Paul Nikolaidis

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.

Utility of diffusion‐weighted MRI in distinguishing benign and malignant hepatic lesions

To evaluate apparent diffusion coefficient (ADC) values for characterization of a variety of focal liver lesions and specifically for differentiation of solid benign lesions (focal nodular hyperplasia [FNH] and adenomas) from solid malignant neoplasms (metastases and hepatocellular carcinoma [HCC]) in a large case series.

Role of the EASL, RECIST, and WHO response guidelines alone or in combination for hepatocellular carcinoma: radiologic-pathologic correlation.

BACKGROUND & AIMS We sought to study receiver-operating characteristics (ROC) of the European Association for the Study of the Liver (EASL), Response Evaluation Criteria in Solid Tumors (RECIST), and World Health Organization (WHO) guidelines for assessing response following locoregional therapies individually and in various combinations. METHODS Eighty-one patients with hepatocellular carcinoma underwent liver explantation following locoregional therapies. Response was assessed using EASL, RECIST, and WHO. Kappa statistics were used to determine inter-method agreement. Uni/multivariate logistic regression analyses were performed to determine the variables predicting complete pathologic necrosis. Numerical values were assigned to the response classes: complete response=0, partial response=1, stable disease=2, and progressive disease=3. Various mathematical combinations of EASL and WHO were tested to calculate scores and their ROCs were studied using pathological examination of the explant as the gold standard. RESULTS Median times (95% CI) to the WHO, RECIST, and EASL responses were 5.3 (4-11.5), 5.6 (4-11.5), and 1.3months (1.2-1.5), respectively. Kappa coefficients for WHO/RECIST, WHO/EASL, and RECIST/EASL were 0.78, 0.28, and 0.31, respectively. EASL response demonstrated significant odds ratios for predicting complete pathologic necrosis on uni/multivariate analyses. Calculated areas under the ROC curves were: RECIST: 0.63, WHO: 0.68, EASL: 0.82, EASL+WHO: 0.82, EASL×WHO: 0.85, EASL+(2×WHO): 0.79 and (2×EASL)+WHO: 0.85. An EASL×WHO Score of ⩽1 had 90.2% sensitivity for predicting complete pathologic necrosis. CONCLUSIONS The product of WHO and EASL demonstrated better ROC than the individual guidelines for assessment of tumor response. EASL×WHO scoring system provides a simple and clinically applicable method of response assessment following locoregional therapies for hepatocellular carcinoma.

Radiographic Response to Locoregional Therapy in Hepatocellular Carcinoma Predicts Patient Survival Times

BACKGROUND & AIMS It is not clear whether survival times of patients with hepatocellular carcinoma (HCC) are associated with their response to therapy. We analyzed the association between tumor response and survival times of patients with HCC who were treated with locoregional therapies (LRTs) (chemoembolization and radioembolization). METHODS Patients received LRTs over a 9-year period (n = 463). Patients with metastases, portal venous thrombosis, or who had received transplants were excluded; 159 patients with Child-Pugh B7 or lower were analyzed. Response (based on European Association for the Study of the Liver [EASL] and World Health Organization [WHO] criteria) was associated with survival times using the landmark, risk-of-death, and Mantel-Byar methodologies. In a subanalysis, survival times of responders were compared with those of patients with stable disease and progressive disease. RESULTS Based on 6-month data, in landmark analysis, responders survived longer than nonresponders (based on EASL but not WHO criteria: P = .002 and .0694). The risk of death was also lower for responders (based on EASL but not WHO criteria: P = .0463 and .707). Landmark analysis of 12-month data showed that responders survived longer than nonresponders (P < .0001 and .004, based on EASL and WHO criteria, respectively). The risk of death was lower for responders (P = .0132 and .010, based on EASL and WHO criteria, respectively). By the Mantel-Byar method, responders had longer survival than nonresponders, based on EASL criteria (P < .0001; P = .596 with WHO criteria). In the subanalysis, responders lived longer than patients with stable disease or progressive disease. CONCLUSIONS Radiographic response to LRTs predicts survival time. EASL criteria for response more consistently predicted survival times than WHO criteria. The goal of LRT should be to achieve a radiologic response, rather than to stabilize disease.

