Josephina A. Vossen

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.

Functional MRI Evaluation of Tumor Response in Patients with Neuroendocrine Hepatic Metastasis Treated with Transcatheter Arterial Chemoembolization

OBJECTIVE The purpose of this study was to evaluate contrast-enhanced and diffusion-weighted MRI changes in neuroendocrine tumors treated with transcatheter arterial chemoembolization (TACE). MATERIALS AND METHODS Sixty-six targeted lesions in 26 patients (18 men, eight women; mean age, 57 years) with hepatic metastasis of neuroendocrine tumors treated with TACE were retrospectively analyzed. MRI studies were performed before and after TACE. Imaging features included tumor size, percentage of enhancement in the arterial and portal venous phases, and diffusion-weighted imaging apparent diffusion coefficients (ADCs) of the tumor, liver, and spleen. Tumor response to treatment was recorded according to World Health Organization criteria and Response Evaluation Criteria in Solid Tumors. Liver function tests were performed, and clinical performance was assessed before and after treatment. Statistical analysis included paired Students t tests and Kaplan-Meier survival curves. RESULTS Mean tumor size and percentage enhancement in the arterial and portal venous phases decreased significantly after treatment (p < 0.0001). The tumor ADC increased from 1.51 x 10(-3) mm2/s before treatment to 1.79 x 10(-3) mm2/s after treatment (p < 0.0001), but the ADCs for the liver and spleen remained unchanged. Despite the change in tumor size, no patient in this cohort achieved complete response according to World Health Organization criteria and Response Evaluation Criteria in Solid Tumors. Partial response was achieved in only 27% and 23% of the patients according to the respective criteria. Results of liver function tests and performance status also remained unchanged. The mean survival period for all patients was 78 months. CONCLUSION Contrast-enhanced and diffusion-weighted imaging showed significant changes after TACE of neuroendocrine tumors and can be used to assess response of targeted tumors.

Receiver Operating Characteristic Analysis of Diffusion-Weighted Magnetic Resonance Imaging in Differentiating Hepatic Hemangioma From Other Hypervascular Liver Lesions

Purpose: To evaluate the role of diffusion-weighted imaging in differentiating between hepatic hemangiomas, both typical and atypical, and other hypervascular liver lesions. Methods: Retrospective review of 182 hypervascular liver lesions in 117 patients was performed. Diffusion and contrast-enhanced magnetic resonance imaging were performed using a 1.5-T unit. Imaging protocol consisted of T2-weighted fast spin-echo images, breath-hold diffusion-weighted echo-planar images, and breath-hold unenhanced and contrast-enhanced T1-weighted 3-dimensional fat-suppressed spoiled gradient-echo images in the arterial phase (20 seconds) and portal venous phase (60 seconds). Signal intensity changes and apparent diffusion coefficient (ADC) values were evaluated for all lesions. Unpaired t test was used to compare the mean ADC values for different lesions, and statistical significance was set at P < 0.01. Receiver operating characteristic analysis was used to determine the accuracy of diffusion-weighted imaging in differentiating hemangiomas from other hypervascular liver lesions. Results: Lesions included typical and atypical hemangioma (n = 38), hepatocellular carcinoma (HCC; n = 58), focal nodular hyperplasia (FNH; n = 22), and neuroendocrine tumor metastasis (NET; n = 64) with a mean tumor size of 5.3 cm. Mean ADC value for hemangioma, HCC, FNH, and NET was 2.29 × 10−3, 1.55 × 10−3, 1.65 × 10−3, and 1.43× 10−3 mm2/s, respectively. There was a statistically significantdifference in the ADC value of hemangioma compared with thatofFNH (P < 0.001), HCC (P < 0.001), and NET (P < 0.001), respectively. The area under the receiver operating characteristic curve was 0.91. Conclusions: Diffusion-weighted magnetic resonance imaging and ADC maps can provide rapid quantifiable information to differentiate typical and atypical hemangiomas from other hypervascular liver lesions.

