Stereotactic Body Radiotherapy For Hepatocellular Carcinoma Research Articles

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

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

The efficacy of radical hepatectomy versus stereotactic body radiotherapy for primary hepatocellular carcinoma: A propensity score matching analysis.

4130 Background: Recent international guidelines have included stereotactic body radiotherapy (SBRT) which outstanding tumor control as a treatment option for hepatocellular carcinoma (HCC) in several settings. However, data evaluating surgery and SBRT are limited, and results published were controversial. The retrospective study aims to compare the efficacy of hepatectomy and SBRT for HCC. Methods: The study population started with patients in databases of primary HCC, treated with curative hepatectomy or SBRT, regardless of tumor number, tumor size, cirrhosis and portal vein thrombosis. Patients with prior cancer treatment other than transarterial chemoembolization were excluded. In order to reduce the potential confounding effect of treatment and selection bias, 3-to-1 propensity score models were constructed based on each patient’s estimated propensity score. The variables significant for overall survival were considered for the match, including age, sex, Child-Pugh score, ECOG performance status score, maximum diameter, BCLC stage, prothrombin time, total bilirubin, albumin, and white blood cell. Overall survival and progression-free survival were compared. Results: A total of 174 patients, 154 in hepatectomy group and 20 in SBRT group, were analyzed. 125 men and 29 women, mean 56.2 years of age, in hepatectomy group. 12 men and 8 women, mean 70.5 years of age, in SBRT group. ECOG was a significant favorable factor for overall survival. Maximum diameter, portal vein embolization, aspartate transferase and albumin was significant favorable factors for disease-free survival of patients with primary hepatocellular carcinomas. Before PSM, patients in the hepatectomy group tended to be younger, had better performance status, less cirrhosis, less tumor number and had better hepatic function than those in the SBRT group ( P &lt; .05). The 3-year overall survival rate and median progression-free survival time for the surgical resection and SBRT groups were 77.9% vs 35.4 (P = .003) and 30 vs 20 month (P = .486), respectively. After PSM, 80 patients, 60 in hepatectomy group and 20 in SBRT group, were analyzed. The 3-year overall survival rate and median progression-free survival time for the surgical resection and SBRT groups were 71.9% vs 56.6 (P = .92) and 17 vs 26 month (P = .656), respectively. The patients of hepatectomy group had less cirrhosis, better liver function and less tumor number than those in 20 with SBRT. Conclusions: For primary HCC, regardless of tumor size and tumor number, stereotactic body radiotherapy can provide similar result on overall survival and tumor control compared to hepatectomy. Stereotactic body radiotherapy can also be less invasive and provide less inpatient time. So stereotactic body radiotherapy can be a effective treatment for patients with primary HCC.

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

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

Feasibility of marker-less stereotactic body radiotherapy for hepatocellular carcinoma

Background The feasibility of marker-less stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) has not yet been established, and, thus, was examined in the present study. Material and methods We retrospectively investigated patients who received marker-less SBRT for locally untreated HCC tumors between July 2005 and December 2018. Radiotherapy planning CT was performed under fixation with vacuum cushions and abdominal compression. The clinical target volume (CTV) was equivalent to the gross tumor volume (GTV). The internal target volume (ITV) margin to CTV was determined from calculations based on the motion of the diaphragm. The planning target volume (PTV) margin to ITV was 5–6 mm. In the set-up, radiotherapy planning CT and linac-integrated cone-beam CT performed in the same imaging and fixation settings were merged by referring to the anatomical components surrounding target tumors. The primary endpoint was the 3-year cumulative local tumor progression rate. The upper limit of the 95% confidence interval for the 3-year cumulative local tumor progression rate was less than 7.0%, which was interpreted as favorable local control and feasible for marker-less SBRT. Local tumor progression was assessed by mRECIST. Results We reviewed 180 patients treated with 35–40 Gy/5 fractions. The median follow-up time for the local tumor progression of censored tumors was 32.3 months (range, 0.3–104). The 3-year cumulative local tumor progression rate was 3.0% (95% CI, 1.1–6.5%). The 3-year overall survival rate was 71.6% (95% CI, 63.5–78.2%). Regarding acute hematologic toxicities, grade 3 hypoalbuminemia and thrombocytopenia were detected in 1 (0.6%) and 5 (2.9%) patients, respectively. Treatment-related death from SBRT was not observed. SBRT was initiated within 7 days after radiotherapy planning CT for 84% (152/180) of patients. Conclusions Marker-less SBRT for HCC achieved favorable local control that fulfilled the threshold. This result suggests that marker-less SBRT with appropriate settings is a feasible treatment strategy.

