Survival, Efficacy, and Safety of Small Versus Large Doxorubicin Drug-Eluting Beads TACE Chemoembolization in Patients With Unresectable HCC

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1 Vascular and Interventional Radiology Original Research Prajapati et al. Doxorubicin Drug-Eluting Beads in TACE of HCC Vascular and Interventional Radiology Original Research Hasmukh J. Prajapati 1 Minzhi Xing 1,2 James R. Spivey 3 Steven I. Hanish 4,5 Bassel F. El-Rayes 6 John S. Kauh 6 Zhengjia Chen 7 Hyun S. Kim 1,2,4,6,8 Prajapati HJ, Xing M, Spivey JR, et al. Keywords: doxorubicin drug-eluting beads transarterial chemoembolization (DEB TACE), small versus large DEB TACE, unresectable hepatocellular carcinoma (HCC) DOI: /AJR Received November 26, 2013; accepted after revision March 24, Division of Interventional Radiology and Image-Guided Medicine, Department of Radiology, Emory University School of Medicine, Atlanta, GA. 2 Division of Interventional Radiology, Department of Radiology, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Presbyterian South Tower, Ste 3950, 200 Lothrop St, Pittsburgh, PA Address correspondence to H. S. Kim (kimk7@upmc.edu). 3 Division of Hepatology, Emory University School of Medicine, Atlanta, GA. 4 Department of Surgery, Emory University School of Medicine, Atlanta, GA. 5 Department of Surgery, University of Maryland, Baltimore, MD. 6 Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA. 7 Department of Biostatistics and Bioinformatics, Emory University School of Medicine, Atlanta, GA. 8 Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA. WEB This is a web exclusive article. AJR 2014; 203:W706 W X/14/2036 W706 American Roentgen Ray Society Survival, Efficacy, and Safety of Small Versus Large Doxorubicin Drug-Eluting Beads TACE Chemoembolization in Patients With Unresectable HCC OBJECTIVE. The purpose of this study was to investigate the overall survival, efficacy, and safety of small ( μm) versus large ( and μm) doxorubicin drugeluting beads transarterial chemoembolization (DEB TACE) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS. Ninety-four consecutive patients with unresectable HCC who underwent 269 DEB TACE procedures in 48 months were studied. DEB TACE procedures were performed using different DEB sizes: μm (Group A, 59 patients) and with mixed and μm DEB (Group B, 35 patients). Survival rates were compared between the groups. RESULTS. The overall median survival in groups A and B were 15.1 and 11.1 months, respectively (p = 0.005). Both groups were similar in demographics, tumor burden, and differential staging (p > 0.5). Substratification of overall survival according to Child-Pugh class and Okuda, Cancer of the Liver Italian Program (CLIP), and Barcelona Clinic Liver Cancer (BCLC) staging were significantly higher in group A than in group B (p < 0.05). Common terminology criteria for adverse events (CTCAE) grade III adverse events and 30-day mortality were significantly lower in group A than in group B (6.8% vs 20%; p = 0.04, and 0% vs 14.3%; p = 0.001, respectively). The particle size, Child-Pugh class, and serum α-fetoprotein level were significant prognostic indicators of survival on multivariate analysis. CONCLUSION. TACE with μm sized DEB is associated with significantly higher survival rate and lower complications than TACE with and μm sized DEB. H epatocellular carcinoma (HCC) is the most common primary hepatic tumor and the third most common cause of cancer-related death worldwide [1, 2]. Its incidence in the United States is increasing and has nearly doubled in the past two decades [3]. The potentially curative treatments for HCC include orthotopic liver transplantation and surgical resection, which are best applied to patients with early-stage disease. Because most patients with HCC present with intermediateand advanced-stage disease, these potentially curative treatments are used in fewer than 20% of HCC patients [4, 5]. Locoregional treatments, such as transarterial chemoembolization (TACE), are frequently