S.M. Ibrahim

Radioembolization for Hepatocellular Carcinoma Using Yttrium-90 Microspheres: A Comprehensive Report of Long-term Outcomes

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) has limited treatment options; long-term outcomes following intra-arterial radiation are unknown. We assessed clinical outcomes of patients treated with intra-arterial yttrium-90 microspheres (Y90). METHODS Patients with HCC (n = 291) were treated with Y90 as part of a single-center, prospective, longitudinal cohort study. Toxicities were recorded using the Common Terminology Criteria version 3.0. Response rate and time to progression (TTP) were determined using World Health Organization (WHO) and European Association for the Study of the Liver (EASL) guidelines. Survival by stage was assessed. Univariate/multivariate analyses were performed. RESULTS A total of 526 treatments were administered (mean, 1.8; range, 1-5). Toxicities included fatigue (57%), pain (23%), and nausea/vomiting (20%); 19% exhibited grade 3/4 bilirubin toxicity. The 30-day mortality rate was 3%. Response rates were 42% and 57% based on WHO and EASL criteria, respectively. The overall TTP was 7.9 months (95% confidence interval, 6-10.3). Survival times differed between patients with Child-Pugh A and B disease (A, 17.2 months; B, 7.7 months; P = .002). Patients with Child-Pugh B disease who had portal vein thrombosis (PVT) survived 5.6 months (95% confidence interval, 4.5-6.7). Baseline age; sex; performance status; presence of portal hypertension; tumor distribution; levels of bilirubin, albumin, and alpha-fetoprotein; and WHO/EASL response rate predicted survival. CONCLUSIONS Patients with Child-Pugh A disease, with or without PVT, benefited most from treatment. Patients with Child-Pugh B disease who had PVT had poor outcomes. TTP and overall survival varied by patient stage at baseline. These data can be used to design future Y90 trials and to describe Y90 as a potential treatment option for patients with HCC.

Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma

BACKGROUND & AIMS Chemoembolization is one of several standards of care treatment for hepatocellular carcinoma (HCC). Radioembolization with Yttrium-90 microspheres is a novel, transarterial approach to radiation therapy. We performed a comparative effectiveness analysis of these therapies in patients with HCC. METHODS We collected data from 463 patients who were treated with transarterial locoregional therapies (chemoembolization or radioembolization) over a 9-year period. We excluded patients who were not appropriate for comparison and analyzed data from 245 (122 who received chemoembolization and 123 who received radioembolization). Patients were followed for signs of toxicity; all underwent imaging analysis at baseline and follow-up time points. Overall survival was the primary outcome measure. Secondary outcomes included safety, response rate, and time-to-progression. Uni- and multivariate analyses were performed. RESULTS Abdominal pain and increased transaminase activity were more frequent following chemoembolization (P < .05). There was a trend that patients treated with radioembolization had a higher response rate than with chemoembolization (49% vs 36%, respectively, P = .104). Although time-to-progression was longer following radioembolization than chemoembolization (13.3 months vs 8.4 months, respectively, P = .046), median survival times were not statistically different (20.5 months vs 17.4 months, respectively, P = .232). Among patients with intermediate-stage disease, survival was similar between groups that received chemoembolization (17.5 months) and radioembolization (17.2 months, P = .42). CONCLUSIONS Patients with HCC treated by chemoembolization or radioembolization with Yttrium-90 microspheres had similar survival times. Radioembolization resulted in longer time-to-progression and less toxicity than chemoembolization. Post hoc analyses of sample size indicated that a randomized study with > 1000 patients would be required to establish equivalence of survival times between patients treated with these two therapies.

A Comparative Analysis of Transarterial Downstaging for Hepatocellular Carcinoma: Chemoembolization Versus Radioembolization

Chemoembolization and other ablative therapies are routinely utilized in downstaging from United Network for Organ Sharing (UNOS) T3 to T2, thus potentially making patients transplant candidates under the UNOS model for end‐stage liver disease (MELD) upgrade for hepatocellular carcinoma (HCC). This study was undertaken to compare the downstaging efficacy of transarterial chemoembolization (TACE) versus transarterial radioembolization. Eighty‐six patients were treated with either TACE (n = 43) or transarterial radioembolization with Yttrium‐90 microspheres (TARE‐Y90; n = 43). Median tumor size was similar (TACE: 5.7 cm, TARE‐Y90: 5.6 cm). Partial response rates favored TARE‐Y90 versus TACE (61% vs. 37%). Downstaging to UNOS T2 was achieved in 31% of TACE and 58% of TARE‐Y90 patients. Time to progression according to UNOS criteria was similar for both groups (18.2 months for TACE vs. 33.3 months for TARE‐Y90, p = 0.098). Event‐free survival was significantly greater for TARE‐Y90 than TACE (17.7 vs. 7.1 months, p = 0.0017). Overall survival favored TARE‐Y90 compared to TACE (censored 35.7/18.7 months; p = 0.18; uncensored 41.6/19.2 months; p = 0.008). In conclusion, TARE‐Y90 appears to outperform TACE for downstaging HCC from UNOS T3 to T2.

