Vascular and Interventional Radiology Original Research

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1 Vascular and Interventional Radiology Original Research Vogl et al. HCC Treated With TACE With Drug-Eluting Beads Vascular and Interventional Radiology Original Research FOCUS ON: Thomas J. Vogl 1 Johannes Lammer 2 Riccardo Lencioni 3 Katerina Malagari 4 Anthony Watkinson 5 Frank Pilleul 6 Alban Denys 7 Clara Lee 1 Vogl Keywords: TJ, Lammer doxorubicin, J, Lencioni drug-eluting R, et bead al. embolization, hepatocellular carcinoma (HCC), toxicity, transarterial chemoembolization (TACE) DOI:1.2214/AJR Received February 2, 21; accepted after revision September 8, 21. Clinical trial registration no. at NCT The study material DC Bead was supplied by Biocompatibles, UK. J. Lammer is a scientific advisor and R. Lencioni is on the speakers board for Biocompatibles, UK. Presented at 21 annual meeting of the American Society of Clinical Oncology, Chicago, IL. 1 Department of Diagnostic and Interventional Radiology, Johann Wolfgang Goethe University Hospital, Theodor Stern Kai 7, D-659 Frankfurt am Main, Germany. Address correspondence to T. J. Vogl (t.vogl@em.uni-frankfurt.de). 2 Department of Diagnostic and Interventional Radiology, Medical University of Vienna, Vienna, Austria. 3 Department of Diagnostic and Interventional Radiology, Cisanello University Hospital, Pisa, Italy. 4 Department of Diagnostic and Interventional Radiology, University of Athens, Athens, Greece. 5 Department of Diagnostic and Interventional Radiology, Royal Devon and Exeter Hospital, Exeter, United Kingdom. 6 Department of Diagnostic and Interventional Radiology, Centre Hospitalier Universitaire, Lyon, France. 7 Department of Diagnostic and Interventional Radiology, Centre Hospitalier Universitaire, Lausanne, Switzerland. WEB This is a Web exclusive article. AJR 211; 197:W562 W X/11/1974 W562 American Roentgen Ray Society Liver, Gastrointestinal, and Cardiac Toxicity in Intermediate Hepatocellular Carcinoma Treated With PRECISION TACE With Drug-Eluting Beads: Results From the PRECISION V Randomized Trial OBJECTIVE. The purpose of our study was to evaluate hepatic, gastrointestinal, and cardiac toxicity after PRECISION transarterial chemoembolization (TACE) with drug-eluting beads (DEB) versus conventional TACE with doxorubicin in the treatment of intermediatestage hepatocellular carcinoma (HCC). SUBJECTS AND METHODS. Two hundred twelve patients (185 men and 27 women; mean age, 67 years) were randomized to TACE with DEB or conventional TACE. The majority of patients (67% in both groups) presented in a more advanced stage. Safety was measured by rate of adverse events (Southwest Oncology Group criteria) and changes in laboratory parameters. Cardiotoxicity was assessed with left ventricular ejection fraction (LVEF) mainly on MRI or echocardiography. RESULTS. The mean maximum postchemoembolization alanine transaminase increase in the DEB group was 5% less than in the conventional TACE group (p <.1) and 41% less in respect to aspartate transaminase (p <.1). End-of-study values returned to approximately baseline levels but with greater variability in conventional TACE patients. Treatmentemergent adverse events in the hepatobiliary system organ class occurred in 16.1% of DEB group patients compared with 25% of conventional TACE patients. There were fewer liver toxicity events in the DEB group. There was a small but statistically significant difference in mean change from baseline in LVEF between the two groups of 4 percentage points for the conventional TACE group (95% CI, ; p =.18). CONCLUSION. PRECISION TACE with DEB loaded with doxorubicin offers a safe therapy option for intermediate-stage HCC, even in patients with more advanced liver disease. H epatocellular carcinoma (HCC) represents the fifth most common malignancy in men and the eighth in women worldwide, with 564, estimated new cases per year and is the leading cause of death in cirrhotic patients [1]. Its incidence is increasing worldwide [2]. Although there are known risk factors and screening is feasible and recommended, the majority of HCC patients present at an advanced stage when curative treatments are no longer available [3, 4]. Surgical and nonsurgical treatment options exist: Resection is the treatment of choice for noncirrhotic patients; transplantation is the preferred treatment option in early-stage unresectable HCC [3, 5]. Nonsurgical modalities include percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), laser-induced thermotherapy (LITT), radioembolization, and TACE, which is recommended as first-line therapy in intermediate HCC because TACE has been shown to significantly prolong survival over best supportive care and systemic chemotherapy [6 8]. There is no standardized therapy regimen for TACE. The optimal schedule, anticancer drug (e.g., mitomycin, cisplatin, and doxorubicin alone or in combination), embolizing agent (e.g., gelatin sponge particles, degradable starch spherical microspheres), use of iodized oil (Lipiodol, Guerbet), or embolization versus chemoembolization, has not been established. In addition, there is still the requirement of new strategies to reduce the risk of post-tace complications [7, 9, 1] of acute liver or renal failure, encephalopathy, ascites, and upper gastrointestinal bleeding, which may be severe [9]. Cardiotoxicity, which, if life-threatening, represents the cumulative dose-limiting toxicity of the drug, is also a known risk of anthracycline treatment. DC Bead (Biocompatibles, UK) is a new spherical embolic microsphere composed of W562 AJR:197, October 211