used to control tumor progression as primary therapy or while waiting for liver transplantation [6 10]. Conventional TACE is currently the established standard of care for selected patients with Barcelona Clinic Liver Cancer (BCLC) intermediate Child-Pugh class A disease (without portal vein thrombosis or metastases) [11, 12]. Conventional TACE has also shown benefit in advanced-stage HCC [13, 14]. Doxorubicin drug-eluting bead (DEB) TACE is a recently developed locoregional treatment of HCC tested by multiple randomized controlled studies and has shown fewer side effects and less toxicity compared with conventional TACE. DEB TACE is at least as effective as conventional TACE [14 16]. Different sizes of available DEB particles were used in these DEB TACE studies. The survival results were variable according to different DEB particle sizes [14 16]. However, no current consensus or data on optimal particle size for use in DEB TACE has been published. Lencioni et al. [17] suggested the use of μm sized particles for DEB TACE. A recent DEB TACE study for the treatment of HCC concluded that, in comparison with μm doxorubicin W706 AJR:203, December 2014

2 Doxorubicin Drug-Eluting Beads in TACE of HCC DEBs, μm doxorubicin DEBs resulted in lower rates of toxicity after treatment and a trend toward complete response on imaging at initial follow-up [18]. However, survival rates were not compared in that study [18]. The purpose of this study was to investigate the survival, efficacy, and safety of μm versus and μm low compression beads used for DEB TACE in patients with unresectable HCC. Materials and Methods Patient Selection This single-institution retrospective analysis of a prospective database with patient informed consent was approved by the local institutional review board and was HIPAA compliant. In a period of 48 months from January 2006 to December 2009, 112 consecutive patients with unresectable HCC were referred to the interventional radiology department for locoregional therapy. All patients underwent DEB TACE treatment. Among these 112 patients, 104 underwent only DEB TACE treatment (n = 269), three underwent resin-based selective internal 90 Y radioembolization therapy after DEB TACE treatment, three underwent radiofrequency ablation after DEB TACE treatment, and two underwent bland embolization before DEB TACE treatment. There were 10 patients who were successfully downstaged for orthotopic liver transplantation (OLT) after DEB TACE treatment. The patients who underwent bland embolization (n = 2), 90 Y radioembolization (n = 3), radiofrequency ablation (n = 3), or OLT (n = 10) were excluded from this study. After exclusion, 94 patients who underwent only DEB TACE as locoregional treatment were included in the study. Patients who underwent sorafenib treatment during or after the DEB TACE treatment (n = 18) were also included in the study. None of the patients with unresectable HCC completed sorafenib treatment before the DEB TACE treatment. Patients with unresectable HCC treated with small ( μm) low-compression beads (Biocompatibles, Farnham, Surrey, UK) were designated as group A. Patients with unresectable HCC treated with large (mixed and μm) low-compression beads were assigned to group B. There were 59 patients in group A and 35 patients in group B. The difference in bead size was according to operator preference. Ninety-eight percent of patients underwent an initial outpatient clinic evaluation, including pertinent medical and physical evaluations. The remaining 2% were assessed when they were admitted and had HCC found on cross-sectional imaging. The Eastern Cooperative Oncology Group (ECOG) performance status of each patient was documented before the DEB TACE procedure. The functional liver status was determined using the Child-Pugh criteria. The American Association for the Study of Liver Disease guidelines [6] were used to diagnose HCC. Diagnosis of HCC was made if MRI showed a mass with the typical vascular pattern of arterial enhancement and