HCC Etiology-Dependent Tumor Control Probability Model After Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: A Pooled Analysis of an Asian Liver Radiation Therapy Group Study

Purpose/Objective(s)Stereotactic body radiation therapy (SBRT) has emerged as an effective local treatment option for hepatocellular carcinoma (HCC). Using a multi-national database from the Asian Liver Radiation Therapy (ALRT) Study Group, we previously reported that higher biologically effective dose (BED) was associated with improved local control (LC). We investigated the tumor control probability (TCP) of HCC using size-adjusted BED (sBED), which has been investigated in prior studies of SBRT for lung cancer.Materials/MethodsALRT database included 519 patients with HCC undergoing SBRT. After excluding 104 patients with vascular invasion, a total of 415 patients without tumor thrombus treated with SBRT for HCC in 7 tertiary-referral hospitals from 2010 to 2016 were retrospectively reviewed. A BED was calculated for each patient using a standard a/b ratio of 10 Gy. Then, sBED was defined as BED minus 10 times the maximal tumor diameter, in centimeters. sBED was incorporated into standard TCP models to predict actuarial 2-year LC rates.ResultsMedian tumor diameter was 2.5 cm (interquartile range, IQR, 1.5-3.9). Median prescribed total and fractional doses for SBRT were 48 (IQR, 40-54) Gy and 10 (IQR, 8-12) Gy, respectively. The median BED was 100 Gy (IQR, 80-116), and the median sBED was 70 Gy (IQR,49-92). The median follow-up duration was 26 months after SBRT, and 73 local failures (18%) were observed. Multivariable analysis showed that sBED was an independent factor associated with LC (hazard ratio, 0.94 per 10 Gy, 95% CI 0.88-0.99, P = 0.028). Initial analyses for non-dosimetric factors demonstrated that hepatitis C virus (HCV) infection was a powerful favorable prognostic factor (HR 1.81, 95% CI 1.01-3.27, P = 0.048) for LC, so TCP modeling was performed separately for HCV-related HCC (n = 125, 2-year LC 88%) and for other tumors (n = 290, 2-year LC 78%). BED values predicted to provide 80%, 85% and 90% 2-year probabilities of local control in various scenarios are provided in Table 1.ConclusionUsing a large, multi-national database, we found a strong association between HCC etiology and local control rates after SBRT. We generated novel TCP models for HCV-related HCC and other HCC etiologies that may be useful for selecting appropriate SBRT schedules. Table. Approximate BEDs required to achieve 80%, 85%, and 90% 2-year tumor control probability for HCV-related and non-HCV-related tumors of selected sizes. Missing values indicate scenarios where results would fall outside the range of commonly used SBRT schedules. Stereotactic body radiation therapy (SBRT) has emerged as an effective local treatment option for hepatocellular carcinoma (HCC). Using a multi-national database from the Asian Liver Radiation Therapy (ALRT) Study Group, we previously reported that higher biologically effective dose (BED) was associated with improved local control (LC). We investigated the tumor control probability (TCP) of HCC using size-adjusted BED (sBED), which has been investigated in prior studies of SBRT for lung cancer. ALRT database included 519 patients with HCC undergoing SBRT. After excluding 104 patients with vascular invasion, a total of 415 patients without tumor thrombus treated with SBRT for HCC in 7 tertiary-referral hospitals from 2010 to 2016 were retrospectively reviewed. A BED was calculated for each patient using a standard a/b ratio of 10 Gy. Then, sBED was defined as BED minus 10 times the maximal tumor diameter, in centimeters. sBED was incorporated into standard TCP models to predict actuarial 2-year LC rates. Median tumor diameter was 2.5 cm (interquartile range, IQR, 1.5-3.9). Median prescribed total and fractional doses for SBRT were 48 (IQR, 40-54) Gy and 10 (IQR, 8-12) Gy, respectively. The median BED was 100 Gy (IQR, 80-116), and the median sBED was 70 Gy (IQR,49-92). The median follow-up duration was 26 months after SBRT, and 73 local failures (18%) were observed. Multivariable analysis showed that sBED was an independent factor associated with LC (hazard ratio, 0.94 per 10 Gy, 95% CI 0.88-0.99, P = 0.028). Initial analyses for non-dosimetric factors demonstrated that hepatitis C virus (HCV) infection was a powerful favorable prognostic factor (HR 1.81, 95% CI 1.01-3.27, P = 0.048) for LC, so TCP modeling was performed separately for HCV-related HCC (n = 125, 2-year LC 88%) and for other tumors (n = 290, 2-year LC 78%). BED values predicted to provide 80%, 85% and 90% 2-year probabilities of local control in various scenarios are provided in Table 1. Using a large, multi-national database, we found a strong association between HCC etiology and local control rates after SBRT. We generated novel TCP models for HCV-related HCC and other HCC etiologies that may be useful for selecting appropriate SBRT schedules. Table. Approximate BEDs required to achieve 80%, 85%, and 90% 2-year tumor control probability for HCV-related and non-HCV-related tumors of selected sizes. Missing values indicate scenarios where results would fall outside the range of commonly used SBRT schedules.