Nonresectable Hepatocellular Carcinoma: Long-term Toxicity in Patients Treated with Transarterial Chemoembolization—Single-Center Experience

PURPOSE To determine the toxicity profile of transarterial chemoembolization (TACE) at 6 months and 1 year after treatment in patients with hepatocellular carcinoma (HCC) in a standardized oncology protocol so that TACE could be compared with systemic chemotherapeutic regimens for liver cancer. MATERIALS AND METHODS The study was authorized by the institutional review board. Between January 2002 and January 2007, 190 patients (155 men, 35 women; median age, 65 years; age range, 18-84 years) with HCC who underwent TACE treatment were identified from a prospectively collected database. Clinical records of complete blood cell counts and chemical profiles at baseline and at 6 and 12 months after treatment were studied retrospectively. Toxicity was graded according to the common terminology criteria for adverse events (CTCAE). A transition (survival) analysis perspective was used to estimate the distribution of toxicity grades. Patient survival from the first TACE session was calculated with Kaplan-Meier analysis. RESULTS Grade 3 or 4 toxicity 6 and 12 months, respectively, after treatment included leukocytopenia (7% and 19%); anemia (9% and 19%); thromobocytopenia (13% and 23%); prolonged activated partial thromboplastin time (8% and 18%); elevated aspartate aminotransferase (15% and 18%), alanine aminotransferase (10% and 18%), and alkaline phosphatase (8% and 18%) levels; hypoalbuminemia (10% and 19%); hyperbilirubinemia (10% and 22%); and alopecia (18%). The cumulative survival rate was 58% at 1 year, 39% at 2 years, and 29% at 3 years. These toxicity rates were considerably lower than those reported after treatment with currently used systemic chemotherapeutic agents. CONCLUSION Study results show that TACE has a favorable long-term toxicity profile in patients with HCC. Data clearly support the role of TACE in the treatment of patients with nonresectable HCC.

Targeting of VX2 rabbit liver tumor by selective delivery of 3-bromopyruvate: A biodistribution and survival study

The aim of this study was to determine the biodistribution and tumor targeting ability of 14C-labeled 3-bromopyruvate ([14C]3-BrPA) after i.a. and i.v. delivery in the VX2 rabbit model. In addition, we evaluated the effects of [14C]3-BrPA on tumor and healthy tissue glucose metabolism by determining 18F-deoxyglucose (FDG) uptake. Last, we determined the survival benefit of i.a. administered 3-BrPA. In total, 60 rabbits with VX2 liver tumor received either 1.75 mM [14C]3-BrPA i.a., 1.75 mM [14C]3-BrPA i.v., 20 mM [14C]3-BrPA i.v., or 25 ml of phosphate-buffered saline (PBS). All rabbits (with the exception of the 20 mM i.v. group) received FDG 1 h before sacrifice. Next, we compared survival of animals treated with i.a. administered 1.75 mM [14C]3-BrPA in 25 ml of PBS (n = 22) with controls (n = 10). After i.a. infusion, tumor uptake of [14C]3-BrPA was 1.8 ± 0.2% percentage of injected dose per gram of tissue (%ID/g), whereas other tissues showed minimal uptake. After i.v. infusion (1.75 mM), tumor uptake of [14C]3-BrPA was 0.03 ± 0.01% ID/g. After i.a. administration of [14C]3-BrPA, tumor uptake of FDG was 26 times lower than in controls. After i.v. administration of [14C]3-BrPA, there was no significant difference in tumor FDG uptake. Survival analysis showed that rabbits treated with 1.75 mM 3-BrPA survived longer (55 days) than controls (18.6 days). Intra-arterially delivered 3-BrPA has a favorable biodistribution profile, combining a high tumor uptake resulting in blockage of FDG uptake with no effects on healthy tissue. The local control of the liver tumor by 3-BrPA resulted in a significant survival benefit.

