Institutional decision to adopt Y90 as primary treatment for hepatocellular carcinoma informed by a 1,000-patient 15-year experience.

Yttrium-90 transarterial radioembolization (TARE) is a locoregional therapy (LRT) for hepatocellular carcinoma (HCC). In this study, we present overall survival (OS) outcomes in a 1,000-patient cohort acquired over a 15-year period. Between December 1, 2003 and March 31, 2017, 1,000 patients with HCC were treated with TARE as part of a prospective cohort study. A comprehensive review of toxicity and survival outcomes was performed. Outcomes were stratified by baseline Child-Pugh (CP) class, United Network for Organ Sharing (UNOS), and Barcelona Clinic Liver Cancer (BCLC) staging systems. Albumin and bilirubin laboratory toxicities were compared to baseline. OS outcomes were reported using censoring and intention-to-treat methodologies. All treatments were outpatient, with a median one treatment per patient. Five hundred six (51%) were CP A, 450 (45%) CP B, and 44 (4%) CP C. Two hundred sixty-three (26%) patients were BCLC A, 152 (15%) B, 541 (54%) C, and 44 (4%) D. Three hundred sixty-eight (37%) were UNOS T1/T2, 169 (17%) T3, 147 (15%) T4a, 223 (22%) T4b, and 93 (9%) N/M. In CP A patients, censored OS for BCLC A was 47.3 (confidence interval [CI], 39.5-80.3) months, BCLC B 25.0 (CI, 17.3-30.5) months, and BCLC C 15.0 (CI, 13.8-17.7) months. In CP B patients, censored OS for BCLC A was 27 (CI, 21-30.2) months, BCLC B 15.0 (CI, 12.3-19.0) months, and BCLC C 8.0 (CI, 6.8-9.5) months. Forty-nine (5%) and 110 (11%) patients developed grade 3/4 albumin and bilirubin toxicities, respectively. CONCLUSION: Based on our experience with 1,000 patients over 15 years, we have made a decision to adopt TARE as the first-line transarterial LRT for patients with HCC. Our decision was informed by prospective data and incrementally reported demonstrating outcomes stratified by BCLC, applied as either neoadjuvant or definitive treatment. (Hepatology 2017).

Comparative study of post-transplant outcomes in hepatocellular carcinoma patients treated with chemoembolization or radioembolization.

PURPOSE: To analyze long-term outcomes in patients bridged/downstaged to orthotopic liver transplantation (OLT) by transarterial chemoembolization (TACE) or yttrium-90 radioembolization (Y90) for hepatocellular carcinoma (HCC). METHODS: 172 HCC patients who underwent OLT after being treated with transarterial liver-directed therapies (LDTs) (Y90: 93; TACE: 79) were identified. Pre-LDT and pre-OLT clinical/imaging/laboratory characteristics including United Network for Organ Sharing (UNOS) staging and alpha-fetoprotein values (AFP) were tabulated. Post-OLT HCC recurrence was assessed by imaging follow-up per standard of care. Recurrence-free (RFS) and overall survival (OS) were calculated. Uni/multivariate and sub-stratification analyses were performed. RESULTS: Time-to-OLT was longer in the Y90 group (Y90: 6.5 months; TACE: 4.8 months; p=0.02). With a median post-OLT follow-up of 26.1 months (IQR: 11.1-49.7), tumor recurrence was found in 6/79 (8%) TACE and 8/93 (9%) Y90 patients. Time-to-recurrence was 26.6 (CI: 7.0-49.5) and 15.9 months (CI: 7.8-46.8) for TACE and Y90, respectively (p=0.48). RFS (Y90: 79 months; TACE: 77 months; p=0.84) and OS (Y90: 57% alive at 100 months; TACE: 84.2 months; p=0.57) were similar. 54/155 patients (Y90: 29; TACE: 25) were downstaged to UNOS T2 or less. RFS hazard ratios for patients downstaged to ≤T2 versus those that were not were 0.6 (CI: 0.33-1.1) and 1.7 (CI: 0.9-3.1) respectively (p=0.13). 17/155 patients (Y90: 8; TACE: 9) that were >T2 were downstaged to UNOS T2 or less (within transplant criteria). Distribution (unilobar/bilobar), AFP, and pre-transplant UNOS stage affected RFS on univariate analyses. CONCLUSION: Despite longer time-to-OLT for Y90 patients, post-OLT outcomes were similar between patients bridged or downstaged by TACE or Y90. A trend towards improved RFS for downstaged patients was identified.