90-Day Hospitalization as a Surrogate for Overall Survival in Hepatocellular Carcinoma (HCC) Patients Treated With Magnetic Resonance-Guided Liver Stereotactic Body Radiation Therapy: Results of a Single-Center Retrospective Study

With the increased utilization of stereotactic body radiation therapy (SBRT) for the management of hepatocellular carcinoma (HCC), it is important to have accurate prognostic factors for survival to guide treatment management decisions. Here, we examine 90-day hospitalization as a prognostic factor in addition to established staging systems including the albumin-bilirubin (ALBI) grade, Child-Pugh score, and Barcelona Clinic Liver Cancer (BCLC) stage.This retrospective single-institution study analyzed 95 patients with HCC treated with SBRT from August 2017 to September 2020. Overall survival (OS) rates were retrospectively analyzed from treatment completion date to death date or last follow-up. Patients were censored from further analysis if subsequent SBRT courses were administered. Patient characteristics, 90-day hospitalization, ALBI grade, Child-Pugh score, and BCLC liver stage were analyzed with the Cox proportional hazard model and log-rank test; any significant factors on univariate analysis were subsequently analyzed in the multivariate analysis.Median overall survival among the entire cohort was 67 months (range 0-38 months). Univariate predictors of overall survival included patient sex (P = 0.02), performance status (P = 0.03), Child-Pugh score (P = 0.003), ALBI grade (P < 0.0001), as well as 90-day hospitalization (P < 0.0001). However, 90-day hospitalization itself was associated with patient male gender (26.9% vs 7.1%; P = 0.03), performance status (P < 0.0001), Child-Pugh score (P = 0.003), ALBI grade (P = 0.003), and BCLC stage (P = 0.002). In the multivariate analysis, patient male sex (P = 0.02), ALBI grade 3 (P = 0.05), and 90-day hospitalization (P = 0.03) remained significant.90-day hospitalization is a significant predictor of overall survival among patients treated with SBRT for HCC. 90-day hospitalization could be used as an early endpoint in trials evaluating liver SBRT.

Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes.

Stereotactic body radiation therapy (SBRT) has high efficacy for early-stage hepatocellular carcinoma (HCC) and is an accepted alternative to radiofrequency ablation (RFA). However, SBRT for HCC may cause subacute liver injury leading to negative clinical outcomes. In this study, we compared changes of liver function and prognosis after SBRT or RFA in patients with single, small HCC by using a propensity-score matching analysis. We reviewed medical records of 140 patients with single ≤3 cm HCC treated with SBRT or RFA at Kurashiki Central Hospital between January 2014 and February 2019. Changes of albumin-bilirubin (ALBI) score, local recurrence, and overall survival were compared between the propensity-score matched groups (31 patients treated with SBRT and 62 treated with RFA). The ALBI score increased modestly but significantly after SBRT, while it was unchanged in the RFA group; the intergroup difference was statistically significant (P=0.004). No local recurrence was identified in the SBRT group, whereas the cumulative recurrence incidence was 9.7% in the RFA group (P=0.023). Overall survival was not significantly different between the two groups (hazard ratio: 1.32, 95% confidence interval: 0.60-2.89, P=0.401). SBRT had modestly negative impact on liver function but with appraisable local control of HCC. Our findings should contribute to the selection of this modality for treatment of single, small 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.

Radiological tumor response and histopathological correlation of hepatocellular carcinoma treated with stereotactic body radiation therapy as a bridge to liver transplantation.