Chemoembolization of Hepatic Metastases from Ocular Melanoma: Assessment of Response with Contrast-Enhanced and Diffusion-Weighted MRI

OBJECTIVE The purpose of this study was to assess the utility of assessment of tumor size and enhancement with diffusion-weighted and conventional MRI in the evaluation of response to transarterial chemoembolization therapy for metastatic ocular melanoma. CONCLUSION In patients with ocular melanoma and liver metastasis treated with transarterial chemoembolization, functional MRI showed significant changes in the lesions. These changes included a decrease in tumor enhancement and an increase in the apparent diffusion coefficient of the tumor, suggesting increasing tumor necrosis and cell death.

Role of functional magnetic resonance imaging in assessing metastatic leiomyosarcoma response to chemoembolization.

Purpose: To assess the value of functional magnetic resonance (MR) imaging in the evaluation of early tumor response after transarterial chemoembolization (TACE) for metastatic leiomyosarcoma and compare tumor response using functional MR imaging versus traditional imaging response assessment, which is based on tumor size. Materials and Methods: We evaluated 31 lesions in 10 patients with liver metastases from leiomyosarcoma using MR imaging studies before and after TACE. Diffusion and contrast-enhanced MR imaging was performed on a 1.5-T unit. Imaging protocol consisted of T2-weighted fast spin-echo images, breath-hold diffusion-weighted echo-planar images, and breath-hold unenhanced and contrast-enhanced T1-weighted 3-dimensional fat-suppressed spoiled gradient-echo images in the arterial phase (20 seconds) and portal venous phase (60 seconds). Parameters evaluated included change in tumor size, enhancement, and apparent diffusion coefficient (ADC) values. Median survival was also calculated for the entire cohort. Results: The 31 lesions evaluated had a mean size of 4.8 cm before treatment. Tumor size decreased only by 2% immediately after treatment. Decrease of tumor enhancement after treatment was significant (P < 0.0001) in the arterial phase (69%) as well as in the portal venous phase (64%). After TACE, mean tumor ADC increased by 20% (P = 0.0015), whereas mean nontreated liver, spleen, and muscle ADC values did not change significantly (P = 0.44, P = 0.287, and P = 0.098, respectively). Patient survival from time of first TACE was 21 months for the entire cohort. Conclusion: In patients with leiomyosarcoma and liver metastases who were treated with TACE, significant early changes in the treated lesions occurred on functional MR imaging. These include decrease in tumor enhancement and increase in tumor ADC value, suggesting increasing tumor necrosis and cell death. Changes in tumor size were small and inadequate to assess treatment response, suggesting limitation of the current response criteria in the early assessment of tumor response.

Diffusion-weighted and Gd-EOB-DTPA-contrast-enhanced magnetic resonance imaging for characterization of tumor necrosis in an animal model.

Purpose: To evaluate the role of diffusion-weighted magnetic resonance imaging (MRI) in determining tumor necrosis and contrast-enhanced MRI using gadoxetic acid disodium (Gd-EOB-DTPA) in determining maximum tumor size measurement and tumor delineation compared with criterion-standard histologic measurements in the rabbit VX2 liver tumor model. Materials and Methods: VX2 tumors were implanted in the livers of 13 rabbits. Magnetic resonance imaging was performed using a 1.5-T MRI scanner and an extremity coil. The imaging protocol included T2-weighted fast spin-echo images, 3-dimensional T1-weighted spoiled gradient-echo with and without fat suppression after administration of Gd-EOB-DTPA, and diffusion-weighted echo planar images. Rabbits were killed, and the tumor was harvested and sliced at 4-mm intervals in the axial plane. The MRI parameters evaluated were tumor size, tumor delineation, and tumor apparent diffusion coefficient (ADC) values. Histologic sections were evaluated to quantify tumor necrosis. Results: On contrast-enhanced MRI (obtained from 11 rabbits), the mean tumor sizes were 20, 19, and 20 mm in the arterial, portal venous, and delayed phases, respectively. Tumor delineation was most distinguishable in the delayed phase. On diffusion-weighted MRI (acquired in 13 rabbits), the mean tumor ADC value was 1.84 × 10−3 mm2/s. The mean tumor size at pathology was 16 mm. The mean percent necrosis at the tumors pathologic condition was 36%. The correlation between ADC value and percent necrosis showed an R value of 0.68. Conclusions: Contrast-enhanced MRI using Gd-EOB-DTPA may provide additional information about tumor outline in the liver. Moreover, we showed a remarkable correlation between ADC values and tumor necrosis. Thus, diffusion-weighted imaging may be useful to assess tumor necrosis; nevertheless, the search for new modalities remains important.

