Hepatobiliary PET with [68Ga]Ga-BP-IDA – preclinical evaluation and its translational potential for liver function monitoring

439 Background: TARE is available in several countries for the treatment of hepatic malignancies, including unresectable HCC. Liver function deterioration in pts treated with TARE has been reported in real-world practice but less is known about incidence at a national US level. To better understand the prevalence of liver function deterioration after TARE, a retrospective analysis was performed using a database of US HCC pts. Methods: HCC pts treated with index TARE between Jan 1, 2010 and Dec 31, 2015 were identified in Optum’s integrated database using standard codes. Eligible pts had at least one laboratory (lab) value at baseline ( < 30 days before TARE), acute period ( < 30 days post TARE), and chronic period (90–180 days post TARE) and did not undergo additional/repeat HCC treatment before any further lab test in the chronic period. Due to lack of universally accepted criteria for liver function deterioration, clinically meaningful lab parameter changes were predefined by experts (Table). Changes in liver function from baseline were assessed in the acute and chronic periods. Results: Of 790 Optum TARE pts, 78 (10%) were eligible. Majority of pts were excluded due to lack of lab data and due to additional HCC treatments prior to lab tests in the chronic period. 50 (64%) were male and median age was 66 yrs. At baseline, 20 pts (26%) had extrahepatic spread (EHS). The incidence of liver function deterioration varied by parameter (Table). Albumin was the parameter most likely to be changed in both the acute and chronic periods. Conclusions: Although anti-tumor effects are thought to be optimized about 3 months after TARE, this retrospective, post-hoc, real-world analysis demonstrated decreased liver function 90–180 days after TARE. TARE, a liver-directed therapy, was used in some pts with EHS. Limitations include missing data, small sample size, and difficulty establishing causation. These results suggest that chronic liver function deterioration 90–180 days after TARE may be observed in some HCC pts. [Table: see text]

Background and Aims: For hepatocellular carcinoma (HCC) with vascular invasion, systemic treatment is recommended but transarterial radioembolization (TARE) is often used in clinical practice. The aim of this study was to investigate the current usage of TARE vs. systemic therapy as a first-line treatment for HCC with vascular invasion in the United States (US). Method: We performed a retrospective cohort study using the National Cancer Database (NCDB), which represents more than 70 percent of newly diagnosed cancer cases nationwide. All HCC patients diagnosed between 2010 and 2015 with the tumor stage of T3BN0M0 according to the 7th edition of the American Joint Committee on Cancer TNM staging system (tumor involving a major branch of a large vein of the liver without lymph nodes or extrahepatic metastasis) and received TARE or systemic treatment as a first-line treatment were included. Multivariable logistic regression was used to estimate factors associated with the utilization of TARE vs. systemic therapy. Results: A total of 1979 patients who received systemic treatment and 524 patients who received TARE were included. The proportion of patients receiving TARE increased from 15.7% in 2010 to 31.4% in 2015 (P<0.01). The median tumor size of the largest lesion was comparable (7.0cm for TARE vs. 7.1 cm for systemic treatment, P=0.43). Factors independently associated with increased likelihood of receiving TARE over systemic treatment were: advanced age (Odds Ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01 - 1.03, p=0.005), insurance status: private (OR: 3.06, 95% CI: 1.61 - 5.65, p<0.001), Medicaid/Medicare (OR: 2.91, 95% CI: 1.52 - 5.31, p<0.001), others (OR: 4.85, 95% CI: 1.90 - 11.62, p<0.001) vs. no insurance, and receiving care in the Midwest vs. Northeast region of the US (OR: 1.89, 95% CI: 1.38 - 2.53, p<0.001). Patients were significantly less likely to receive TARE if receiving treatment at community cancer program (OR: 0.24, 95% CI: 0.098 - 0.49, p<0.001) or comprehensive community cancer program (OR: 0.62, 95% CI: 0.48 - 0.82, p<0.001) vs. academic cancer program. Larger tumor size (OR per 1cm: 0.97, 95% CI: 0.95 - 1.00, p=0.03) and higher Charlson comorbidity index of ≥3 vs. 0 (OR: 0.53, 95% CI: 0.38 - 0.73, p<0.001) were inversely associated with receiving TARE. Recent HCC diagnosis year was associated with an increased likelihood of receiving TARE (OR: 1.23, 95% CI:1.16 - 1.32, p<0.001). Conclusion: The proportion of patients receiving TARE as a first-line treatment for HCC with macrovascular invasion has been increasing in the US. Age, comorbidities, insurance status, tumor size, and the type and location of cancer centers are associated with the usage of TARE vs. systemic treatment in HCC patients with vascular invasion. Citation Format: Joseph C. Ahn, Michael Luu, Walid Ayoub, Alexander Kuo, Andrew Hendifar, Jun Gong, Kambiz Kosari, Shelly Lu, Nicholas Nissen, Ju Dong Yang. Transarterial radioembolization versus systemic treatment for the management of hepatocellular carcinoma with vascular invasion: Analysis of the US National Cancer Database [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2350.

