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Survival Outcomes of Very Small Drug-Eluting Beads Used in Chemoembolization of Unresectable Hepatocellular Carcinoma
CLINICAL STUDY
Survival Outcomes of Very Small Drug-Eluting Beads Used in Chemoembolization of Unresectable Hepatocellular Carcinoma Ahmed Kamel Abdel Aal, MD, PhD, Sherif Moawad, MD, Patrick Vande Lune, MD, Husameddin El Khudari, MD, Mauro Mitusru Hanaoka, MD, Noha Abouldahab, MD, Andrew J. Gunn, MD, Jared White, MD, Mohamed Shoreibah, MD, Yufeng Li, MD, Souheil Saddekni, MD, and Khalid Mahmoud, MD ABSTRACT Purpose: To assess the safety and efficacy of transarterial chemoembolization using a 75-μm drug-eluting embolic (DEE) in patients with unresectable hepatocellular carcinoma (HCC). Materials and Methods: The medical records of 109 patients with a mean age of 64.1 years (range 85–49) treated for unresectable HCC between November 2013 and August 2016 with transarterial chemoembolization using a 75-μm DEE were retrospectively reviewed. Patients who had prior therapy for HCC were excluded. Child-Pugh A patients and Barcelona Clinic Liver Cancer stages A/B patients constituted 68.8% and 65.1% of the patients, respectively. The mean size of the index tumors was 5.8 cm (range 18.5–1.2) with 42 (39%) patients with central tumors around the porta-hepatis region. Portal vein invasion was seen in 10 (9.2%) patients. Tumor response was categorized according to the modified Response Evaluation Criteria in Solid Tumors 1.1, and the toxicity profile was assessed using Common Terminology Criteria for Adverse Events, version 4.03. Results: At 1-month follow-up, complete response, objective response, and disease control was seen in 23%, 66%, and 90%, respectively. The median progression-free survival was 11.2 months. The median overall survival was 25.1 months (33.4 months for Child-Pugh A and 28.2 months for Barcelona Clinic Liver Cancer stages A/B), and transplant-free survival was 21.3 months. The 6-, 12-, and 24-month survivals were 91.7%, 75.5%, and 50.5%, respectively. Grade 3 toxicity was seen in 1.8% of the patients; no grade 4 or 5 toxicity was reported. Conclusions: Transarterial chemoembolization using 75-μm DEE is safe and efficacious in the treatment of HCC.
ABBREVIATIONS AFP ¼ alfa fetoprotein, BCLC ¼ Barcelona Clinic Liver Cancer, CI ¼ confidence interval, CR ¼ complete response, DC ¼ disease control, DEE ¼ drug-eluting embolic, HCC ¼ hepatocellular carcinoma, OR ¼ objective response, OS ¼ overall survival, PFS ¼ progression-free survival, PR ¼ partial response, PV ¼ portal vein
INTRODUCTION Transarterial chemoembolization is considered the standard of care for intermediate-stage hepatocellular carcinoma From the Departments of Radiology (A.K.A.A., S.M., P.V.L., H.E.K., M.M.H., N.A., A.J.G., S.S., K.M.), Surgery (J.W.), Internal Medicine, Division of Hepatology and Gastroenterology (M.S.), and Department of Medicine (Y.L.), Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL 35249. Received May 3, 2019; final version accepted May 6, 2019. Address correspondence to A.K.A.A.; E-mail: akamel66@hotmail. com; Twitter handle: @ahmed_kamel_ir A.K.A.A. is a paid consultant for Boston Scientific (Marlborough, Massachusetts), Bard Peripheral Vascular (Tempe, Arizona), Baxter Healthcare (Deerfield, Illinois), Sirtex Medical (New South Wales, Australia), and Abbott Vascular (Chicago, Illinois); and receives research grants from Boston
(HCC) (1). Drug-eluting embolic (DEE)-transarterial chemoembolization releases cytotoxic drugs in a controlled and sustained manner (2). There are existing data regarding Scientific. S.S. is a paid consultant for Abbott Vascular. A.J.G. is a paid consultant for BTG (London, United Kingdom). None of the other authors have identified a conflict of interest. Figures E1 and E2 and Tables E1 and E2 can be found by accessing the online version of this article on www.jvir.org and clicking on the Supplemental Material tab. © SIR, 2019 J Vasc Interv Radiol 2019; ▪:1–10 https://doi.org/10.1016/j.jvir.2019.05.006
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the outcomes of transarterial chemoembolization-DEE using 100–300, 300–500, and 500–700 μm size (3,4). There is scarce literature on the 75–150 μm DEE (LC Beads M1, BTG, United Kingdom), which demonstrated superior tumor coverage in comparison to the 100–300 μm DEE, and induces a greater burst release of doxorubicin (5). One possible disadvantage to the use of smaller DEEs, however, is an increased risk of hepatobiliary complications (6). The objective of this study was to assess the safety and effectiveness of a 75-μm DEE used in transarterial chemoembolization for patients with unresectable HCC.
MATERIALS AND METHODS Study Design This study was compliant with Health Insurance Portability and Accountability Act regulations and approved by the authors’ institutional review board. A retrospective chart review was performed for all patients receiving transarterial chemoembolization, from the electronic database at the authors’ institution, between November 2013 and August 2016. Inclusion Criteria. Patients diagnosed with HCC and subjected to DEE-transarterial chemoembolization as their first treatment, using a 75-μm DEE (Oncozene, Boston Scientific) loaded with doxorubicin, were included. HCC was diagnosed according to the American Association for the Study of Liver Diseases criteria (7). Biopsy was performed in indeterminate lesions. The decision to perform transarterial chemoembolization in patients with HCC was made by a consensus of a multidisciplinary liver tumor board that includes Medical Oncologists, Hepatologists, Interventional Radiologists, and Liver Transplant Surgeons according to Association for the Study of Liver Diseases practice guidelines. Exclusion Criteria. Patients who had non-HCC malignancies, recurrent HCC following liver resection or transplantation, previously treated with systemic chemotherapeutic agents, treated previously with other locoregional therapies, or treated with DEE-transarterial chemoembolization with different DEE size were excluded.