To assess the imaging findings of hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT) as a bridging therapy prior to liver transplantation (LT), with histopathological correlation at liver explant. Our institutional review board approved this retrospective study. The study subjects included 25 HCC lesions in 23 patients (20 males; median age, 60 years; range 41-68 years) who underwent LT after SBRT for HCC as a bridge to LT in a single tertiary referral institution over a 12-year period. Target HCC lesions were assessed for imaging biomarkers on contrast-enhanced CT or MRI including change in HCC diameter and assessment of percentage necrosis. The radiologic response at pre-LT imaging was compared to explant pathology. There was a positive correlation between the tumor size (Spearman's ρ = 0.86; p < 0.001) and percentage necrosis (p < 0.001) on Pre-LT imaging and those on pathology. Partial response (PR), stable disease (SD), and progressive disease (PD) according to RECIST 1.1 were seen in 8 (32%), 15 (60%), and 2 (8%) lesions on pre-LT imaging, respectively. Of the 15 lesions with radiologic SD, 5/15 (33%) showed necrosis of more than 50% on post-SBRT imaging, while 9/15 (60%) showed necrosis of more than 50% at explant pathologic analysis, showing a tendency to underestimate the degree of tumor necrosis compared to pathology. RECIST 1.1 radiologic response criteria may underestimate the response to treatment with SBRT, and radiologic estimation of percent tumor necrosis was more closely correlated with pathologic percent tumor necrosis.

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.

Preoperative Stereotactic Body Radiotherapy to Portal Vein Tumour Thrombus in Hepatocellular Carcinoma: Clinical and Pathological Analysis

The prognosis of hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT) is poor. We conducted a prospective study to evaluate the efficacy and safety of tri-modality therapy, including preoperative stereotactic body radiotherapy (SBRT) and surgery, followed by hepatic arterial infusion chemotherapy (HAIC) in HCC patients with PVTT. In this report, we investigated the pathology of the irradiated PVTT specimen in resected cases and SBRT-related acute toxicity. A total of 8 HCC patients with PVTT received preoperative SBRT targeting the PVTT at a dose of 48 Gy in 4 fractions at our institute from 2012 to 2016. Of the eight patients, six underwent surgery, while the remaining two did not because of disease progression. At the pathological examination, all patients’ irradiated PVTT specimens showed necrotic tissue, and three of six patients showed complete pathological response. Two patients showed 30% necrosis with high degeneration and one patient, with 30% necrosis without degeneration, was the only recurrent case found during the follow-up period (median: 22.5, range: 5.9–49.6 months). No SBRT-related acute toxicity worse than grade 2 was observed from SBRT to surgery. In conclusion, the preoperative SBRT for HCC was pathologically effective and the acute toxicities were tolerable.

Prediction of Hepatic Parenchymal Change in Gd-EOB-DTPA MR Images after Stereotactic Body Radiation Therapy by Cycle GAN Deep Neural Network

Stereotactic body radiation therapy (SBRT) is known to be an excellent ablative treatment option for small hepatocellular carcinoma (HCC), while possibly deteriorating hepatic function due to inevitable irradiation to surrounding non-tumorous liver parenchyma. A previous work attempted to reveal the threshold dose of parenchymal change after SBRT to be around 20 Gy by analyzing hypo-signal intensity on the hepatobiliary phase (HBP) of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) images. However, it found that estimating the parenchymal change is hard as the threshold dose can be patient-specific, ranging from 18 to 33 Gy. Thus, this work proposes to construct a prediction model for the hepatic parenchymal change after SBRT in Gd-EOB-DTPA enhanced MR images by using an image-based deep neural network. The deep learning with convolutional neural network encouraged numerous applications to the image-based prediction. This study aims to build an image-based deep-neural network that predicts the hepatic parenchymal change on HBP in follow-up enhanced MR images by correlating 3-channel input images of pre-treatment enhanced MR, CT and dose images to the output of the follow-up enhanced MR images. The recent advance in deep learning enabled for translating different types of medical imaging modalities by so-called generative adversarial network (GAN). The prediction accuracy could be further enhanced by placing additional generator in reverse direction to be robust to the image misalignment across different imaging modalities, which is named cycle-consistent GAN (cGAN). In this work, the proposed network based on cGAN was trained and tested with 36 and 7 patient cases, respectively. The prediction accuracy was assessed by comparing the predicted and enhanced follow-up MR images in root-mean-squared error (RMSE) and structural similarity (SSIM). For the seven testing cases, the image similarity was measured only inside the manually drawn liver contours, and 5 Gy iso-dose line. Inside the liver contours, the RMSE and SSIM between the reference follow-up MR and predicted MR images from cGAN were 591.21, and 0.9242, which outperformed the results from GAN. For the 5 Gy iso-dose lines, the structural similarity (SSIM) was reduced to 0.6511, which is mainly due to smoothed intensity transition in the predicted MR images. When visually checked, the locations with the signal intensity transition in predicted images correspond to the reference images. The image-based deep neural network with cGAN could possibly predict the hepatic parenchymal change in the follow-up enhanced MR images after SBRT for HCC.Abstract 2305; Table 1Comparison in prediction accuracy of GAN and cGAN deep neural networkLiver Contour>5Gy iso-dose lineRMSESSIMRMSESSIMGAN514.620.6217854.10.9127cGAN350.40.6511623.90.9242 Open table in a new tab

Imaging post-stereotactic body radiation therapy responses for hepatocellular carcinoma: typical imaging patterns and pitfalls.

