Diane K. Reyes

Phase II Trial of Sorafenib Combined With Concurrent Transarterial Chemoembolization With Drug-Eluting Beads for Hepatocellular Carcinoma

PURPOSE To evaluate safety and efficacy of combined transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEB) and sorafenib in patients with advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS A prospective single-center phase II study was undertaken involving patients with unresectable HCC. The protocol involved sorafenib 400 mg twice per day combined with DEB-TACE. Safety and response were assessed. Results DEB-TACE in combination with sorafenib was successfully administered in 35 patients: mean age, 63 years; Childs A, 89%; Barcelona Clinic Liver Cancer stage C, 64%; Eastern Cooperative Oncology Group performance status of 0 and 1, 46% and 54%, respectively; and mean index tumor size, 7.7 cm (standard deviation, ± 4.2 cm). Patients underwent 128 cycles of therapy (sorafenib plus DEB-TACE, 60 cycles; sorafenib alone, 68 cycles). Median number of cycles per patient was two (range, one to five cycles); median number of days treated with sorafenib was 71 (range, 4 to 620 days). The most common toxicities during cycle one were fatigue (94%), anorexia (67%), alterations in liver enzymes (64%), and dermatologic adverse effects (48%). Although most patients experienced at least one grade 3 to 4 toxicity, most toxicities were minor (grade 1 to 2, 83% v grade 3 to 4, 17%). Toxicity during cycle two was decreased. Over the course of the study, there were 40 sorafenib dose interruptions and 25 sorafenib dose reductions. Sorafenib plus DEB-TACE was associated with a disease control rate of 95% (Response Evaluation Criteria in Solid Tumors Group)/100% (European Association for the Study of the Liver [EASL]), with an objective response of 58% (EASL). CONCLUSION The combination of sorafenib and DEB-TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib. Toxicity is manageable with dose adjustment of sorafenib. Preliminary efficacy data are promising.

The Role of Functional MR Imaging in the Assessment of Tumor Response after Chemoembolization in Patients with Hepatocellular Carcinoma

PURPOSE To assess treatment response of hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) with use of diffusion and dynamic contrast medium-enhanced magnetic resonance (MR) imaging. MATERIALS AND METHODS MR imaging studies before and after TACE in 38 patients with HCC (33 male patients and five female patients) were evaluated. Diffusion and dynamic contrast medium-enhanced MR imaging was performed on a 1.5-T unit. The imaging protocol included T2-weighted fast spin-echo, breath-hold diffusion-weighted echoplanar, and breath-hold unenhanced and contrast medium-enhanced T1-weighted three-dimensional fat-saturation gradient-recalled echo imaging in the arterial and portal venous phases. Tumor size, percent enhancement, and apparent diffusion coefficient (ADC) values were recorded before and after treatment. Survival analysis was also performed. RESULTS The study included 38 lesions with a mean diameter of 8.0 cm. Mean reduction in tumor diameter was 8 mm after treatment (t test; P = .0005), which did not fulfill Response Evaluation Criteria in Solid Tumors for complete or partial response. Reduction in tumor enhancement in the arterial (30%) and venous (47%) phases was statistically significant (signed-rank test; P = .0003 and P < 0.00005, respectively). Tumor ADC value increased from 0.0015 mm(2)/sec to 0.0018 mm(2)/sec after treatment (t test; P = .026), whereas the ADC values for the liver, spleen, and muscle remained unchanged. Median patient survival was 19 months. CONCLUSIONS After TACE, tumors demonstrated decreased size and enhancement with increases in ADC values. In this cohort, diffusion and dynamic contrast medium-enhanced MR imaging parameters were significantly altered after TACE, and these could be useful tools in the assessment of tumor response.