2 HCC Treated With TACE With Drug-Eluting Beads a modified polyvinyl alcohol monomer that is capable of loading anthracycline drugs, such as doxorubicin, before administration in a TACE procedure. DC Bead loaded with doxorubicin releases the chemotherapeutic agent in a controlled manner, maximizing local ischemia and tumor necrosis [11 13]. Varela et al. [14] showed a significantly lower systemic concentration of doxorubicin after PRECISION TACE with DC Bead than with conventional TACE. Previously published results from the prospective randomized phase 2 study, PRECI- SION V, showed that PRECISION TACE with DC Bead loaded with doxorubicin is effective in the treatment of intermediate-stage HCC [15]. In this article, we conducted further analysis to evaluate safety with a focus on liver, gastrointestinal, and cardiac toxicity with drug-eluting beads (DEB) loaded with doxorubicin in comparison with conventional TACE. Subjects and Methods Study Design and Procedures The PRECISION (Prospective Randomized Study of Doxorubicin in the Treatment of Hepatocellular Carcinoma by Drug-Eluting Bead Embolization) V study was designed as a multicenter single-blind randomized controlled study and was compliant with good clinical practice and the Declaration of Helsinki, approved by local independent review boards, reported according to Consolidated Standards of Reporting Trials recommendations [16], and monitored by independent data and safety monitoring boards. Informed consent was obtained for all patients and also for the randomization process. The primary efficacy endpoint of the study was 6-month tumor response rate assessed by MRI. The primary safety endpoint was the incidence of treatment-related serious adverse events (SAEs) occurring within 3 days of a procedure. Secondary endpoints included change in the tumor marker α-fetoprotein and incidence and severity of treatment-emergent adverse events (AEs) and SAEs, laboratory parameters, and cardiac function. The total duration of hospitalization for treatments and SAEs was also evaluated. Followup was conducted at 12 days (telephone contact) and 1, 3, and 6 months after the first treatment. Randomization was centralized and stratified by Child-Pugh class (A or B), Eastern Cooperative Oncology Group performance status (ECOG) or 1, prior curative treatment (yes or no), and bilobar disease (yes or no). Patients were randomized (1:1) to either the DEB or conventional TACE group. Patients eligible to enter the study had a confirmed diagnosis of HCC (based on the European Association for the Study of the Liver criteria [17]) and were staged according to the Barcelona Clinic Liver Cancer (BCLC) criteria [8] (BCLC A or B without portal invasion or extrahepatic spread), ECOG or 1, and preserved liver function (Child-Pugh class A or B). Main Inclusion Criteria The inclusion criteria were patients older than 18 years with HCC unsuitable for resection or percutaneous ablation; no prior chemotherapy, radiotherapy, or TACE (with or without chemotherapy); eligible for chemoembolization before transplantation with an expected waiting time exceeding 6 months; or recurrence after resection or ablation. Exclusion criteria were advanced HCC (including vascular invasion, extrahepatic spread, or diffuse HCC with > 5% tumor burden), bilirubin levels > 3 mg/dl, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 upper limit of normal or > 25 IU/L, any contraindication for doxorubicin administration or hepatic embolization procedures, or patients with another primary tumor. Patients received one chemoembolization treatment at baseline and 2 and 4 months for a maximum of three chemoembolizations during the whole study. Patients were admitted to the hospital for each chemoembolization treatment. Pain management and monitoring during the hospital stay were according to standard hospital practice. In the DEB group patients received 4 ml of DC Bead with doxorubicin (1 vial 3 5 μm and 1 vial 5 7 μm) at 37.5 mg/ml for a total dose of 15 mg per treatment mixed with a nonionic contrast medium, e.g., iohexol (Omnipaque, GE Healthcare), iopamidol (Isovue, Bracco), or iomeprol (Iomeron, Bracco), to make a 5% by weight solution according to the instructions for use. Lipiodol was not used. No dose adjustment was made for bilirubin concentration or body surface area. Additional Bead Block (hydrogel microspheres [Biocompatibles, UK]) could be used to achieve stasis in second- or third-order branches depending on tumor anatomy. The size used was at investigator discretion. In the conventional TACE group patients received an