portal venous washout. For lesions between 1 and 2 cm, two different studies were used to detect the typical pattern, and for nodules > 2 cm in diameter, only one study was used. Biopsy for pathologic confirmation was performed if lesions showed inconclusive features on imaging. Patient Population Ninety-four patients were included in this study. Overall, there were 78 men (83%) and 16 women (17%), and age ranged from 28 to 91 years (mean age [± SD], ± years). The majority of patients were white (63.8%, n = 60) and African American (24.5%, n = 23). The most common causative factors were hepatitis C (50%, n = 47), followed by cryptogenic cirrhosis (19.1%, n = 18) and alcoholism (12.8%, n = 12). Child-Pugh class A, B, or C disease was present in 58.5% (n = 55), 30.9% (n = 29), and 10.6% (n = 10) of cases, respectively. Most patients (55.3%, n = 52) had ECOG performance status 1 at initial presentation. Cirrhosis diagnosed by imaging was present in 97.9% (n = 92) of patients. Similarly, portal venous hypertension was present according MRI features in 52.1% (n = 49) of patients. The imaging features of portal venous hypertension were varices at the sites of portosystemic anastomosis and splenomegaly with or without ascites. Multifocal HCCs were present in 57.4% (n = 54) of patients. The mean size of the index tumor was 6.1 ± 3.9 cm. In 18.1% (n = 17) of patients, the index tumor size was greater than 10 cm. Bilobar tumors were present in 30.9% of patients (n = 29). Portal vein thrombosis or invasion was present in 30.9% of patients, and extrahepatic metastases were present in 20.2% of patients at the time of initial presentation. Detailed patient demographics, tumor characteristics, and staging at the time of initial presentation in groups A and B are shown in Table 1. Both groups were similar in age, sex, race, Child- Pugh class, Okuda staging, Cancer of the Liver Italian Program (CLIP) staging, BCLC staging, ECOG performance status, portal vein thrombosis, extrahepatic metastasis, and tumor burden (p > 0.5) (Table 1). DEB TACE Procedure There were 269 DEB TACE procedures performed in 94 patients (mean, 2.8 ± 2.1; range, 1 11). All of the therapies were performed under moderate sedation and local analgesia. Large lowcompression beads ( and μm) were used in 37.2% of patients (n = 35) and small low-compression beads ( μm) were used in 62.8% of patients (n = 59). After ultrasound-guided femoral artery cannulation, each first-time procedure was initiated with diagnostic celiac and superior mesenteric angiograms with a 5-French Simmons 1 (Terumo) catheter to outline the anatomy, delineate the tumors, and identify the portal vein. The third- or fourthorder branches of feeding vessels supplying the HCC were catheterized with a 2.8-French (Renegade Hi-Flo, Boston Scientific) or a 2.1-French microcatheter (STC Renegade Hi-Flo, Boston Scientific). Then, the tumors were embolized with a slow fluoroscopy-guided injection of iodinated contrast material mixed with and μm low-compression beads or with μm low-compression beads impregnated with 50 mg of doxorubicin in each vial. The first- and second-order branches of the right or left hepatic arteries were kept patent and documented on postembolization completion angiography. The endpoint for treatment included the administration of the two vials of DEBs or sluggish flow in the subsegmental branches of the hepatic artery to the region of the tumor without an effect on the flow in the main or lobar hepatic artery. After two vials of DEB TACE, no additional embolization was performed despite persistent high flow within the tumor. In cases of arterioportal shunting, slurry absorbable gelatin powder (Gelfoam, Pfizer) was injected before injection of doxorubicinimpregnated low-compression beads. Otherwise, no additional embolization was performed. Follow-Up Patients who had large tumors of more than 5 cm or multifocal disease were brought back in 4 weeks for a repeat session, and the remainder of the patients were followed up in the clinic in 4 weeks with liver function tests and MRI of the liver. Liver function tests and formation of ascites and encephalopathy were monitored during follow-up visits to assess for liver toxicity. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used to report clinical adverse events [19]: grade 0, no adverse events or within normal limits; grade 1, mild adverse events with marginal clinical relevance; grade 2, moderate adverse events requiring minimal, local, and noninvasive intervention; grade 3, severe undesirable adverse events requiring hospitalization, invasive intervention, transfusion, or surgery; grade 4, life-threatening or disabling adverse events; and grade 5, fatal adverse events. During follow-up clinic visits at 4 weeks from last treatment, cross-sectional imaging was performed. AJR:203, December 2014 W707

3 TABLE 1: Demographics and Clinical and Laboratory Characteristics of Patients Treated With Drug-Eluting Beads Transarterial Chemoembolization Prajapati et al. Age at diagnosis (y) Parameters Group A HCC Treated With μm Low-Compression Beads Group B HCC Treated With Mixed or μm Low-Compression Beads p Mean ± SD ± ± Sex Male 49 (83.1) 29 (82.9) 0.98 Female 10 (16.9) 6 (17.1) Ethnicity White 38 (64.4) 22 (62.9) 0.19 African American 16 (27.1) 7 (20) Others 5 (8.5) 6 (17.1) Cause HCV 34 (57.6) 13 (37.1) 0.32 HBV 4 (6.8) 4 (11.4) Alcoholism 6 (10.2) 6 (17.1) Cryptogenic cirrhosis 11 (18.6) 7 (20) Other cause of chronic liver disease 3 (5.1) 4 (11.4) No chronic liver disease 1 (1.7) 1 (2.8) Child-Pugh class A 35 (59.3) 20 (57.1) 0.46 B 19 (32.2) 10 (28.6) C 5 (8.5) 5 (13.1) Okuda stage I 32 (54.2) 15 (42.8) 0.19 II 23 (39) 17 (48.6) III 4 (6.8) 3 (8.6) CLIP stage Early 8 (13.6) 7 (20) 0.06 Intermediate 46 (78) 20 (57.2) Advanced 5 (8.5) 8 (22.8) EGOG performance status score 0 24 (40.7) 9 (25.7) (49.2) 23 (65.7) 2 or more 6 (10.2) 3 (8.6) BCLC stage Early 7 (11.9) 3 (8.6) 0.36 Intermediate 6 (10.2) 5 (14.3) Advanced 41 (69.5) 21 (60) End stage 5 (8.4) 6 (17.1) Tumor burden Single HCC 21 (35.6) 19 (54.3) 0.08 Multifocal HCC 38 (64.4) 16 (45.7) Unilobar HCC 37 (62.7) 28 (80) 0.07 Bilobar HCC 22 (37.3) 7 (20) Index HCC size < 5 cm 33 (55.9) 18 (51.4) 0.65 Index HCC size 5 10 cm 17 (28.8) 9 (25.7) Index HCC size > 10 cm 9 (15.3) 8 (22.9) (Table 1 continues on next page) W708 AJR:203, December 2014

4 Doxorubicin Drug-Eluting Beads in TACE of HCC TABLE 1: Demographics and Clinical and Laboratory Characteristics of Patients Treated With Drug-Eluting Beads Transarterial Chemoembolization (continued) Parameters Further decisions were based on clinical evaluation, laboratory values, and imaging response. If there was progressive disease on follow-up MRI at 4 weeks, patients were scheduled for an appointment with an oncologist to evaluate for systemic therapy. Simultaneously, these patients were retreated with DEB TACE if there were no contraindications, such as marked acute deterioration of liver function. If follow-up MRI showed residual or recurrent HCC, the patients were retreated with DEB TACE. If patients showed complete response on MRI after DEB TACE, they were followed up every 3 months for the first 2 years with MRI of the abdomen. Afterward, they were followed up every 6 months with MRI of the abdomen until death. The patients were scheduled for DEB TACE if MRI showed recurrence of HCC and ECOG performance status less than 2. Study Objectives and Statistical Analysis The primary objectives of the study were to compare the survival and efficacy in group A and B patients as well as overall survival in subgroups on the basis of different staging systems and presence or absence of extrahepatic metastasis or portal vein thrombosis and to determine prognostic factors for survival in unresectable HCC patients treated with DEB TACE. Secondary aims were to compare safety among these two groups. Patients were stratified on the basis of age, sex, cause, tumor burden, Okuda staging, ECOG performance status, Child- Pugh class, and CLIP and BCLC staging. Statistical