Patient Demographics A total of 109 patients were included. The study sample consisted of 89 (82%) males and 20 (18%) females with a mean age of 64.1 years (range 49–85). The demographics and clinical characteristics of the study group are presented in Table 1. The median Eastern Cooperative Oncology Group status of the patients was 1 (range 0–4). The mean size of the index tumors was 5.8 cm (range 1.2–18.5) with 42 (39%) patients having central tumors around the
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Table 1. Patient Demographics Characteristic Age
No. (%) 64.1 (8.3)*
Gender Male
89 (81.7)
Female
20 (18.3)
Race White
78 (71.6)
Black
15 (13.8)
Other Etiology
16 (14.7)
HCV
66 (60.6)
HBV
6 (5.5)
EtoH
31 (28.4)
NASH
18 (16.5)
Other
9 (8.1)
Child-Pugh Stage A B/C
75 (68.8) 34 (31.2)
BCLC A
34 (31.2)
B
37 (33.9)
CD
38 (34.9)
ECOG score 0
45 (41.3)
1 2
47 (43.1) 11 (10.1)
3
4 (3.7)
4
2 (1.8)
No. of lesions 1
52 (47.7)
2
25 (22.9)
þ2
32 (29.4)
Tumor location Central
42 (38.5)
Peripheral
67 (61.5)
PV invasion Total
10 (9.2)
Main PV
4 (3.7)
Main right PV branch
3 (2.8)
Peripheral PV branch Mean index tumor diameter, cm
3 (2.8) 5.8 (1.2–18.5)*
BCLC ¼ Barcelona Clinic Liver Cancer; ECOG ¼ Eastern Cooperative Oncology Group; EtoH ¼ ethyl alcohol; HBV ¼ hepatitis B virus; HCV ¼ hepatitis C virus; NASH ¼ nonalcoholic steatohepatitis; PV ¼ portal vein. *Data expressed as mean (range).
porta-hepatis region. Portal vein (PV) invasion was seen in 10 (9.2%), with main PV invasion in 4 (3.7%), right main branch invasion in 3 (2.8%), and peripheral branch invasion in 3 (2.8%) patients. Fifty-two patients (48%) had a single hepatic lesion, 25 (23%) had 2 lesions, and 32 (29%) had more than 2 lesions.
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Transarterial Chemoembolization Protocol A total of 5 interventional radiologists with 5–25 years of experience performed DEE-transarterial chemoembolization using 3 mL of 75-μm DEE that were loaded with doxorubicin. The dose of doxorubicin was either 50 mg (n ¼ 100) or 100 mg (n ¼ 9), and the variability in the dose was based on physician preference, not on tumor size. One vial of the DEE was used for each patient. DEE was delivered until stasis was reached or the total dose was delivered. Bland embolization was performed after DEE administration in 25 (22.9%) patients when complete stasis was not achieved with the DEE, using 100 (n ¼ 8), 250 (n ¼ 6), 400 (n ¼ 8), and 500 μm (n ¼ 3) Embozene embolic particles (Boston Scientific, Massachusetts). Technical success was defined as successful advancement of the delivery microcatheter to the intended arterial branch and delivery of the DEE. Ninety-five percent (n ¼ 103) of DEE-transarterial chemoembolization procedures were performed with the catheter placed in the segmental artery or subsegmental hepatic arterial branches. Lobar DEE-transarterial chemoembolization was performed in multifocal or invasive HCC without a dominant mass.
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Table 2. Adverse Events Laboratory adverse events Grade 2
1 (0.9%)
ALT
1 (0.9%)
ALP
1 (0.9%)
Bilirubin
1 (0.9%)
INR
1 (0.9%)
Platelets
1 (0.9%)
WBC Grade 3
2 (1.8%) Total 2 (1.8%)
AST and ALT
1 (0.9%)
WBC
1 (0.9%)
Clinical adverse events Grades 1 and 2 Postembolization syndrome
Tumor Response Radiological tumor response was assessed according to modified Response Evaluation Criteria in Solid Tumors 1.1 criteria (8) at 1, 6, and 12 months. Objective response (OR) was defined as the sum of complete response (CR) and partial response (PR), whereas disease control (DC) was defined as the sum of CR, PR, and stable disease. Tumor response according to Child-Pugh score, Barcelona Clinic Liver Cancer (BCLC) stage, location of the tumor, portal vein invasion, tumor size, and alfa fetoprotein (AFP) level was analyzed.
21 (19.3%) 3 (2.8%)
Fatigue Skin erythema
8 (7.3%) 2 (1.8%)
Grade 4 GI bleeding
Total 1 (0.9%) 1 (0.9%)
Hepatobiliary injuries Asymptomatic biloma
Imaging was performed before and after DEE-transarterial chemoembolization in all patients using multiphasic contrast-enhanced computed tomography or magnetic resonance imaging scans as part of the authors’ institutional protocol. The pretransarterial chemoembolization imaging was performed at a mean 33.1 days (range 1–92). The first posttransarterial chemoembolization imaging was performed at a mean of 38.3 days (range 21–106). The 1-, 6-, and 12-month imaging follow-up was obtained for 109 (100%), 86 (78.9%), and 62 (56.9%) patients, respectively. The imaging studies were read specifically for this study by 2 of the authors. Each study was read by 1 author.
Total 23 (21.1%)
Worsening ascites
Grade 1
Imaging before and after Transarterial Chemoembolization
Total 6 (5.5%)
AST
Total 9 (8.3%) 9 (8.3%)
Grade 2
Total 3 (2.8%)
Portal vein thrombosis Grade 4
3 (2.8%) Total 1 (0.9%)
Liver abscess
1 (0.9%)
ALT ¼ alanine transaminase; AST ¼ aspartate transaminase; GI ¼ gastrointestinal; INR ¼ international normalized ratio; WBC ¼ white blood cell.
chemoembolization. Hepatobiliary injuries were evaluated on posttransarterial chemoembolization imaging and included 4 classes: bile duct dilatation, portal vein narrowing, portal vein thrombosis, and biloma/liver infarct (9). Clinical and laboratory toxicity as well as hepatobiliary injuries were graded according to Common Terminology Criteria for Adverse Events, version 4.03 (10).
Survival Analysis The mean follow-up was 19.8 months (range 1.4–49.9). Progression-free survival (PFS) and overall survival (OS) were calculated from Kaplan-Meier curves. Correlation between PFS and OS with patient demographics, pretransarterial chemoembolization laboratory values, tumor size and location, PV invasion, tumor response, and ChildPugh score and BCLC staging was analyzed.
Statistical Analysis Adverse Events Assessment The adverse events of the 75-μm DEE were assessed clinically and by laboratory values that were obtained at a mean of 38.6 days (range 21–106) after DEE-transarterial
To compare continuous variables between the 2 groups, 2 sample t tests were conducted. Careful attention was given to the normality assumption, which was examined by normal probability plots and histograms. To compare
4 ▪ Outcomes of a 75-μm Drug-Eluting Embolic
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Figure 1. Kaplan-Meier progression-free survival curve for all patients with a median progression-free survival of 12.2 months.
categorical variables, chi-squared tests of association were conducted. PFS and OS were analyzed using Kaplan-Meier method. The 6-, 12-, 18-, and 24-month PFS and OS were estimated from KM curves. Association between PFS and OS with patient demographics, pretransarterial chemoembolization laboratory values, tumor size and location, PV invasion, tumor response, Child-Pugh score, and BCLC staging was evaluated using Cox regression model. For all inferences, the significant level was set to P < .05. All analyses were conducted using SAS v.9.4 (SAS Inc., Cary, North Carolina).
