Effect of transarterial chemoembolization prior to selective internal radiation therapy on yttrium-90 microsphere delivery in hepatocellular carcinoma patients.

Purpose:Selective‐internal‐radiation‐therapy (SIRT) and transarterial‐chemoembolization (TACE) are commonly used for treatment of liver tumors. The use of TACE, which is macroembolic, prior to SIRT may cause hemodynamic changes in tumor vasculature that impair yttrium‐90 (90Y) microsphere delivery to the targeted lesions. This work aims to quantify dosimetric tumor coverage using 90Y positron emission tomography (PET) dosimetry after SIRT alone compared to TACE followed by SIRT.Methods:A total of 40 consecutive hepatocellular carcinoma (HCC) SIRT patients who had a post‐SIRT 90Y PET/CT scan were evaluated. The patient‐specific‐3D‐dose was reconstructed from the PET images. Patients were categorized into two groups: patients received TACE prior SIRT procedure (n=18) and patient received SIRT alone (n=22). The lesions and liver were delineated by a senior radiologist. We evaluated both the lesion‐specific dose‐volume‐histogram (DVH) and the selectivity index (SI) defined as the ratio of the average dose inside the total lesion(s) and the average dose of the normal liver. The SI values of patients were compared based on whether TACE was previously used.Results:A wide spectrum was observed in the lesion‐specific DVH‐evaluation and SI appeared to be suitable of evaluating the quality of each SIRT infusion. The average SI of the entire patient group was 3.0, i.e. targeted lesion receiving three times higher dose than normal liver. The average SI was 1.8 for patients who had prior TACE and 3.9 for patients who did not have prior TACE (p=0.008). 85% of the patients with prior TACE demonstrated poor 90Y‐microsphere delivery (SI <2) while none demonstrated excellent delivery (SI >4). On the other hand, the incidence SI >4 among patients with no prior TACE was 37%.Conclusion:3D dose evaluation using post‐SIRT PET suggests that 90Y microsphere delivery to liver tumors is impaired among patients who received prior TACE compared to those who receive SIRT alone.

Transarterial Radioembolization for Hepatocellular Carcinoma: Who, When… and Y(90)?

The emerging questionable benefit of sorafenib as a neo-adjuvant in HCC patients treated with Y-90 radioembolization pending liver transplantation

Beneficio sobre la supervivencia con las técnicas intraarteriales en el carcinoma hepatocelular

9066 Background: The liver is the first site of metastasis in >80% of patients with UM. Transarterial chemoembolization (TACE) has been used to control hepatic metastases, however, patients eventually progress through or experience complications related to TACE. We report our results using SIRT as salvage therapy for patients with UM liver metastases who are no longer candidates for TACE. Methods: Patients with UM liver metastases previously treated with TACE were treated with SIRT. Patients were followed 1-month post-SIRT for acute toxicity then every 3 months for tumor response evaluation and for complications of delayed toxicity. Common Toxicity Criteria 3.0 (CTC) was used for toxicity assessment. Best radiographic tumor response was determined by MRI using RECIST criteria. Results: Five men and 7 women, ages 48–81 (median 65) with UM liver metastases were treated with SIRT after tumor progression post-TACE (n=9), complications of TACE (n=1) or patient preference (n=2). Pretreatment whole liver tumor burdens were as follows: <25% (n=10), 25–50% (n=1) and >50% (n=1). Patients had both hepatic lobes treated on separate occasions (n=7), one lobe (n=3) or whole liver (n=2) therapy. Treatment dose per patient was reduced by 25% due to prior TACE procedures. The mean total SIRT dose delivered was 1.0 GBq (0.62–1.47 GBq). Five patients had an increase in hepatic enzymes (Grade 1–4) at 1-month follow-up. No procedure related deaths or serious adverse events were experienced. Best tumor response was as follows: CR (n=0), PR (n=0), SD (n=8), PD (n=4), with a median follow-up of 7.8 months (1.0–16.0). The median time to liver progression was 7.0 months (1.0- 15.5). Nine of the 12 patients, including 2 patients with >25% pretreatment tumor burden, died due to progression of liver disease (n=6), extrahepatic disease (n=1) or both (n=2). Post-SIRT, median overall patient survival was 10.8 months (1.0–19.0). Three patients (ECOG 0 performance status) are still alive at 13.5–19.0 months (median 16.2 months) following SIRT. Conclusions: SIRT was safely used and showed a potential clinical benefit for patients previously treated with TACE. Further investigation is warranted to determine if SIRT should be employed as a first line therapy for patients with UM liver metastases. No significant financial relationships to disclose.