e16275 Background: The optimal sequencing of available locoregional therapies and systemic treatments for patients with hepatocellular carcinoma (HCC) remains uncertain. This study compared the impact of transarterial radioembolization (TARE) as a first-line (FL) versus second-line or subsequent-line (SL) treatment and examined the role of immune checkpoint inhibitors (ICIs) within these treatment sequences. Methods: A single center retrospective review was conducted evaluating patients with HCC receiving at least one TARE treatment between 1/2015 and 8/2022. Patient clinical and pathological characteristics were elucidated. The Kaplan–Meier method was used to estimate overall survival (OS; from diagnosis to death or loss to follow-up) and TARE-specific OS (OS-TARE; from TARE procedure to death or loss to follow-up). Results: In this cohort of 141 patients, the median age was 65 (range: 49-88); they were predominantly Caucasian (80%), male (80%), and Child-Pugh class A (75%). Fifty-nine patients (42%) had FL TARE and only 39 (28%) had ICI at some point (five before TARE). Baseline characteristics such as age, tumor characteristics, liver function, and prior therapy were comparable between FL and SL groups, except for a higher incidence of portal vein tumor thrombosis (PVTT) in the FL group (49% vs. 6%, p < 0.01) and lower rates of hepatic encephalopathy (19% vs. 37%, p = 0.02). Survival analysis is summarized below. While FL TARE showed improved OS-TARE compared to SL, the OS appeared numerically longer in the SL group (not significant). The addition of ICI in patients after TARE in FL improved survival while only OS-TARE improved in the SL group. Conclusions: Early use of TARE (FL) may provide survival benefits directly related to the procedure (OS-TARE), but overall outcomes are influenced by disease burden including the presence of PVTT. The addition of ICIs is associated with improved survival outcomes (both OS and OS-TARE), emphasizing their role as a critical component in the treatment strategy for HCC. Optimizing the sequencing of TARE and ICIs appears to play an essential role in improving outcomes, and future randomized controlled trials should further investigate this element of the HCC treatment paradigm. Survival analysis of patients with HCC managed with TARE with or without ICI. Survival FL vs. SL (p) ICI not received vs. received, (p) FL sub-group SL sub-group OS* 558 vs. 901(0.06) 401 vs. 1,102 (0.01) 887 vs. 1,080 (0.2) OS-TARE* 502 vs. 239 (0.024) 353 vs. 1,028 (0.02) 202 vs. 627 (0.001) *in days.

