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Automated feature quantification of Lipiodol as imaging biomarker to predict therapeutic efficacy of conventional transarterial chemoembolization of liver cancer.

ABSTRACT: Conventional transarterial chemoembolization (cTACE) is a guideline-approved image-guided therapy option for liver cancer using the radiopaque drug-carrier and micro-embolic agent Lipiodol, which has been previously established as an imaging biomarker for tumor response. To establish automated quantitative and pattern-based image analysis techniques of Lipiodol deposition on 24 h post-cTACE CT as biomarker for treatment response. The density of Lipiodol deposits in 65 liver lesions was automatically quantified using Hounsfield Unit thresholds. Lipiodol deposition within the tumor was automatically assessed for patterns including homogeneity, sparsity, rim, and peripheral deposition. Lipiodol deposition was correlated with enhancing tumor volume (ETV) on baseline and follow-up MRI. ETV on baseline MRI strongly correlated with Lipiodol deposition on 24 h CT (p?

SUBMITTER: Stark S

PROVIDER: S-EPMC7582153 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Automated feature quantification of Lipiodol as imaging biomarker to predict therapeutic efficacy of conventional transarterial chemoembolization of liver cancer.

Stark Sophie S Wang Clinton C Savic Lynn Jeanette LJ Letzen Brian B Schobert Isabel I Miszczuk Milena M Murali Nikitha N Oestmann Paula P Gebauer Bernhard B Lin MingDe M Duncan James J Schlachter Todd T Chapiro Julius J

Scientific reports 20201022 1

Conventional transarterial chemoembolization (cTACE) is a guideline-approved image-guided therapy option for liver cancer using the radiopaque drug-carrier and micro-embolic agent Lipiodol, which has been previously established as an imaging biomarker for tumor response. To establish automated quantitative and pattern-based image analysis techniques of Lipiodol deposition on 24 h post-cTACE CT as biomarker for treatment response. The density of Lipiodol deposits in 65 liver lesions was automatic ...[more]

PMID: 33093524

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Project description:BackgroundDrug-eluting embolic transarterial chemoembolization (DEE-TACE) is an advance in TACE technique. However, at present there is insufficient evidence to support that DEE-TACE is superior to conventional TACE (cTACE) for hepatocellular carcinoma (HCC). The aim of this meta-analysis is to evaluate the efficacy and safety of TACE with CalliSpheres® microspheres (CSM-TACE) compared with cTACE in patients with HCC.Data sourcesPubMed, Embase, Web of Science, CNKI and Wanfang Databases were searched to identify relevant articles published before March 26, 2020. The data regarding treatment response, survival profile, adverse events and liver function indexes were retrieved.ResultsA total of 16 studies with 1454 HCC patients (722 treated with CSM-TACE and 732 with cTACE) were included. Patients receiving CSM-TACE had higher 1-month complete response (CR), objective response rate (ORR), disease control rate (DCR) (odds ratio (OR): 2.00, 95% confidence interval (95% CI): 1.29-3.09; OR: 2.87, 95% CI: 2.15-3.83; OR: 2.01, 95% CI: 1.37-2.95, respectively), 3-month CR, ORR, DCR (OR: 4.04, 95%CI: 2.46-6.64; OR: 3.39, 95%CI: 2.45-4.70; OR: 1.71, 95%CI: 1.14-2.55 respectively), and 6-month CR, ORR, DCR (OR: 4.02, 95%CI: 2.26-7.16; OR: 3.00, 95%CI: 2.05-4.38; OR: 2.66, 95%CI: 1.70-4.16 respectively) than those treated with cTACE. Furthermore, CSM-TACE exhibited a trend toward improved progression free survival (hazard ratio (HR): 0.86, 95%CI: 0.67-1.11) and overall survival (HR: 0.79, 95%CI: 0.59-1.07) over cTACE although these differences did not reach statistical significance. In terms of safety, the two TACE treatments showed similar post-treatment pain (OR: 0.84, 95%CI: 0.55-1.28), fever (OR: 0.99, 95%CI: 0.60-1.63), nausea/vomiting (OR: 0.84, 95% CI: 0.60-1.17), as well as 1-month follow-up alanine aminotransferase (Mean difference (MD): -3.66, 95%CI: -10.38-3.07), aspartate aminotransferase (MD: -2.30, 95%CI: -8.91-4.31) and total bilirubin (MD: -0.15, 95%CI: -2.26-1.96).ConclusionCSM-TACE displays superior treatment response, non-inferior survival profile and safety over cTACE in HCC patients.

