after SBRT.

Defining radiation induced liver toxicity in the treatment of hepatocellular carcinoma: Which metric is most predictive for survival?

361 Background: Radiation induced liver disease (RILD) is of critical concern in the treatment of hepatocellular carcinoma (HCC) with radiation therapy (RT). Variability exists in metrics used to define RILD with no consensus on which best predict for overall survival (OS) and RILD-specific survival (RILDSS). We examined the correlation between toxicity metrics and clinical outcomes in a heavily pre-treated population that received RT. Methods: The charts of 37 HCC patients treated from 2013 - 2015 were reviewed retrospectively. At baseline, 62% were Child-Pugh (CP)-A, 32% CP-B and 5% CP-C. The majority (59%) had prior liver-directed therapy (LDT), 43% received stereotactic body RT and 49% proton RT. Pre-treatment, toxicity ( ≤ 6 months from treatment) and outcomes data were collected. Deaths from RILD were scored. Pre-treatment factors and toxicity outcomes were assessed by univariate Cox models for association with OS and RILDSS. Statistically significant predictors formed the basis for stepwise multivariate Cox regression to retain independent predictors of survival. Results: At a median follow-up of 8 months, 14 patients had an increase in CP score ( ≥ 2, n = 7) and 3 had ≥ G3 RTOG transaminitis. There were 11 deaths, 5 from RILD. On univariate analysis (UA), tumor size, pre-treatment liver function, prior LDT and 5 toxicity metrics (CP score increases and transaminitis) were significantly associated with OS. An increase of ≥ 1 CP score (HR 22.7, p = 0.005), pre-treatment ALBI grade (HR 6.0, p = 0.02) and tumor size (HR 1.2, p = 0.01) were independent predictors of OS on multivariate analysis (MVA). Similar factors were associated with RILDSS on UA, including ≥ 2 CP score increase and ≥ G3 ALT elevation; however, only pre-treatment CP score (HR 4.0, p = 0.01) and tumor size (HR 1.5, p = 0.03) were independently predictive on MVA. Conclusions: Pre-treatment liver functional status and tumor size were highly predictive of OS and RILDSS, suggesting that baseline functional hepatic reserve is the primary determinant in developing fatal RILD rather than post-RT changes in liver function. Further work is needed to define dosimetric parameters and pre-treatment factors that predict RILD toxicity.

Threshold Doses for Focal Liver Reaction After Stereotactic Ablative Body Radiation Therapy for Small Hepatocellular Carcinoma Depend on Liver Function: Evaluation on Magnetic Resonance Imaging With Gd-EOB-DTPA

Focal liver reaction (FLR) appears on radiographic images after stereotactic ablative body radiation therapy (SABR) in patients with hepatocellular carcinoma (HCC) and chronic liver disease. We investigated the threshold dose (TD) of FLR and possible factors affecting the TD on gadoxetate acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI). In 50 patients who were treated with SABR for small HCC and followed up by MRI for >6 months, FLR, seen as a hypointense area, was evaluated on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI. The follow-up MRI with the largest extent of FLR was fused to the planning computed tomography (CT) image, and patients with good image fusion concordance were eligible. After delineating the border of the FLR manually, a dose-volume histogram was used to identify the TD for the FLR. Clinical and volumetric factors were analyzed for correlation with the TD. A total of 45 patients were eligible for analysis with a median image fusion concordance of 84.9% (range, 71.6-95.4%). The median duration between SABR and subsequent hepatobiliary phase MRI with the largest extent of FLR was 3 months (range, 1-6 months). The median TD for FLR was 28.0 Gy (range, 22.3-36.4 Gy). On univariate analysis, pre-treatment Child-Pugh (CP) score and platelet count were significantly correlated with the TD. On multiple linear regression analysis, CP score was the only parameter that predicted TD. Median TDs were 30.5 Gy (range, 26.2.3-36.4 Gy) and 25.2 Gy (range, 22.3-27.5 Gy) for patients with CP-A and CP-B disease, respectively. The TD was significantly correlated with baseline liver function. We propose 30 Gy for CP-A disease and 25 Gy for CP-B disease in 5 fractions as TDs for FLR after SABR for patients with HCC and chronic liver disease. Use of these TDs will help to predict potential loss of liver tissue after SABR.

