Nikhil Bhagat

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.

Intraprocedural C-Arm Dual-Phase Cone-Beam CT: Can It Be Used to Predict Short-term Response to TACE with Drug-eluting Beads in Patients with Hepatocellular Carcinoma?

PURPOSE To investigate whether C-arm dual-phase cone-beam computed tomography (CT) performed during transcatheter arterial chemoembolization (TACE) with doxorubicin-eluting beads can help predict tumor response at 1-month follow-up in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS This prospective study was compliant with HIPAA and approved by the institutional review board and animal care and use committee. Analysis was performed retrospectively on 50 targeted HCC lesions in 29 patients (16 men, 13 women; mean age, 61.9 years ± 10.7) treated with TACE with drug-eluting beads. Magnetic resonance (MR) imaging was performed at baseline and 1 month after TACE. Dual-phase cone-beam CT was performed before and after TACE. Tumor enhancement at dual-phase cone-beam CT in early arterial and delayed venous phases was assessed retrospectively with blinding to MR findings. Tumor response at MR imaging was assessed according to European Association for the Study of the Liver (EASL) guidelines. Two patients were excluded from analysis because dual-phase cone-beam CT scans were not interpretable. Logistic regression models for correlated data were used to compare changes in tumor enhancement between modalities. The radiation dose with dual-phase cone-beam CT was measured in one pig. RESULTS At 1-month MR imaging follow-up, complete and/or partial tumor response was seen in 74% and 76% of lesions in the arterial and venous phases, respectively. Paired t tests used to compare images obtained before and after TACE showed a significant reduction in tumor enhancement with both modalities (P < .0001). The decrease in tumor enhancement seen with dual-phase cone-beam CT after TACE showed a linear correlation with MR findings. Estimated correlation coefficients were excellent for first (R = 0.89) and second (R = 0.82) phases. A significant relationship between tumor enhancement at cone-beam CT after TACE and complete and/or partial tumor response at MR imaging was found for arterial (odds ratio, 0.95; 95% confidence interval [CI]: 0.91, 0.99; P = .023) and venous (odds ratio, 0.96; 95% CI: 0.93, 0.99; P = .035) phases with the multivariate logistic regression model. Radiation dose for two dual-phase cone-beam CT scans was 3.08 mSv. CONCLUSION Intraprocedural C-arm dual-phase cone-beam CT can be used immediately after TACE with doxorubicin-eluting beads to predict HCC tumor response at 1-month MR imaging follow-up.

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.

Semiautomatic volumetric tumor segmentation for hepatocellular carcinoma: comparison between C-arm cone beam computed tomography and MRI.

RATIONALE AND OBJECTIVES To evaluate the precision and reproducibility of a semiautomatic tumor segmentation software in measuring tumor volume of hepatocellular carcinoma (HCC) before the first transarterial chemo-embolization (TACE) on contrast-enhancement magnetic resonance imaging (CE-MRI) and intraprocedural dual-phase C-arm cone beam computed tomography (DP-CBCT) images. MATERIALS AND METHODS Nineteen HCCs were targeted in 19 patients (one per patient) who underwent baseline diagnostic CE-MRI and an intraprocedural DP-CBCT. The images were obtained from CE-MRI (arterial phase of an intravenous contrast medium injection) and DP-CBCT (delayed phase of an intra-arterial contrast medium injection) before the actual embolization. Three readers measured tumor volumes using a semiautomatic three-dimensional volumetric segmentation software that used a region-growing method employing non-Euclidean radial basis functions. Segmentation time and spatial position were recorded. The tumor volume measurements between image sets were compared using linear regression and Students t-test, and evaluated with intraclass-correlation analysis (ICC). The inter-rater Dice similarity coefficient (DSC) assessed the segmentation spatial localization. RESULTS All 19 HCCs were analyzed. On CE-MRI and DP-CBCT examinations, respectively, 1) the mean segmented tumor volumes were 87 ± 8 cm(3) (2-873) and 92 ± 10 cm(3) (1-954), with no statistical difference of segmented volumes by readers of each tumor between the two imaging modalities and the mean time required for segmentation was 66 ± 45 seconds (21-173) and 85 ± 34 seconds (17-214) (P = .19); 2) the ICCs were 0.99 and 0.974, showing a strong correlation among readers; and 3) the inter-rater DSCs showed a good to excellent inter-user agreement on the spatial localization of the tumor segmentation (0.70 ± 0.07 and 0.74 ± 0.05, P = .07). CONCLUSION This study shows a strong correlation, a high precision, and excellent reproducibility of semiautomatic tumor segmentation software in measuring tumor volume on CE-MRI and DP-CBCT images. The use of the segmentation software on DP-CBCT and CE-MRI can be a valuable and highly accurate tool to measure the volume of hepatic tumors.

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.

Dual-phase cone-beam computed tomography to see, reach, and treat hepatocellular carcinoma during drug-eluting beads transarterial chemo-embolization.