intraarterial injection of an emulsion of doxorubicin at a dose of 5 75 mg/m 2 to a maximum of 15 mg adjusted for bilirubin concentration and body surface area, with Lipiodol, a viscous oil that is specifically retained by neoplastic cells. Each procedure began with a 1:1 mixture of doxorubicin and Lipiodol, and 5% was saved to dilute the Lipiodol, if necessary, (up to 4:1 doxorubicin:lipiodol) in the event of backflow, with the aim of delivering the entire dose of chemotherapy. This was followed by particle embolization with an embolic agent of the investigator s preference: Selection of the embolic agent and particle size was based on the anatomy of the feeding vessels and included Gelfoam (Pfizer), Curaspon (CuraMedical), or Spongel (Yamanouchi) particles (but not Gelfoam powder) and Contour SE (Boston Scientific) or polyvinyl alcohol (PVA) particles, Embosphere (BioSphere Medical), or Bead Block. In both treatment groups, nonionic contrast media was used to guide the injection. After performing diagnostic angiography to detect anatomic variants and ensuring patency of the portal vein, selective catheterization of the tumor-feeding hepatic artery was performed; a microcatheter could be used to select a branch feeding the tumor. Embolization was performed until stasis in a second- or third-order branch was achieved. After the embolization, the catheter was removed and hemostasis was achieved by manual compression or with a percutaneous closure device. Safety Monitoring and Adverse Events All toxicity AEs were graded according to the Southwest Oncology Group (SWOG) criteria for severity [18]. Relatedness to study treatment was assessed by the investigators. Treatment-related AEs were defined as those assessed as other than not related. Treatment-emergent AEs were defined as those events occurring at or after the start of a TACE procedure. Intensity was characterized as mild, grade 1; moderate, grade 2; severe, grade 3; life-threatening, grade 4; or fatal, grade 5. SAEs were defined as those resulting in death, immediately life-threatening, resulting in permanent or significant disability or incapacity, or requiring or extending hospitalization. All AEs were coded centrally, according to the Medical Dictionary for Regulatory Affairs (MedDRA, version 9.1). Postembolization syndrome was defined by postprocedural appearance of fever, nausea, vomiting, and abdominal pain. In this study, the frequency and incidence of postembolization syndrome was documented separately next to postembolization symptoms and symptoms commonly associated with postembolization syndrome because there was no MedDRA code for postembolization syndrome itself. Blood samples for hematology and biochemistry analysis were taken at baseline, preembolization, before discharge, and at every follow-up visit. Alpha-fetoprotein was assessed at baseline, the day before the second and third treatments, and at 6 months or early withdrawal. Cardiotoxicity was assessed by measuring the left ventricular ejection fraction (LVEF) in % on MRI, isotopic ventriculography, or echocardiography at baseline and at study exit (6 months or at early withdrawal if earlier). A substantial decrease from baseline in LVEF, defined as at least AJR:197, October 211 W563

3 Vogl et al. a 1% decline to below the lower limit of normal (normal range, 5 65%) or an absolute LVEF of 45%, or 2% decline in LVEF at any level, was judged as indicative of deterioration in cardiac function associated with doxorubicin. Statistical Analysis The size of the study was based on statistical criteria for the primary efficacy endpoint [15]. Group comparisons for secondary efficacy and all safety endpoints were not subject to power analysis, hence the p values obtained were interpreted descriptively and in the exploratory sense. The incidence of complications (all and treatment-related) was analyzed using the chi-square test TABLE 1: Patient Demographics and the 95% CI for the true difference in incidence rates (DC Bead conventional TACE) was presented. Because of the small group sizes, a subgroup of more advanced patients was defined as those who met the higher risk criteria for one or more of the four prognostic factors, i.e., Child Pugh B, ECOG 1, bilobar disease, or recurrent disease. The incidence of complications in this subgroup was analyzed similarly. All other AE data were presented descriptively using frequency (overall and per 1 treatments) and incidence (by MedDRA and SWOG system, toxicity, and grade). To capture postembolization syndrome events, all treatment-emergent AEs of postembolization syndrome and postembolization symptoms were considered. Characteristics DC Bead (n = 12) Conventional TACE (n = 11) Mean age (± SD) (y) 67. (± 9.2) 67.3 (± 8.8) Sex Men Women Cause a Hepatitis C 2 12 Hepatitis B Alcohol alone Other and mixed Okuda stage I II 14 6 BCLC classification b A B C Prior curative treatment c No Yes Bilobar disease c No Yes Child-Pugh classification c A B ECOG performance status c Note DC Bead manufactured by Biocompatibles, UK. TACE = transarterial chemoembolization. a Multiple responses per