Project description:BACKGROUND:Therapeutic options for patients with hepatocellular carcinoma (HCC) are limited. Transarterial chemoembolization (TACE) is an interventional procedure used to deliver chemotherapy and embolizing agents directly to the tumor and is the procedure of choice for patients with intermediate stage HCC. While effective, more than 40% of patients do not respond to therapy, highlighting the need to investigate possible mechanisms of resistance. We sought to evaluate mechanisms of TACE resistance and evaluate a potential therapeutic target to overcome this resistance. METHODS:Using a prognostic gene signature which predicts TACE response (TACE Navigator) in a cohort of HCC patients who received TACE, patients were classified as responders and non-responders. Transcriptomic and gene pathway analysis were used to identify potential drivers of TACE resistance. Knockdown of the gene encoding rate limiting enzyme PKM2 using shRNA in HCC cell lines, as well as pharmacologic inhibition of PKM2 with shikonin using an in vitro TACE model measured response to chemotherapy under hypoxia. Finally, we replicated the TACE model with shikonin using patient derived cell line organoids (PDC). Functional studies were performed in vitro using immunoblotting, quantitative polymerase chain reaction, glycolysis and hypoxia assays. RESULTS:In patient non-responders, we identified enrichment of the glycolysis pathway, specifically of the gene encoding the rate-limiting enzyme PKM2. We identified four HCC cell lines which recapitulated a TACE responder-like and non-responder-like phenotype. PKM2 knockdown in HCC cell lines demonstrated a less proliferative and aggressive phenotype as well as improved drug sensitivity to both doxorubicin and cisplatin. In vitro TACE model demonstrated that TACE non-responder-like cells overcame therapeutic resistance and rendered them susceptible to therapy through PKM2 knockdown. Lastly, we obtained similar results using a pharmacologic PKM2 inhibitor, shikonin in both cell lines, and PDC organoids. CONCLUSION:Elevated PKM2 is associated with treatment resistance and abbreviated survival in patients receiving TACE. Elevated PKM2 in vitro is associated with increased utilization of the glycolysis pathway, resulting in oxygen independent cell metabolism. Through PKM2 knockdown as well as with pharmacologic inhibition with shikonin, non-responder cells can be reprogrammed to act as responders and could improve TACE efficacy in patients.

Project description:PURPOSE:The purpose of this study is to evaluate the use of density measurements in the diagnosis of an underlying residual tumor beyond iodine depositions after Lipiodol-based conventional transarterial chemoembolization (cTACE). METHOD AND MATERIALS:Thirty follow-up CT scans of 20 patients 6-12 weeks after Lipiodol-based cTACE, receiving a digital subtraction angiography at the same time, were analyzed. Reference for the detection of a residual tumor was the angiography, and a visible contrast enhancement was categorized as a residual tumor (n = 16 with residual tumor; n = 14 without residual tumor). The density of the iodine depositions was measured in all containing slices in non-contrast-, arterial- and portal venous-phase CT scans, with a slice thickness of 5.00 mm. The mean density of the iodine deposition during the portal venous phase was subtracted from the mean density of the arterial phase to calculate the density changes (a positive enhancement score represents washout in the portal venous phase). In addition, a quotient relating to the non-contrast measurement was evaluated. RESULTS:Patients with a residual tumor displayed significantly higher enhancement scores in favor of density reduction between the arterial and portal venous phases, compared to patients without a residual tumor (1.41 ± 3.59, n = 14 vs. -13.97 ± 2.88, n = 16; p-value < 0.01). Furthermore, 87.75% of patients with an enhancement score higher than -1.00 (n = 9) had a residual tumor, whereas 100.00% of patients with an enhancement score lower than -20.00 (n = 6) were shown to be tumor-free. The enhancement score quotient resulted in similar findings. CONCLUSION:After cTACE in patients with hepatocellular carcinoma (HCC), the presence of a viable tumor correlated with enhancement scores based on the density measurements of iodine depositions in different phases of the CT scan. Low enhancement scores were associated with completely treated tumors and can aid the decision process to avoid possibly unnecessary angiographies.