6-mo overall progressionfree rate
109
32
5
69.95
12-mo overall progressionfree rate
72
19
11
49.97
18-mo overall progressionfree rate
42
8
8
39.45
RESULTS Tumor Response
24-mo overall progressionfree rate
26
5
5
31.05
At the first postprocedure imaging, CR was observed in 25 (23%), PR in 47 (43%), stable disease in 26 (24%), and progressive disease in 11 (10%) patients. Objective response and DC were observed in 72 (66%) and 98 (90%) patients, respectively. Tumor response at 6 and 12 months are shown in Table E1 (available online on the article’s Supplemental Material page at www.jvir.org). There was no significant difference in the tumor response based on the Child-Pugh score or BCLC stage. For patients who are most likely to receive transarterial chemoembolization, Child-Pugh A patients had 26.7% CR, 64% OR, and 89.3% DC, whereas BCLC stage B patients showed 18.9% CR, 73% OR, and 91.9% DC at first postprocedure follow-up. The mean number of transarterial chemoembolization procedures per patient was 2 (range 1–9). On repeat
Table 3. Estimated PFS Patients Progression Censored Estimated (n) (n) (n) PFS Rate, %
PFS ¼ progression-free survival.
transarterial chemoembolization, the hepatic arteries involved in transarterial chemoembolization showed diminutive angioarchitecture, which was not different compared with conventional transarterial chemoembolization or transarterial chemoembolization using DEE of larger size. Table E2 (available online on the article’s Supplemental Material page at www.jvir.org) shows the tumor response according to the location of the tumor, portal vein invasion, size of the tumor, and AFP level. Peripheral tumors had significantly higher DC rate compared with central tumors (95.5% vs 80.9%, respectively; P ¼ .014). The
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Figure 2. Kaplan-Meier curves of progression-free survival stratified according to Child-Pugh score. There was no significant difference in the progression-free survival between Child-Pugh A (median 12.1 months) versus Child-Pugh B and C (median 10.1 months).
radiologic response of patients without PV invasion was significantly better than those with PV invasion in terms of OR (70.7% vs 20%; P ¼ .003) and DC (92.9% vs 60%, P ¼ .009). In regard to tumor size, patients with small tumor size <3 cm showed the best radiologic response in terms of CR, OR, and DC compared with tumors that are 3–5 cm and >5 cm.
Adverse Events Table 2 shows the clinical and laboratory adverse events of the patients in the study. There was no 30-day mortality recorded. The majority of patients (n ¼ 49, 45%) had grade 1 laboratory adverse events. Grade 2 and 3 laboratory adverse events were seen in 6 (5.5%) and 2 (1.8%) patients, respectively, and laboratory values returned to baseline in all patients after a mean 60.1 days (range 32–120). There were no grade 4 or 5 laboratory adverse events. Grade 1 and 2 clinical adverse events occurred in 23 (21.1%) patients, of whom 21 (19.3%) experienced postembolization syndrome and were treated conservatively without consequences. Patients who developed new or worsening ascites were treated with diuretics. Two patients had skin erythema and were advised to keep their skin clean and dry. A grade 4 clinical adverse event occurred in 1 (0.9%) patient who developed esophageal varices and hematemesis caused by worsening of portal hypertension. The patient was hospitalized in the intensive care unit, was managed by blood transfusion and variceal banding, and was discharged after 1 week.
Grade 1 hepatobiliary injuries were seen in 9 (8%) patients who had biloma that were asymptomatic and required no further treatment. Grade 2 hepatobiliary injuries were seen in 3 (2.8%) patients who developed portal vein thrombosis. Grade 4 hepatobiliary injuries occurred in 1 (0.9%) patient, who developed liver abscess resulting in sepsis and was hospitalized and treated with intravenous antibiotic and percutaneous abscess drainage. The mean hospital stay for all patients was 1 day (range 0–4).
Survival Outcomes The median PFS was 11.2 (95% confidence interval [CI] 8.9–17.6) months (Fig 1). The estimated 6-, 12-, 18-, and 24-month PFS was 70%, 50%, 39.5%, and 31.1%, respectively (Table 3). There was no association between PFS and age, gender, pretransarterial chemoembolization AFP level, tumor size, tumor location, or PV invasion. PFS was not statistically different based on the Child-Pugh score (P ¼ .471) (Fig 2) or the BCLC stage (P ¼ .434) (Fig 3, Table 4). There was a significant difference between the PFS based on tumor response (P ¼ .0001) (Fig E1 [available online on the article’s Supplemental Material page at www.jvir.org]), with the highest PFS seen in patients who had CR. The median OS was 25.1 (95% CI 20.5–33.4) months (Fig 4). The estimated 6, 12, 18, and 24 months OS was 91.7%, 75.5%, 66.9%, and 50.5%, respectively (Table 5). After excluding 15 patients who underwent liver transplant following transarterial chemoembolization, the median transplant-free survival was 21.3 (95% CI
6 ▪ Outcomes of a 75-μm Drug-Eluting Embolic
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Figure 3. Kaplan-Meier curves of progression-free survival stratified according to BCLC staging. There was no significant difference in the progression-free survival between BCLC stages A and B (median 12.1 months) versus BCLC stages C and D (median 11 months).
17.7–25.6) months. OS was not affected by age, gender, pretransarterial chemoembolization AFP level, tumor size, tumor location, or PV invasion. OS was statistically higher in Child-Pugh A patients compared to Child-Pugh B and C patients (33.4 months vs 15.4 months, P ¼ .0004) (Fig 5, Table 4). OS was also higher in BCLC stages A and B patients compared with BCLC stages C and D patients (28.2 months vs 18.2 months, P ¼ .014) (Fig 6, Table 4). In particular, BCLC stage A patients had a median OS of 39.9 months and BCLC stage B patients had a median OS of 25.1 months. When the OS was stratified based on tumor response, there was a significant difference in the OS between the different categories of the modified Response Evaluation Criteria in Solid Tumors (P ¼ .016) (Fig E2 [available online on the article’s Supplemental Material page at www.jvir.org]), with patients who had CR showing the highest OS (39.9 months) and patients who had progressive disease showing the least OS (9.5 months). At the end of the follow-up period, 36 (33%) patients received curative therapy (liver transplantation, liver resection, or ablation). Ten (9.2%) patients were successfully bridged to liver transplantation, and 26 (23.8%) were successfully downstaged, of which 20 (18.3%) patients received ablation, 5 (4.6%) received liver transplantation, and 1 (0.9%) received liver resection (Table 6).