patient were possible. b Barcelona Clinic Liver Cancer (BCLC) classification according to tumor stage [17]. c Stratification factors: numbers of patients counting for modified intent-to-treat population (DC Bead, 93; conventional TACE, 18). Absolute change in LVEF was analyzed using analysis of variance with treatment group and the four stratification factors in the model. A 95% CI for the estimate of difference in least squares means between treatment groups was presented. Change in α-fetoprotein between last postbaseline observation carried forward (6-month LOCF) and baseline was analyzed similarly, also including baseline α-fetoprotein in the model and after logarithmic transformation. The maximum fold change across all procedures (predischarge to prechemoembolization) in liver enzymes ALT and AST was analyzed using the Student t test after log transformation. Least squares treatment estimates and 95% CIs were presented as fold change on the ratio scale after back transformation. Change between the 6-month LOCF assessment from baseline was presented descriptively using arithmetic means. All endpoints were presented using descriptive statistical methods, and where statistical analysis was performed, two-sided testing was conducted at the 5% level of significance. Results Patients Between November 25 and June 27, 212 intermediate HCC patients were randomized to receive PRECISION TACE with DEB (n = 12) or conventional TACE (n = 11). Patient demographics were similar in both groups (Table 1). The mean baseline LVEF in patients with both baseline and end of study assessments was similar (DEB patients, mean 65.8% ± SD 8.4% and conventional TACE patients, 64.6% ± 7.7%). The modified intention-to-treat population received at least one treatment: 93 and 18 for the DEB and conventional TACE groups, respectively. Sixty-seven percent of patients in both groups were considered more advanced. Extent of Exposure In the course of the study, 82% of patients in both groups received a second and 61% and 57%, respectively, received a third treatment. The mean total dose of doxorubicin administered was higher in the DEB group compared with the conventional TACE group (295 ± mg vs 223 ± 12.6 mg) at each level of stratification factor and in the subgroup of more advanced patients (33 ± mg vs 27 ± mg). Of the 235 DEB chemoembolizations, 168 (71.5%) involved the use of 3 5 µm or 5 7 µm (or both) procedures, during which the number of procedures using 1 3 µm or other combinations of DC Bead W564 AJR:197, October 211

4 HCC Treated With TACE With Drug-Eluting Beads sizes was lower than 1%. The DC Bead size of 7 9 µm was not used. The pattern of usage was similar across procedures. Additional Bead Block was used to complete the embolization in 12.3% of procedures. Sizes used ranged from 3 to 9 µm; 69% and 41% of procedures involved the use of 5 7 µm and 3 5 µm, respectively. A small number of procedures (14%) involved the use of both sizes. DC Bead at the size of 7 9 µm was not used and Bead Block was used once at this size. There were 261 conventional TACE chemoembolizations. The mean volume of Lipiodol given was approximately 1 ml at each procedure (range, 1 3 ml); 27.8% of conventional TACE patients had no embolics used during any procedures. Bead Block was most commonly used at first (22.2% of patients) and second procedures (18.2% of patients). At third procedures, Embosphere was most commonly used (16.7% of patients). Gelfoam, Spongel, or Curaspon was used in 13.4% of procedures, PVA or a combination of embolics was used in fewer than 6% of procedures. Across all procedures, the size ranges used, for the more commonly used embolics, ranged from 1 to 12 µm (Bead Block, 3 5 µm used in 61% of these procedures) and 3 12 µm (Embosphere, 3 5 µm used in 41% of procedures with size recorded). The mean total length of hospital stay for all procedures and SAEs was 12 ± 9 days in both treatment groups. Liver Toxicity Postprocedural increases in the liver enzymes, ALT and AST, were significantly lower in the DEB group than in the conventional TACE group. The mean maximum ALT increase postprocedure in the DEB ALT (IU/L) TP1 TP2 TP3 TP4 TP5 TP6 TP7 TP8 TP9 Time group was 5% less than in the conventional TACE group (95% CI, 39 65%; p <.1) and 41% less in respect to AST (95% CI, 46 76%; p <.1) (Figs. 1 and 2). At 6-month LOCF, both ALT and AST values returned to approximately baseline levels, with a marginal increase for ALT observed in the conventional TACE group. The DEB group ALT mean change was 1.9 ± 71.6 IU/L, and the conventional TACE group ALT mean change was ± 9.39 IU/L. For AST, the DEB group mean change was ± IU/L, and the conventional TACE group mean change was ± IU/L. For total bilirubin, there were also distinctive although reduced peaks postchemoembolization. Mean levels at 6-month LOCF returned to approximately baseline levels; however, there was greater variability among conventional TACE-treated patients, particularly in early withdrawn patients (DC Bead mean change, 5.3 ± μmol/l and conventional TACE mean change ± μmol/l (Fig. 3). Tumor Marker Changes in