Alpha-Fetoprotein Response After Locoregional Therapy for Hepatocellular Carcinoma: Oncologic Marker of Radiologic Response, Progression, and Survival

PURPOSE Alpha-fetoprotein (AFP) is considered to be an indicator of tumor activity in hepatocellular carcinoma (HCC). We present a novel correlation of AFP response to radiologic response, time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS) in patients treated with locoregional therapies. PATIENTS AND METHODS Four hundred sixty-three patients with HCC were treated with chemoembolization or radioembolization at our institution. One hundred twenty-five patients with baseline AFP higher than 200 ng/mL were studied for this analysis. AFP response was defined as more than 50% decrease from baseline. One hundred nineteen patients with follow-up imaging were studied for the AFP imaging correlation analysis. AFP response was correlated to radiologic response, TTP, PFS, and OS. Multivariate analyses were performed. RESULTS Eighty-one patients (65%) showed AFP response. AFP response was seen in 26 (55%) of 47 and 55 (70%) of 78 of patients treated with chemoembolization and radioembolization, respectively (P = .12). WHO response was seen in 41 (53%) of 77 and 10 (24%) of 42 of AFP responders and nonresponders, respectively (P = .002). The hazard ratio (HR) for TTP in AFP nonresponders compared with responders was 2.8 (95% CI, 1.5 to 5.1). The HR for PFS was 4.2 (95% CI, 2.4 to 7.2) in AFP nonresponders compared with responders. The HR for OS in AFP nonresponders compared with responders was 5.5 (95% CI, 3.1 to 9.9) and 2.7 (95% CI, 1.6 to 4.6) on univariate and multivariate analyses, respectively. CONCLUSION The data presented support the use of AFP response seen after locoregional therapy as an ancillary method of assessing tumor response and survival, as well as an early objective screening tool for progression by imaging.

Radioembolization of colorectal hepatic metastases using yttrium‐90 microspheres

The objective of the current study was to determine the safety and efficacy of Yttrium‐90 (Y90) microsphere treatment in patients with liver‐dominant colorectal metastases.

Chemoembolization for Hepatocellular Carcinoma: Comprehensive Imaging and Survival Analysis in a 172-Patient Cohort

PURPOSE To determine comprehensive imaging and long-term survival outcome following chemoembolization for hepatocellular carcinoma (HCC). MATERIALS AND METHODS One hundred seventy-two patients with HCC treated with chemoembolization were studied retrospectively in an institutional review board approved protocol; this study was HIPAA compliant. Baseline laboratory and imaging characteristics were obtained. Clinical and laboratory toxicities following treatment were assessed. Imaging characteristics following chemoembolization were evaluated to determine response rates (size and necrosis) and time to progression (TTP). Survival from the time of first chemoembolization treatment was calculated. Subanalyses were performed by stratifying the population according to Child-Pugh, United Network for Organ Sharing, and Barcelona Clinic for Liver Cancer (BCLC) staging systems. RESULTS Cirrhosis was present in 157 patients (91%); portal hypertension was present in 139 patients (81%). Eleven patients (6%) had metastases at baseline. Portal vein thrombosis was present in 11 patients (6%). Fifty-five percent of patients experienced some form of toxicity following treatment; 21% developed grade 3 or 4 bilirubin toxicity. Post-chemoembolization response was seen in 31% and 64% of patients according to size and necrosis criteria, respectively. Median TTP was 7.9 months (95% confidence interval: 7.1, 9.4) but varied widely by stage. Median survival was significantly different between patients with BCLC stages A, B, and C disease (stage A, 40.0 months; B, 17.4 months; C, 6.3 months; P < .0001). CONCLUSION The determination of TTP and survival in patients with HCC is confounded by tumor biology and background cirrhosis; chemoembolization was shown to be a safe and effective therapy in patients with HCC.

Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study.

The objective of this report was to present data from an open‐label cohort study in which patients with intrahepatic cholangiocarcinoma (ICC) underwent radioembolization with yttrium‐90 (90Y) microspheres.