DISCUSSION Recent studies have suggested that smaller diameter DEE may have a superior therapeutic effect in the treatment of
Table 4. PFS and OS Based on Child-Pugh Classification and BCLC Staging PFS Months (95% CI)
OS P
Months (95% CI)
P
Child Pugh score A
12.1 (9.5–20.7)
B and C BCLC staging
10.1 (5.7–18.8)
A and B
12.1 (8.9–18.8)
C and D
11.0 (5.5–20.7)
.471 33.4 (22.6– 42.7) .0004 15.4 (8.7–21.5) .434 28.2 (22.6–42.7) .0136 18.2 (11.5–22.4)
OS ¼ overall survival; PFS ¼ progression-free survival.
HCC compared with larger diameter DEE (11,12). This may be due to occlusion of more distal vessels with smaller particle sizes, resulting in more localized chemotherapeutic delivery. Lee et al used 100- to 300-μm particles in an animal model and demonstrated increased penetration of liver tumors when compared with 300- to 500-μm particles, which were distributed at the periphery of the tumors (13). Distal embolization has been demonstrated with a 40-μm DEE by Tanaka et al in a rabbit tumor model with the deposition of the microspheres documented histologically inside the tumor (14). Similarly, Dreher et al (5) showed that microspheres 70–150 μm have a better penetration and distribution inside the tumor compared with larger embolics (15). The need for distal embolization at the level of intratumoral vessels is also apparent from the fact that therapeutic levels of
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Figure 4. Kaplan-Meier overall survival curve for all patients, with a median overall survival of 25.1 months.
doxorubicin (0.55–6.80 M) extend up to 600 μm from the surface of the embolics, and proximity of the microsphere to the neoplastic cells is essential, therefore necessitating the use of DEE <300 μm (16). Pharmaceutical research continues to focus on the development of smaller DEE. The efficacy and safety of the tested 75-μm DEE is not well-studied clinically. To the authors’ knowledge, the only study investigating the 75-μm DEE in humans thus far was performed by Malagari et al (17), and included 52 patients. They used 40-μm DEEs for tumors <6 cm in diameter, 75-μm DEEs for tumors 6–10 cm in diameter, and 100-μm DEEs for tumors >10 cm in diameter, resulting in a CR, OR, and DC rates of 13.72%, 57.69%, and 98.08%, respectively, after the first transarterial chemoembolization treatments. The CR, OR, and DC rates in the current study were comparable to those seen in the Malagari et al study (17). Regarding safety, there is concern that smaller particle size would result in extrahepatic toxicity resulting from passage via small collateral hepatic vessels (18); however, in the current study, mild systemic adverse effects of doxorubicin were observed, which is consistent with results published with larger diameter DEE (19,20). Grade 3 and 4 adverse events reported the current study, were also comparable to previously published data ranging from 2.9% to 6.6% (20,21). There was no 30-day mortality or tumor rupture observed. Concern for hepatobiliary injury is a common reservation regarding the use of DEE with a size <100 μm (22,23) and is thought to be a result of ischemia of the hypertrophied
Table 5. Estimated OS Patients (n)
Death (n)
Censored (n)
Estimated OS rate, %
6-mo OS rate
109
9
1
91.71
12-mo OS rate
99
17
6
75.47
18-mo OS rate
76
8
11
66.9
24-mo OS rate
57
13
8
50.49
OS ¼ overall survival.
peribiliary capillary plexus seen in cirrhotic patients (4,9), and also nontarget embolization of healthy liver tissue (6,24). The hepatobiliary injuries of 11.9% in the current study are in the lower range of the existing literature (6,9) and were mostly asymptomatic biloma (69%) that required no intervention. The drivers behind the difference in the reported hepatobiliary injuries might be due to the difference in the technique of transarterial chemoembolization, in which large number of patients underwent lobar transarterial chemoembolization (6). In comparison, most of the patients in this study received DEE-transarterial chemoembolization with very selective catheter approach, making it less likely to cause nontarget embolization and less likely to cause widespread embolization of the peribiliary capillary plexus. The difference might also be due to the type of DEE used in this study, which offers tight
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Figure 5. Kaplan-Meier curves of overall survival stratified according to Child-Pugh score. There was a significant difference in the overall survival between Child-Pugh A (median 33.4 months) versus Child-Pugh B and C (median 15.4 months).
Figure 6. Kaplan-Meier curves of overall survival stratified according to BCLC staging. There was a significant difference in the overall survival between BCLC stages A and B (median 28.2 months) versus BCLC stages C and D (median 18.2 months).
calibration (75 ± 15 μm) with shrinkage of 9% after loading with doxorubicin, compared with 20%–24% seen in other products (25). The change in size following drug loading
resulting in more variability in size might cause embolization of the nontarget liver tissue with more effect on the peribiliary capillary plexus.
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Table 6. Subsequent Curative Therapy after First DEBTransarterial Chemoembolization Subsequent potentially curative therapy No. of patients (%) after DEB-transarterial chemoembolization Ablation
20 (18.3)
Resection
1 (0.9)
Liver transplantation (downstaged)
5 (4.6)
Liver transplantation (bridged)
10 (9.2)
Total
36 (33%)
DEB ¼ drug-eluting beads.
This study is not without limitations. It is retrospective in nature; hence, selection bias is an inherent limitation. The study does not offer direct comparison between small- and large-diameter DEE. In the absence of head-to-head comparisons between different DEE particle sizes in the present population, there is no guarantee that the DEE particle size contributes to outcomes. The present experience includes 1 formulation of small DEE particles, and conclusions cannot be drawn about small DEE particles in general. Another limitation is the lack of stratification by baseline patient or tumor characteristics, which could have helped to identify subgroups of patients who would gain the most benefit from transarterial chemoembolization with small DEE particles. The study offers limited long-term data on safety and outcomes and further follow-up will provide more information on these DEE particles. The present study reports experiences in a single center that, despite suggesting relative consistency in technique of DEE-transarterial chemoembolization between patients, some patients underwent bland embolization following DEE-transarterial chemoembolization using different sizes of embolics, which does not provide uniformity in the technique and might affect the results of the study. In addition, DEE-transarterial chemoembolization techniques are likely to vary among centers and so the results of this study cannot be generalized; however, the present cohort, including a broad range of patients, provides reliable findings and offers a reasonable safety and survival outcome data. In conclusion, this study adds more to the existing literature on the safety and efficacy of the tested 75 μm DEE in the treatment of HCC not eligible for surgical resection, ablation, or liver transplant. The tested DEE shows lower incidence of significant adverse events and hepatobiliary injuries compared with the published literature, which might be related to the technique of transarterial chemoembolization. Within the limitations of this retrospective study, the tested DEE demonstrated promising radiologic response and survival rates.