α-fetoprotein levels at 6-month LOCF showed a marked reduction in both treatment groups: In the DEB group, mean levels were ± IU/mL (geometric mean ± coefficient of variance) at baseline and ± IU/mL at 6 months or early withdrawal. In the conventional TACE group, mean levels were ± IU/mL and ± IU/mL, respectively. The ratio (DC Bead to conventional TACE) of fold change α-fetoprotein at 6-month LOCF relative to baseline was not statistically significant (least squares mean ratio, 1.29; 95% CI, ; p =.23); however, the baseline α-fetoprotein level had a statistically significant influence on the magnitude of the fold change (p <.1). Fig. 1 Graph shows time course (mean and 95% CI) of alanine aminotransferase (ALT) for DC Bead (Biocompatibles, UK) ( ) and conventional transarterial chemoembolization (O). TP1 = T1 before embolization, TP2 = T1 before discharge, TP3 = 1-month follow-up, TP4 = T2 before embolization, TP5 = T2 before discharge, TP6 = 3-month followup, TP7 = T3 before embolization, TP8 = T3 before discharge, TP9 = 6-month follow-up. Postembolization Syndrome The incidence of postembolization syndrome was similar in both treatment groups: 35 events in 23 DEB (24.7%) and 43 in 28 conventional TACE (25.9%) patients. The overall incidence of postembolization syndrome or postembolization symptoms was 72.% in both treatment groups. Of the symptoms commonly associated with postembolization syndrome and occurring in more than 1% of patients in either treatment group, abdominal pain and fatigue occurred more frequently and with greater incidence in DEB patients, whereas pyrexia was more common in conventional TACE patients (Table 2). Cardiotoxicity Cardiotoxicity assessments were performed by echocardiography in 26 (51%) DEB and 31 (49%) conventional TACE patients and by MRI in 18 (32%) DEB and 27 (43%) conventional TACE patients with evaluable data. A small number of patients had assessments by isotopic ventriculography (three DEB and no conventional TACE) or by different assessment methods at each assessment (four DEB and five conventional TACE patients). There was a small but statistically significant difference in mean change from baseline in LVEF between the DEB and conventional TACE groups of 4 percentage points (95% CI, ; p =.18). The corresponding individual adjusted least squares mean differences for the DEB group was.2 (95% CI, 4.11 to 4.8) and for the conventional TACE group was 4.3 percentage points (95% CI, 7.83 to.2), with a small but statistically significant drop observed in the conventional TACE group only (p =.38). There was a trend for larger decreases in LVEF in the conventional TACE patients (Table 3). No DEB and six conventional TACE patients experienced a substantial decrease in LVEF. Interpretation of these findings was limited because more than 41% of patients in both groups with missing or nonevaluable assessments, with the majority of missing assessments among early withdrawn patients in both groups (DC Bead, 89%; conventional TACE, 85%). In evaluable patients, the mean total doxorubicin dose was higher in the DEB (DC Bead mean, 326 ± mg) than the conventional TACE group (241 ± mg). Adverse Events Incidence rates for treatment-related complications were similar: 2.4% and 19.4% for DEB and conventional TACE, respectively AJR:197, October 211 W565

5 Vogl et al AST (IU/L) TP1 TP2 TP3 TP4 TP5 TP6 TP7 TP8 TP9 Time Fig. 2 Graph shows time course (mean and 95% CI) of aspartate aminotransferase (AST) for DC Bead (Biocompatibles, UK) ( ) and conventional transarterial chemoembolization (O). TP1 = T1 before embolization, TP2 = T1 before discharge, TP3 = 1-month follow-up, TP4 = T2 before embolization, TP5 = T2 before discharge, TP6 = 3-month follow-up, TP7 = T3 before embolization, TP8 = T3 before discharge, TP9 = 6-month follow-up. Total Bilirubin (µmol//l) (p =.86; 95% CI, 1.1 to 12.1%), despite the greater total dose of doxorubicin administered in the DEB group. Treatment-emergent AEs occurred in a similar proportion of patients in both treatment groups (Table 2). System organ classes with a 1% or more increased incidence in the DEB group compared with the conventional TACE group were gastrointestinal disorders (61.3% compared with 45.4%). In the hepatobiliary system organ classes, events occurred in greater frequency and incidence in conventional TACE patients: 22 events were observed in 15 DEB patients (16.1%), and 28 events in 27 conventional TACE patients (25.