Prospective study of Lipiodol distribution as an imaging marker for doxorubicin pharmacokinetics during conventional transarterial chemoembolization of liver malignancies.

OBJECTIVES: To evaluate the prognostic potential of Lipiodol distribution for the pharmacokinetic (PK) profiles of doxorubicin (DOX) and doxorubicinol (DOXOL) after conventional transarterial chemoembolization (cTACE). METHODS: This prospective clinical trial ( ClinicalTrials.gov : NCT02753881) included 30 consecutive participants with liver malignancies treated with cTACE (5/2016-10/2018) using 50 mg DOX/10 mg mitomycin C emulsified 1:2 with ethiodized oil (Lipiodol). Peripheral blood was sampled at 10 timepoints for standard non-compartmental analysis of peak concentrations (Cmax) and area under the curve (AUC) with dose normalization (DN). Imaging markers included Lipiodol distribution on post-cTACE CT for patient stratification into 1 segment (n = 10), ≥ 2 segments (n = 10), and lobar cTACE (n = 10), and baseline enhancing tumor volume (ETV). Adverse events (AEs) and tumor response on MRI were recorded 3-4 weeks post-cTACE. Statistics included repeated measurement ANOVA (RM-ANOVA), Mann-Whitney, Kruskal-Wallis, Fisher's exact test, and Pearson correlation. RESULTS: Hepatocellular (n = 26), cholangiocarcinoma (n = 1), and neuroendocrine metastases (n = 3) were included. Stratified according to Lipiodol distribution, DOX-Cmax increased from 1 segment (DOX-Cmax, 83.94 ± 75.09 ng/mL; DN-DOX-Cmax, 2.67 ± 2.02 ng/mL/mg) to ≥ 2 segments (DOX-Cmax, 139.66 ± 117.73 ng/mL; DN-DOX-Cmax, 3.68 ± 4.20 ng/mL/mg) to lobar distribution (DOX-Cmax, 334.35 ± 215.18 ng/mL; DN-DOX-Cmax, 7.11 ± 4.24 ng/mL/mg; p = 0.036). While differences in DN-DOX-AUC remained insignificant, RM-ANOVA revealed significant separation of time concentration curves for DOX (p = 0.023) and DOXOL (p = 0.041) comparing 1, ≥ 2 segments, and lobar cTACE. Additional indicators of higher DN-DOX-Cmax were high ETV (p = 0.047) and Child-Pugh B (p = 0.009). High ETV and tumoral Lipiodol coverage also correlated with tumor response. AE occurred less frequently after segmental cTACE. CONCLUSIONS: This prospective clinical trial provides updated PK data revealing Lipiodol distribution as an imaging marker predictive of DOX-Cmax and tumor response after cTACE in liver cancer. KEY POINTS: • Prospective pharmacokinetic analysis after conventional TACE revealed Lipiodol distribution (1 vs. ≥ 2 segments vs. lobar) as an imaging marker predictive of doxorubicin peak concentrations (Cmax). • Child-Pugh B class and tumor hypervascularization, measurable as enhancing tumor volume (ETV) at baseline, were identified as additional predictors for higher dose-normalized doxorubicin Cmax after conventional TACE. • ETV at baseline and tumoral Lipiodol coverage can serve as predictors of volumetric tumor response after conventional TACE according to quantitative European Association for the Study of the Liver (qEASL) criteria.

Lipiodol transarterial chemoembolization for hepatocellular carcinoma: A systematic review of efficacy and safety data.