ACKNOWLEDGMENTS This work was funded by a research grant from Boston Scientific.
REFERENCES 1. Llovet JM. Update treatment approach to hepatocellular carcinoma. J Gastroenterol 2005; 40:225–235. 2. Nicolini A, Martinetti L, Crespi S, Maggioni M, Sangiovanni A. Transarterial chemoembolization with epirubicin-eluting beads versus transarterial embolization before liver transplantation for hepatocellular carcinoma. J Vasc Interv Radiol 2010; 21:327–332. 3. Padia SA, Shivaram G, Bastawrous S, et al. Safety and efficacy of drugeluting bead chemoembolization for hepatocellular carcinoma: comparison of small-versus medium-size particles. J Vasc Interv Radiol 2013; 24: 301–306. 4. Joskin J, de Baere T, Auperin A, et al. Predisposing factors of liver necrosis after transcatheter arterial chemoembolization in liver metastases from neuroendocrine tumor. Cardiovasc Intervent Radiol 2015; 38: 372–380. 5. Dreher MR, Sharma KV, Woods DL, et al. Radiopaque drug-eluting beads for transcatheter embolotherapy: experimental study of drug penetration and coverage in swine. J Vasc Interv Radiol 2012; 23:257–264. 6. Deipolyi A, Oklu R, Al-Ansari S, et al. Safety and efficacy of 70–150μm and 100–300μm drug-eluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2015; 26:516–522. 7. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53:1020. 8. Lencioni R, Llovet JM. Medified (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30:52–60. 9. Odisio BC, Ashton A, Yan Y, et al. Transarterial hepatic chemoembolization with 70–150 μm drug-eluting beads: assessment of clinical safety and liver toxicity profile. J Vasc Interv Radiol 2015; 26:965–971. 10. U.S. Department of Health and Human Services, National Institutes of Health, and National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.03 2010. 11. Malagari K, Chatzimichael K, Alexopoulou E, et al. Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: results of an open-label study of 62 patients. Cardiovasc Intervent Radiol 2008; 31:269–280. 12. Lencioni R, de Baere T, Burrel M, et al. Transcatheter treatment of hepatocellular carcinoma with doxorubicin-loaded DC beads (DEBDOX): technical recommendations. Cardiovasc Intervent Radiol 2012; 35: 980–985. 13. Malagari K, Pomoni M, Moschouris H, et al. Chemoembolization of hepatocellular carcinoma with Hepasphere 30–60 lm. Safety and efficacy study. Cardiovasc Intervent Radiol 2014; 37:165–175. 14. Lee KH, Liapi E, Ventura VP, et al. Evaluation of different calibrated spherical polyvinyl alcohol microspheres in transcatheter arterial chemoembolization: VX2 tumor model in rabbit liver. J Vasc Interv Radiol 2008; 19:1065–1069. 15. Tanaka T, Nishiofuku H, Hukuoka Y, et al. Pharmacokinetics and antitumor efficacy of chemoembolization using 40 lm irinotecan-loaded microspheres in a rabbit liver tumor model. J Vasc Interv Radiol 2014; 25: 1037–1044. 16. Guiu B, Schmitt A, Reinhardt S, et al. Idarubicin-loaded ONCOZENE drugeluting embolic agents for chemoembolization of hepatocellular carcinoma: in vitro loading and release and in vivo pharmacokinetics. J Vasc Interv Radiol 2015; 26:262–270. 17. Namur J, Wassef M, Millot JM, Lewis AL, Manfait M, Laurent A. Drugeluting beads for liver embolization: concentration of doxorubicin in tissue and in beads in a pig model. J Vasc Interv Radiol 2010; 21:259–267. 18. Malagari K, Kiakidis T, Pomoni M, et al. Pharmacokinetics, safety, and efficacy of chemoembolization with doxorubicin-loaded tightly calibrated small microspheres in patients with hepatocellular carcinoma. Cardiovasc Intervent Radiol 2016; 39:1379–1391. 19. Malagari K, Pomoni M, Spyridopoulos TN, et al. Safety profile of sequential transcatheter chemoembolization with DC Bead™: results of 237 hepatocellular carcinoma (HCC) patients. Cardiovasc Intervent Radiol 2011; 34:774–785. 20. Song MJ, Chun HJ, Song DS, et al. Comparative study between doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. J Hepatol 2012; 57:1244–1250. 21. Sacco R, Bargellini I, Bertini M, et al. Conventional versus doxorubicineluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2011; 22:1545–1552.
10 ▪ Outcomes of a 75-μm Drug-Eluting Embolic
22. Cho KJ, Lunderquist A. Experimental hepatic artery embolization with Gelfoam powder. Microfil perfusion study of the rabbit liver. Invest Radiol 1983; 18:189–193. 23. Demachi H, Matsui O, Takashima T. Scanning electron microscopy of intrahepatic microvasculature casts following experimental hepatic artery embolization. Cardiovasc Intervent Radiol 1991; 14:158–162.
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24. Lencioni R, de Baere T, Soulen MC, et al. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: a systematic review of efficacy and safety data. Hepatology 2016; 64:106–116. 25. de Baere T, Plotkin S, Yu R, Sutter A, Wu Y, Cruise GM. An in vitro evaluation of four types of drug-eluting microspheres loaded with doxorubicin. J Vasc Interv Radiol 2016; 27:1425–1431.
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10.e1
Figure E1. Kaplan-Meier curves of progression-free survival stratified according to the tumor response by modified Response Evaluation Criteria in Solid Tumors showing significant difference in the progression-free survival between the different categories of modified Response Evaluation Criteria in Solid Tumors.
Figure E2. Kaplan-Meier curves of overall survival stratified according to the tumor response by modified Response Evaluation Criteria in Solid Tumors showing significant difference in the overall survival between the different categories of modified Response Evaluation Criteria in Solid Tumors.