Unresectable Hepatocellular Carcinoma: Serial Early Vascular and Cellular Changes after Transarterial Chemoembolization as Detected with MR Imaging

PURPOSE To prospectively assess serial changes in contrast material-enhanced and diffusion-weighted (DW) magnetic resonance (MR) imaging values within 1 month after transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS Institutional review board approval was obtained for this prospective HIPAA-compliant study. MR imaging was performed before and within 24 hours after TACE in 24 patients with HCC (21 male, three female; mean age, 59 years and 62 years, respectively). Serial MR imaging was subsequently performed 1, 2, 3, and 4 weeks after therapy. The imaging protocol included fast spin-echo T2-weighted MR imaging, breath-hold DW echo-planar MR imaging, and breath-hold unenhanced and contrast-enhanced T1-weighted three-dimensional fat-suppressed gradient-recalled-echo MR imaging in the arterial and portal venous phases. Tumor size, enhancement, and apparent diffusion coefficient (ADC) values were recorded before and sequentially after treatment. Regression models for the correlated data were used to assess changes in these parameters over time after TACE. RESULTS Mean tumor size was 7.5 cm and was unchanged up to 4 weeks after therapy. Reduction in tumor enhancement in the arterial phase occurred immediately after TACE, with a consistent reduction occurring 1-3 weeks after therapy (P = .001). Reduction in tumor enhancement in the portal venous phase also occurred immediately after TACE, with a consistent reduction occurring 1-3 weeks after therapy (P = .0003). The increase in tumor ADC value was significant 1-2 weeks after therapy (P = .004), borderline significant 3 weeks after therapy, and insignificant 24 hours and 4 weeks after therapy. CONCLUSION Significant reduction in tumor enhancement occurred within 24 hours after TACE and persisted up to 4 weeks after TACE. Lesser changes in the ADC value appeared 1 week after TACE, persisted through 2 weeks after TACE, and became less apparent 3 and 4 weeks after TACE. No change in tumor size was recorded during the follow-up period.

Single-center phase II trial of transarterial chemoembolization with drug-eluting beads for patients with unresectable hepatocellular carcinoma: initial experience in the United States.

Purpose:This prospective phase II pilot study evaluated safety and efficacy of transarterial chemoembolization (TACE) with drug-eluting beads (DEBs) loaded with doxorubicin in patients with unresectable hepatocellular carcinoma (HCC). Methods:Twenty patients with unresectable HCC (75% Childs A, 95% Eastern Cooperative Oncology Group performance status 0 to 1, 60% Barcelona Clinic Liver Cancer C, tumor size 6.9 cm) underwent 34 DEB-TACE sessions. Primary endpoints were tumor response, assessed by contrast-enhanced magnetic resonance imaging at 1 month after treatment, using size (response evaluation criteria in solid tumors [RECIST]), contrast-enhancement (European Association for the Study of the Liver) and apparent diffusion coefficient values, and safety assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Secondary endpoints included feasibility, progression-free survival, and overall survival. Results:DEB-TACE was successfully performed in 34 sessions and demonstrated a favorable safety profile. On initial (1 month) postprocedural magnetic resonance imaging, treated lesions had a mean decrease in size of 4% (P = 0.1129). Using RECIST, partial response was achieved in 2 patients (10%), and 18 patients (90%) had stable disease. Treated tumors demonstrated a mean decrease in contrast enhancement of 64% (P < 0.0001). By European Association for the Study of the Liver criteria, 12 patients (60%) had objective tumor response, and 8 (40%) had stable disease. No patients had progression of a treated lesion while undergoing treatment. At 6 months, the disease control rate was 95% using RECIST. Overall survival rates at 1 and 2 years were 65% and 55%, respectively; median overall survival was 26 months. Discussion:DEB-TACE is safe and effective in achieving local tumor control in patients with unresectable HCC.