Stereotactic body radiation therapy (SBRT) has increased utility in the management of hepatocellular carcinoma (HCC) ranging from local therapy in early-stage HCC not suitable for other focal therapies to end-stage HCC. As the indications for the use of SBRT in HCC expand, diagnostic imaging is being increasingly used to assess response to treatment. The imaging features of tumor response do not parallel those of other focal therapies such as radiofrequency ablation or trans-arterial chemoembolization that immediately devascularize the tumor. The tumor response to SBRT on imaging takes much longer and often shows gradual changes including the reduction of enhancement and size over several months. It is essential to recognize the typical imaging patterns of response, as well as the appearance of focal liver reaction in the non-target liver that can confound image interpretation. The timing of treatment response assessment imaging is fundamental to minimize the potential for false negative response. The purpose of this article is to review the variable post-SBRT imaging features of HCC and adjacent liver parenchyma and discuss the potential pitfalls of imaging evaluation after SBRT for HCC.

Worsening of Child-Pugh Score after Stereotactic Body Radiation Therapy Significantly Impacts Survival of Patients Treated for Hepatocellular Carcinoma

The risk of occurrence of radiation-induced liver injury has historically limited the applicability of radiation for the treatment of liver cancer, especially for patients with underlying liver dysfunction. Our purpose was to determine the impact of liver function decline after stereotactic body radiation therapy (SBRT) on survival outcomes of patients with hepatocellular carcinoma (HCC). We reviewed the patients treated with SBRT for HCC from July 2004 to June 2017 at our institution. A total of 59 patients were identified, but 10 were excluded for unavailable serial liver function tests on follow-up. Liver function was assessed prior to SBRT and at 1, 3 and 6 months after SBRT using the Child-Pugh (CP) score classification. The worst CP score on follow-up was compared to the baseline score. Patients were censored after extensive tumor progression in the liver or liver transplant. Time-to-events were calculated from date of SBRT. Median follow-up time was 15 months (1-74 months). Median age was 67 years (49-84 years). Underlying liver disease in this cohort included 33 (67%) with cirrhosis, 22 (45%) with chronic hepatitis C and 7 (14%) with chronic hepatitis B infection. SBRT median total dose was 40 Gy (22-50 Gy) delivered in a median of 5 fractions (1-7 fractions). Median GTV volume was 54 cc (2-607 cc). At baseline, 17 (35%) patients were CP class A5, 19 (39%) were A6, 9 (18%) were B7, and 4 (8%) were B8. After SBRT, 23 (47%) patients had no increase in CP score, 11 (22%) had a 1-point increase, 9 (18%) had 2 points, and 6 (13%) had > 2 points increase in CP score. Sixteen (33%) patients had a change in CP class: 8 from A to B, 5 from B to C and 3 from A to C. Only 2 (4%) patients returned to previous CP class on follow-up. For the whole group, the 1- and 2-years and median overall survival (OS) was of 82%, 59%, and 28 months (95% C.I. 20-53 mos.), respectively. Overall survival of patients with only a 1-point increase in CP score was not significantly different from those with stable CP score (53 vs. 58 months, P = .86). Pair-wise survival analysis in a model including 3 groups showed that patients who had an increase ≥ 2 points in CP score had a significantly worse OS compared to those with a 1-point increase (20 vs. 53 mos, P = .01) and those with stable CP score (20 vs. 58 mos, P = .004). Patients who presented an increase ≥ 3 points in CP had a worse OS compared to those with a 1-point increase or stable CP score (17 vs. 53 mos, P = .001), but not different from those with a 2-points increase in CP score (17 vs. 20 mos, P = 83). A measurable decline of hepatic function after liver SBRT is common in patients with underlying liver dysfunction. The magnitude of this decline assessed by the CP score has prognostic implications. Overall survival of patients with HCC treated with SBRT is most impacted by a worsening of 2 or more points in CP score within 6 months from treatment.

