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Purpose: To correlate the imaging findings of treated hepatocellular carcinoma (HCC) after stereotactic body radiation therapy (SBRT) with explant pathology and alpha-fetoprotein (AFP) response., Methods and Materials: From 2007 to 2015, of 146 patients treated with liver SBRT for Barcelona Clinic Liver Cancer stage A hepatocellular carcinoma, 10 were identified with inclusion criteria and had regular interval follow-up magnetic resonance imaging/triple phase computed tomography and explant pathology or declining AFP values for radiology-pathology response correlation. Reference standards for successful response were >90% necrosis on explant pathology or pretreatment AFP >75 ng/mL normalizing to <10 ng/mL within 1 year after SBRT without other treatment. Subjects were treated with 24 to 50 Gy in 3 to 5 fractions. Multiphasic magnetic resonance imaging or computed tomography performed at 3, 6, 9, and 12 months after SBRT was compared with pretreatment imaging by 2 expert radiologists. Descriptive statistics were calculated., Results: There were 10 subjects with 10 treated HCCs, classified as 3 Organ Procurement and Transplantation Network (OPTN) 5a, 4 OPTN 5b, and 3 OPTN 5x. All had successfully treated HCCs, according to explant pathology or declining AFP. Four of 10 HCCs had persistent central arterial hyperenhancement 3 to 12 months after SBRT; persistent wash-out was common up to 12 months (9 of 10). Of 10 treated HCCs, 9 exhibited decreased size at 12 months. Liver parenchyma adjacent to the lesion showed early (3-6 months) hyperemia followed by late (6-12 months) capsular retraction and delayed enhancement. No patient had a significant decline in liver function., Conclusions: In the absence of increasing size, persistent central arterial hyperenhancement and wash-out can occur within the first 12 months after SBRT in successfully treated HCCs and may not represent residual viable tumor. Liver parenchyma adjacent to the treated lesion showed inflammation followed by fibrosis, without significant change in hepatic function. Until a radiologic signature of tumor control is determined, freedom from local progression seems to be the best measure of HCC control after SBRT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) are widely used therapies for the treatment of intrahepatic metastases; however, direct comparisons are lacking. We sought to compare outcomes for these 2 modalities., Methods and Materials: From 2000 to 2015, 161 patients with 282 pathologically diagnosed unresectable liver metastases were treated with RFA (n = 112) or SBRT (n = 170) at a single institution. The primary outcome was freedom from local progression (FFLP). The effect of treatment and covariates on FFLP was modeled using a mixed-effects Cox model with application of inverse probability treatment weighting to adjust for potential imbalances in treatment modality., Results: The median follow-up period was 24.6 months. Patients receiving SBRT had larger tumors than those treated with RFA (median, 2.7 cm vs 1.8 cm; P < .01). On univariate analysis, tumor size was associated with worse FFLP for RFA (hazard ratio [HR]; 1.57; 95% confidence interval [CI], 1.15-2.14; P < .01) but not for SBRT (HR, 1.38; 95% CI, 0.76-2.51; P = .3). The 2-year FFLP rate was 88.2% compared with 73.9%, favoring SBRT (P = .06). For tumors ≥2 cm in diameter, SBRT was associated with improved FFLP (HR, 0.28; 95% CI, 0.09-0.93; P < .01). On multivariate analysis, treatment with SBRT (HR, 0.21; 95% CI, 0.07-0.62; P = .005) and smaller tumor size (HR, 0.65; 95% CI, 0.47-0.91; P = .01) were associated with improved FFLP. The 2-year overall survival rate was 51.1%, with no difference between groups (P = .8). Grade ≥3 treatment-related toxicity was rare, with no difference between SBRT (n = 4) and RFA (n = 3)., Conclusions: Treatment with SBRT or RFA is well tolerated and provides excellent and similar local control for intrahepatic metastases <2 cm in size. For tumors ≥2 cm in size, treatment with SBRT is associated with improved FFLP and may be the preferable treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To develop normal tissue complications (NTCP) models for hepatocellular cancer (HCC) patients who undergo liver radiation therapy (RT) and to evaluate the potential role of functional imaging and measurement of blood-based circulating biological markers before and during RT to improve the performance of these models., Methods and Materials: The data from 192 HCC patients who had undergone RT from 2005 to 2014 were evaluated. Of the 192 patients, 146 had received stereotactic body RT (SBRT) and 46 had received conventional RT to a median physical tumor dose of 49.8 Gy and 50.4 Gy, respectively. The physical doses were converted into 2-Gy equivalents for analysis. Two approaches were investigated for modeling NTCP: (1) a generalized Lyman-Kutcher-Burman model; and (2) a generalization of the parallel architecture model. Three clinical endpoints were considered: the change in albumin-bilirubin (ALBI), change in Child-Pugh (C-P) score, and grade ≥3 liver enzymatic changes. Local dynamic contrast-enhanced