Radioembolization for neuroendocrine liver metastases: safety, imaging, and long-term outcomes.

PURPOSE To present long-term outcomes on the safety and efficacy of Yttrium-90 radioembolization in the treatment of unresectable hepatic neuroendocrine metastases refractory to standard-of-care therapy. METHODS AND MATERIALS This study was approved by our institutional review board and was compliant with the Health Insurance Portability and Accountability Act. Forty patients with hepatic neuroendocrine metastases were treated with (90)Y radioembolization at a single center. Toxicity was assessed using National Cancer Institute Common Terminology Criteria v3.0. Response to therapy was assessed by World Health Organization (WHO) guidelines for size and European Association for the Study of the Liver disease (EASL) guidelines for necrosis. Time to response and overall survival were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed. RESULTS The median dose was 113 Gy (29-299 Gy). Clinical toxicities included fatigue (63%), nausea/vomiting (40%), abdominal pain (18%), fever (8%), diarrhea and weight loss (5%); Grade 3 and 4 bilirubin toxicities were experienced by 2 patients and 1 patient, respectively. Different responses were noted by WHO (complete response, 1.2%; partial response, 62.7%) and EASL (complete response, 20.5%; partial response, 43.4%). Median time to response was 4 and 4.9 months by lesion and patient, respectively. The 1-, 2-, and 3-year overall survival rates were 72.5%, 62.5%, and 45%, respectively. Eastern Cooperative Oncology Group (ECOG) performance score 0 (p < 0.0001), tumor burden ≤25% (p = 0.0019), albumin ≥3.5 g/dL (p = 0.017), and bilirubin ≤1.2 mg/dL (p = 0.002) prognosticated survival on univariate analysis; only ECOG performance score 0 and bilirubin ≤1.2 mg/dL prognosticated better survival outcome on multivariate analysis (p = 0.0001 and p = 0.02). CONCLUSION Yttrium-90 therapy for hepatic neuroendocrine metastases leads to satisfactory tumor response and patient survival with low toxicity, in line with published national guidelines recommending radioembolization as a potential option for unresectable hepatic neuroendocrine metastases.

Diffusion-weighted MR imaging in pancreatic endocrine tumors correlated with histopathologic characteristics

To retrospectively assess apparent diffusion coefficients (ADCs) of different subtypes of pancreatic endocrine tumors based on the World Health Organization (WHO) classification system and analyze the potentially responsible histopathologic characteristics.

Diffusion-weighted magnetic resonance imaging of pancreatic adenocarcinomas: association with histopathology and tumor grade.

To evaluate the utility of diffusion‐weighted magnetic resonance imaging (DWI) in pancreatic ductal adenocarcinoma with various grades of differentiation.

Utility of Diffusion-Weighted MRI in Characterization of Adrenal Lesions

OBJECTIVE The purpose of our study was to evaluate the utility of apparent diffusion coefficient (ADC) values for characterizing adrenal lesions and determine if diffusion-weighted imaging (DWI) can distinguish lipid-rich from lipid-poor adenomas. MATERIALS AND METHODS We retrospectively evaluated 160 adrenal lesions in 156 patients (96 women and 60 men; mean age, 63 years). ADCs and signal intensity (SI) decrease on chemical shift imaging were measured in adrenal lesions with a wide variety of pathologies. Lipid-rich and lipid-poor adenomas were identified by unenhanced CT. The overall predictive power of ADC, SI decrease, and lesion size were determined by receiver operating characteristic (ROC) analysis. Areas under the ROC curve (AUC) were compared for equivalence using nonparametric methods. Sensitivity, specificity, and positive and negative predictive values were calculated. Correlation coefficients were used to assess ADCs versus percentage SI decrease and ADCs versus CT attenuation. RESULTS ADCs of adrenal malignancies (median, 1.67 x 10(-3) mm(2)/s; interquartile range, 1.41-1.84 x 10(-3) mm(2)/s) were not different compared with those of benign lesions (1.61 x 10(-3) mm(2)/s; 1.27-1.96 x 10(-3) mm(2)/s; p > 0.05). Cysts (2.93 x 10(-3) mm(2)/s; 2.70-3.09 x 10(-3) mm(2)/s) showed higher ADCs than the remaining adrenal lesions (p < 0.05). The median ADCs of lipid-rich adenomas did not differ from those of lipid-poor ones (p > 0.05). The CT attenuation had no negative or positive correlation with the ADCs of adrenal adenomas (r = -0.05, p = 0.97). CONCLUSION Unlike lesion size and percentage decrease in SI, the ADCs were not useful in distinguishing benign from malignant adrenal lesions. Lipid-poor adenomas could not be distinguished from lipid-rich adenomas and all other nonfatty lesions of the adrenal gland with DWI.

Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: a subgroup analysis.

BACKGROUND & AIMS Alpha-fetoprotein (AFP) is a universally recognized tumor marker in hepatocellular carcinoma (HCC). Its utility in assessing response to treatment remains controversial. We sought to study the: (a) correlation between AFP response and imaging response, and (b) ability of AFP, EASL, and WHO response to predict survival outcomes in patients with solitary HCC. METHODS Six hundred and twenty-nine HCC patients were treated with transarterial locoregional therapies over an 11-year period. To eliminate confounding factors, we included patients with single tumors, baseline AFP ≥200ng/ml, and no extrahepatic disease; this identified our study cohort of 51 patients. AFP response was defined as>50% decrease from baseline; this was correlated to EASL and WHO response criteria by Kappa agreement, Pearson correlation and receiver operating curves. Survival analyses were performed by Landmark, risk-of-death and Mantel-Byar methodologies. None of the patients received sorafenib. RESULTS Three months post-treatment, AFP and EASL response correlated well (Kappa: 0.83; Pearson: 0.84); the sensitivity, specificity, positive and negative predictive values of AFP in predicting EASL response at 3 months were 96.6%, 85.7%, 92.3%, and 93.3%, respectively. Correlation with WHO response was low. From the 3-month landmark, WHO, EASL, and AFP responders survived longer than non-responders (p=0.006, 0.0001, and <0.0001, respectively). The risk of death was lower for EASL and AFP responders by both risk-of-death and Mantel-Byar methodologies (p <0.05). CONCLUSIONS Response by AFP and EASL are predictors of survival outcome in patients with solitary HCC. AFP correlates with imaging response assessment by EASL guidelines. Achieving AFP response should be one of the therapeutic intents of locoregional therapies (LRTs).

Extrahepatic metastases occur in a minority of hepatocellular carcinoma patients treated with locoregional therapies: Analyzing patterns of progression in 285 patients

Although most cancers are considered predominantly systemic processes, this may not hold true for hepatocellular carcinoma (HCC). The literature regarding patterns of progression of HCC (local versus systemic) has been relatively sparse. Our objectives were to: (1) analyze patterns of progression in HCC patients presenting with intrahepatic disease from initial treatment until death, and (2) identify clinically relevant risk factors for the development of metastases. Over a 9‐year period, 285 patients treated with transarterial locoregional therapies underwent scheduled imaging follow‐up from treatment until death and were categorized by pattern of progression: (i) intrahepatic (increased tumor enhancement/size, development/progression of vascular invasion, new hepatic lesions) progression or (ii) extrahepatic (adrenal/bone/lung/lymph node) metastases. Uni/multivariate analyses assessing the risk factors for the development of metastases were performed. The median time from last scan to death was 2.4 months (interquartile range: 1.3‐4.8 months). The time to development of metastases, vascular invasion, and/or new lesions was 13.8 months (confidence interval: 11.3‐17.7 months). Of the 209 patients followed until death, only 50 developed extrahepatic metastases (24%). Multivariate analyses identified age <65 years (P = 0.038), alpha‐fetoprotein >200 ng/mL (P = 0.04), and vascular invasion (P = 0.017) as significant predictors of metastases development. Conclusion: Knowledge of the risk factors associated with the development of metastases may help guide assessment of patient prognosis. Because 76% of patients presenting with local disease treated with locoregional therapies die without developing extrahepatic metastases, the notion of HCC as a systemic disease, as detected by imaging, may be reconsidered. (HEPATOLOGY 2011)