Project description:ImportanceDefining early reliable surrogate end points for survival in patients with hepatocellular carcinoma (HCC) after conventional transarterial chemoembolization (cTACE) is of great value.ObjectiveTo evaluate the association between sustained response duration (SRD) and overall survival (OS) after cTACE for intermediate HCC.Design, setting, and participantsThis multicenter cohort study enrolled 2403 consecutive patients in China with naive intermediate HCC between June 1, 2000, and December 31, 2008, as the primary cohort, and 331 consecutive patients with intermediate naive HCC between January 1, 2011, to June 30, 2012, as the validation cohort. All patients received cTACE as an initial treatment. Initial response and best response were defined as the radiological response after first cTACE or best radiological response after 2 or more sessions of cTACE, respectively. Responders were those who experienced complete response or partial response. Sustained response duration was defined as the time between the date when complete response, partial response, or stable disease was achieved and the date progressive disease occurred after cTACE. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors. Information about patients in the study was collected from January 1, 2018, to March 31, 2018, and analysis of these data was performed in April 2018.Main outcomes and measuresOverall survival.ResultsA total of 2734 total patients (2499 of 2734 [91.4%] male; median [range] age, 56.5 [18-75] years) were included in the analysis. In the primary cohort, SRD of 6 months or more was found to have the strongest association with 5-year OS after cTACE among different durations of sustained response. Patients with SRD of 6 months or more (387 of 430 male; median [range] age, 57 [18-75] years) had the longest median (range) OS (67.7 [64.8-72.1] months), followed by initial responders (760 of 874 male; median [range] age, 56 [18-75] years; median [range] OS, 55.8 [55.0-57.7] months) and best responders (939 of 1032 male; median [range] age, 57 [18-75] years; median [range] OS, 53.2 [52.2-54.6] months). Response duration of 6 months or more was found to be an independent prognostic factor for OS (hazard ratio, 0.145; 95% CI, 0.124-0.170; P < .001). The significance of SRD as a factor associated with OS was confirmed in the validation cohort.Conclusions and relevanceSustained response duration of 6 months or more was associated with OS and may serve as an early surrogate end point after cTACE for intermediate HCC.

Project description:AimsThe purpose of the present study was to compare the efficacies of transarterial chemoembolization (TACE) combined with sorafenib versus TACE monotherapy for treating patients with advanced hepatocellular carcinoma (HCC).MethodsWe enrolled 321 patients and selected 280 with advanced HCC (Barcelona Clinic Liver Cancer stage C) who underwent TACE therapy between February 2009 and February 2013. TACE alone (monotherapy group) was administered to 198 patients (70.7%), and the remaining 82 (29.3%) underwent repeat combined TACE and sorafenib therapy (combined group). To minimize selection bias, these latter 82 patients were matched using propensity-score matching at a 1∶2 ratio with 164 patients who received TACE monotherapy. The primary endpoints were overall survival (OS) and related subgroup analysis. The secondary endpoints were time to progression (TTP) and treatment-related adverse events.ResultsOf the respective patients in the combined and monotherapy groups, 64.6% and 49.2% had vascular invasion, 87.8% and 91.1% had extrahepatic metastasis, and 54.3% and 47.1% had both. In the propensity-score-matched cohort, the OS survival of the combined group was significantly higher compared with the monotherapy group (7.0 months vs. 4.9 months, respectively, P = 0.003). The TTP was significantly longer in the combined group (2.6 months vs. 1.9 months, respectively, P = 0.001). Subgroup analysis showed that the outcomes of patients with advanced HCC without main portal vein invasion who were treated with combined therapy were significantly better compared with those who received monotherapy (P<0.05). Univariate and subsequent multivariate analyses revealed that the addition of sorafenib was an independent predictor of favorable OS and TTP (adjusted hazard ratios, 0.63 and 0.62, respectively; P<0.05 for both).ConclusionSorafenib plus TACE was more effective than TACE monotherapy for treating patients with advanced HCC without main portal vein invasion. Future trials with larger samples are required to validate these preliminary findings.

Dataset Information

Automated feature quantification of Lipiodol as imaging biomarker to predict therapeutic efficacy of conventional transarterial chemoembolization of liver cancer.

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Automated feature quantification of Lipiodol as imaging biomarker to predict therapeutic efficacy of conventional transarterial chemoembolization of liver cancer.

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