%). The most common symptoms reported (with incidence 1% of patients overall) were predominantly those commonly associated with postembolization syndrome (Table 2). Treatment-emergent AEs of cardiac disorders were few in number (four events in four (4.3%) patients in the DEB group and 11 events in eight patients (7.4%) in the conventional TACE group. These included six TP1 TP2 TP3 TP4 TP5 TP6 TP7 TP8 TP9 Time Fig. 3 Graph shows time course (mean and 95% CI) of total bilirubin for DC Bead (Biocompatibles, UK) ( ) and conventional transarterial chemoembolization (O). TP1 = T1 before embolization, TP2 = T1 before discharge, TP3 = 1-month follow-up, TP4 = T2 before embolization, TP5 = T2 before discharge, TP6 = 3-month follow-up, TP7 = T3 before embolization, TP8 = T3 before discharge, TP9 = 6-month follow-up. serious events: cardiomegaly resulting in death in one DC Bead event, one conventional TACE patient with life-threatening acute cardiac failure, and one conventional TACE patient with coronary artery occlusion, stenosis, and syndrome. In the six patients with a substantial decrease in LVEF, there were two patients with cardiac disorders (both cardiac failure), one of which was life threatening. AEs leading to withdrawal were hepatobiliary disorders (four in each group), infections TABLE 2: Frequency and Incidence of Postembolization Syndrome, Postembolization Symptoms, and Symptoms Commonly Associated With Postembolization Syndrome DC Bead (n = 93) Conventional TACE (n = 18) MedDRA Preferred Term Events Patients Events Patients All treatment-emergent adverse events 417 (1) 79 (84.9) 491 (1) 88 (81.5) Postembolization syndrome 35 (37.6) a 23 (24.7) 43 (39.8) a 28 (25.9) Postembolization syndrome and symptoms 67 (72.) a 34 (36.6) 78 (72.2) a 41 (38.) Treatment-emergent events commonly associated with postembolization syndrome and occurring in > 1% of patients in either treatment group Abdominal pain 24 (5.8) 2 (21.5) 24 (4.9) 19 (17.6) Nausea 19 (4.6) 15 (16.1) 2 (4.1) 15 (13.9) Vomiting 13 (3.1) 1 (1.8) 16 (3.3) 14 (13.) Upper abdominal pain 12 (2.9) 12 (12.9) 5 (1.) 4 (3.7) Pyrexia 2 (4.8) 16 (17.2) 42 (8.6) 26 (24.1) Fatigue 15 (3.6) 13 (14.) 6 (1.2) 6 (5.6) Postprocedural complications b 35 (8.4) 23 (24.7) 44 (9.) 29 (26.9) Note Data are number with percentage in parentheses. DC Bead manufactured by Biocompatibles, UK. MedDRA = Medical Dictionary for Regulatory Affairs. TACE = transarterial chemoembolization. a Events per 1 patients. b All but one event was recorded by the investigator as postembolization syndrome. W566 AJR:197, October 211

6 HCC Treated With TACE With Drug-Eluting Beads SAE Event Rates Child Pugh B ECOG-1 and infestations (three in each group), general disorders and administration site conditions (three DEB and two conventional TACE), gastrointestinal disorders (two DEB and one conventional TACE), cardiac disorders (one patient in each group), and other (one DEB and three conventional TACE including two due to increased blood bilirubin). The most commonly occurring SAEs were those of the SWOG gastrointestinal and liver organ system (total frequency, 2 DEB and 21 conventional TACE SAEs). Of the 41 events, the most commonly reported diagnoses were for liver toxicity (three DEB and nine conventional TACE) and pancreatic or gallbladder abnormality (six DEB and five conventional TACE) (Figs. 4 and 5). The incidence of treatment-emergent AEs of grade 4 toxicity was similar (approximately 13%) in both treatment groups. Grade 4 toxicities were most common in the liver: five events occurred in five (5.4%) DEB patients compared with eight events in eight (7.4%) conventional TACE patients. In the conventional TACE procedures, the Lipiodol dose used at the last procedure before the AE was 5 ml (one AE), 1 ml (five AEs), and 2 ml (two AEs). Grade 3 toxicities were reported with greater incidence in conventional TACE patients: 35.5% DEB and 42.6% conventional TACE. With the exception of abdominal pain (14 events in 9.7% DEB and 16 events in 12.% of conventional TACE patients) (Table 4), there were only isolated incidents of grade 3 toxicities and no consistent trends between the treatment groups. For most treatment-emergent AEs, the outcome was reported as completely recovered: 311 events in 69 of 93 (74.2%) and 365 events in 79 of 18 (73.1%) patients in the DEB and Bilobar disease Recurrent disease Fig. 4 Graph shows incidence of serious adverse events (SAEs) within 3 days of treatment for advanced patients in both groups: DC Bead (Biocompatibles, UK) (gray) and conventional transarterial chemoembolization (black). For all stratification factors, incidence of SAEs was higher in the conventional transarterial chemoembolization group. SAE event rates are per 1 patients within 3 days of treatment. ECOG = Eastern Cooperative Oncology Group. Liver toxicity Pacreatic and gallbladder abnormality Gastrointestinal bleeding Abscess and infection Gastrointestinal ulcer Ascites Hospitalization for TIPS Intratumoral bleeding Other conventional TACE groups, respectively, and a further 3 treatment-emergent AEs in 21 of 93 (22.6%) DEB patients and 37 treatment-emergent AEs in 22 of 18 (2.4%) conventional TACE patients were not recovered but the condition was improved by the end of the study No. 8 1 Fig. 5 Graph shows frequency of treatment-emergent serious adverse events (SAEs) involving liver and organ system toxicities in both groups: DC Bead (Biocompatibles, UK) (gray) and conventional transarterial chemoembolization (black). TIPS = transjugular intrahepatic portosystemic shunt. Discussion TACE is the standard of care for the treatment of unresectable intermediate or advanced HCC in patients with preserved liver function and asymptomatic multinodular tumors without vascular invasion or