Evaluation of comparative effectiveness and cost–effectiveness is an essential component in the integration of new technologies into medical management, with data from prospective clinical trials (e.g., health-related quality of life using validated tools) being mandated by most health authorities. Health economics has its own vocabulary and so a glossary of terms is provided in Table 1 for the uninitiated. One of the key issues in assessing the comparative costs and cost–effectiveness of locoregional therapies for primary and secondary cancers in the liver is the limited number prospective trials. Health economic models, however, are valuable tools for overcoming such limitations that bring together information from different sources in order to assess the expected costs and outcomes. Such information is essential for healthcare reimbursement agencies and payers at national, regional and local levels when making funding decisions in order to ensure that the allocation of limited resources is optimized. Selective internal radiation therapy versus conventional transarterial chemoembolization One of the most detailed studies comparing the cost–effectiveness of selective internal radiation therapy (SIRT) versus conventional transarterial chemoembolization (TACE) was conducted by a group from Cleveland (OH, USA) in patients with unresectable hepatocellular carcinoma (HCC) [1]. This study recorded significantly greater costs associated with conventional TACE than SIRT, largely due the greater number of mean hospital days for the initial procedure (3.5 ± 0.7 vs 0.5 ± 0.2; p < 0.001) and for readmissions (7.9 ± 1.7 vs 3.6 ± 0.6; p = 0.03) with TACE. While the rates of postembolization syndrome were similar between the procedures in this study, the severity of postembolization syndrome was significantly worse with TACE, as would be expected from a purely embolic approach, and required additional hospitalization and treatment in a significantly greater number of patients compared with SIRT (p = 0 .02) [1]. Otherwise, there were no significant differences between the groups in major or minor complication rates (p = 0.58) or 30-day mortality (p = 0.07) [1]. Subsequently, a systematic review of the literature examining the comparative safety and effectiveness of SIRT and conventional TACE for the treatment of HCC concluded that the two procedures had a similar efficacy (defined by tumor response and patient survival), with significantly longer time to progression and lower toxicity with SIRT [2]. Compared with SIRT, the meta-analysis found that conventional TACE was associated with a statistically greater overall toxicity, as well as a higher rate of abdominal pain and hepatic transaminase elevation postprocedure. Numerous studies have also consistently observed a significantly shorter postprocedure hospital stay with SIRT compared with conventional TACE [2]. Although conventional TACE costs less in the majority of cases, SIRT was less expensive in 33.4% of cost analysis simulations that compared the two procedures [2].

Streamlining TARE or personalizing SIRT? Different philosophies to treat different HCCs with Yttrium-90…