UNLABELLED: Transarterial chemoembolization (TACE) using lipiodol-based regimens, including the administration of an anticancer-in-oil emulsion followed by embolic agents, is widely used in the treatment of hepatocellular carcinoma (HCC). This approach has been supported by meta-analyses of randomized, controlled trials (RCTs) performed more than a decade ago. We performed a systematic review to understand current efficacy and safety data of lipiodol TACE in treatment of HCC. A search of the literature published between January 1, 1980 and June 30, 2013 was performed using MEDLINE and EMBASE databases. All potentially relevant publications were reviewed and articles were selected based on predefined inclusion and exclusion criteria. Of a total of 1,564 articles reviewed, 101 articles, including a total of 10,108 patients treated with lipiodol TACE, were selected for the efficacy analysis. Objective response rate was 52.5% (95% confidence interval [CI]: 43.6-61.5). Overall survival (OS) was 70.3% at 1 year, 51.8% at 2 years, 40.4% at 3 years, and 32.4% at 5 years. Median OS was 19.4 months (95% CI: 16.2-22.6). A total of 217 articles presenting precise description on numbers of adverse events (AEs) were selected for the safety review: In these studies, a total of 21,461 AEs were reported in 15,351 patients. Liver enzyme abnormalities were the most commonly observed AE, followed by the symptoms associated with postembolization syndrome. Overall mortality rate was 0.6% and the most common cause of death was related to acute liver insufficiency. CONCLUSIONS: In a systematic literature review, survival figures of HCC patients undergoing lipiodol TACE appear to be in line with those reported in previous RCTs, and no new or unexpected safety concerns were identified. (Hepatology 2016;64:106-116).

Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study.

BACKGROUND & AIMS: GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) is a prospective, observational registry study evaluating the safety of sorafenib and treatment practices in hepatocellular carcinoma patients. This large global database allowed for assessment of the use and tolerability of sorafenib in patients with liver dysfunction. METHODS: Baseline characteristics and medical/treatment history were collected in patients for whom a decision to treat with sorafenib had been made. Adverse event, dosing, and outcomes data were collected during follow-up. RESULTS: In the overall safety population (n=3202), 1968 patients (61%) had Child-Pugh A status and 666 (21%) had Child-Pugh B. The majority of Child-Pugh A (72%) and Child-Pugh B (70%) patients received an initial sorafenib dose of 800mg, consistent with the label, and dose reduction rates were 40% and 29%, respectively. The type and incidence of adverse events were generally consistent across Child-Pugh subgroups. The incidence of drug-related adverse events leading to discontinuation was similar between Child-Pugh A and Child-Pugh B patients (17% and 21%). In the intent-to-treat population (n=3213), median overall survival (months [95% confidence interval]) was longer in Child-Pugh A patients (13.6 [12.8-14.7]) compared with Child-Pugh B patients (5.2 [4.6-6.3]). CONCLUSIONS: In clinical practice, the safety profile of sorafenib appeared to be consistent across Child-Pugh A and Child-Pugh B patients. Findings suggest sorafenib may be safely used in some Child-Pugh B patients and indicate the importance of careful patient evaluation when making treatment decisions. LAY SUMMARY: The GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) study is a large prospective registry of patients with liver cancer who were treated with sorafenib. The aims were to evaluate the safety and tolerability of sorafenib among those in which the liver was not functioning properly. The study showed that the safety profile of sorafenib was consistent across patients with preserved liver function and those in which the liver was not functioning properly, and therefore, suggesting that sorafenib may be a valid treatment for some patients with liver impairment.

A Review and Update of Treatment Options and Controversies in the Management of Hepatocellular Carcinoma.

OBJECTIVE: To review the current management, outline recent advances and address controversies in the management of hepatocellular carcinoma (HCC). SUMMARY OF BACKGROUND DATA: The treatment of HCC is multidisciplinary involving hepatologists, surgeons, medical oncologists, radiation oncologists, radiologists, interventional radiologists, and other disciplines. Each of these disciplines brings its unique perspective and differing opinions that add to controversies in the management of HCC. METHODS: A focused literature review was performed to identify recent studies on the management of HCC and thereby summarize relevant information on the various therapeutic modalities and controversies involved in the treatment of HCC. RESULTS: The main treatment algorithms continue to rely on hepatic resection or transplantation with controversies involving patients harboring early stage disease and borderline hepatic function. The other treatment strategies include locoregional therapies, radiation, and systemic therapy used alone or in combination with other treatment modalities. Recent advances in locoregional therapies, radiation, and systemic therapies have provided better therapeutic options with curative intent potential for some locoregional therapies. Further refinements in combination therapies such as algorithms consisting of locoregional therapies and systemic or radiation therapies are likely to add additional options and improve survival. CONCLUSIONS: The management of HCC has witnessed significant strides with advances in existing options and introduction of several new treatment modalities of various combinations. Further refinements in these treatment options combined with enrollment in clinical trials are essential to improve the management and outcomes of patients with HCC.