Targeting Accuracy of Image-Guided Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Real-Life Clinical Practice: In Vivo Assessment Using Hepatic Parenchymal Changes on Gd-EOB-DTPA–Enhanced Magnetic Resonance Images

Stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) has emerged as an alternative treatment option when curative treatment modalities cannot be applied. Although excellent local tumor control has been achieved with SBRT, the targeting accuracy in real-life practice remains poorly understood. We proposed an invivo assessment of targeting accuracy using hepatic parenchymal changes observed on gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) images and applied this method to investigate the "real-life" targeting accuracy of image-guided SBRT. We selected 29 patients with available follow-up MR images acquired 2 to 4months after completion of SBRT. All patients were administered 45Gy in 3 fractions. The treated HCC and the region of hepatic parenchymal changes in the hepatobiliary phase of MR images were delineated. We evaluated the discrepancies between the center of the HCC and that of the parenchymal change area (intercenter discrepancy [ICD]). We also analyzed the difference in ICDs between those who underwent SBRT with intrahepatic marker guidance and those with diaphragm guidance. The median ICD in the 3-dimensional direction was 6.81mm (interquartile range [IQR], 4.27-9.61mm). Those for the craniocaudal, left-right, and anteroposterior components were 2.70mm (IQR, 1.83-4.06mm), 1.63mm (IQR, 0.76-3.49), and 4.12mm (IQR, 1.20-6.96mm), respectively. The median ICD for patients who underwent treatment with intrahepatic marker guidance and those with diaphragm guidance was 7.53mm (IQR, 6.63-10.86mm) and 5.60mm (IQR, 4.28-8.18mm), respectively. There was no significant difference in ICD between those who underwent treatment with intrahepatic marker guidance and those with diaphragm guidance (P=.296). The hepatic parenchymal changes observed on Gd-EOB-DTPA-enhanced MR images can be used to assess the targeting accuracy after SBRT for HCC.

The albumin-bilirubin (ALBI) model in hepatocellular carcinoma (HCC) may better predict hepatic failure in patients with traditionally low-risk cirrhosis following definitive stereotactic body radiotherapy (SBRT)

Stereotactic body radiotherapy (SBRT) in hepatocellular carcinoma (HCC) is safe and effective in Child Pugh (CP) A cirrhosis, though a subset of patients may be at higher risk for progressive liver failure. The albumin-bilirubin (ALBI) model is a simple, novel, and validated prognostic assessment of hepatic cirrhosis in patients with HCC, but its utilization during liver SBRT is not well studied. Compared to conventional stratifications of cirrhosis, we hypothesize that the ALBI model is a sensitive predictor of hepatic function, survival, and liver failure following definitive SBRT for HCC in patients with CP-A cirrhosis. From 2009 to 2016, 40 patients with HCC and CP-A cirrhosis completed SBRT. The mean dose was 45 Gy (40 to 50 Gy) in 4–5 fractions. Local control defined as the absence of tumor progression was assessed with CT or MRI every 3–6 months after SBRT. ALBI, MELD (model of end stage liver disease), and CP scores were recorded before treatment and every 3–4 months after. ALBI scores were calculated from the formula (log(bilirubin[mcmol/L]) × 0.66) − (albumin[g/L] × 0.085) and classified as ALBI-1, ALBI-2, or ALBI-3. Initial scores were measured against progression to CP-B cirrhosis and survival. Kaplan-Meier statistical analysis was conducted via MedCalc software. Forty patients with 49 HCC lesions were analyzed in this IRB approved retrospective study. Median tumor diameter was 3.5 cm (1.4–8.9 cm). Eight patients underwent orthotropic liver transplant (median time to transplant was 12 months). Prior to SBRT, 17 patients had ALBI-1 and 23 had ALBI-2 scores.The actuarial local control at 2 years was 98%. With the median follow-up of 23.4 months, overall survival (OS) was 92 and 60% at 1 and 2 years. Freedom from progression to CP-B was 74 and 62% at 1 and 2 years. Compared to pre-treatment ALBI-2 patients, ALBI-1 patients correlated with higher freedom from CP progression (HR = 3.66, P = 0.03), but not OS (P = 0.09). At the last follow-up, 22 of 40 patients (55%) progressed to a higher ALBI grade (12 from ALBI-1 to 2 and 10 from ALBI-2 to ALBI-3). The 2-year OS for patients with an ALBI-1 (n = 5), ALBI-2 (n = 25), and ALBI-3 (n = 10) at last follow-up was 80, 74, and 30%, respectively (P = 0.03). Our study indicates that the ALBI index more precisely predicted liver failure and survival in HCC following SBRT compared to CP scoring. Its application may help select the most ideal candidates for SBRT among the often heterogeneous CP-A population. Further study regarding precautionary measures such as functional treatment planning for ALBI-2 patients treated with liver SBRT may be warranted.