The advent of cone-beam computed tomography (CBCT) in the angiography suite has been revolutionary in interventional radiology. CBCT offers 3 dimensional (3D) diagnostic imaging in the interventional suite and can enhance minimally-invasive therapy beyond the limitations of 2D angiography alone. The role of CBCT has been recognized in transarterial chemo-embolization (TACE) treatment of hepatocellular carcinoma (HCC). The recent introduction of a CBCT technique: dual-phase CBCT (DP-CBCT) improves intra-arterial HCC treatment with drug-eluting beads (DEB-TACE). DP-CBCT can be used to localize liver tumors with the diagnostic accuracy of multi-phasic multidetector computed tomography (M-MDCT) and contrast enhanced magnetic resonance imaging (CE-MRI) (See the tumor), to guide intra-arterially guidewire and microcatheter to the desired location for selective therapy (Reach the tumor), and to evaluate treatment success during the procedure (Treat the tumor). The purpose of this manuscript is to illustrate how DP-CBCT is used in DEB-TACE to see, reach, and treat HCC.

Multimodality Imaging of Ethiodized Oil–loaded Radiopaque Microspheres during Transarterial Embolization of Rabbits with VX2 Liver Tumors

Purpose To assess the visibility of radiopaque microspheres during transarterial embolization (TAE) in the VX2 rabbit liver tumor model by using multimodality imaging, including single-snapshot radiography, cone-beam computed tomography (CT), multidetector CT, and micro-CT. Materials and Methods The study was approved by the institutional animal care and use committee. Fifteen VX2-tumor-bearing rabbits were assigned to three groups depending on the type of embolic agent injected: 70-150-μm radiopaque microspheres in saline (radiopaque microsphere group), 70-150-μm radiopaque microspheres in contrast material (radiopaque microsphere plus contrast material group), and 70-150-μm radiolucent microspheres in contrast material (nonradiopaque microsphere plus contrast material group). Rabbits were imaged with single-snapshot radiography, cone-beam CT, and multidetector CT. Three to 5 weeks after sacrifice, excised livers were imaged with micro-CT and histologic analysis was performed. The visibility of the embolic agent was assessed with all modalities before and after embolization by using a qualitative three-point scale score reading study and a quantitative assessment of the signal-to-noise ratio (SNR) change in various regions of interest, including the tumor and its feeding arteries. The Kruskal-Wallis test was used to compare the rabbit characteristics across groups, and the Wilcoxon signed rank test was used to compare SNR measurements before and after embolization. Results Radiopaque microspheres were qualitatively visualized within tumor feeding arteries and targeted tissue with all imaging modalities (P < .05), and their presence was confirmed with histologic examination. SNRs of radiopaque microsphere deposition increased after TAE on multidetector CT, cone-beam CT, and micro-CT images (P < .05). Similar results were obtained when contrast material was added to radiopaque microspheres, except for additional image attenuation due to tumor enhancement. For the group with nonradiopaque microspheres and contrast material, retained tumoral contrast remained qualitatively visible with all modalities except for micro-CT, which demonstrated soluble contrast material washout over time. Conclusion Radiopaque microspheres were visible with all imaging modalities and helped increase conspicuity of the tumor as well as its feeding arteries after TAE in a rabbit VX2 liver tumor model. (©) RSNA, 2015.

Image quality improvements in C-Arm CT (CACT) for liver oncology applications: Preliminary study in rabbits

Abstract Introduction: C-Arm CT (CACT) is a new imaging modality in liver oncology therapy that allows for the acquisition of 3D images intra-procedurally. CACT has been used to enhance intra-arterial therapies for the liver by improving lesion detection, avoiding non-target embolization, and allowing for more selective delivery of agents. However, one of the limitations of this technology is image artifacts created by respiratory motion. Purpose: To determine in this preliminary study improvements in image acquisition, motion compensation, and high resolution 3D reconstruction that can improve CACT image quality (IQ). Material and methods: Three adult male New Zealand white rabbits were used for this study. First, a control rabbit was used to select the best x-ray acquisition imaging protocol and then two rabbits were implanted with liver tumor to further develop 3D image reconstruction and motion compensation algorithms. Results: The best IQ was obtained using the low 80 kVp protocol with motion compensated reconstruction with high resolution and fast acquisition speed (60 fps, 5 s/scan, and 312 images). Conclusion: IQ improved by: (1) decreasing acquisition time, (2) applying motion-compensated reconstruction, and (3) high resolution 3D reconstruction. The findings of this study can be applied to future animal studies and eventually could be translated into the clinical environment.

Prospective phase II study of chemoembolization with drug-eluting beads for hepatic neuroendocrine metastases: Interim analysis.

331 Background: To evaluate safety and efficacy of transarterial chemoembolization with doxorubicin eluting beads (DEB-TACE) in 30 patients with hepatic neuroendocrine metastases (NET) in a prospective phase II study. We report the interim analysis on 10 patients. Methods: Patients who met inclusion criteria (NET liver-dominant metastases, ECOG 0-1, treatment naive) underwent up to 4 DEB-TACE sessions (100-300 micron beads loaded with up to 100mg of doxorubicin) within a 6-month period. Statistical plan included interim analysis of initial 10 patients to assess therapeutic efficacy (defined as objective response≥50%). Tumor response was assessed by MR imaging 1 month after treatment using contrast-enhancement (EASL) and tumor size (RECIST). Safety was assessed by NCI Common Terminology Criteria. Results: DEB-TACE was successfully performed in 10 patients (22 targeted lesions). Patient characteristics included mean age 65 yrs; ECOG 0/1 (6/4); carcinoid syndrome (n=2); tumor burden range (4-75%), and mean t...