analysis of the difference between the means of continuous variables of both groups was tested using the independent Student t test. The chisquare test was used to compare the categoric variables. A p value of 0.05 or less was considered significant. At this p value, the power analysis of our study with 35 patients in group A and 59 in group B has a reasonable power of 81%. Survival was calculated from the time of first DEB TACE therapy. The Group A HCC Treated With μm Low-Compression Beads Kaplan Meier method with the log rank test was used to estimate survival and difference. Patients who were alive at the end of the study period were censored. SPSS software, version 20.0 (IBM) was used to perform the statistical analyses. Results DEB TACE Procedures Overall, 269 DEB TACE procedures were performed in 94 patients (mean, 2.8 ± 2.1; range, 1 11). In group A, 193 DEB TACE procedures were performed in 59 patients (mean, 3.1 ± 2; range, 1 11). In group B, 76 DEB TACE procedures were performed in 35 patients (mean, 2.2 ± 2; range, 1 10). The mean dose of doxorubicin used for DEB TACE was 55 mg in group A and 61 mg in group B (p = 0.7). Group B HCC Treated With Mixed or μm Low-Compression Beads p Portal vein thrombosis Yes 17 (28.8) 12 (34.3) 0.58 No 42 (71.2) 23 (65.7) Extrahepatic metastasis Yes 14 (23.7) 7 (20) 0.67 No 45 (76.3) 28 (80) Adjuvant treatment with sorafenib Yes 18 (31.6) 7 (20) 0.23 Note Data in parentheses are percentages. HCV = hepatitis C virus, HBV = hepatitis B virus, CLIP = Cancer of the Liver Italian Program, ECOG = Eastern Cooperative Oncology Group, BCLC = Barcelona Clinic Liver Cancer, HCC = hepatocellular carcinoma. Fig. 1 Kaplan-Meier survival graph shows survival difference between group A (small-particle μm eluting beads) and group B (large-particle or μm eluting beads). DEB TACE = drugeluting beads transarterial chemoembolization. Survival Analysis The overall median and mean survival rates of the 94 patients were 12.1 and 21.0 months, respectively. The overall median survival rates in HCC patients with patent and thrombosed portal veins treated with DEB TACE were 17.2 and 6.4 months, respectively (p < 0.001). Median survival in patients without extrahepatic metastasis compared with patients with extrahepatic metastasis were 15.0 and 5.6 months, respectively (p = 0.03). The overall median survival rates in group A (TACE with μm sized DEB) and group B (TACE with mixed and μm sized DEB) were 15.1 and 11.1 months, respectively (p = 0.004). The mean survival rates in groups A and B were 25.7 and 14 months, respectively (p = 0.004). Substratification survival analyses were performed for different categories as shown in Table 2. The overall survival rates between group A and group B were significantly different when stratified according to the Child-Pugh class; tumor burden; portal vein thrombosis; extrahepatic metastases; and Okuda, CLIP, and BCLC staging (Table 2). Kaplan-Meier survival analysis showed a significant survival difference between group A and group B (Fig. 1). The median survival rates in patients with Child-Pugh class A, B, and C were 19.3, 12.1, and 7.4 months in group A, and 18.8, 2.2, and 0.8 months in group B, respectively (p < 0.001). In particular, the survival rates were significantly different in Child- Cumulative Survival Large particle 2 Small particle 1.0-Censored 2.0-Censored Survival From First DEB TACE (mo) AJR:203, December 2014 W709