Assessment of Tumoricidal Efficacy and Response to Treatment with 18F-FDG PET/CT After Intraarterial Infusion with the Antiglycolytic Agent 3-Bromopyruvate in the VX2 Model of Liver Tumor

The purpose of this study was to determine the effects of 3-bromopyruvate (3-BrPA) on tumor glucose metabolism as imaged with 18F-FDG PET/CT at multiple time points after treatment and compare them with those after intraarterial control injections of saline. Methods: Twenty-three New Zealand White rabbits implanted intrahepatically with VX2 tumors were assigned to 1 of 2 groups: 14 rabbits were assigned to the treatment group (TG) and 9 to the saline control group (SG). All animals were infused with 25 mL of either 1.75 mM 3-BrPA or saline over 1 h via a 2-French catheter, which was secured in the hepatic artery. For PET/CT, the animals were injected with 37 MBq of 18F-FDG at 1 d before treatment and 2 h, 24 h, and 1 wk after treatment. Tumor size, tumor and liver maximal standardized uptake value (SUVmax), and tumor-to-background ratios were calculated for all studies. Seven TG and 5 SG animals were sacrificed at 1 wk after treatment for histopathologic analysis. Results: Intense 18F-FDG uptake was seen in untreated tumors. A significant reduction in tumor SUVmax was noted in TG animals, when compared with SG animals, at 1 wk after treatment (P = 0.006). The tumor–to–liver background ratio in the TG animals, compared with the SG animals, was significantly reduced as early as 24 h after treatment (P = 0.01) and remained reduced at 1 wk (P = 0.003). Tumor SUVmax increased from the baseline levels at 7 d in controls (P = 0.05). The histopathologic analysis of explanted livers revealed increased tumor necrosis in all TG samples. There was a significant inverse correlation (r2 = 0.538, P = 0.005) between the percentage of tumor necrosis on histopathology and tumor SUVmax on 18F-FDG PET at 7 d after treatment with 3-BrPA. Conclusion: Intraarterial injection of 3-BrPA resulted in markedly decreased 18F-FDG uptake as imaged by PET/CT and increased tumor necrosis on histopathology at 1 wk after treatment in the VX2 rabbit liver tumor. PET/CT appears to be a useful means to follow antiglycolytic therapy with 3-BrPA.

Quantitative Proton MR Spectroscopy as a Biomarker of Tumor Necrosis in the Rabbit VX2 Liver Tumor

PURPOSE To compare metabolic magnetic resonance (MR) imaging findings (ie, quantification of tumor choline concentration) with percentage of necrosis on pathologic examination in rabbits bearing VX2 liver tumors. MATERIALS AND METHODS VX2 tumors were implanted in the livers of 16 rabbits. MR imaging was performed with a 1.5-T MR scanner and extremity coil, and a hydrogen-1 ((1)H) proton MR spectroscopy ((1)H MRS) imaging protocol was used. Rabbits were euthanized immediately after imaging, and the tumor was harvested and sliced at 4-mm intervals in the axial plane. Choline concentration was calculated and was compared with the percentage of tumor necrosis on pathologic examination. RESULTS Mean tumor size at pathologic examination was 16 mm (range, 12-22 mm). Mean percentage of necrosis at pathologic examination was 22% (range, 4%-44%). Choline concentration showed a relatively high inverse correlation with percentage of necrosis on pathologic examination, with an r value of 0.78 (P < .002). CONCLUSIONS Choline concentration showed a relatively high inverse correlation with tumor necrosis on pathologic examination. Therefore, (1)H MRS may be useful to assess tumor necrosis.