Salvage Therapy for Liver-dominant Colorectal Metastatic Adenocarcinoma: Comparison between Transcatheter Arterial Chemoembolization versus Yttrium-90 Radioembolization

PURPOSE To compare transarterial chemoembolization (CE) versus yttrium-90 ((90)Y) radioembolization (RE) for liver-dominant metastatic colorectal adenocarcinoma as salvage therapy. MATERIALS AND METHODS Of 36 patients, 21 underwent CE (37 procedures; 11 men; mean age, 67 years; 16 with Child-Pugh class A disease) and 15 underwent (90)Y RE (19 procedures; 11 men; mean age, 64 years; 13 with Child-Pugh class A disease) for liver-dominant colorectal adenocarcinoma. Mean index dominant lesion sizes were 9.3 cm and 8.2 cm in the CE and RE groups, respectively. Multilobar disease was seen in 67% and 87% of the respective groups, and extrahepatic metastases were seen in 43% and 33%, respectively. Mean times from diagnosis of liver metastasis to CE or RE were 17.6 months and 22.6 months, respectively. RESULTS A total of 37 CE procedures with cisplatin, doxorubicin, and mitomycin were performed, and 19 RE procedures with (90)Y were performed; 43% of patients in the CE group and 20% in the RE group received multiple treatment sessions, and 100% of procedures were technically successful. Median survival times were 7.7 months for the CE group and 6.9 months for the RE group (P = .27). The 1-, 2-, and 5-year survival rates were 43%, 10%, and 0%, respectively, in the CE group; and 34%, 18%, and 0%, respectively, in the RE group. There was one major complication (2.7%) in the CE group (pulmonary embolism), with a 30-day mortality rate of 5.4% (n = 2). There were no major complications in the RE group, with a 30-day mortality rate of 5.2% (n = 1). CONCLUSIONS Patients with unresectable liver colorectal metastases that progress despite systemic chemotherapy can undergo palliative treatment with CE or RE with similar survival benefit.

Quantitative and Volumetric European Association for the Study of the Liver and Response Evaluation Criteria in Solid Tumors Measurements: Feasibility of a Semiautomated Software Method to Assess Tumor Response after Transcatheter Arterial Chemoembolization

PURPOSE To show that hepatic tumor volume and enhancement pattern measurements can be obtained in a time-efficient and reproducible manner on a voxel-by-voxel basis to provide a true three-dimensional (3D) volumetric assessment. MATERIALS AND METHODS Magnetic resonance (MR) imaging data obtained from 20 patients recruited for a single-institution prospective study were retrospectively evaluated. All patients had a diagnosis of hepatocellular carcinoma (HCC) and underwent drug-eluting beads (DEB) transcatheter arterial chemoembolization for the first time. All patients had undergone contrast-enhanced MR imaging before and after DEB transcatheter arterial chemoembolization; poor image quality excluded 3 patients, resulting in a final count of 17 patients. Volumetric RECIST (vRECIST) and quantitative EASL (qEASL) were measured, and segmentation and processing times were recorded. RESULTS There were 34 scans analyzed. The time for semiautomatic segmentation was 65 seconds±33 (range, 40-200 seconds). vRECIST and qEASL of each tumor were computed<1 minute for each. CONCLUSIONS Semiautomatic quantitative tumor enhancement (qEASL) and volume (vRECIST) assessment is feasible in a workflow-efficient time frame. Clinical correlation is necessary, but vRECIST and qEASL could become part of the assessment of intraarterial therapy for interventional radiologists.

Neuroendocrine Liver Metastasis Treated by Using Intraarterial Therapy: Volumetric Functional Imaging Biomarkers of Early Tumor Response and Survival

