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

Abstract

Purpose: To identify risk factors associated with a decline in liver function after stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma. Methods and Materials: Data were analyzed from patients with hepatocellular carcinoma treated on clinical trials of 6-fraction SBRT. Liver toxicity was defined as an increase in Child-Pugh (CP) score ≥2 three months after SBRT. Clinical factors, SBRT details, and liver dose-volume histogram (DVH) parameters were tested for association with toxicity using logistic regression. CP class B patients were analyzed separately. Results: Among CP class A patients, 101 were evaluable, with a baseline score of A5 (72%) or A6 (28%). Fifty-three percent had portal vein thrombus. The median liver volume was 1286 cc (range, 766-3967 cc), and the median prescribed dose was 36 Gy (range, 27-54 Gy). Toxicity was seen in 26 patients (26%). Thrombus, baseline CP of A6, and lower platelet count were associated with toxicity on univariate analysis, as were several liver DVH-based parameters. Absolute and spared liver volumes were not significant. On multivariate analysis for CP class A patients, significant associations were found for baseline CP score of A6 (odds ratio [OR], 4.85), lower platelet count (OR, 0.90; median, 108 × 10{sup 9}/L vs 150 × 10{sup 9}/L), higher mean liver dose (OR, 1.33; median,more » 16.9 Gy vs 14.7 Gy), and higher dose to 800 cc of liver (OR, 1.11; median, 14.3 Gy vs 6.0 Gy). With 13 CP-B7 patients included or when dose to 800 cc of liver was replaced with other DVH parameters (eg, dose to 700 or 900 cc of liver) in the multivariate analysis, effective volume and portal vein thrombus were associated with an increased risk. Conclusions: Baseline CP scores and higher liver doses (eg, mean dose, effective volume, doses to 700-900 cc) were strongly associated with liver function decline 3 months after SBRT. A lower baseline platelet count and portal vein thrombus were also associated with an increased risk.« less

Authors:
 [1];  [2];  [1];  [3];  [4]; ; ; ; ; ;  [1];  [3];  [1];  [3]
  1. Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario (Canada)
  2. Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards, New South Wales (Australia)
  3. (Canada)
  4. Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario (Canada)
Publication Date:
OSTI Identifier:
22649883
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 97; Journal Issue: 5; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; CLINICAL TRIALS; GY RANGE 01-10; GY RANGE 10-100; HEPATOMAS; LIVER; MULTIVARIATE ANALYSIS; PATIENTS; RADIATION DOSES; RADIATION HAZARDS; RADIOTHERAPY; TOXICITY; VEINS

Citation Formats

Velec, Michael, Haddad, Carol R., Craig, Tim, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Wang, Lisa, Lindsay, Patricia, Brierley, James, Brade, Anthony, Ringash, Jolie, Wong, Rebecca, Kim, John, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Dawson, Laura A., E-mail: Laura.Dawson@rmp.uhn.on.ca, and Department of Radiation Oncology, University of Toronto, Toronto, Ontario. Predictors of Liver Toxicity Following Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma. United States: N. p., 2017. Web. doi:10.1016/J.IJROBP.2017.01.221.
Velec, Michael, Haddad, Carol R., Craig, Tim, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Wang, Lisa, Lindsay, Patricia, Brierley, James, Brade, Anthony, Ringash, Jolie, Wong, Rebecca, Kim, John, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Dawson, Laura A., E-mail: Laura.Dawson@rmp.uhn.on.ca, & Department of Radiation Oncology, University of Toronto, Toronto, Ontario. Predictors of Liver Toxicity Following Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma. United States. doi:10.1016/J.IJROBP.2017.01.221.