extrahepatic spread [8, 19, 2]. There is no worldwide agreement on a standard method of TACE. Simultaneously, there is a need for more effective drugs [9, 21], with minimal toxicity to maintain patients quality of life because TACE is generally used as a palliative therapy option [22]. The development of doxorubicin-eluting beads is an attempt to standardize the technique of chemoembolization [15, 19, 23, 24]. DEB have been developed to increase local effectiveness, decrease systemic side effects, and enable a more consistent procedure to be performed. Among these, the ability to load and release doxorubicin was highest with DC Bead [13, 25, 26]. Cammà et al. [21] reported in a meta-analysis of randomized controlled trials that firm conclusions about the results of comparisons among different chemoembolization procedures are hampered by the fact that complications are not formally reported in many trials. They concluded that data, especially about the safety profile, are needed. We report further analysis of safety data from the PRECISION V study, with a focus on liver, gastrointestinal, and cardiac toxicity for DC Bead loaded with doxorubicin in comparison with conventional TACE. For the primary safety endpoint of incidence of treatment-related complications, no TABLE 3: Modified Intention-to-Treat Summary of Substantial Decrease in Left Ventricular Ejection Fraction (LVEF) Decrease in LVEF Group DC Bead Conventional TACE Total No decrease 34 (36.6) 31 (28.7) 65 (32.3) Nonsubstantial decrease 17 (18.3) 26 (24.1) 43 (21.4) Substantial decrease (.) 6 (5.6) 6 (3.) Not known 42 (45.2) 45 (41.7) 87 (43.3) Total 93 (1.) 18 (1.) 21 (1.) Note Data are number with percentage in parentheses. Substantial decrease is defined as a drop from baseline of at least 1% in LVEF to below lower limit of normal, absolute LVEF of 45%, or at least a 2% drop in LVEF at any level. Normal range is 5 65%. Nonsubstantial decrease is defined as drop in LVEF from baseline but not fulfilling criteria for substantial decease. No decrease is defined baseline value end of study value. Percentages are of total treatment group size. DC Bead manufactured by Biocompatibles, UK. TACE = transarterial chemoembolization. AJR:197, October 211 W567

7 Vogl et al. TABLE 4: Treatment-Emergent Adverse Events of the Liver and Gastrointestinal Southwest Oncology Group (SWOG) Organ Systems by Toxicity and Grade Treatment Group SWOG System, Toxicity, DC Bead (n = 93) Conventional TACE (n = 18) and Grade Events Patients Events Patients Total no. of SWOG toxicities 417 (1) 79 (84.9) 491 (1) 88 (81.5) Fever in absence of infection 26 (6.2) 2 (21.5) 51 (1.4) 33 (3.6) Gastrointestinal 89 (21.3) 5 (53.8) 95 (19.3) 42 (38.9) Grade 1 44 (1.6) 31 (33.3) 51 (1.4) 29 (26.9) Grade 2 3 (7.2) 21 (22.6) 35 (7.1) 24 (22.2) Constipation 11 (2.6) 1 (1.8) 17 (3.5) 13 (12.) Nausea 28 (6.7) 22 (23.7) 28 (5.7) 22 (2.4) Grade 1 19 (4.6) 18 (19.4) 15 (3.1) 13 (12.) Vomiting 16 (3.8) 13 (14.) 19 (3.9) 15 (13.9) Liver 46 (11.) 22 (23.7) 43 (8.8) 31 (28.7) Grade 3 15 (3.6) 12 (12.9) 19 (3.9) 15 (13.9) Transaminase (AST and ALT) 17 (4.1) 9 (9.7) 18 (3.7) 16 (14.8) Abdominal pain 5 (12.) 35 (37.6) 46 (9.4) 32 (29.6) Grade 1 19 (4.6) 13 (14.) 12 (2.4) 1 (9.3) Grade 2 16 (3.8) 14 (15.1) 18 (3.7) 15 (13.9) Grade 3 14 (3.4) 9 (9.7) 16 (3.3) 13 (12.) Note Focus is on system organ class liver and gastrointestinal disorders (only terms occurring for 1% (2 patients in both treatment groups combined). Data in parentheses are percentages. TACE = transarterial chemoembolization, AST = aspartate aminotransferase, ALT = alanine aminotransferase. statistically significant difference was found between the two groups. The observed incidence rates of approximately 2% in both groups were lower than previously reported for patients treated with chemoembolization (27.5%) [7]. The frequency and incidence of all AEs was similar in both groups. The profile of AEs was similar to those reported in prior studies [7, 9, 22, 27 3]. No new unexpected events were observed for this new treatment. Thus, it can be concluded regarding the primary safety endpoint that DEB chemoembolization is at least as safe as conventional TACE. In a recent review, Marelli et al. [9] showed that for most patients liver function returned to its pretreatment level after TACE. However, 3% had irreversible hepatic decompensation. In prior studies using DC Bead, Poon et al. [31] reported that none of their patients (n = 35) developed any systemic toxicity and there was no treatment-related death after TACE with DC Bead and doxorubicin. Varela et al. [14] treated 27 Child-Pugh class A cirrhotics with DC Bead at doses adjusted for bilirubin and body surface area (mean dose of doxorubicin, 128 mg). The procedures were well tolerated. After the first treatment, 37% of the patients presented a clinically relevant postembolization syndrome, whereas after the second procedure (n = 22), 18% presented postembolization syndrome. Postembolization syndrome has been seen in almost 6 8% of patients undergoing solid organ arterial embolization [32]. In our study, lower but similar