Regional differences in sorafenib-treated patients with hepatocellular carcinoma: GIDEON observational study.

BACKGROUND & AIMS: Treatment approaches for hepatocellular carcinoma (HCC) vary across countries, but these differences and their potential impact on outcomes have not been comprehensively assessed. Data from the multinational GIDEON (Global Investigation of therapeutic DEcisions in HCC and Of its treatment with sorafeNib) registry evaluated differences in patient characteristics, practice patterns and outcomes in HCC across geographical regions in patients who received sorafenib. METHODS: GIDEON is a non-randomised, observational registry study conducted in 39 countries across five global regions. HCC patients in whom a decision to treat with sorafenib was made in clinical practice and according to local practices were included. RESULTS: 3202 patients were evaluable for safety analysis: Asia-Pacific (n = 928), Japan (n = 508), Europe (n = 1113), USA (n = 563) and Latin America (n = 90). Patients in Japan had earlier-stage disease at initial diagnosis compared with patients in other regions (Barcelona Clinic Liver Cancer stage A; 43.7% vs 9.1-24.3%). Use of locoregional therapies before sorafenib, including transarterial chemoembolisation, was more common in Japan (84.4%) and Asia-Pacific (67.2%) compared with the USA (49.4%) and Europe (43.5%). Treatment patterns with respect to sorafenib also differed, with a shorter duration of treatment reported in the USA and Asia-Pacific. Time from initial diagnosis to death was longer in Japan compared with other regions (median, 79.6 months vs 14.8-25.0 months). CONCLUSIONS: Data from GIDEON highlight regional variations in the management of HCC and patient outcomes. Greater standardisation of management may help optimise outcomes for HCC patients.

Evaluation of 70-150-µm doxorubicin-eluting beads for transcatheter arterial chemoembolization in the rabbit liver VX2 tumour model.

AIM: To evaluate the pharmacokinetic profile (PK) and embolization effect of 70-150-µm doxorubicin eluting beads (DEBs) following intra-arterial injection (i.a.) in the rabbit liver VX2 tumour model. MATERIALS AND METHODS: In this ACUC-approved study, 25 white New Zealand rabbits were randomly assigned into a small DEB group (SDB, n = 7, 70-150-µm DEBs), large DEB group (LDB, n = 7, 100-300-µm DEBs), untreated controls (n = 7), and doxorubicin controls (n = 4, without tumour, received i.a. 12.5 mg doxorubicin). Plasma PK was assessed up to 180 min post-injection. Drug tissue and liver enzyme levels, radiologic tumor response and histopathologic tumour necrosis were assessed at 7 days. RESULTS: Mean tumour doxorubicin concentrations were 922.83 nM (SD = 722.05) and 361.48 nM (SD = 473.23) for the SDB and LDB, respectively (p = 0.005). There was no statistically significant difference in tumour doxorubicinol, plasma doxorubicin and doxorubicinol PK values. More beads were observed in the SDB tumours (p = 0.01). Liver enzymes increased and gradually declined over the observation period, with significantly higher values in the SDB. CONCLUSION: In this preclinical study, plasma PK of i.a.-injected 70-150-µm DEBs was not different than that of 100-300-µm DEBs. More beads and higher tissue doxorubicin levels were observed in the SDB tumours. KEY POINTS: • Small and large doxorubicin-eluting beads show similar plasma pharmacokinetic profiles. • Higher tissue doxorubicin levels were observed in the small bead group. • Liver enzymes were overall significantly higher in the small bead group.

Open-Label Single-Arm Phase II Trial of Sorafenib Therapy with Drug-eluting Bead Transarterial Chemoembolization in Patients with Unresectable Hepatocellular Carcinoma: Clinical Results.