5 Prajapati et al. TABLE 2: Median Overall Survival Analyses From First Drug-Eluting Beads Transarterial Chemoembolization (DEB TACE) Using Kaplan-Meier Univariate Analysis in Patients With Unresectable Hepatocellular Carcinoma (HCC) Treated With DEB TACE Parameters Median Survival in Group A (mo) Median Survival in Group B (mo) p Overall 15.1 ( ) 11.1 ( ) Sex Male 15.3 ( ) 13.5 ( ) 0.08 Female 10.5 ( ) 1.3 ( ) Child-Pugh class A 19.3 (7.4 31) 18.8 ( ) < B 12.1 (4 20.3) 2.2 ( ) C 7.4 ( ) 0.8 ( ) Okuda stage I 15.1 (4.1 26) 22 ( ) II 12.2 ( ) 5.9 (1.9 11) III 5.6 ( ) 1.3 ( ) CLIP stage Early 21 ( ) 28.4 ( ) < Intermediate 12.1 ( ) 11.1 ( ) Advanced 7.4 ( ) 1.2 ( ) BCLC stage Early 19.3 ( ) 23.7 ( ) < Intermediate 10.1 ( ) 22.4 ( ) Advanced 15.3 (6 24.5) 11.1 ( ) End stage 4.1 ( ) 0.8 ( ) No. of HCCs Single HCC 21 ( ) 16.6 ( ) Multiple HCCs 10.5 ( ) 2.1 ( ) Portal vein thrombosis No 19.3 ( ) 15.8 ( ) 0.04 Yes 8.8 ( ) 1.4 (0.1 4) Extrahepatic metastasis No 15.3 ( ) 13.4 ( ) Yes 10.5 ( ) 1.3 ( ) Adjuvant treatment with sorafenib Yes 15.8 (5.3 26) 16.8 ( ) 0.06 No 14.4 ( ) 5.4 (0.1 13) Note Data in parentheses are 95% CI. Group A patients were treated with μm low-compression beads. Group B patients were treated with or μm low-compression beads. CLIP = Cancer of the Liver Italian Program, ECOG = Eastern Cooperative Oncology Group, BCLC = Barcelona Clinic Liver Cancer. Pugh class B and C among both groups (Fig. 2). The median survival rates in patients with BCLC early, intermediate, advanced, and end stage were 19.3, 10.1, 15.3, and 4.1 months in group A and 23.7, 22.4, 11.1, and 0.8 months in group B, respectively (p < 0.001). Survival rates were significantly different in BCLC advanced stage among both groups, which was shown in a Kaplan-Meier survival graph. The overall median survival rates in HCC patients with patent and thrombosed portal veins treated with DEB TACE were 19.3 and 8.8 months in group A and 15.8 and 1.4 months in group B, respectively (p = 0.04) (Fig. 3). Multivariate Analysis Multivariate analysis was performed including different variables (Table 3). The Child-Pugh class, serum α-fetoprotein level, and particle size of DEB TACE were the only significant prognostic indicators of survival on multivariate analyses (Table 3). Safety The 30-day mortality rate was 0% in group A and 14.3% (n = 5) in group B (p = 0.001). All patients had Child-Pugh class C disease W710 AJR:203, December 2014

6 Doxorubicin Drug-Eluting Beads in TACE of HCC TABLE 3: Multivariate Survival Analyses With Cox Model Including All Important Covariates in Cohort of 94 Patients (Both Groups) Variables Hazard Ratio p () p (Overall) Sex Male 0.7 Female 1.1 ( ) 1.1 Race White 0.85 ( ) African American 0.72 ( ) 0.57 Other Cause Hepatitis C 0.28 ( ) Hepatitis B 1.2 ( ) 0.67 Alcoholism 0.25 ( ) 0.2 Cryptogenic 0.16 ( ) 0.17 Other causes of cirrhosis 0.6 ( ) 0.7 No cirrhosis Maximum baseline dimension (cm) < ( ) ( ) 0.67 > 10 Lobe involvement Unilobar 0.86 ( ) Bilobar Distribution Single 0.72 ( ) Multiple Size of low-compression DEB used for TACE Mixed and μm 2.7 ( ) μm Portal vein thrombosis No 1.1 ( ) Yes Extrahepatic metastasis No 0.8 ( ) Yes Child-Pugh class A 0.28 ( ) B 0.32 ( ) 0.04 C ECOG performance status ( ) ( ) or more (Table 3 continues on next page) AJR:203, December 2014 W711

7 Prajapati et al. TABLE 3: Multivariate Survival Analyses With Cox Model Including All Important Covariates in Cohort of 94 Patients (Both Groups) (continued) Variables Hazard Ratio p () p (Overall) Okuda stage I 0.5 ( ) II 0.82 ( ) 0.49 III CLIP stage Early 0.19 ( ) Intermediate 0.47 ( ) 0.18 Advanced Adjuvant treatment with sorafenib No 1.2 ( ) Yes Serum α-fetoprotein level (ng/dl) < Note Data in parentheses are 95% CI. ECOG = Eastern Cooperative Oncology Group, CLIP = Cancer of the Liver Italian Program. Cumulative Survival Large particle 2 Small particle 1.0-Censored 2.0-Censored with extensive tumor burden revealed on MRI and died of a combination of disease progression and liver failure. The comparisons of adverse events after DEB TACE between the two groups are listed in Table 4. There were significantly higher common terminology criteria for adverse events (CTCAE) grade III adverse events present in group B compared with group A (20% vs 6.8%, p = 0.04). CT- CAE grade I or II adverse events were present in 30.5% (n = 18) in group A and 31.4% (n = 11) in group B. One patient in group A and one patient in group B had pseudoaneurysms from femoral punctures, which required thrombin injection under ultrasound guidance. One patient in group A had bradycardia after the procedure, which