Twelve-year experience of radioembolization for colorectal hepatic metastases in 214 patients: survival by era and chemotherapy.

PURPOSE: The aim of this study was to analyze the safety, treatment characteristics and survival outcomes of Yttrium-90 (Y90) radioembolization for unresectable colorectal carcinoma (CRC) liver metastases refractory to standard of care therapy. METHODS: A total of 214 patients with CRC metastases were treated with Y90 radioembolization over 12 years. Toxicity was assessed using National Cancer Institute common terminology criteria. Overall survival was analyzed from date of diagnosis of primary cancer, hepatic metastases and from the first Y90. Uni/multivariate analyses were performed. Substratification by era of chemotherapeutics was performed. RESULTS: Most patients were male (60 %) and <65 years old (61 %). Of them, 98 % had been exposed to chemotherapy. Grade 3 lymphocyte, bilirubin, albumin, ALP and AST toxicities were observed in 39 %, 11 %, 10 %, 8 % and 4 % of patients, respectively. Grade 4 lymphocyte and ALP toxicities were observed in 5 % and 3 % of patients, respectively. Median overall survival was 43.0, 34.6, and 10.6 months from date of diagnosis of primary cancer, hepatic metastases and first Y90, respectively. Survival was significantly longer in patients: (1) who received ≤2 cytotoxic drugs (n = 104) than those who received 3 (n = 110) (15.2 vs. 7.5 months, p = 0.0001); and (2) who received no biologic agents (n = 52) compared with those that did (n = 162) (18.6 vs. 9.4 months, p = 0.0001). Multivariate analyses identified ≤2 cytotoxic agents, no exposure to biologics, ECOG 0, tumor burden <25 %, lack of extrahepatic disease and albumin >3 g/dL as independent predictors of survival. CONCLUSION: In this largest metastatic CRC series published to date, Y90 radioembolization was found to be safe; survival varied by prior therapy. Further studies are required to further refine the role of Y90 in metastatic CRC.

Hepatic yttrium-90 radioembolization for metastatic melanoma: a single-center experience.

The aim of the study was to analyze the safety and efficacy of yttrium-90 ((90)Y) radioembolization in the treatment of unresectable hepatic melanoma metastases refractory to previous systemic/locoregional therapy. Between February 2004 and April 2010, 16 patients with hepatic melanoma metastases (ocular=7, skin=4, other sites=5) were treated with (90)Y radioembolization at a single center. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria, version 3.0. Response to therapy was assessed by size and necrosis criteria. Progression-free survival (hepatic) and overall survival were calculated using the Kaplan-Meier method. The median dose to the treatment site was 108.57 Gy. Grade 1 and 2 clinical toxicities included fatigue (44%), nausea (19%), and vomiting (12%). Grade 3 absolute lymphocyte toxicity and aspartate aminotransferase toxicity were noted in 2 (12%) and 1 (7%) patients, respectively. Grade 4 bilirubin toxicity was observed in 1 (7%) patient. Overall, 13 (81%) patients showed disease control (response+stable disease) according to WHO, European Association for the Study of the Liver, and Response Evaluation Criteria for Solid Tumors. Progressive disease was observed in 3 (19%) patients according to WHO, European Association for the Study of the Liver, and Response Evaluation Criteria for Solid Tumors. The median overall and hepatic progression-free survival times were 7.63 and 4.23 months. Patients with disease control (responders+stable disease) survived longer than those with progressive disease (9.97 vs. 2.13 months, P<0.0001). Results from this small and single-center experience show that radioembolization is a safe therapy and its potential for being an efficacious therapy for hepatic melanoma metastases should be explored further. Radioembolization should be considered for liver-dominant disease refractory to other forms of systemic therapies.