Predictive Factors for Child-Pugh Score Elevation in Hepatocellular Carcinoma Patients Treated with Conformal Radiation Therapy: Dose-Volume Histogram Analysis

We designed the study to identify the clinical and dose-volumetric parameters associated with the risk of Child-Pugh score elevation in hepatocellular carcinoma patients treated with conformal radiation therapy. All 161 hepatocellular carcinoma patients in the study underwent 4D-computed tomography simulation, and a dose-volume histogram was generated after radiotherapy planning. Patients who had an elevated Child-Pugh (e-CP) score of 2 or more without progressive disease within 3 months were defined as e-CP positive. Twenty-six of 142 patients without progressive disease were e-CP positive. Pretreatment Child-Pugh class, further treatment within 30 days of radiotherapy, lymph node metastasis, mean liver dose, V(20 Gy), V(25 Gy), and V(30 Gy) were significantly correlated with e-CP positivity. The e-CP developed in 13 of 106 patients (12.3%) with V(30 Gy) of ≤28.1% and in 13 of 36 patients (36.1%) with V(30 Gy) >28.1% (P = 0.001). Our data demonstrate that mean liver dose, V(10 Gy), V(20 Gy), V(25 Gy), and V(30 Gy) are independent dose-volumetric predictors for e-CP positivity in hepatocellular carcinoma patients treated with conformal radiation therapy. V(30 Gy) should be limited to less than 28.1% to minimize the risk of e-CP.

Dosimetric parameter predicting the deterioration of hepatic function after helical tomotherapy in patients with unresectable locally advanced hepatocellular carcinoma

BackgroundThe purpose of this study was to identify parameters capable of predicting the deterioration of hepatic function after helical tomotherapy in patients with unresectable locally advanced hepatocellular carcinoma.MethodsBetween March 2006 and February 2012, 72 patients were eligible for this study. All patients received hypofractionated radiotherapy using the TomoTherapy Hi-Art (TomoTherapy, Madison, WI, USA) at Seoul St. Mary's Hospital and Incheon St. Mary's Hospital, the Catholic University of Korea. The radiation dose was a median 50 Gy (range: 40–50 Gy) in 10 fractions to 95% of the planning target volume. Radiation-induced hepatic toxicity was defined as an increase of at least 2 points in the Child-Pugh (CP) score within 3 months after completion of helical tomotherapy.ResultsAn increase of at least 2 points in the CP score occurred in 32 of the 72 patients (44.4%). Multivariate logistic regression analysis revealed that pretreatment CP class and V15Gy were significant parameters associated with an increase in CP score (p = 0.009 and p < 0.001, respectively). The area under receiver operating characteristic curve was 0.863 for V15Gy (p < 0.001). For V15Gy, with a cutoff value of 43.2%, the accuracy was 0.806 (58/72) with a sensitivity of 0.938 and a specificity of 0.725.ConclusionsAn increase of at least 2 points in the CP score is a radiation dose-limiting factor, and the non-target normal liver receiving a dose more than 15 Gy (V15Gy) should be <43.2% to reduce the risk of the deterioration of hepatic function.

Prognostic Accuracy of 12 Liver Staging Systems in Patients with Unresectable Hepatocellular Carcinoma Treated with Transarterial Chemoembolization

The objective of the present study was to rank the most common liver staging systems according to prognostic accuracy in patients with unresectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE). Survival of 172 consecutive patients with unresectable HCC treated with TACE was correlated with the pretreatment Child-Pugh (categoric and nominal), Okuda, Cancer of the Liver Italian Program, Barcelona Clinic Liver Cancer, Model for End-stage Liver Disease, Chinese University Prognostic Index (CUPI), Japanese Integrated Staging, Tumor/Node/Metastasis, Group d'Etude de Traitement du Carcinoma Hepatocellulaire, Liver Cancer Study Group of Japan, and Tokyo staging systems. The systems were ranked according to error reduction in predicting median survival (Kaplan-Meier survival curve and Cox regression analysis). The error reduction was normalized to the error in predicting survival in the absence of a staging system. Median survival was 80 weeks. The error in predicting survival of an unstaged population was 51 weeks. The Child-Pugh nominal, CUPI, and Tokyo scores yielded the largest reduction in survival prediction error, at 20.8%, 21.6%, and 19.6%, respectively. Their actual error measurements in predicting survival were 40.4, 40.0, and 41.0 weeks, respectively. Child-Pugh nominal, CUPI, and Tokyo scores provide the best prognostic accuracy among the systems studied. However, those of the Tokyo and CUPI methods are artificially enhanced because of their greater number of staging levels. The Child-Pugh nominal liver staging system is the most accurate in predicting survival of patients with unresectable HCC treated with TACE, and it is recommended that it be adopted as the standard for HCC staging in such patients.