Stereotactic Body Radiation Therapy for Large Hepatocellular Carcinomas

To evaluate efficacy and safety of Stereotactic Body Radiation Therapy (SBRT) for hepatocellular carcinoma (HCC) patients with primary lesion at least 5 cm in diameter. Through an IRB-approved retrospective review of departmental records, we identified 194 patients treated with SBRT for HCC at our institution from 2004-2015. After reviewing all available radiographic and clinical records, 36 patients were found to have a primary lesion greater than or equal to 5 cm in maximum diameter. We recorded radiographic response and treatment toxicities (using CTCAE 3.0). Gender distribution was 32 (89%) male and 4 (11%) female with median age 71 (range 53-93) years at the time of diagnosis and SBRT. Median Zubrod performance score was 1 (range 0-2). Among 35 patients with calculable Child Pugh classification, 23 (66%), 10 (28%), and 2 (6%) of patients were class A, B, and C respectively. Median lesion size was 6 (range 5-14) cm. Radiotherapy was delivered using stereotactic technique and prescribed to isocenter with a median dose of 42.5 (range 30 to 62.5) Gy. All patients were treated in either 5 or 10 total fractions. Assuming an alpha/beta ratio of 10, median biologically equivalent dose (BED) for all patients was 72 (range 39-141) Gy. SBRT was the initial treatment modality for 29 (81%) patients, while 19% of patients had undergone prior treatment [transarterial chemoembolization (TACE) in 4 (11%) patients and radiofrequency ablation (RFA) in 3 (8%) patients]. The 3 month local radiographic response was complete in 6%, partial in 47%, stable in 38%, and progressive disease in 9% of patients (2 were unknown). 58% of patients experienced no treatment toxicity, 19% experienced grade 1 toxicity, and 14% experienced grade 2 toxicity (unknown for 3 patients). No acute or late grade 3 radiation toxicities were reported. SBRT is a safe and effective treatment modality for patients with large HCC lesions, especially if they are not amendable to other therapeutic interventions.

In Vivo Assessment of the Spatial Distribution of Liver Injury Following Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

To improve understanding of the relationship between delivered radiation dose and functional response of the liver using Gd-EOB-DTPA (EOB) enhanced MRI. EOB is a hepatobiliary-specific gadolinium based intravenous contrast agent for MR imaging with approximately 50% of the injected dose taken up by functional hepatocytes allowing for the distinction of functional regions of hepatocytes from non-functional zones. We hypothesized that decreased EOB uptake in post-treatment imaging will correspond to a specific iso-dose distribution after liver stereotactic body radiation therapy (SBRT). We reviewed pre/post liver function tests (LFT) for patients treated at our institution with SBRT for hepatocellular carcinoma (HCC) between 2010 and 2015. Patients with pre- and 3-month post-treatment MRI with EOB were retained for the analysis. The 3D-dosimetric data from CT planning scan were deformed to MRI with quality of deformation assessed by DICE coefficient. Images were visually reviewed for the regions of liver hypointensity (LHI) on T1-w images by independent reviewers that were blinded to 3D-dosimetric data. Based on the volumetric data, a dose-volume-histogram was calculated. We estimated the threshold function loss as the D90 (i.e., the dose achieved in 90% of the LHI volume). The volume of LHI were also recorded and correlated to the volume corresponding to various iso-dose using Pearson’s correlation as confirmation. Associations between LFT and liver enhancement normalized to the spleen were estimated with linear regression. Thirty patients met inclusion criteria. All patients were treated with five fractions of SBRT, with doses ranging from 31.5 to 54 Gy based on mean liver dose (MLD) and tumors’ proximity to organs at risk. MLD was 8.8 ± 3.8 Gy and the median PTV volume was 70.9 cc (IQR = 44.7-126.9). The median MELD score at baseline and 3 months after treatment were 9 (IQR = 7-11) and 9 (IQR = 7-12) respectively which were not significantly different (P = 0.70). Higher direct bilirubin was associated with decrease hepatobiliary enhancement (-0.25 signal intensity ± 0.1, P < 0.05). The 20 Gy volume corresponded most closely to the LHI volume with a ratio of LHI to iso-dose of 1.1 ± 0.16 and r = 0.58 (P < 0.01). The mean DICE coefficient for deformation of 3D-dosimetric data to MRI was 0.82 ± 0.05. The D90 was 16.5 ± 7.9 Gy for the whole cohort and 19.4 ± 5.5 Gy for patients with DICE coefficient > 0.8. The mean liver volume was 1590 ± 483 cc and mean liver – hypointense volume was 1357 ± 480 cc. We found that SBRT to the liver resulted in decreased spatial function on MRI that corresponded to a threshold dose. However, direct bilirubin is inversely correlated to hepatobiliary enhancement and may decrease the sensitivity of this method in patients with elevated direct bilirubin. This spatial function relationship can potentially be used to image and monitor regions of radiation liver injury and can be used for better dose allocation in patients needing liver re-irradiation.