Simple Summary166Ho-based transarterial radioembolization (TARE) procedures for liver cancer treatment can be safely applied in a hospital setting. It has been shown that a fraction of the injected radioactivity is excreted. Knowledge of the amount and nature of these excretions is vital for dosimetry, radiation protection, record keeping, and compliance with national and international regulations regarding waste disposal. Radioprotection measures should be taken, with particular attention to the urine of patients after treatment procedures. Regulations regarding radioactive waste must be considered.After transarterial radioembolization (TARE) with microspheres loaded with holmium-166, radioactivity is excreted from the body. The aim of this study was to evaluate radioactive renal and intestinal excretions after TARE planning and treatment procedures with holmium-166-loaded microspheres and to correlate the findings with the intratherapeutic effective half-life. Urinary and intestinal excretions of patients who underwent TARE procedures were collected during postinterventional intervals of 24 h (TARE planning) and 48 h (TARE treatment). Whole-body effective half-life measurements were performed. Calibrations of the 166Ho measuring system showed evidence of long-living nuclides. For excretion determination, 22 TARE planning procedures and 29 TARE treatment procedures were evaluated. Mean/maximum total excretion proportions of the injected 166Ho were 0.0038%/0.0096% for TARE planning procedures and 0.0061%/0.0184% for TARE treatment procedures. The mean renal fractions of all measured excretions were 97.1% and 98.1%, respectively. Weak correlations were apparent between the injected and excreted activities (R2 planning/treatment: 0.11/0.32). Mean effective 166Ho half-lives of 24.03 h (planning) and 25.62 h (treatment) confirmed low excretions. Radioactive waste disposal regulations of selected jurisdictions can be met but must be reviewed before implementing this method into clinical practice. Inherent long-living nuclide impurities should be considered.

Transarterial radioembolization (TARE) is a relatively new treatment optionavailable for unresectable hepatocellular carcinoma (HCC). TARE therapy involves the delivery of radiation directly to the tumor to cause tumor necrosis. Yttrium-90 (Y90) is commonly used as a source of radioembolization in TARE. TARE is very well tolerated and has a low rate of complications. Main complications of TARE for HCC include postembolization syndrome and radiation-induced injury to nearby organs such as the liver, gallbladder, and stomach, causing hepatitis, cholecystitis, or gastric ulceration. A side effect not previously described in TARE literature is portal venous gas after TARE therapy. We present the first ever reported case of portal and variceal venous gas in a 77-year-old male patient who had unresectable HCC and had previously failed chemotherapy. He underwent Y90 TARE for HCC. Following TARE, he presented with right upper quadrant abdominal pain, and imaging showed portal and variceal venous gas. He was treated with antibiotics, with resolution of symptoms and improvement in portal and variceal venous gas on repeat imaging.

Hepatocellular Carcinoma Radiation Therapy: Review of Evidence and Future Opportunities

The purpose of our study was to evaluate the reproducibility of Modified Response Evaluation Criteria in Solid Tumors (mRECIST) in hepatocellular carcinoma (HCC) lesions undergoing transarterial radioembolization (TARE) therapy and to determine whether mRECIST reproducibility is affected by the enhancement pattern of HCC. One hundred and three HCC lesions from 103 patients treated with TARE were evaluated. The single longest diameter of viable tumor tissue was measured by two radiologists at baseline; response to therapy was evaluated according to mRECIST. The enhancement pattern of HCC lesions was correlated with their mRECIST response. The response rate between mRECIST and RECIST 1.1 was compared. Wilcoxon signed-rank test, paired t test, Lin's concordance correlation coefficient (ρc ), Bland-Altman plot, kappa statistics, and Fisher's exact test were used to assess intra- and interobserver reproducibilities and to compare response rates. There were better intra- than interobserver agreements in the measurement of single longest diameter of viable tumor tissue (bias = 0 cm intraobserver versus bias = 0.3 cm interobserver). For mRECIST, good intraobserver (ĸ = 0.70) and moderate interobserver (ĸ = 0.56) agreements were noted. The mRECIST response for HCC lesions with homogeneous enhancement at both baseline and follow-up imaging showed better intra- and interobserver agreements (ĸ = 0.77 and 0.60, respectively) than lesions with heterogeneous enhancement at both scans (ĸ = 0.54 and 0.40, respectively). In the early follow-up period mRECIST showed a significantly higher response rate than RECIST (40.8% versus 3.9%; P = 0.025). In HCC patients treated with TARE, mRECIST captures a significantly higher response rate compared with RECIST; it also demonstrates acceptable intra- and interobserver reproducibilities for HCC lesions treated with TARE, and mRECIST reproducibility may be lower for HCC lesions with heterogeneous distribution of the viable tumor tissue.