required prolonged hospitalization for cardiac workup and treatment. One patient in group A had upper gastrointestinal bleeding from gastric ulceration from left gastric artery pseudoaneurysm, which required coil embolization. One patient in group A and three patients in group B required more than 48 hours of hospitalization because of excessive postembolization symptoms. Most adverse events were grade I and II and included abdominal pain, nausea, and vomiting after DEB TACE procedures Survival From First DEB TACE (mo) Survival From First DEB TACE (mo) A B Fig. 2 Survival according to Child-Pugh class. A and B, Kaplan-Meier survival graphs show survival difference between group A (small-particle μm eluting beads) and group B (large-particle or μm eluting beads) according to Child-Pugh class B (A) and C (B). DEB TACE = drug-eluting beads transarterial chemoembolization. Cumulative Survival Large particle 2 Small particle Discussion Conventional TACE for hepatic tumors has been reported in the medical literature over the past two decades with various success rates [20, 21]. However, there have been wide differences in embolization technique, type and combinations of chemotherapeutic drugs, and size and type of embolic particles that have led to different operator preferences, practice types, and results across different institutions and countries. Recently, numerous studies have been reported with favorable outcomes using DEB TACE for HCC [13 16, 18, 22 25]. DEB Cumulative Survival Large particle 2 Small particle 1.0-Censored 2.0-Censored Survival From First DEB TACE (mo) Fig. 3 Kaplan-Meier survival graph shows survival difference between group A (small-particle μm eluting beads) and B (large-particle or μm eluting beads) according to portal vein thrombosis. DEB TACE = drug-eluting beads transarterial chemoembolization. W712 AJR:203, December 2014

8 Doxorubicin Drug-Eluting Beads in TACE of HCC TABLE 4: Comparison of Complications in Patients With Unresectable Hepatocellular Carcinoma Complications Group A Group B p Grades I and II 18 (30.5) 11 (31.4) 0.9 Abdominal pain 11 (18.6) Mild (pain score 1 3) 6 (10.1) 4 (11.4) Moderate (pain score 4 6) 3 (5.1) 3 (8.6) Severe (pain score 7 10) 2 (3.4) 2 (5.7) Nausea with or without vomiting 8 (13.6) 6 (17.1) Fever 2 (3.4) 1 (2.9) Groin pain (pain score > 4/10) 2 (3.4) 1 (2.9) Grade III 4 (6.8) 7 (20) 0.04 Femoral artery pseudoaneurysm 1 (1.7) 1 (2.9) Severe bradycardia 1 (1.7) 0 Prolonged hospitalization due to severe abdominal pain 1 (1.7) 3 (8.6) Encephalopathy 0 3 (8.6) Gastric ulceration and bleeding 1 (1.7) 0 Note Except for p, data are number with percentage in parentheses. Group A patients were treated with μm low-compression beads. Group B patients were treated with or μm low-compression beads. TACE has shown improved survival, better tolerability, and fewer side effects compared with conventional TACE [14 16, 25]. With DEB TACE, the amount of chemotherapy in relation to the amount of embolic material is more consistent than in conventional chemoembolization with different combinations of chemotherapeutic drugs. However, the size of the embolic particles used in different DEB TACE studies has ranged from to μm with different survival results that ranged from 13.5 to 24.5 months [7, 16, 23, 24, 26 28]. To our knowledge, there have not been any randomized DEB TACE studies that investigated the optimum size of particles for the achievement of greatest survival in DEB TACE procedures. However, a few nonrandomized studies in conventional TACE and bland embolization have reported an advantage of μm size particles over larger particles. For example, Amesur et al. [29] reported higher treatment response rates using μm particles compared with μm particles, and Maluccio et al. [30] concluded that bland embolization of the terminal vessels with small particles is an effective treatment method for patients with unresectable HCC. In this study, the survival, efficacy, and safety of DEB TACE with μm versus and μm low-compression