incidence rates (approximately 25%) were seen in both treatment groups. However, the overall incidence of postembolization syndrome or postembolization symptoms reported was approximately 72% in both groups. Postembolization syndrome or postembolization symptoms may not have been reported as such, which may have contributed to the reduced incidence observed. The patients showed improved tolerability with respect to liver toxicity SAEs after treatment with DEB compared with conventional TACE (three DEB and nine conventional TACE). Moreover, in all treatment-emergent AEs, grade 4 toxicities occurred most commonly in the liver and in greater frequency and incidence in conventional TACE compared with DEB. The postchemoembolization increase in liver transaminases (AST and ALT) after TACE with DEB was significantly (p <.1) less than that for conventional TACE. By the end of the study, however, liver transaminase levels had returned to approximately baseline levels in both groups. Similar findings were observed for total bilirubin. Changes from baseline values were less variable in the DEB group (mean change 5.3 ± μmol/l) than in the conventional TACE group (mean change from baseline, ± μmol/l). These findings might indicate less postembolization toxicity to functional liver with DC Bead compared with conventional TACE and improved tolerability with respect to liver toxicity. Until recently, systemic chemotherapy provided marginal benefit to patients with HCC [6, 7]. An inability to deliver the full dose of drug because of systemic side effects and the low response rates have limited the use of chemotherapy in this indication. The development of new targeted systemic therapies (e.g., sorafenib) has raised interest in the ability to combine systemic chemotherapy with locoregional treatments such as TACE. However, there is concern over increasing toxicity with multiple drug treatments, particularly in patients with underlying liver cirrhosis. For example, the area under the curve for doxorubicin was found to increase by 21% in combination with sorafenib [33]. In our study, there were similar reductions in the tumor marker α-fetoprotein in both treatment groups, with baseline α-fetoprotein having a significant influence on the magnitude of the reduction (p <.1). Lower frequencies per 1 treatments of probably or definitely related SWOG toxicity grade 3 or 4 treatment-emergent AEs were observed in 13 DEB events compared with 17 conventional TACE events. This was despite the higher mean total doxorubicin doses administered in the DEB group. The minimal systemic availability of doxorubicin could make DEB loaded with doxorubicin an ideal embolic agent to investigate the combination of TACE with targeted systemic therapies. Cardiotoxicity is a known risk of anthracycline treatment. The probability of developing impaired myocardial function is estimated to be 1 2% at a total cumulative dose of 3 mg/m 2 of doxorubicin, 3 5% at a dose of 4 mg/m 2, and 5 8% at a dose of 45 mg/m 2 given in a schedule of a bolus injection once every 3 weeks (FDA-approved labeling, 23). In our study, cardiac function was maintained in the DEB group whereas there was a small but statistically significant (p =.38) deterioration in LVEF in the conventional TACE group. In addition, no DEB W568 AJR:197, October 211

8 HCC Treated With TACE With Drug-Eluting Beads patients experienced substantial reduction in cardiac function compared with six in the conventional TACE group. An increased incidence of cardiac events was observed in the conventional TACE group (4.3% of DEB and 7.4% of conventional TACE patients) and two of the six patients with a substantial decrease experienced clinical symptoms of cardiac failure. Our study has some limitations. In contrast to Lipiodol, which can be detected on a CT control image after conventional TACE, a possible displacement of beads cannot be assessed because they are not visible on posttreatment imaging because the beads are administered without Lipiodol. Consequently, it was not possible to counteract in the ensuing procedures, e.g., by more selective catheterization. Second, given that we followed the study patients over a 6-month period, long-term toxicity could not be assessed in an appropriate way. Cardiotoxicity was assessed only at baseline and at final assessment. Interpretation was limited because of the high level of nonevaluable patients, particularly in withdrawn patients, limiting the interpretation of the LVEF findings. Third, most of our patients developed HCC on the basis of alcohol abuse, whereas most of the HCC cases worldwide emerge due to hepatitis B or C infection. In this evaluation of safety, it was our aim to conduct further analysis with regard to toxicity. Chemoembolization with DEB was associated with reduced incidence of AEs relating to doxorubicin toxicity (pyrexia, decreased liver function and liver toxicities, and increased cardiotoxicity), whereas the embolic potential of DEB was reflected in more events resulting from embolization (abdominal pain and fatigue). 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