Outcomes of Transarterial Hepatic Embolization versus Yttrium-90 Radioembolization for Treatment of Patients with Hepatocellular Carcinoma >7 cm.

Patients with hepatocellular carcinoma (HCC) of intermediate stage (BCLC-B according to the Barcelona Clinic Liver Cancer classification) are a heterogeneous group with different degrees of liver function impairment and tumour burden. The recommended treatment is transarterial chemoembolization (TACE). However, patients in this group may be judged as poor candidates for TACE because the risk-benefit ratio is low. Such patients may receive transarterial radioembolization (TARE) only by entering a clinical trial. Experts have proposed that the stage could be further divided into four substages based on available evidence of treatment benefit. We report here, for the first time, the outcome in patients with BCLC-B2 substage HCC treated with TARE. A retrospective analysis of the survival of 126 patients with BCLC-B2 substage HCC treated with TARE in three European hospitals was performed. Overall median survival in patients with BCLC-B2 substage was not significantly different in relation to tumour characteristics; 19.35months (95% CI 8.27-30.42months) in patients with a single large (>7cm) HCC, and 18.43months (95% CI 15.08-21.77months) in patients with multinodular HCC (p = 0.27). However, there was a higher proportion of long-term survivors at 36months among those with a single large tumour (29%) than among those with multiple tumours (16.8%). Given the poor efficacy of TACE in treating patients with BCLC-B2 substage HCC, TARE treatment could be a better choice, especially in those with a large tumour.

Is Radioembolization Ready for the Barcelona Clinic Liver Cancer Staging System?

BackgroundUsing data collected in the prospective observational study CIRSE Registry for SIR-Spheres Therapy, the present study aimed at identifying predictors of adverse events (AEs) following transarterial radioembolization (TARE) with Yttrium-90 resin microspheres for liver tumours.MethodsWe analysed 1027 patients enrolled between January 2015 and December 2017 and followed up for 24 months. Four hundred and twenty-two patients with hepatocellular carcinoma (HCC), 120 with intrahepatic carcinoma (ICC), 237 with colorectal liver metastases and 248 with liver metastases from other primaries were included. Prognostic factors were calculated with a univariable analysis by using the overall AEs burden score (AEBS).ResultsAll-cause AEs were reported in 401/1027 (39.1%) patients, with AEs associated with TARE, such as abdominal pain (16.6%), fatigue (17%), and nausea (11.7%) reported most frequently. Grade 3 or higher AEs were reported in 92/1027 (9%) patients. Reports on grade ≥ 3 gastrointestinal ulcerations (0.4%), gastritis (0.3%), radiation cholecystitis (0.2%) or radioembolization-induced liver disease (0.5%) were uncommon. Univariable analysis showed that in HCC, AEBS increased for Eastern Cooperative Oncology Group (ECOG) 0 (p = 0.0045), 1 tumour nodule (0.0081), > 1 TARE treatment (p = 0.0224), no prophylactic embolization (p = 0.0211), partition model dosimetry (p = 0.0007) and unilobar treatment target (0.0032). For ICC, > 1 TARE treatment was associated with an increase in AEBS (p = 0.0224), and for colorectal liver metastases, ECOG 0 (p = 0.0188), > 2 prior systemic treatments (p = 0.0127), and 1 tumour nodule (p = 0.0155) were associated with an increased AEBS.ConclusionOur study confirms that TARE is a safe treatment with low toxicity and a minimal impact on quality of life.