PURPOSE: To determine the efficacy of combined continuous sorafenib therapy and drug-eluting bead (DEB) transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This study was conducted in accordance with the principles of the Declaration of Helsinki, and all patients provided written informed consent prior to enrollment. Inclusion criteria included unresectable HCC, a treatment naïve status, an Eastern Cooperative Oncology Group score of 0-1, and a Child-Pugh score of A-B7. Continuous sorafenib therapy (400 mg twice daily) was started 1 week before the first round of DEB TACE, which was performed in 6-week cycles. Up to four rounds of DEB TACE therapy were allowed on demand within 6 months. The primary end point was safety. Secondary end points were time to progression (TTP), response rate, and overall survival (OS) and were stratified by the Barcelona Clinic Liver Cancer (BCLC) stage and the duration of sorafenib therapy. OS was assessed with Kaplan-Meier estimates, and the Mantel-Cox log-rank test was used to determine differences in survival. A two-sided P value of less than .05 was considered to indicate a significant difference. The study was approved by the Johns Hopkins institutional review board and remained open from March 2009 to January 2012. RESULTS: Fifty patients--of whom 76% were male, 92% had a Child-Pugh score of A, and 62% had BCLC stage C disease--underwent a median of three cycles of therapy. The 6-month disease control rate (defined as complete response plus partial response plus stable disease) was 94% according to the response evaluation criteria in solid tumors. Median TTP and OS were 13.9 and 20.4 months, respectively, and 81% of toxicities were grades 1-2. There was one death that was possibly treatment related. CONCLUSION: Combined continuous sorafenib therapy and on-demand DEB TACE provided excellent local disease control and did not lead to multiplicative toxicities. Long-term administration of sorafenib therapy in combination with DEB TACE may have a survival benefit in patients with advanced HCC.

Feasibility of a Modified Cone-Beam CT Rotation Trajectory to Improve Liver Periphery Visualization during Transarterial Chemoembolization.

PURPOSE: To compare liver coverage and tumor detectability by using preprocedural magnetic resonance (MR) images as a reference, as well as radiation exposure of cone-beam computed tomography (CT) with different rotational trajectories. MATERIALS AND METHODS: Fifteen patients (nine men and six women; mean age ± standard deviation, 65 years ± 5) with primary or secondary liver cancer were retrospectively included in this institutional review board-approved study. A modified cone-beam CT protocol was used in which the C-arm rotates from +55° to -185° (open arc cone-beam CT) instead of -120° to +120° (closed arc cone-beam CT). Each patient underwent two sessions of transarterial chemoembolization between February 2013 and March 2014 with closed arc and open arc cone-beam CT (during the first and second transarterial chemoembolization sessions, respectively, as part of the institutional transarterial chemoembolization protocol). For each cone-beam CT examination, liver volume and tumor detectability were assessed by using MR images as the reference. Radiation exposure was compared by means of a phantom study. For statistical analysis, paired t tests and a Wilcoxon signed rank test were performed. RESULTS: Mean liver volume imaged was 1695 cm(3) ± 542 and 1857 cm(3) ± 571 at closed arc and open arc cone-beam CT, respectively. The coverage of open arc cone-beam CT was significantly higher compared with closed arc cone-beam CT (97% vs 86% of the MR imaging liver volume, P = .002). In eight patients (53%), tumors were partially or completely outside the closed arc cone-beam CT field of view. All tumors were within the open arc cone-beam CT field of view. The open arc cone-beam CT radiation exposure by means of weighted CT index was slightly lower compared with that of closed arc cone-beam CT (-5.1%). CONCLUSION: Open arc cone-beam CT allowed for a significantly improved intraprocedural depiction of peripheral hepatic tumors while achieving a slight radiation exposure reduction.

A new angiographic imaging platform reduces radiation exposure for patients with liver cancer treated with transarterial chemoembolization.