magnetic resonance imaging portal venous perfusion information was used as an imaging biomarker for local liver function. Four candidate inflammatory cytokines were considered as biological markers. The imaging findings and cytokine levels were incorporated into NTCP modeling, and their role was evaluated using goodness-of-fit metrics., Results: Using dosimetric information only, the Lyman-Kutcher-Burman model for the ALBI/C-P change had a steeper response curve compared with grade ≥3 enzymatic changes. Incorporating portal venous perfusion imaging information into the parallel architecture model to represent functional reserve resulted in relatively steeper dose-response curves compared with dose-only models. A larger loss of perfusion function was needed for enzymatic changes compared with ALBI/C-P changes. Increased transforming growth factor-β1 and eotaxin expression increased the trend of expected risk in both NTCP modeling approaches but did not reach statistical significance., Conclusions: The incorporation of imaging findings and biological markers into NTCP modeling of liver toxicity improved the estimates of expected NTCP risk compared with using dose-only models. In addition, such generalized NTCP models should contribute to a better understanding of the normal tissue response in HCC SBRT patients and facilitate personalized treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To conduct a large single-institution comparison of transarterial chemoembolization (TACE) and stereotactic body radiation therapy (SBRT) outcomes in similar groups of patients with hepatocellular carcinoma (HCC)., Methods and Materials: From 2006 to 2014, 209 patients with 1 to 2 tumors underwent TACE (n=84) to 114 tumors or image guided SBRT (n=125) to 173 tumors. Propensity score analysis with inverse probability of treatment weighting was used to compare outcomes between treatments while adjusting for imbalances in treatment assignment. Local control (LC), toxicity, and overall survival (OS) were retrospectively analyzed., Results: The TACE and SBRT groups were similar with respect to the number of tumors treated per patient, underlying liver disease, and baseline liver function. Patients treated with SBRT were older (65 vs 61 years, P=.01), had smaller tumors (2.3 vs 2.9 cm, P<.001), and less frequently underwent liver transplantation (8% vs 18%, P=.01). The 1- and 2-year LC favored SBRT: 97% and 91%, respectively, for SBRT and 47% and 23% for TACE (hazard ratio 66.5, P<.001). For patients treated with TACE, higher alpha-fetoprotein (hazard ratio 1.11 per doubling, P=.008) and segmental portal vein thrombosis (hazard ratio 9.9, P<.001) were associated with worse LC. Predictors associated with LC after SBRT were not identified. Grade 3+ toxicity occurred after 13% and 8% of TACE and SBRT treatments, respectively (P=.05). There was no difference in OS between patients treated with TACE or SBRT., Conclusions: Stereotactic body radiation therapy is a safe alternative to TACE for 1 to 2 tumors and provides better LC, with no observed difference in OS. Prospective comparative trials of TACE and SBRT are warranted., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To test the hypothesis that mid-treatment measures of the retention of indocyanine green after 15 minutes (ICGR15) would improve the prediction of posttreatment liver function in the setting of hepatocellular carcinoma., Methods and Materials: Between 2006 and 2015, 144 patients with hepatocellular carcinoma received 175 courses of stereotactic body radiation therapy (SBRT). Patient data, such as age, sex, portal vein thrombosis, cirrhosis, Child-Pugh (CP) score, prior liver-directed therapies, and liver function tests, including albumin-bilirubin (ALBI) and ICG clearance, and dosimetric data, such as tumor volume and radiation dose, were collected. Toxicity was evaluated as a 2-point increase in CP score or a change in ALBI score at 3 months from start of SBRT. Logistic or linear regression was used to build toxicity prediction models based on patient and tumor characteristics and ICG clearance variables. Performance of the models for the binary CP outcome was summarized using area under the curve and receive operating characteristic curves. Likelihood ratio tests were used to evaluate whether the model fit improved after incorporating the ICG variable information., Results: In multivariable analysis age, baseline ICGR15, and change in ICGR15 were associated with toxicity defined by increased CP score. For the continuous ALBI outcome, being female, having cirrhosis, and increasing radiation dose were associated with increased toxicity. When incorporating ICGR15 into these models, an increase in ICGR15 from baseline to mid-treatment was most consistently significantly associated with an increase in toxicity., Conclusions: Incorporation of ICGR15 variables significantly improves the prediction of post-SBRT liver function. The use of ICGR15 can facilitate the delivery of the maximum safe dose of radiation for patients with hepatocellular carcinoma and has the potential to improve uncomplicated tumor control and survival., (Copyright © 2017 Elsevier Inc. All rights reserved.)