PURPOSE To determine if volumetric changes of diffusion-weighted and contrast material-enhanced magnetic resonance (MR) imaging can help assess early tumor response to intraarterial therapy (IAT) in neuroendocrine liver metastasis (NELM). MATERIALS AND METHODS This retrospective single-center comprehensive imaging analysis was performed in compliance with HIPAA and was institutional review board approved. Informed patient consent was waived. Seventy-one patients (39 men; mean age, 62.3 years) with NELM treated with IAT were analyzed retrospectively. MR studies were performed before and 3-4 weeks after therapy. The index lesion was segmented to provide volumetric functional analysis of apparent diffusion coefficient (ADC) and contrast-enhanced MR imaging in the hepatic arterial phase (HAP) and portal venous phase (PVP). Tumor response was defined as increase in volumetric ADC of 15% or greater and decrease in volumetric enhancement of 25% or greater during the HAP or of 50% or greater during the PVP. Patient overall survival was the primary end point after therapy initiation. Univariate analysis included Kaplan-Meier survival curves. The Cox proportional hazards regression model was used to detect interactions between volumetric ADC and contrast-enhanced MR imaging and to calculate the hazard ratio. RESULTS There was significant increase in mean volumetric ADC (27%, P < .0001) and significant decrease in mean volumetric enhancement during the HAP (-25.3%, P < .0001) and the PVP (-22.4%, P < .0001) in all patients. Patients who had 15% or greater volumetric ADC increase (n = 49) after therapy had better prognosis than those who had less than 15% increase in volumetric ADC (n = 22) (log-rank test, P < .002). Patients who had 25% or greater decrease in volumetric arterial enhancement (n = 40) or 50% or greater decrease in venous enhancement (n = 18) had better prognosis than those who had less than 25% decrease in volumetric arterial enhancement (n = 31) or less than 50% decrease in venous enhancement (n = 53) (log-rank test, P < .02). CONCLUSION Volumetric functional MR imaging criteria may act as biomarkers of early response, indicating that these criteria may be important to incorporate in future NELM clinical trials.

Intrahepatic Cholangiocarcinoma Treated with Local-Regional Therapy: Quantitative Volumetric Apparent Diffusion Coefficient Maps for Assessment of Tumor Response

PURPOSE To evaluate volumetric changes in apparent diffusion coefficient (ADC) and contrast material enhancement on contrast-enhanced (CE) magnetic resonance (MR) images in hepatic arterial and portal venous phases for assessing early response in cholangiocarcinoma treated with transcatheter arterial chemoembolization (TACE). MATERIALS AND METHODS Twenty-nine patients with unresectable cholangiocarcinoma, including 11 men (mean age, 60 years; standard deviation, 16.8) and 18 women (mean age, 63 years; standard deviation, 11.5) were included in this retrospective institutional review board-approved, HIPAA-compliant study; informed consent was waived. Sixty-nine TACE procedures were performed during the observational time (range, one to five TACE sessions). No patients received another form of therapy after treatment with TACE. MR Imaging was performed before and 3-4 weeks after TACE, and images were analyzed with a semiautomatic volumetric software package. Patients were stratified as responders and nonresponders on the basis of overall survival (OS) as the primary end point. Differences between responders and nonresponders were analyzed with paired t tests, and OS was calculated with the Kaplan-Meier method. Significant differences were analyzed with the log-rank test. RESULTS Mean volumetric ADC increased from 1.54×10(-3) mm2/sec to 1.92×10(-3) mm2/sec (P<.0001), with no significant decrease in mean volumetric enhancement in hepatic arterial (40.6% vs 37.5%, P=.546) and portal venous (79.0% vs 70.0%, P=.105) phases. Patients who demonstrated improved survival of 10 months or more had a significant increase in mean volumetric ADC and volumetric ADC above the threshold level of 1.60×10(-3) mm2/sec (P<.002). Patients with 45% or greater (n=21; log-rank test, P<.02) and 60% or greater (n=12; log-rank test, P<.009) ADC changes for the whole tumor volume demonstrated better OS compared with patients in whom these ADC changes were not achieved. CONCLUSION Patients with percentage tumor volume increase in ADC of 45% or greater and 60% or greater above the threshold level of 1.60×10(-3) mm2/sec had favorable response to therapy and improved survival.