OBJECTIVES: To quantify the reduction of radiation liver cancer patients are exposed to during transarterial chemoembolization (TACE), while maintaining diagnostic image quality, using a new C-arm imaging platform. METHODS: In this prospective, HIPAA-compliant, IRB-approved, two-arm trial, 78 consecutive patients with primary or secondary liver cancer were treated with TACE on a C-arm imaging platform before and after an upgrade incorporating optimized acquisition parameters and advanced real-time image processing algorithms. Dose area product (DAP) and radiation time of each digital fluoroscopy (DF), digital subtraction angiography (DSA) and cone beam CT (CBCT) were recorded. DSA image quality was assessed by two blinded and independent readers on a four-rank scale. RESULTS: Both cohorts showed no significant differences with regard to patient characteristics and tumour burden. The new system resulted in a statistically significant reduction of cumulative DAP of 66% compared to the old platform (median 132.9 vs. 395.8 Gy cm(2)). Individually, DAP of DF, DSA and CBCT decreased by 52%, 79% and 15% (p < 0.01, p < 0.01, p = 0.51), respectively. No statistically significant differences in DSA image quality were found between the two imaging platforms. CONCLUSIONS: The new imaging platform significantly reduced radiation exposure for TACE procedures without increased radiation time or negative impact on DSA image quality. KEY POINTS: • The new C-arm system allowed reduction of radiation exposure by two thirds • The procedure's course was not affected by the new platform • No decrease in DSA image quality was observed after the radiation reduction.

Volumetric assessment of tumour response using functional MR imaging in patients with hepatocellular carcinoma treated with a combination of doxorubicin-eluting beads and sorafenib.

OBJECTIVE: To prospectively assess treatment response using volumetric functional magnetic resonance imaging (MRI) metrics in patients with hepatocellular carcinoma (HCC) treated with the combination of doxorubicin-eluting bead-transarterial chemoembolization (DEB TACE) and sorafenib. METHODS: A single center study enrolled 41 patients treated with systemic sorafenib, 400 mg twice a day, combined with DEB TACE. All patients had a pre-treatment and 3-4 week post-treatment MRI. Anatomic response criteria (RECIST, mRECIST and EASL) and volumetric functional response (ADC, enhancement) were assessed. Statistical analyses included paired Student's t-test, Kaplan-Meier curves, Cohen's Kappa, and multivariate cox proportional hazard model. RESULTS: Median tumour size by RECIST remained unchanged post-treatment (8.3 ± 4.1 cm vs. 8.1 ± 4.3 cm, p = 0.44). There was no significant survival difference for early response by RECIST (p = 0.93). EASL and mRECIST could not be analyzed in 12 patients. Volumetric ADC increased significantly (1.32 × 10(-3) mm(2)/sec to 1.60 × 10(-3) mm(2)/sec, p < 0.001), and volumetric enhancement decreased significantly in HAP (38.2% to 17.6%, p < 0.001) and PVP (76.6% to 41.2%, p < 0.005). Patients who demonstrated ≥ 65% decrease PVP enhancement had significantly improved overall survival compared to non-responders (p < 0.005). CONCLUSION: Volumetric PVP enhancement was demonstrated to be significantly correlated with survival in the combination of DEB TACE and sorafenib for patients with HCC, enabling precise stratification of responders and non-responders. KEY POINTS: • PVP enhancement is significantly correlated with survival in responders (p < 0.005). • There was no significant survival difference for early response using RECIST (p = 0.93). • mRECIST or EASL could not assess tumour response in 29% of patients.

Response stratification and survival analysis of hepatocellular carcinoma patients treated with intra-arterial therapy using MR imaging-based arterial enhancement fraction.