Functional image-guided stereotactic body radiation therapy planning for patients with hepatocellular carcinoma

The aim of the current planning study is to evaluate the ability of gadoxetate disodium-enhanced magnetic resonance imaging (EOB-MRI)–guided stereotactic body radiation therapy (SBRT) planning by using intensity-modulated radiation therapy (IMRT) techniques in sparing the functional liver tissues during SBRT for hepatocellular carcinoma. In this study, 20 patients with hepatocellular carcinoma were enrolled. Functional liver tissues were defined according to quantitative liver-spleen contrast ratios ≥ 1.5 on a hepatobiliary phase scan. Functional images were fused with the planning computed tomography (CT) images; the following 2 SBRT plans were designed using a “step-and-shoot” static IMRT technique for each patient: (1) an anatomical SBRT plan optimization based on the total liver; and (2) a functional SBRT plan based on the functional liver. The total prescribed dose was 48 gray (Gy) in 4 fractions. Dosimetric parameters, including dose to 95% of the planning target volume (PTV D95%), percentages of total and functional liver volumes, which received doses from 5 to 30 Gy (V5 to V30 and fV5 to fV30), and mean doses to total and functional liver (MLD and fMLD, respectively) of the 2 plans were compared. Compared with anatomical plans, functional image-guided SBRT plans reduced MLD (mean: plan A, 5.5 Gy; and plan F, 5.1 Gy; p < 0.0001) and fMLD (mean: plan A, 5.4 Gy; and plan F, 4.9 Gy; p < 0.0001), as well as V5 to V30 and fV5 to fV30. No differences were noted in PTV coverage and nonhepatic organs at risk (OARs) doses. In conclusion, EOB-MRI–guided SBRT planning using the IMRT technique may preserve functional liver tissues in patients with hepatocellular carcinoma (HCC).

Predictors of Liver Toxicity Following Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma

Identifying risk factors associated with declining liver function after stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) may improve future treatment design. Therefore, clinical and dosimetric parameters were investigated for their association with liver toxicity following SBRT for HCC. Data was analyzed from patients treated on Phase I/II clinical trials of 6 fractions SBRT for HCC. Dose was individually prescribed based on the liver effective volume irradiated and estimated risk of liver toxicity based on a normal tissue complication probability (NTCP) model adjusted for the dose/fraction. Toxicity was defined as an increase in Child-Pugh (CP) score ≥2 within 3 months of SBRT. Patients with baseline lower liver function (CP ≥7, class B) were excluded. Clinical parameters, SBRT details, and cumulative dose-volume histograms (DVH) of the liver (excluding gross tumor) were tested for association with toxicity using logistic regression. A total of 101 patients were evaluable with a baseline CP score of A5 (72%) or A6 (28%), 53% had portal vein HCC thrombus, 80% were male and 91% had underlying liver disease (37% Hepatitis B, 40% Hepatitis C). The median total HCC volume was 121 mL (range 2-1913 mL) and median liver volume (excluding HCC) was 1286 mL (range 766-3967 mL). The median prescribed dose was 36 Gy in 6 fractions (range 27-54 Gy). At 3 months, 26 patients (26%) had toxicity. Portal vein HCC thrombus, CP score of A6, and lower platelet count at baseline were associated with toxicity on univariate analysis. Underlying liver disease was not. Dosimetric parameters of the liver volume receiving at least 5, 10, 15, 20, or 25 Gy, mean liver dose, liver effective volume, NTCP, and dose to 800 mL (D800mL) were significant on univariate analysis and tended to be highly correlated. The spared liver volume, or volumes receiving less than 5, 10, 15, 20 or 25 Gy were not associated with toxicity. Significant associations with toxicity on multivariate analysis were found for baseline CP score (odds ratio (OR) 4.85 [1.47-16.05]), platelet count (OR 0.90 [0.82-0.98] per 10 unit increase, median 108x109/L with toxicity, vs. 150x109/L without), mean liver dose (OR 1.33 [1.04-1.69], median 17.0 Gy with toxicity vs. 15.2 Gy without) and D800mL (OR 1.11 [1.02-1.21], median 14.3 Gy with toxicity vs. 6.0 Gy without). For CP class A patients, baseline CP score, platelet count, mean liver dose, and D800mL are associated with an increase in CP score by 2 or more 3 months following SBRT for HCC.