Radiation lobectomy: time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection.

BACKGROUND & AIMS: Portal vein embolization (PVE) is a standard technique for patients not amenable to liver resection due to small future liver remnant ratio (FLR). Radiation lobectomy (RL) with (90)Y-loaded microspheres (Y90) is hypothesized to induce comparable volumetric changes in liver lobes, while potentially controlling the liver tumor and limiting tumor progression in the untreated lobe. We aimed at testing this concept by performing a comprehensive time-dependent analysis of liver volumes following radioembolization. METHODS: 83 patients with right unilobar disease with hepatocellular carcinoma (HCC; N=67), cholangiocarcinoma (CC; N=8) or colorectal cancer (CRC; N=8) were treated by Y90 RL. The total liver volume, lobar (parenchymal) and tumor volumes, FLR and percentage of FLR hypertrophy from baseline (%FLR hypertrophy) were assessed on pre- and post-Y90 CT/MRI scans in a dynamic fashion. RESULTS: Right lobe atrophy (p=0.003), left lobe hypertrophy (p<0.001), and FLR hypertrophy (p<0.001) were observed 1 month after Y90 and this was consistent at all follow-up time points. Median %FLR hypertrophy reached 45% (5-186) after 9 months (p<0.001). The median maximal %FLR hypertrophy was 26% (-14 → 86). Portal vein thrombosis was correlated to %FLR hypertrophy (p=0.02). Median Child-Pugh score worsening (6 → 7) was seen at 1 to 3 months (p=0.03) and 3 to 6 months (p=0.05) after treatment. Five patients underwent successful right lobectomy (HCC N=3, CRC N=1, CC N=1) and 6 HCCs were transplanted. CONCLUSIONS: Radiation lobectomy by Y90 is a safe and effective technique to hypertrophy the FLR. Volumetric changes are comparable (albeit slightly slower) to PVE while the right lobe tumor is treated synchronously. This novel technique is of particular interest in the bridge-to-resection setting.

Increased quality of life among hepatocellular carcinoma patients treated with radioembolization, compared with chemoembolization.

BACKGROUND & AIMS: Quality of life (QoL) is an important aspect of any palliative treatment. However, few data are available from studies comparing how embolotherapy affects QoL for patients with hepatocellular carcinoma (HCC). We performed a health-related QoL study in patients with HCC treated by transarterial chemoembolization (TACE) or (90)Y radioembolization. METHODS: We performed a prospective study of patients undergoing (90)Y radioembolization (n = 29) or TACE (n = 27) for HCC. We assessed patients before treatment and 2 and 4 weeks after treatment using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) survey. We compared differences in health-related QoL between the treatment groups using linear regression repeated-measures analysis. RESULTS: At baseline, the groups had comparable baseline Child-Pugh class and performance statuses, although patients undergoing TACE had lower tumor burdens (P = .018) and less-advanced disease, based on United Network for Organ Sharing and Barcelona stage (P = .03 and P = .02, respectively), permitting injections at segmental arteries (P < .0001). There were no significant differences between groups in overall FACT-Hep health-related QoL scores (P = .055, effect size [ES], .54), owing to a limited sample size. Despite the more advanced disease of patients who received (90)Y radioembolization, they had a significantly better QoL, based on social well being (P = .019; ES, .65), functional well-being (P = .031; ES, .60), and embolotherapy-specific scores (P = .018; ES, .67). They also had a trend toward better overall QoL (P = .055; ES, .54) and higher Trial Outcome Index (P = .05; ES, .56) and FACT-Hep scores (P = .071; ES, .52). CONCLUSIONS: In a prospective study, although (90)Y radioembolization was used to treat patients with more advanced disease, those who received this treatment had significant increases in several features of QoL, whereas patients who received TACE had decreases in QoL scores. However, because of the limited sample size, there was no significant difference in overall FACT-Hep health-related QoL scores. The increase was greatest in the embolotherapy-specific score. ClinicalTrials.gov, number NCT00739167.