10.e2 ▪ Outcomes of a 75-μm Drug-Eluting Embolic
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Table E1. Radiologic Response at 1, 6, and 12 Months 1 Mo n ¼ 109
6 Mo n ¼ 86
12 Mo n ¼ 62
CR
25 (23%)
35 (41%)
36 (58%)
PR
47 (43%)
34 (39%)
13 (21%)
SD
26 (24%)
4 (5%)
1 (2%)
PD
11 (10%)
13 (15%)
12 (19%)
OR
72 (66%)
69 (80%)
49 (79%)
DC
98 (90%)
73 (85%)
50 (81%)
Radiologic Response
CR ¼ complete response; DC ¼ disease control; OR ¼ objective response; PD ¼ progressive disease; PR ¼ partial response; SD ¼ stable disease.
Table E2. Radiologic Response According to Tumor Location, Portal Vein Invasion, Tumor Size, and AFP Level CR
OR
DC
Tumor location Central
29.3%
Peripheral
19.4%
P ¼ .268
61.0%
P ¼ .254
70.2%
80.5%
P ¼ .014
95.5%
Portal vein invasion Yes
10.0%
No Tumor size, cm
24.2%
P ¼ .449
20.0%
P ¼ .003
70.7% P ¼ .044
60.0%
<3
34.3%
3–5
22.9%
70.8%
95.8%
>5
7.7%
46.2%
73.1%
74.3%
P ¼ .009
92.9% P ¼ .053
94.3%
P ¼ .009
AFP level 400
24.2%
>400
16.7%
P ¼ .759
71.4%
P ¼ .013
38.9%
AFP ¼ alpha fetoprotein; CR ¼ complete response; DC ¼ disease control; OR ¼ overall response.
92.3% 77.8%
P ¼ .082
Survival Outcomes of Very Small Drug-Eluting Beads Used in Chemoembolization of Unresectable Hepatocellular Carcinoma Ahmed Kamel Abdel Aal, MD, PhD, Sherif Moawad, MD, Patrick Vande Lune, MD, Husameddin El Khudari, MD, Mauro Mitusru Hanaoka, MD, Noha Abouldahab, MD, Andrew J. Gunn, MD, Jared White, MD, Mohamed Shoreibah, MD, Yufeng Li, MD, Souheil Saddekni, MD, and Khalid Mahmoud, MD ABSTRACT Purpose: To assess the safety and efficacy of transarterial chemoembolization using a 75-μm drug-eluting embolic (DEE) in patients with unresectable hepatocellular carcinoma (HCC). Materials and Methods: The medical records of 109 patients with a mean age of 64.1 years (range 85–49) treated for unresectable HCC between November 2013 and August 2016 with transarterial chemoembolization using a 75-μm DEE were retrospectively reviewed. Patients who had prior therapy for HCC were excluded. Child-Pugh A patients and Barcelona Clinic Liver Cancer stages A/B patients constituted 68.8% and 65.1% of the patients, respectively. The mean size of the index tumors was 5.8 cm (range 18.5–1.2) with 42 (39%) patients with central tumors around the porta-hepatis region. Portal vein invasion was seen in 10 (9.2%) patients. Tumor response was categorized according to the modified Response Evaluation Criteria in Solid Tumors 1.1, and the toxicity profile was assessed using Common Terminology Criteria for Adverse Events, version 4.03. Results: At 1-month follow-up, complete response, objective response, and disease control was seen in 23%, 66%, and 90%, respectively. The median progression-free survival was 11.2 months. The median overall survival was 25.1 months (33.4 months for Child-Pugh A and 28.2 months for Barcelona Clinic Liver Cancer stages A/B), and transplant-free survival was 21.3 months. The 6-, 12-, and 24-month survivals were 91.7%, 75.5%, and 50.5%, respectively. Grade 3 toxicity was seen in 1.8% of the patients; no grade 4 or 5 toxicity was reported. Conclusions: Transarterial chemoembolization using 75-μm DEE is safe and efficacious in the treatment of HCC.
ABBREVIATIONS AFP ¼ alfa fetoprotein, BCLC ¼ Barcelona Clinic Liver Cancer, CI ¼ confidence interval, CR ¼ complete response, DC ¼ disease control, DEE ¼ drug-eluting embolic, HCC ¼ hepatocellular carcinoma, OR ¼ objective response, OS ¼ overall survival, PFS ¼ progression-free survival, PR ¼ partial response, PV ¼ portal vein
INTRODUCTION Transarterial chemoembolization is considered the standard of care for intermediate-stage hepatocellular carcinoma From the Departments of Radiology (A.K.A.A., S.M., P.V.L., H.E.K., M.M.H., N.A., A.J.G., S.S., K.M.), Surgery (J.W.), Internal Medicine, Division of Hepatology and Gastroenterology (M.S.), and Department of Medicine (Y.L.), Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL 35249. Received May 3, 2019; final version accepted May 6, 2019. Address correspondence to A.K.A.A.; E-mail: akamel66@hotmail. com; Twitter handle: @ahmed_kamel_ir A.K.A.A. is a paid consultant for Boston Scientific (Marlborough, Massachusetts), Bard Peripheral Vascular (Tempe, Arizona), Baxter Healthcare (Deerfield, Illinois), Sirtex Medical (New South Wales, Australia), and Abbott Vascular (Chicago, Illinois); and receives research grants from Boston
(HCC) (1). Drug-eluting embolic (DEE)-transarterial chemoembolization releases cytotoxic drugs in a controlled and sustained manner (2). There are existing data regarding Scientific. S.S. is a paid consultant for Abbott Vascular. A.J.G. is a paid consultant for BTG (London, United Kingdom). None of the other authors have identified a conflict of interest. Figures E1 and E2 and Tables E1 and E2 can be found by accessing the online version of this article on www.jvir.org and clicking on the Supplemental Material tab. © SIR, 2019 J Vasc Interv Radiol 2019; ▪:1–10 https://doi.org/10.1016/j.jvir.2019.05.006
2 ▪ Outcomes of a 75-μm Drug-Eluting Embolic
the outcomes of transarterial chemoembolization-DEE using 100–300, 300–500, and 500–700 μm size (3,4). There is scarce literature on the 75–150 μm DEE (LC Beads M1, BTG, United Kingdom), which demonstrated superior tumor coverage in comparison to the 100–300 μm DEE, and induces a greater burst release of doxorubicin (5). One possible disadvantage to the use of smaller DEEs, however, is an increased risk of hepatobiliary complications (6). The objective of this study was to assess the safety and effectiveness of a 75-μm DEE used in transarterial chemoembolization for patients with unresectable HCC.