PURPOSE: To investigate the feasibility that arterial enhancement fraction (AEF) is associated with response of hepatocellular carcinoma (HCC) following intra-arterial therapy (IAT) and to compare AEF response with currently used tumor response metrics. MATERIALS AND METHODS: The AEF, Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), and European Association for the Study of the Liver (EASL) of the largest treated index lesion and AEF of the tumor-free hepatic parenchyma was measured on representative axial images in 131 patients (108 male; mean age, 61.9 years). Clinical measures and patient survival were assessed. Statistical analysis included Wilcoxon signed-rank test and the COX proportional hazards model. RESULTS: After IAT, the mean AEF of the tumor decreased by 22% (66.7-44.8%, P < 0.0001), while the mean AEF of the tumor-free parenchyma remained unchanged (27.2-26.5%, P = 0.50). Median survival of all 131 patients with liver cancer was 17 months. Patients were stratified into AEF-responders if they had an AEF-decrease ≥35% (AEF-responders: n = 67; AEF-nonresponders: n = 64). AEF-responders survived longer than nonresponders (34.8 months versus 10.8 months, hazard ratio = 0.39; P < 0.0001). Responders according to RECIST, mRECIST, or EASL did not survive significantly longer compared with nonresponders. CONCLUSION: Evaluating the AEF values based on tri-phasic MRI is associated with tumor response in patients with unresectable HCC treated with IAT.

Tumor glycolysis as a target for cancer therapy: progress and prospects.

Altered energy metabolism is a biochemical fingerprint of cancer cells that represents one of the "hallmarks of cancer". This metabolic phenotype is characterized by preferential dependence on glycolysis (the process of conversion of glucose into pyruvate followed by lactate production) for energy production in an oxygen-independent manner. Although glycolysis is less efficient than oxidative phosphorylation in the net yield of adenosine triphosphate (ATP), cancer cells adapt to this mathematical disadvantage by increased glucose up-take, which in turn facilitates a higher rate of glycolysis. Apart from providing cellular energy, the metabolic intermediates of glycolysis also play a pivotal role in macromolecular biosynthesis, thus conferring selective advantage to cancer cells under diminished nutrient supply. Accumulating data also indicate that intracellular ATP is a critical determinant of chemoresistance. Under hypoxic conditions where glycolysis remains the predominant energy producing pathway sensitizing cancer cells would require intracellular depletion of ATP by inhibition of glycolysis. Together, the oncogenic regulation of glycolysis and multifaceted roles of glycolytic components underscore the biological significance of tumor glycolysis. Thus targeting glycolysis remains attractive for therapeutic intervention. Several preclinical investigations have indeed demonstrated the effectiveness of this therapeutic approach thereby supporting its scientific rationale. Recent reviews have provided a wealth of information on the biochemical targets of glycolysis and their inhibitors. The objective of this review is to present the most recent research on the cancer-specific role of glycolytic enzymes including their non-glycolytic functions in order to explore the potential for therapeutic opportunities. Further, we discuss the translational potential of emerging drug candidates in light of technical advances in treatment modalities such as image-guided targeted delivery of cancer therapeutics.

Phase 2 trial of concurrent bevacizumab and transhepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma.

BACKGROUND: Vascular endothelial growth factor is up-regulated in hepatocellular carcinoma (HCC) and is further up-regulated after transhepatic arterial chemoembolization. The authors of this report conducted a phase 2 trial to evaluate the safety and efficacy of bevacizumab combined with chemoembolization in patients with unresectable HCC. METHODS: Patients who had an Eastern Cooperative Oncology Group performance of status 0 to 2, a Child-Pugh score of A or B, and Barcelona Clinic Liver Cancer stage B or C HCC were eligible. Treatment consisted of bevacizumab every 2 weeks and chemoembolization during the third week of a 6-week cycle for up to 3 cycles over 6 months. The primary endpoints were safety and efficacy. RESULTS: Twenty-five patients received chemoembolization and bevacizumab. The most common grade 3 and 4 events after the first treatment cycle were leukocytopenia (12%), fatigue (12%), and hyponatremia (12%). Serious toxicities that had a known association with bevacizumab were observed in 4 patients. Thirty-day mortality was 0%. The median time to tumor progression for the targeted lesions was not reached, and overall survival was 10.8 months. The objective response rate was 60% using enhancement response evaluation criteria, and the disease control rate was 100%. CONCLUSIONS: Concurrent treatment with bevacizumab and chemoembolization was safe in carefully selected patients and demonstrated antitumor activity in patients with unresectable HCC. These results support the further development of bevacizumab combined with chemoembolization as a treatment for unresectable HCC.

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.

Unresectable hepatocellular carcinoma: MR imaging after intraarterial therapy. Part II. Response stratification using volumetric functional criteria after intraarterial therapy.