Biliary Sequelae following Radioembolization with Yttrium-90 Microspheres

PURPOSE Yttrium-90 (90Y) radioembolization has emerged as a promising and safe therapeutic modality for patients with hepatocellular carcinoma (HCC) or metastatic liver cancer. The present report describes biliary sequelae following intraarterial 90Y therapy in patients with HCC or liver metastases. MATERIALS AND METHODS All patients were treated with 90Y therapy according to standard lobar treatment protocol. Pre- and posttreatment imaging, liver function tests, and serum total bilirubin measurements were performed. Three to 6 months after treatment, biliary sequelae were evaluated with computed tomography and magnetic resonance imaging, and any liver-related laboratory adverse events were noted. RESULTS A total of 327 patients (HCC, n=190; liver metastases, n=137) received 569 infusions of 90Y. At follow-up imaging, 33 patients (10.1%; liver metastases, n=26; HCC, n=7) had 40 imaging findings related to the biliary tree, including biliary necrosis (n=17), biloma (n=3), cholecystitis (n=2), gallbladder wall enhancement (n=6), gallbladder wall rent (n=3), abscess (n=1), and stricture (n=8). A total of 31 patients exhibited grade 3/4 bilirubin toxicities (13 [6.8%] with HCC, 18 [13.1%] with liver metastases). Unplanned interventions prompted by biliary sequelae were necessary in six of 327 patients (1.8%). CONCLUSIONS 90Y therapy in patients with HCC or metastatic disease to the liver is associated with an acceptable rate of biliary toxicities. Further studies assessing long-term biliary sequelae are warranted.

Incidence of radiation pneumonitis after hepatic intra-arterial radiotherapy with yttrium-90 microspheres assuming uniform lung distribution.

Objective:To assess the incidence of clinical and imaging radiation pneumonitis (RP) in a cohort of patients treated with >30 Gy cumulative lung dose (CLD) using Y90 microspheres. Materials and Methods:Four hundred three patients were treated with Y90 microspheres during a 4-year period. Of these, 58 patients received >30 Gy CLD. Patients were followed for toxicities suggestive of imaging or clinical RP. Toxicities were graded using the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Late Radiation Morbidity Scoring Schema. Patients were also followed for survival from time of first treatment. Results:There were 44 men and 14 women. Forty-three patients had hepatocellular carcinoma (HCC), whereas 15 had liver metastases. Mean and median follow-up were 7.3 and 6.0 months, respectively. Mean lung shunt fraction was slightly greater in the patients with HCC versus metastases (20% vs. 16.7%, P = 0.2308). The lifetime CLD for metastases and HCC groups were not statistically different (54.04 Gy vs. 48.44 Gy, P = 0.4303). Forty-three of 53 patients demonstrated no lung imaging findings suggestive of pneumonitis. Imaging findings in 10 patients included pleural effusions, atelectasis, and ground glass attenuation. There were no cases of clinical or imaging RP. Survival varied depending on stage as well as single and CLD. None of the patient deaths were attributed to respiratory compromise. Conclusion:RP was not predicted using the currently used Y90 dosimetry models that assume uniform distribution in the lungs. Further investigation and dose escalation studies are required to more precisely define the radiation tolerance of lung parenchyma using this mode of therapy.

Yttrium-90 Radioembolization for Liver Malignancies: Prognostic Factors Associated with Survival

PURPOSE To identify key prognostic clinical and imaging variables in patients undergoing yttrium-90 radioembolization ((90)Y) for liver malignancies. MATERIALS AND METHODS Patients with liver malignancies that progressed despite standard-of-care therapy were treated with (90)Y from 2002 to 2006. Baseline functional status, laboratory values, and diagnostic imaging were assessed before therapy. Imaging follow-up was performed 1 month after treatment and subsequently at 3-month intervals. Patients were followed for survival from the time of their first (90)Y treatment. RESULTS Patients with follow-up imaging after radioembolization (N = 130) were included in this analysis. Primary malignancies included colon, neuroendocrine, and others. The following clinical variables had a significant effect on survival on multivariate analysis: Eastern Cooperative Oncology Group (ECOG) performance status (PS) greater than 0 (hazard ratio [HR], 7.98; 95% CI, 3.98-16), hepatic tumor burden of 51%-75% (HR, 2.46; 95% CI, 1.01-6.02), bilirubin level greater than 1.3 mg/dL (HR, 2.60; 95% CI, 1.27-5.34), hepatic metastases from breast cancer (HR, 2.51; 95% CI, 1.13-5.61), response on imaging based on World Health Organization (WHO) criteria (HR, 0.48; 95% CI, 0.24-0.94), and lymphocyte depression (HR, 0.56; 95% CI, 0.31-0.96). Among patients with colorectal cancer metastases to the liver, the HR for survival on univariate analysis for responders compared with nonresponders (per WHO criteria) was 0.26 (95% CI, 0.10-0.69). CONCLUSIONS Cancer-related symptoms (ie, ECOG PS > 0), hepatic tumor burden greater than 50%, increased bilirubin levels, and hepatic metastases from breast cancer were found to be negative prognostic factors. Tumor response to therapy and lymphocyte depression were associated with favorable prognosis. Additionally, WHO response was identified to be a favorable prognostic factor in patients with colorectal cancer metastases. These findings may be useful when counseling patients regarding prognosis of their hepatic disease.