MATERIALS AND METHODS Study Design This study was compliant with Health Insurance Portability and Accountability Act regulations and approved by the authors’ institutional review board. A retrospective chart review was performed for all patients receiving transarterial chemoembolization, from the electronic database at the authors’ institution, between November 2013 and August 2016. Inclusion Criteria. Patients diagnosed with HCC and subjected to DEE-transarterial chemoembolization as their first treatment, using a 75-μm DEE (Oncozene, Boston Scientific) loaded with doxorubicin, were included. HCC was diagnosed according to the American Association for the Study of Liver Diseases criteria (7). Biopsy was performed in indeterminate lesions. The decision to perform transarterial chemoembolization in patients with HCC was made by a consensus of a multidisciplinary liver tumor board that includes Medical Oncologists, Hepatologists, Interventional Radiologists, and Liver Transplant Surgeons according to Association for the Study of Liver Diseases practice guidelines. Exclusion Criteria. Patients who had non-HCC malignancies, recurrent HCC following liver resection or transplantation, previously treated with systemic chemotherapeutic agents, treated previously with other locoregional therapies, or treated with DEE-transarterial chemoembolization with different DEE size were excluded.
Patient Demographics A total of 109 patients were included. The study sample consisted of 89 (82%) males and 20 (18%) females with a mean age of 64.1 years (range 49–85). The demographics and clinical characteristics of the study group are presented in Table 1. The median Eastern Cooperative Oncology Group status of the patients was 1 (range 0–4). The mean size of the index tumors was 5.8 cm (range 1.2–18.5) with 42 (39%) patients having central tumors around the
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Table 1. Patient Demographics Characteristic Age
No. (%) 64.1 (8.3)*
Gender Male
89 (81.7)
Female
20 (18.3)
Race White
78 (71.6)
Black
15 (13.8)
Other Etiology
16 (14.7)
HCV
66 (60.6)
HBV
6 (5.5)
EtoH
31 (28.4)
NASH
18 (16.5)
Other
9 (8.1)
Child-Pugh Stage A B/C
75 (68.8) 34 (31.2)
BCLC A
34 (31.2)
B
37 (33.9)
CD
38 (34.9)
ECOG score 0
45 (41.3)
1 2
47 (43.1) 11 (10.1)
3
4 (3.7)
4
2 (1.8)
No. of lesions 1
52 (47.7)
2
25 (22.9)
þ2
32 (29.4)
Tumor location Central
42 (38.5)
Peripheral
67 (61.5)
PV invasion Total
10 (9.2)
Main PV
4 (3.7)
Main right PV branch
3 (2.8)
Peripheral PV branch Mean index tumor diameter, cm
3 (2.8) 5.8 (1.2–18.5)*
BCLC ¼ Barcelona Clinic Liver Cancer; ECOG ¼ Eastern Cooperative Oncology Group; EtoH ¼ ethyl alcohol; HBV ¼ hepatitis B virus; HCV ¼ hepatitis C virus; NASH ¼ nonalcoholic steatohepatitis; PV ¼ portal vein. *Data expressed as mean (range).
porta-hepatis region. Portal vein (PV) invasion was seen in 10 (9.2%), with main PV invasion in 4 (3.7%), right main branch invasion in 3 (2.8%), and peripheral branch invasion in 3 (2.8%) patients. Fifty-two patients (48%) had a single hepatic lesion, 25 (23%) had 2 lesions, and 32 (29%) had more than 2 lesions.
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Transarterial Chemoembolization Protocol A total of 5 interventional radiologists with 5–25 years of experience performed DEE-transarterial chemoembolization using 3 mL of 75-μm DEE that were loaded with doxorubicin. The dose of doxorubicin was either 50 mg (n ¼ 100) or 100 mg (n ¼ 9), and the variability in the dose was based on physician preference, not on tumor size. One vial of the DEE was used for each patient. DEE was delivered until stasis was reached or the total dose was delivered. Bland embolization was performed after DEE administration in 25 (22.9%) patients when complete stasis was not achieved with the DEE, using 100 (n ¼ 8), 250 (n ¼ 6), 400 (n ¼ 8), and 500 μm (n ¼ 3) Embozene embolic particles (Boston Scientific, Massachusetts). Technical success was defined as successful advancement of the delivery microcatheter to the intended arterial branch and delivery of the DEE. Ninety-five percent (n ¼ 103) of DEE-transarterial chemoembolization procedures were performed with the catheter placed in the segmental artery or subsegmental hepatic arterial branches. Lobar DEE-transarterial chemoembolization was performed in multifocal or invasive HCC without a dominant mass.
3
Table 2. Adverse Events Laboratory adverse events Grade 2
1 (0.9%)
ALT
1 (0.9%)
ALP
1 (0.9%)
Bilirubin
1 (0.9%)
INR
1 (0.9%)
Platelets
1 (0.9%)
WBC Grade 3
2 (1.8%) Total 2 (1.8%)
AST and ALT
1 (0.9%)
WBC
1 (0.9%)
Clinical adverse events Grades 1 and 2 Postembolization syndrome
Tumor Response Radiological tumor response was assessed according to modified Response Evaluation Criteria in Solid Tumors 1.1 criteria (8) at 1, 6, and 12 months. Objective response (OR) was defined as the sum of complete response (CR) and partial response (PR), whereas disease control (DC) was defined as the sum of CR, PR, and stable disease. Tumor response according to Child-Pugh score, Barcelona Clinic Liver Cancer (BCLC) stage, location of the tumor, portal vein invasion, tumor size, and alfa fetoprotein (AFP) level was analyzed.
21 (19.3%) 3 (2.8%)
Fatigue Skin erythema
8 (7.3%) 2 (1.8%)
Grade 4 GI bleeding
Total 1 (0.9%) 1 (0.9%)
Hepatobiliary injuries Asymptomatic biloma
Imaging was performed before and after DEE-transarterial chemoembolization in all patients using multiphasic contrast-enhanced computed tomography or magnetic resonance imaging scans as part of the authors’ institutional protocol. The pretransarterial chemoembolization imaging was performed at a mean 33.1 days (range 1–92). The first posttransarterial chemoembolization imaging was performed at a mean of 38.3 days (range 21–106). The 1-, 6-, and 12-month imaging follow-up was obtained for 109 (100%), 86 (78.9%), and 62 (56.9%) patients, respectively. The imaging studies were read specifically for this study by 2 of the authors. Each study was read by 1 author.
Total 23 (21.1%)
Worsening ascites
Grade 1
Imaging before and after Transarterial Chemoembolization
Total 6 (5.5%)
AST
Total 9 (8.3%) 9 (8.3%)
Grade 2
Total 3 (2.8%)
Portal vein thrombosis Grade 4
3 (2.8%) Total 1 (0.9%)
Liver abscess
1 (0.9%)
ALT ¼ alanine transaminase; AST ¼ aspartate transaminase; GI ¼ gastrointestinal; INR ¼ international normalized ratio; WBC ¼ white blood cell.
chemoembolization. Hepatobiliary injuries were evaluated on posttransarterial chemoembolization imaging and included 4 classes: bile duct dilatation, portal vein narrowing, portal vein thrombosis, and biloma/liver infarct (9). Clinical and laboratory toxicity as well as hepatobiliary injuries were graded according to Common Terminology Criteria for Adverse Events, version 4.03 (10).