PURPOSE: To assess whether volumetric functional magnetic resonance (MR) results 3-4 weeks after initial intraarterial therapy can aid accurate distinction between responders and nonresponders, to determine whether overall survival (OS) is improved, and to compare volumetric functional MR response with anatomic response criteria (Response Evaluation Criteria in Solid Tumors [RECIST], modified RECIST [mRECIST], European Association for the Study of the Liver [EASL]), as well as α1-fetoprotein [AFP] level. MATERIALS AND METHODS: In this single-institution HIPAA-compliant retrospective, institutional review board-approved study, informed consent was waived; 143 patients with hepatocellular carcinoma underwent intraarterial therapy between October 2005 and February 2011. Volumetric functional MR response (25% or more increase in apparent diffusion coefficient, 65% or more decrease in enhancement) was stratified as follows: Dual-parameter responders fulfilled both criteria, single-parameter responders fulfilled one criterion, and those with stable disease (SD) fulfilled neither. RECIST, mRECIST, EASL, and AFP response criteria were determined. Kaplan-Meier technique, log-rank tests, and the Cox proportional hazards model were used to test whether OS was different per response. RESULTS: OS differed significantly between single-parameter responders and dual-parameter responders (P = .01) and between single-parameter responders and those with SD (P = .001). Dual-parameter responders' response improved OS compared with single-parameter responders; risk of death decreased (hazard ratio [HR] = 0.28, P = .01). In those with SD compared with single-parameter responders, risk of death increased (HR = 2.09, P = .001). RECIST, mRECIST, and EASL stratification was short of significant; most lesions were classified as SD. Baseline AFP level increased in 55 patients; AFP responders versus AFP nonresponders had decreased risk of death (HR = 0.36, P = .002). Agreement between anatomic response criteria and volumetric functional MR findings (κ = 0.06-0.12) and between AFP response and imaging criteria (κ = -0.04 to 0.14) was low. CONCLUSION: Volumetric functional MR response 3-4 weeks after initial intraarterial therapy showed improved OS. Volumetric functional MR was superior to current imaging (RECIST, mRECIST, and EASL) and biochemical (AFP level) response criteria.

Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis.

BACKGROUND: Many patients with intrahepatic cholangiocarcinoma (ICC) present with advanced and inoperable disease. Data on the safety and efficacy of intra-arterial therapy (IAT) for ICC are limited. METHODS: Between 1992 and 2012, a total of 198 patients with advanced ICC treated with IAT were retrospectively identified from the databases of five major hepatobiliary institutions. Data on clinicopathological factors, morbidity, response rates, and overall survival were collected and analyzed. RESULTS: Median patient age was 61 years. Median tumor size was 8.1 cm, and 47.5% patients had a solitary lesion. IAT consisted of conventional transarterial chemoembolization (cTACE) (64.7%), drug-eluting beads (DEB) (5.6%), bland embolization (TAE) (6.6%), or yttrium-90 radioembolization (23.2%). Median number of IAT sessions was 2 (range 1-8). The median time between IAT sessions was 48 days. The periprocedural morbidity was 29.8%; most complications were minor (n = 43); however, 16 patients had a grade 3-4 complication. Assessment of tumor response revealed complete or partial response in 25.5% patients, while 61.5% had stable disease; 13.0% had progressive disease. Median overall survival was 13.2 months and did not differ on the basis of the type of IAT (cTACE, 13.4 months vs. DEB 10.5 months vs. TAE, 14.3 months vs. yttrium-90, 11.3 months; P = 0.46). IAT response on modified response evaluation criteria in solid tumors (mRECIST; hazard ratio for complete-partial response 0.49, 95% confidence interval 0.30-0.81; P < 0.001) was independently associated with better survival. CONCLUSIONS: IAT for ICC was safe and led to stable disease or partial to complete response in up to three-quarters of patients. Among patients with an IAT response, overall survival was prolonged. The role of IAT therapy for ICC warrants further prospective evaluation in clinical trials.

Consensus recommendations and review by an International Expert Panel on Interventions in Hepatocellular Carcinoma (EPOIHCC).