Clinical studies conducted in different geographic regions using different methods to compare transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) have demonstrated discordant results. Meta-analyses in this field indicate comparable overall survival (OS) with TACE and TARE, while reporting a longer time to progression and a higher downstaging effect with TARE treatment. In terms of isolated procedure costs, treatment with TARE is 2 to 3 times more, and in some countries even more, expensive than TACE. However, relevant literature indicates that TARE is more advantageous compared to TACE regarding the need for repeat procedures, costs of complication management, total hospital stay and quality of life. Heterogeneity of hepatocellular carcinoma (HCC) patients as well as the shortcomings of clinical classifications, randomized clinical trials and cost-effectiveness studies make it difficult to choose between treatment alternatives in this field. As in other countries, these challenges lead to differences in treatment choice across different centers in Turkey. The present expert panel used two round modified Delphi method to investigate the resources and clinical parameters referenced while selecting patients for drug-eluting beads (DEB)-TACE and TARE treatment modalities in Turkish clinical practice. The cost-effectiveness parameters and comparisons of these treatments have also been evaluated at a prediction level. The panelists stated that they most commonly use the BCLC staging system for the management of HCC patients in Turkey. However, they did not find any of the staging systems or treatment guidelines sufficient enough for their clinical practice in terms of covering the down-staging intent of treatments. Since living donor transplant preference is higher in Turkey than the rest of the Western countries, down-staging treatments are thought to be more prioritized in Turkey than that in other Western countries. The panelists reached a consensus that TARE may provide improved OS and reduce the number of repeat procedures compared to DEB-TACE in intermediate-stage patients with a single tumor spanning a diameter above 5 cm who experience recurrence after previous treatment with TACE and most TACE-naïve patient groups in intermediate stage. Based on the consensus on OS and the number of procedures, the panelists assumed that TARE would be more cost-effective than DEB-TACE in most groups of TACE-naïve patients in intermediate stage and in those with a single tumor spanning a diameter above 5 cm. It was also stated that the predicted cost-effectiveness advantage of TARE could be more pronounced in patients with a tumor diameter greater than 7 cm.

Treatment for Hepatocellular Carcinoma in South Asia

Real-World Data for the Evaluation of Transarterial Radioembolization versus Sorafenib in Hepatocellular Carcinoma: A Cost-Effectiveness Analysis.

Studies have shown intra-arterial therapies to be effective in controlling neuroendocrine liver metastases (NELMs), but the evidence supporting the selection of specific methods is limited. This meta-analysis is the first to compare survival outcomes between transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) in the treatment of NELM. A systematic search according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in PubMed and Embase databases was conducted in February 2020 for published studies comparing survival outcomes between TACE and TARE in the treatment of NELM. Six eligible cohort studies with a total of 643 patients were identified. The TACE and TARE groups were similar in terms of age, sex, hepatic tumor burden, tumor grade, and Eastern Cooperative Oncology Group (ECOG) score. The patients treated with TACE had significantly better overall survival (odds ratio [OR], 1.92; 95% confidence interval [CI] 1.14-3.22, p=0.014) than those treated with TARE. Overall survival ranged from 16.8 to 81.9 months with TACE and from 14.5 to 66.8months with TARE. No significant differences in hepatic progression-free survival (OR, 1.01; 95% CI 0.75-1.35; p=0.96) or tumor response were observed within the first 3 months (OR, 2.87; 95% CI 0.81-10.21; p=0.10) or thereafter (OR, 0.98; 95% CI 0.12-7.86; p=0.99). The complication rates were similar between the two groups, with 6.9% of the TACE patients versus 8.5% of TARE patients reporting major complications (OR, 1.16; 95% CI 0.54-2.48; p=0.71) and respectively 44.6% and 58.8% of the TACE and TARE patients reporting minor adverse events (OR, 1.08; 95% CI 0.39-2.99; p=0.88). Despite similar tumor responses, an overall survival benefit was associated with TACE treatment of NELM compared with TARE treatment. Randomized controlled trials are warranted to confirm this finding and clarify whether certain subpopulations benefit from different transarterial methods.