Unresectable Hepatocellular Carcinoma: MR Imaging after Intraarterial Therapy. Part I. Identification and Validation of Volumetric Functional Response Criteria

PURPOSE To identify and validate the optimal thresholds for volumetric functional MR imaging response criteria to predict overall survival after intraarterial treatment (IAT) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS Institutional review board approval and waiver of informed consent were obtained. A total of 143 patients who had undergone MR imaging before and 3-4 weeks after the first cycle of IAT were included. MR imaging analysis of one representative HCC index lesion was performed with proprietary software after initial treatment. Subjects were randomly divided into training (n = 114 [79.7%]) and validation (n = 29 [20.3%]) data sets. Uni- and multivariate Cox models were used to determine the best cutoffs, as well as survival differences, between response groups in the validation data set. RESULTS Optimal cutoffs in the training data set were 23% increase in apparent diffusion coefficient (ADC) and 65% decrease in volumetric enhancement in the portal venous phase (VE). Subsequently, 25% increase in ADC and 65% decrease in VE were used to stratify patients in the validation data set. Comparison of ADC responders (n = 12 [58.6%]) with nonresponders (n = 17 [34.5%]) showed significant differences in survival (25th percentile survival, 11.2 vs 4.9 months, respectively; P = .008), as did VE responders (n = 9 [31.0%]) compared with nonresponders (n = 20 [69.0%]; 25th percentile survival, 11.5 vs 5.1 months, respectively; P = .01). Stratification of patients with a combination of the criteria resulted in significant differences in survival between patients with lesions that fulfilled both criteria (n = 6 [20.7%]; too few cases to determine 25th percentile), one criterion (n = 9 [31.0%]; 25th percentile survival, 6.0 months), and neither criterion (n = 14 [48.3%]; 25th percentile survival, 5.1 months; P = .01). The association between the two criteria and overall survival remained significant in a multivariate analysis that included age, sex, Barcelona Clinic for Liver Cancer stage, and number of follow-up treatments. CONCLUSION After IAT for unresectable HCC, patients can be stratified into significantly different survival categories based on responder versus nonresponder status according to MR imaging ADC and VE cutoffs.

Islet Cell Liver Metastases: Assessment of Volumetric Early Response with Functional MR Imaging after Transarterial Chemoembolization

PURPOSE To assess early response to transarterial chemoembolization by using volumetric functional magnetic resonance (MR) imaging in patients with islet cell liver metastases (ICLMs). MATERIALS AND METHODS This retrospective institutional review board-approved HIPAA-compliant study included 215 ICLMs in 26 patients (15 men, 11 women; mean age, 59.7 years; age range, 37-79 years). Volumetric measurements were performed by an experienced radiologist on diffusion-weighted and contrast material-enhanced MR images at baseline and 1-month follow-up. Measurements included mean change (three-dimensional [3D] mean apparent diffusion coefficient [ADC], 3D mean enhancement) and percentage of tumor with change above a predetermined threshold (3D threshold ADC, 3D threshold enhancement). Response by volumetric measurements at 1-month follow-up was compared with Response Evaluation Criteria in Solid Tumors (RECIST) at 6-month follow-up. Lesions that had complete or partial response were considered responders, while those with stable or progressive disease were considered nonresponders. Statistical analysis included the t test, receiver operating characteristic (ROC) curve analysis, and logistic regression analysis. RESULTS RECIST criteria at 6-month follow-up indicated 78 (36.3%) lesions responded, while 137 (63.7%) did not. The increase in 3D mean ADC was significantly higher in responders than in nonresponders (median, 26.2% vs 10.9%; P<.001). The 3D threshold ADC was 71.1% in responders and 47.6% in nonresponders (P<.001). Decrease in 3D mean arterial enhancement (AE) was significantly higher in responders than in nonresponders (median, 40.5% vs 18.0%; P<.001). Decrease in 3D mean venous enhancement (VE) was significantly higher in responders than in nonresponders (median, 28.0% vs 10.0%; P<.001). The 3D threshold VE and 3D threshold AE did not differ between responders and nonresponders. In unadjusted logistic regression analyses, 3D mean ADC and 3D threshold ADC had the highest odds ratio (1.02 and 1.03, respectively) and the largest area under the ROC curve (0.698 and 0.695, respectively). CONCLUSION Volumetric functional MR imaging could be used to predict early response of hepatic ICLMs to therapy and to distinguish between responders and nonresponders.