Hepatocellular carcinoma (HCC) presents with a high burden of disease in East Asian countries. Intermediate-stage HCC as defined by the Barcelona Clinic Liver Cancer (BCLC) staging system poses a clinical challenge as it includes a heterogeneous population of patients that can vary widely in terms of tumour burden, liver function and disease aetiology. Intermediate HCC patients often have unsatisfactory clinical outcomes with repeated transarterial chemoembolization (TACE, due to non-response of the target tumour or the development of further metastasis indicating progressive disease. In September 2011, an Expert Panel Opinion on Interventions in Hepatocellular Carcinoma (EPOIHCC) was convened in HK in an attempt to provide a consensus on the practice of TACE. To that end, current clinical practice throughout Asia was reviewed in detail including safety and efficacy data on TACE alone as well as in combination with targeted systemic therapies. This review summarises the evidence discussed at the meeting and provides expert recommendation regarding the available therapeutic options for unresectable intermediate stage HCC. A key consensus of the Expert Panel was that in order to improve patient outcomes and long-term survival, the possibility of using TACE in combination with targeted agents given systemically should be explored. While the currently available clinical data is promising, the expected completion of several pivotal phase II and III RCTs will provide further evidence in support of the rationale for combination therapy regimens.

Antiglycolytic therapy combined with an image-guided minimally invasive delivery strategy for the treatment of breast cancer.

PURPOSE: The antiglycolytic agent 3-bromopyruvate (3-BrPA) promotes anticancer effects in multiple tumor models. This study evaluated the therapeutic efficacy of ultrasound (US)-guided intratumoral delivery of 3-BrPA in an orthotopic tumor model of breast cancer. MATERIALS AND METHODS: Human breast cancer cell line MDA MB 231 was used for in vitro and in vivo studies. The anticancer effect of 3-BrPA was evaluated by viability assay, quantification of adenosine triphosphate (ATP) and lactate levels, and activity of matrix metalloproteinase (MMP)-9. In animal experiments, 15 nude mice with MDA MB 231 breast tumors were divided into three groups for US-guided intratumoral treatment with 1.75 mM 3-BrPA (group 1), 5 mM 3-BrPA (group 2), and saline solution (group 3). Tumor size was measured and subjected to histopathologic examination. RESULTS: In vitro, treatment with 3-BrPA resulted in a dose-dependent decrease in cell viability. A decrease in ATP and lactate levels, invasion, and MMP9 activity and expression was observed after treatment with concentrations of 3-BrPA that did not affect cell viability. In vivo, a significant difference in tumor volume was observed between 3-BrPA-treated and control animals. At the end of the study, tumor volumes in the 3-BrPA groups were 1,876 mm(3)±346 and 426 mm(3)±180 in the 1.75-mM and 5-mM 3-BrPA groups, respectively, versus 4,447 mm(3)±571 in the control group (P< .05). CONCLUSIONS: US-guided intratumoral injection of 3-BrPA effectively blocks breast cancer progression in an orthotopic mouse tumor model.

Anti-Glycolytic Drugs in the Treatment of Hepatocellular Carcinoma: Systemic and Locoregional Options.

Hepatocellular cancer (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death. Locoregional therapies, including transarterial embolization (TAE: bland embolization), chemoembolization (TACE), and radioembolization, have demonstrated survival benefits when treating patients with unresectable HCC. TAE and TACE occlude the tumor's arterial supply, causing hypoxia and nutritional deprivation and ultimately resulting in tumor necrosis. Embolization blocks the aerobic metabolic pathway. However, tumors, including HCC, use the "Warburg effect" and survive hypoxia from embolization. An adaptation to hypoxia through the Warburg effect, which was first described in 1956, is when the cancer cells switch to glycolysis even in the presence of oxygen. Hence, this is also known as aerobic glycolysis. In this article, the adaptation mechanisms of HCC, including glycolysis, are discussed, and anti-glycolytic treatments, including systemic and locoregional options that have been previously reported or have the potential to be utilized in the treatment of HCC, are reviewed.