Velec, Michael, Haddad, Carol R., Craig, Tim, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Wang, Lisa, Lindsay, Patricia, Brierley, James, Brade, Anthony, Ringash, Jolie, Wong, Rebecca, Kim, John, Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Dawson, Laura A., E-mail: Laura.Dawson@rmp.uhn.on.ca, and Department of Radiation Oncology, University of Toronto, Toronto, Ontario. Sat . "Predictors of Liver Toxicity Following Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma". United States. doi:10.1016/J.IJROBP.2017.01.221.
@article{osti_22649883,
title = {Predictors of Liver Toxicity Following Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma},
author = {Velec, Michael and Haddad, Carol R. and Craig, Tim and Department of Radiation Oncology, University of Toronto, Toronto, Ontario and Wang, Lisa and Lindsay, Patricia and Brierley, James and Brade, Anthony and Ringash, Jolie and Wong, Rebecca and Kim, John and Department of Radiation Oncology, University of Toronto, Toronto, Ontario and Dawson, Laura A., E-mail: Laura.Dawson@rmp.uhn.on.ca and Department of Radiation Oncology, University of Toronto, Toronto, Ontario},
abstractNote = {Purpose: To identify risk factors associated with a decline in liver function after stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma. Methods and Materials: Data were analyzed from patients with hepatocellular carcinoma treated on clinical trials of 6-fraction SBRT. Liver toxicity was defined as an increase in Child-Pugh (CP) score ≥2 three months after SBRT. Clinical factors, SBRT details, and liver dose-volume histogram (DVH) parameters were tested for association with toxicity using logistic regression. CP class B patients were analyzed separately. Results: Among CP class A patients, 101 were evaluable, with a baseline score of A5 (72%) or A6 (28%). Fifty-three percent had portal vein thrombus. The median liver volume was 1286 cc (range, 766-3967 cc), and the median prescribed dose was 36 Gy (range, 27-54 Gy). Toxicity was seen in 26 patients (26%). Thrombus, baseline CP of A6, and lower platelet count were associated with toxicity on univariate analysis, as were several liver DVH-based parameters. Absolute and spared liver volumes were not significant. On multivariate analysis for CP class A patients, significant associations were found for baseline CP score of A6 (odds ratio [OR], 4.85), lower platelet count (OR, 0.90; median, 108 × 10{sup 9}/L vs 150 × 10{sup 9}/L), higher mean liver dose (OR, 1.33; median, 16.9 Gy vs 14.7 Gy), and higher dose to 800 cc of liver (OR, 1.11; median, 14.3 Gy vs 6.0 Gy). With 13 CP-B7 patients included or when dose to 800 cc of liver was replaced with other DVH parameters (eg, dose to 700 or 900 cc of liver) in the multivariate analysis, effective volume and portal vein thrombus were associated with an increased risk. Conclusions: Baseline CP scores and higher liver doses (eg, mean dose, effective volume, doses to 700-900 cc) were strongly associated with liver function decline 3 months after SBRT. A lower baseline platelet count and portal vein thrombus were also associated with an increased risk.},
doi = {10.1016/J.IJROBP.2017.01.221},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 5,
volume = 97,
place = {United States},
year = {Sat Apr 01 00:00:00 EDT 2017},
month = {Sat Apr 01 00:00:00 EDT 2017}
}
  • Purpose: 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). Methods and Materials: 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 computedmore » 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. Results: 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. Conclusion: 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.« less