Radiological-pathological analysis of WHO, RECIST, EASL, mRECIST and DWI: Imaging analysis from a prospective randomized trial of Y90 ± sorafenib.

UNLABELLED: The aim of this study was to compare radiological and pathological changes and test the adjunct efficacy of Sorafenib to Y90 as a bridge to transplantation in hepatocellular carcinoma (HCC). 15 patients with 16 HCC lesions were randomized to Y90 without (Group A, n = 9) or with Sorafenib (Group B, n = 7). Size (WHO, RECIST), enhancement (EASL, mRECIST) and diffusion-weighted imaging criteria (apparent diffusion coefficient, ADC) measurements were obtained at baseline, then at 1 and every 3 months after treatment until transplantation. Percentage necrosis in explanted tumors was correlated with imaging findings. 100%, 50%-99% and <50% pathological necrosis was observed in 6 (67%), 1 (11%), and 2 (22%) tumors in Group A and 3 (42%), 2 (28%), and 2 (28%) in Group B, respectively (P = 0.81). While ADC (P = 0.46) did not change after treatment, WHO (P = 0.06) and RECIST (P = 0.08) response at 1 month failed to reach significance, but significant responses by EASL (P < 0.01/0.03) and mRECIST (P < 0.01/0.03) at 1 and 3 months were observed. Response was equivalent by EASL or mRECIST. No difference in response rates was observed between groups A and B at 1 and 3 months by WHO, RECIST, EASL, mRECIST or ADC measurements. Despite failing to reach significance, smaller baseline size was associated with complete pathological necrosis (CPN) (RECIST: P = 0.07; WHO: P = 0.05). However, a cut-off size of 35 mm was predictive of CPN (P = 0.005). CPN could not be predicted by WHO (P = 0.25 and 0.62), RECIST (P = 0.35 and 0.54), EASL (P = 0.49 and 0.46), mRECIST (P = 0.49 and 0.60) or ADC (P = 0.86 and 0.93). CONCLUSION: The adjunct of Sorafenib did not augment radiological or pathological response to Y90 therapy for HCC. Equivalent significant reduction in enhancement at 1 and 3 months by EASL/mRECIST was noted. Neither EASL nor mRECIST could reliably predict CPN.

Prospective evaluation of patients with early-/intermediate-stage hepatocellular carcinoma with disease progression following arterial locoregional therapy: candidacy for systemic treatment or clinical trials.

PURPOSE: During the course of cancer treatment, patients whose disease progresses despite therapy are offered alternative options. Similarly, patients with hepatocellular carcinoma (HCC) whose disease progresses following arterial locoregional therapies (LRTs) cross over to undergo systemic therapies or participate in clinical trials. Per current guidelines, patients must meet inclusion criteria (most importantly Child-Pugh class A status) to qualify for systemic options. The present study analyzed the candidacy for systemic agents or clinical trials of patients whose disease progresses despite LRTs. MATERIALS AND METHODS: A total of 245 patients with HCC were treated with LRTs (chemoembolization, n = 123; yttrium-90 [(90)Y] radioembolization, n = 122) as part of a previously published comparative effectiveness study; 96 patients exhibiting disease progression were followed prospectively. Modes of progression (cancer stage, Child-Pugh class) were analyzed to determine candidacy for systemic therapy or clinical trials, as well as assess ultimate treatment(s) received. RESULTS: Among the 96 patients with disease progression, 52% and 48% had Child-Pugh class A and class B/C disease, respectively, thereby substantially limiting the latter group's eligibility for systemic therapy and/or clinical trials. Of those whose disease progressed who had advanced-stage HCC, 63% had Child-Pugh class B/C disease. By size and necrosis criteria, the local disease progression rate was higher with chemoembolization than with (90)Y radioembolization (P = .006 and P = .016, respectively). Of the 96 patients with disease progression, only 13 (13%) ultimately received systemic agents or entered clinical trials. CONCLUSIONS: Most patients with advanced HCC that progresses following LRTs were not candidates for clinical trials or systemic agents. There is a need for future research efforts directed at treatment options or novel trial designs that will permit inclusion of patients with progressive liver disease and suboptimal liver function.