beads were compared in patients with unresectable HCC. DEB TACE with μm beads achieved 15.1 months of overall median survival compared with 11.1 months overall median survival with DEB TACE using and μm beads (p = 0.004). The increased necrosis may be the contributing factor for higher survival and tumor response in the group with μm DEB TACE. This is supported by the study of Lewis et al. [31] in young adult Yucatan pigs, which showed that larger areas of tumor pannecrosis developed when small doxorubicin-loaded μm beads were used compared with larger μm beads, and the authors concluded that the larger areas of necrosis may be due to the increased surface area of smaller beads, inducing a greater burst release of doxorubicin within the tumor. Recently, Padia et al. [18] reported that μm doxorubicin DEBs had lower rates of toxicity after treatment and a trend toward complete response on imaging at initial follow-up compared with μm DEBs. The limitations of the study were a small sample size and lack of long-term follow-up. Thus, time to progression and survival rates could not be assessed. The major complications and 30-day mortality were significantly lower in this study after DEB TACE with μm compared with DEB TACE with and μm eluting beads. The reason for the lower toxicity with smaller particles may be related to reduced embolic effect of small-particle nontarget embolization on normal liver parenchyma compared with larger particles because the side effects of TACE are mainly related to effect of nontarget embolization and treatment-induced ischemic damage to the nontumoral liver parenchyma, which precipitates or potentiates liver failure, especially in advanced chronic liver disease. In theory, larger particles result in more proximal embolization and a greater degree of stasis within the hepatic vasculature; this would effectively treat a larger volume of liver, inducing more global ischemia. However, it is difficult to compare degrees of stasis in a quantitative fashion, as highlighted by Wigmore et al. [32], who found that patients who experienced cytolysis, possibly due to damage to normal liver, had a higher incidence of postembolization symptoms. Kothary et al. [33] also showed that patients who underwent lobar chemoembolization in large tumors fared worse than those who underwent subselective chemoembolization. In this study, the survival difference was higher (among groups A and B) in patients with Child-Pugh class B and C, advanced-stage HCC (according to CLIP and BCLC staging), portal venous thrombosis, and extrahepatic metastatic disease. The reason for lower survival in the larger-particle group of patients may be related to higher embolic effect of large-particle nontarget embolization on normal liver parenchyma, especially in patients with advanced HCC disease or advanced chronic liver disease. Our study has several limitations that deserve mention. The total study population is relatively small within a single institution nonrandomized retrospective analysis of a prospective database; therefore, selection and late-look bias may be inherent, and the results AJR:203, December 2014 W713

9 Prajapati et al. must be considered preliminary. Because the size of beads used was at the discretion of the attending physicians, operator bias cannot be entirely excluded. Although demographic characteristics, disease staging, and tumor burden were balanced between the two treatment groups, more patients were treated with smaller beads than with larger beads. Given that the study had a power of 81% and was still able to show considerably significant differences in survival between the two groups, we believe that smaller particle size is at least partially contributory to longer survival. Therefore, taking into account the preliminary data in this study, further randomized controlled trials are required for confirmation. Conclusion TACE with μm DEBs is effective and safe in patients with unresectable HCC. 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