  • Purpose: Lower radiation tolerance of the whole liver hinders dose escalations of stereotactic body radiation therapy (SBRT) in hepatocellular carcinoma (HCC) treatment. This study was conducted to define the exact doses that result in radiation-induced liver disease (RILD) as well as to determine dose constraints for the critical organs at risk (OARs) in mice; these parameters are still undefined in HCC SBRT. Methods: This study consisted of two phases. In the primary phase, mice treated with helical tomotherapy-based SBRT were stratified according to escalating radiation doses to the livers. The pathological differences, signs [such as mouse performance status (MPS)], andmore » serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/albumin levels were observed. Radiation-induced disease severities of the OARs were scored using systematic evaluation standards. In the validation phase in humans, 13 patients with HCC who had undergone radiotherapy before hepatectomy were enrolled to validate RILD pathological changes in a mouse study. Results: The evaluation criteria of the mouse liver radiotherapy-related signs were as follows: MPS ≥ 2.0 ± 0.52, AST/ALT ≥ 589.2 ± 118.5/137.4 ± 15.3 U/L, serum albumin ≤ 16.8 ± 2.29 g/L. The preliminary dose constraints of the OARs were also obtained, such as those for the liver (average dose ≤ 26.36 ± 1.71 Gy) and gastrointestinal tract (maximum dose ≤ 22.63 Gy). Mouse RILD models were able to be developed when the livers were irradiated with average doses of ≥31.76 ± 1.94 Gy (single fraction). RILD pathological changes in mice have also been validated in HCC patients. Conclusions: Mouse RILD models could be developed with SBRT based on the dose constraints for the OARs and evaluation criteria of mouse liver radiotherapy-related signs, and the authors’ results favor the study of further approaches to treat HCC with SBRT.« less
  • Purpose: To investigate the relationship between physical and biological effective dose (BED) to liver toxicity for SBRT fractionations. Methods: A total of 16 patients (13–10×3Gy, 2–5×10Gy and 1–3×15Gy were selected. Physical dose distributions were converted to voxel based BED values using the linear-quadratic (LQ) and linear-quadratic linear (LQ-L) models for doses per fraction larger than 6Gy. Patients were graded for effective toxicity (post-treatment minus pre-treatment grades) using the RTOG Late Radiation Morbidity Scoring Schema associated with Radiation Induced Liver Disease (RILD). Evaluated physical dose-volume levels consisted of V10Gy, V15Gy, V20Gy, V25Gy and V30Gy which were then converted to BED valuesmore » corresponding to V16.7Gy3, V30Gy3, V46.7Gy3, V66.7Gy3 and V90Gy3, respectively. All levels were normalized to their respective patient normal liver volumes (NLV) and evaluated for correlation to RILD. Results were measured quantitatively using R-squared regression analysis. Results: Mean Dose Tolerable to Normal Liver (MDTNL) against RILD grade resulted in an R-squared value of 0.0104. NLV-normalized physical dose linear regression fit of V10Gy, V15Gy, V20Gy, V25Gy and V30Gy against RILD yielded R-squared values of 0.1041, 0.0895, 0.0698, 0.0398 and 0.0009 while BED levels of V16.7Gy3, V30Gy3, V46.7Gy3, V66.7Gy3 and V90Gy3 resulted in values of 0.0002, 0.0153, 0.0533, 0.0427 and 0.0072, respectively. The average NLV-normalized V10Gy, V15Gy, V20Gy, V25Gy and V30Gy per grade plotted against RILD grade yielded R-squared correlations of 0.8092, 0.6362, 0.5899, 0.5846 and 0.0224 while the BED levels of V16.7Gy3, V30Gy3, V46.7Gy3, V66.7Gy3 and V90Gy3 resulted in R-squared correlations of 0.0003, 0.3831, 0.8476, 0.678 and 0.076, respectively. Conclusion: Regression analysis between physical dose, BED and RILD showed strong correlation for the V30Gy and V46.7Gy3 dose-levels. Average BED and physical dose per grade both exhibit strong correlations to RILD however, a lack of statistical significance exists due to small patient sample size.« less