BackgroundImmunotherapy represents a promising option for treatment of hepatocellular carcinoma (HCC) in cirrhotic patients but its efficacy is currently inconsistent and unpredictable. Locoregional therapies inducing immunogenic cell death, such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT), have the potential to act synergistically with immunotherapy. For the development of new approaches combining locoregional treatments with immunotherapy, a better understanding of the respective effects of TACE and SIRT on recruitment and activation of immune cells in HCC is needed. To address this question, we compared intra-tumor immune infiltrates in resected HCC after preoperative treatment with TACE or SIRT.MethodsData fromr patients undergoing partial hepatectomy for HCC, without preoperative treatment (SURG, n = 32), after preoperative TACE (TACE, n = 16), or preoperative SIRT (n = 12) were analyzed. Clinicopathological factors, tumor-infiltrating lymphocytes (TILs), CD4+ and CD8+ T cells, and granzyme B (GZB) expression in resected HCC, and postoperative overall and progression-free survival were compared between the three groups.ResultsClinicopathological and surgical characteristics were similar in the three groups. A significant increase in TILs, CD4+ and CD8+ T cells, and GZB expression was observed in resected HCC in SIRT as compared to TACE and SURG groups. No difference in immune infiltrates was observed between TACE and SURG patients. Within the SIRT group, the dose of irradiation affected the type of immune infiltrate. A significantly higher ratio of CD3+ cells was observed in the peri-tumoral area in patients receiving < 100 Gy, whereas a higher ratio of intra-tumoral CD4+ cells was observed in patients receiving > 100 Gy. Postoperative outcomes were similar in all groups. Irrespective of the preoperative treatment, the type and extent of immune infiltrates did not influence postoperative survival.ConclusionsSIRT significantly promotes recruitment/activation of intra-tumor effector-type immune cells compared to TACE or no preoperative treatment. These results suggest that SIRT is a better candidate than TACE to be combined with immunotherapy for treatment of HCC. Evaluation of the optimal doses for SIRT for producing an immunogenic effect and the type of immunotherapy to be used require further evaluation in prospective studies.

To compare selective internal radiation therapy (SIRT) with transarterial chemoembolization (TACE), the standard-of-care for intermediate-stage unresectable, hepatocellular carcinoma (HCC), as first-line treatment. SIRTACE was an open-label multicenter randomized-controlled pilot study, which prospectively compared primarily safety and health-related quality of life (HRQoL) changes following TACE and SIRT. Patients with unresectable HCC, Child-Pugh ≤B7, ECOG performance status ≤2 and ≤5 liver lesions (≤20cm total maximum diameter) without extrahepatic spread were randomized to receive either TACE (at 6-weekly intervals until tumour enhancement was not observed on MRI or disease progression) or single-session SIRT (yttrium-90 resin microspheres). Twenty-eight patients with BCLC stage A (32.1%), B (46.4%) or C (21.4%) received either a mean of 3.4 (median 2) TACE interventions (N=15) or single SIRT (N=13). Both treatments were well tolerated. Despite SIRT patients having significantly worse physical functioning at baseline, at week-12, neither treatment had a significantly different impact on HRQoL as measured by Functional Assessment of Cancer Therapy-Hepatobiliary total or its subscales. Both TACE and SIRT were effective for the local control of liver tumours. Best overall response-rate (RECIST 1.0) of target lesions were 13.3% and 30.8%, disease control rates were 73.3% and 76.9% for TACE and SIRT, respectively. Two patients in each group were down-staged for liver transplantation (N=3) or radiofrequency ablation (N=1). Single-session SIRT appeared to be as safe and had a similar impact on HRQoL as multiple sessions of TACE, suggesting that SIRT might be an alternative option for patients eligible for TACE.

Liver function after combined selective internal radiation therapy or sorafenib monotherapy in advanced hepatocellular carcinoma

A retrospective analysis of selective internal radiation therapy (SIRT) with yttrium-90 microspheres in patients with unresectable hepatic malignancies

Intra arterial treatment of hepatocellular carcinoma: Comparison of MELD score variations between radio-embolization and chemo-embolization

Hepatocellular carcinoma (HCC) is one of the most common neoplasms worldwide and the third most common cause of cancer-related death. Several liver-targeted intra-arterial therapies are available for unresectable HCC, including selective internal radiation therapy (SIRT) and trans-arterial chemoembolization (TACE). Those two are the most used treatment modalities in localized non-operable HCC. TACE is the treatment option for patients with stage B, according to the BCLC staging system. In contrast, SIRT does not have an official role in the treatment algorithm, but recent studies showed promising outcomes in patients treated with SIRT. Although TACE is globally a safe procedure, it might provoke several vascular complications such as spasms, inflammatory constriction, and, in severe cases, occlusion, dissection, or collateralization. Hence, it is acclaimed that those complications could restrain the targeted response of the radio-embolization when we use it as second-line therapy post TACE. In this study, we will assess the efficacity of SIRT using Yttrium 90 Microspheres post incomplete or failure response to TACE. In our retrospective study, we had 23 patients who met the inclusion criteria. Furthermore, those patients have been followed radiologically and biologically. Then, we evaluated the therapeutic effect according to the mRECIST criteria, in addition to the personalized dose analysis. We found 8 patients were treated with TheraSphere®, with a median tumor absorbed dose of 445 Gy, while 15 received SIR-Spheres® treatment with a mean tumor dose of 268 Gy. After radiological analysis, 56.5% of the patients had a complete response, and 17.3% showed partial response, whereas 13% had stable disease and 13% had progressive disease. For patients treated with SIRT after an incomplete response or failure to TACE, we found an objective response rate of 73.8%. Despite the known vascular complications of TACE, SIRT can give a favorable response.