  • Purpose: To identify dosimetric predictors of hepatobiliary (HB) toxicity associated with stereotactic body radiation therapy (SBRT) for liver tumors. Methods and Materials: We retrospectively reviewed 96 patients treated with SBRT for primary (53%) or metastatic (47%) liver tumors between March 2006 and November 2013. The central HB tract (cHBT) was defined by a 15-mm expansion of the portal vein from the splenic confluence to the first bifurcation of left and right portal veins. Patients were censored for toxicity upon local progression or additional liver-directed therapy. HB toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.0. Tomore » compare different SBRT fractionations, doses were converted to biologically effective doses (BED) by using the standard linear quadratic model α/β = 10 (BED10). Results: Median follow-up was 12.7 months after SBRT. Median BED10 was 85.5 Gy (range: 37.5-151.2). The median number of fractions was 5 (range: 1-5), with 51 patients (53.1%) receiving 5 fractions and 29 patients (30.2%) receiving 3 fractions. In total, there were 23 (24.0%) grade 2+ and 18 (18.8%) grade 3+ HB toxicities. Nondosimetric factors predictive of grade 3+ HB toxicity included cholangiocarcinoma (CCA) histology (P<.0001), primary liver tumor (P=.0087), and biliary stent (P<.0001). Dosimetric parameters most predictive of grade 3+ HB toxicity were volume receiving above BED10 of 72 Gy (V{sub BED10}72) ≥ 21 cm{sup 3} (relative risk [RR]: 11.6, P<.0001), V{sub BED10}66 ≥ 24 cm{sup 3} (RR: 10.5, P<.0001), and mean BED10 (Dmean{sub BED10}) cHBT ≥14 Gy (RR: 9.2, P<.0001), with V{sub BED10}72 and V{sub BED10}66 corresponding to V40 and V37.7 for 5 fractions and V33.8 and V32.0 for 3 fractions, respectively. V{sub BED10}72 ≥ 21 cm{sup 3}, V{sub BED10}66 ≥ 24 cm{sup 3}, and Dmean{sub BED10} cHBT ≥14 Gy were consistently predictive of grade 3+ toxicity on multivariate analysis. Conclusions: V{sub BED10}72, V{sub BED10}66, and Dmean{sub BED10} to cHBT are associated with HB toxicity. We suggest V{sub BED10}72 < 21 cm{sup 3} (5-fraction: V40 < 21 cm{sup 3}; 3-fraction: V33.8 < 21 cm{sup 3}), V{sub BED10}66 < 24 cm{sup 3} (5-fraction: V37.7 < 24 cm{sup 3}; 3-fraction: V32 < 24 cm{sup 3}) as potential dose constraints for the cHBT when clinically indicated.« less
  • Purpose: To examine the safety and efficacy of Cyberknife stereotactic body radiation therapy (SBRT) and its effect on survival in patients of recurrent hepatocellular carcinoma (HCC). Methods and Materials: This was a matched-pair study. From January 2008 to December 2009, 36 patients with 42 lesions of unresectable recurrent HCC were treated with SBRT. The median prescribed dose was 37 Gy (range, 25 to 48 Gy) in 4-5 fractions over 4-5 consecutive working days. Another 138 patients in the historical control group given other or no treatments were selected for matched analyses. Results: The median follow-up time was 14 months formore » all patients and 20 months for those alive. The 1- and 2-year in-field failure-free rates were 87.6% and 75.1%, respectively. Out-field intrahepatic recurrence was the main cause of failure. The 2-year overall survival (OS) rate was 64.0%, and median time to progression was 8.0 months. In the multivariable analysis of all 174 patients, SBRT (yes vs. no), tumor size ({<=}4 cm vs. >4 cm), recurrent stage (stage IIIB/IV vs. I) and Child-Pugh classification (A vs. B/C) were independent prognostic factors for OS. Matched-pair analysis revealed that patients undergoing SBRT had better OS (2-year OS of 72.6% vs. 42.1%, respectively, p = 0.013). Acute toxicities were mild and tolerable. Conclusion: SBRT is a safe and efficacious modality and appears to be well-tolerated at the dose fractionation we have used, and its use correlates with improved survival in this cohort of patients with recurrent unresectable HCC. Out-field recurrence is the major cause of failure. Further studies of combinations of SBRT and systemic therapies may be reasonable.« less