Most patients with hepatocellular carcinoma are diagnosed at intermediate or advanced stages (BCLC B or C) and undergo palliative local treatments such as transarterial chemoembolization or selective internal radiation therapy, also called radioembolization. In terms of liver function and tumor extent, stages BCLC B and C comprise a wide spectrum of tumor manifestations. Predictors of survival in these patients undergoing transarterial chemoembolization and selective internal radiation therapy might help stratification into different prognostic groups and help to select the optimal treatment modality. In this retrospective study, all patients with hepatocellular carcinoma who underwent transarterial chemoembolization between January 2010 and December 2014 and all hepatocellular carcinoma patients who underwent selective internal radiation therapy between August 2012 and December 2016 were recruited. The prognostic value of pretherapeutic clinical and laboratory parameters for the prediction of overall survival was analyzed using uni- and multi-variable Cox regression models. We enrolled 129 patients in the transarterial chemoembolization group and 34 patients in the selective internal radiation therapy group. The predictive value of the albumin-bilirubin grade was validated for both the transarterial chemoembolization and the selective internal radiation therapy group. Multivariable analysis identified albumin-bilirubin grade and tumor size as independent predictors for the transarterial chemoembolization group and tumor size, serum albumin and serum sodium as independent predictors for the selective internal radiation therapy group. While measures of liver dysfunction predicted survival similarly in both cohorts, we found tumor size to predict survival differently in transarterial chemoembolization- and selective internal radiation therapy-treated patients. Tumor size might help to select the most appropriate treatment in hepatocellular carcinoma patients, although this finding has to be validated in further studies.

546 Background: For advanced hepatocellular cancers (HCCs) and colorectal cancers (CRCs) with liver metastasis, the impact of selective internal radiation therapy(SIRT) with yttrium-90 on survival outcomes is not established. A meta-analysis of randomized clinical trials (RCT) was performed to determine the relative risk (RR) of hepatic and hematological toxicities with the use of SIRT, compared to therapies not including SIRT. For patients with advanced HCC or CRC, we assessed the RR of high grade (grades 3 and 4) hyperbilirubinemia, fatigue, leucopenia, thrombocytopenia and elevated liver enzymes (AST and ALT) with use of SIRT. Methods: Citations from PubMed/Medline, clinical trials.gov, package inserts, and abstracts from major conferences were reviewed to include RCTs comparing arms with or without SIRT. Potential publication bias was assessed using the Egger test for funnel plot asymmetry. There was no publication bias and the trials were of high quality per Jadad scoring. Patients in control arms received trans-arterial chemo-embolization (TACE) or sorafenib for HCC or FOLFOX for CRC. The proportion and 95% confidence intervals (CIs) for patients with adverse events were derived for each arm of each study and used to calculate the RR. For the meta-analysis, both the fixed-effects model and the random-effects model were considered; the method proposed by DerSimonian and Laird was used to estimate the random-effects model. Results: The RR of grade 3/4 leucopenia was consistently high across high with the use of SIRT across all the studies (RR 2.05, 95% CI (1.22-3.42), p-value 0.027). The risk of hepatic dysfunction and fatigue was higher with SIRT but not statistically significant. Conclusions: Since SIRT is associated with increased risk of high-grade leukopenia, caution is advised in selecting patients with HCC’s with underlying decompensated cirrhosis or with CRCs and on cytotoxic therapy. Proper selection of patients would reduce toxicities from SIRT alone or SIRT in combination with systemic chemotherapy.