Survival Analysis The mean follow-up was 19.8 months (range 1.4–49.9). Progression-free survival (PFS) and overall survival (OS) were calculated from Kaplan-Meier curves. Correlation between PFS and OS with patient demographics, pretransarterial chemoembolization laboratory values, tumor size and location, PV invasion, tumor response, and ChildPugh score and BCLC staging was analyzed.
Statistical Analysis Adverse Events Assessment The adverse events of the 75-μm DEE were assessed clinically and by laboratory values that were obtained at a mean of 38.6 days (range 21–106) after DEE-transarterial
To compare continuous variables between the 2 groups, 2 sample t tests were conducted. Careful attention was given to the normality assumption, which was examined by normal probability plots and histograms. To compare
4 ▪ Outcomes of a 75-μm Drug-Eluting Embolic
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Figure 1. Kaplan-Meier progression-free survival curve for all patients with a median progression-free survival of 12.2 months.
categorical variables, chi-squared tests of association were conducted. PFS and OS were analyzed using Kaplan-Meier method. The 6-, 12-, 18-, and 24-month PFS and OS were estimated from KM curves. Association between PFS and OS with patient demographics, pretransarterial chemoembolization laboratory values, tumor size and location, PV invasion, tumor response, Child-Pugh score, and BCLC staging was evaluated using Cox regression model. For all inferences, the significant level was set to P < .05. All analyses were conducted using SAS v.9.4 (SAS Inc., Cary, North Carolina).
6-mo overall progressionfree rate
109
32
5
69.95
12-mo overall progressionfree rate
72
19
11
49.97
18-mo overall progressionfree rate
42
8
8
39.45
RESULTS Tumor Response
24-mo overall progressionfree rate
26
5
5
31.05
At the first postprocedure imaging, CR was observed in 25 (23%), PR in 47 (43%), stable disease in 26 (24%), and progressive disease in 11 (10%) patients. Objective response and DC were observed in 72 (66%) and 98 (90%) patients, respectively. Tumor response at 6 and 12 months are shown in Table E1 (available online on the article’s Supplemental Material page at www.jvir.org). There was no significant difference in the tumor response based on the Child-Pugh score or BCLC stage. For patients who are most likely to receive transarterial chemoembolization, Child-Pugh A patients had 26.7% CR, 64% OR, and 89.3% DC, whereas BCLC stage B patients showed 18.9% CR, 73% OR, and 91.9% DC at first postprocedure follow-up. The mean number of transarterial chemoembolization procedures per patient was 2 (range 1–9). On repeat
Table 3. Estimated PFS Patients Progression Censored Estimated (n) (n) (n) PFS Rate, %
PFS ¼ progression-free survival.
transarterial chemoembolization, the hepatic arteries involved in transarterial chemoembolization showed diminutive angioarchitecture, which was not different compared with conventional transarterial chemoembolization or transarterial chemoembolization using DEE of larger size. Table E2 (available online on the article’s Supplemental Material page at www.jvir.org) shows the tumor response according to the location of the tumor, portal vein invasion, size of the tumor, and AFP level. Peripheral tumors had significantly higher DC rate compared with central tumors (95.5% vs 80.9%, respectively; P ¼ .014). The
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5
Figure 2. Kaplan-Meier curves of progression-free survival stratified according to Child-Pugh score. There was no significant difference in the progression-free survival between Child-Pugh A (median 12.1 months) versus Child-Pugh B and C (median 10.1 months).
radiologic response of patients without PV invasion was significantly better than those with PV invasion in terms of OR (70.7% vs 20%; P ¼ .003) and DC (92.9% vs 60%, P ¼ .009). In regard to tumor size, patients with small tumor size <3 cm showed the best radiologic response in terms of CR, OR, and DC compared with tumors that are 3–5 cm and >5 cm.
Adverse Events Table 2 shows the clinical and laboratory adverse events of the patients in the study. There was no 30-day mortality recorded. The majority of patients (n ¼ 49, 45%) had grade 1 laboratory adverse events. Grade 2 and 3 laboratory adverse events were seen in 6 (5.5%) and 2 (1.8%) patients, respectively, and laboratory values returned to baseline in all patients after a mean 60.1 days (range 32–120). There were no grade 4 or 5 laboratory adverse events. Grade 1 and 2 clinical adverse events occurred in 23 (21.1%) patients, of whom 21 (19.3%) experienced postembolization syndrome and were treated conservatively without consequences. Patients who developed new or worsening ascites were treated with diuretics. Two patients had skin erythema and were advised to keep their skin clean and dry. A grade 4 clinical adverse event occurred in 1 (0.9%) patient who developed esophageal varices and hematemesis caused by worsening of portal hypertension. The patient was hospitalized in the intensive care unit, was managed by blood transfusion and variceal banding, and was discharged after 1 week.
Grade 1 hepatobiliary injuries were seen in 9 (8%) patients who had biloma that were asymptomatic and required no further treatment. Grade 2 hepatobiliary injuries were seen in 3 (2.8%) patients who developed portal vein thrombosis. Grade 4 hepatobiliary injuries occurred in 1 (0.9%) patient, who developed liver abscess resulting in sepsis and was hospitalized and treated with intravenous antibiotic and percutaneous abscess drainage. The mean hospital stay for all patients was 1 day (range 0–4).
Survival Outcomes The median PFS was 11.2 (95% confidence interval [CI] 8.9–17.6) months (Fig 1). The estimated 6-, 12-, 18-, and 24-month PFS was 70%, 50%, 39.5%, and 31.1%, respectively (Table 3). There was no association between PFS and age, gender, pretransarterial chemoembolization AFP level, tumor size, tumor location, or PV invasion. PFS was not statistically different based on the Child-Pugh score (P ¼ .471) (Fig 2) or the BCLC stage (P ¼ .434) (Fig 3, Table 4). There was a significant difference between the PFS based on tumor response (P ¼ .0001) (Fig E1 [available online on the article’s Supplemental Material page at www.jvir.org]), with the highest PFS seen in patients who had CR. The median OS was 25.1 (95% CI 20.5–33.4) months (Fig 4). The estimated 6, 12, 18, and 24 months OS was 91.7%, 75.5%, 66.9%, and 50.5%, respectively (Table 5). After excluding 15 patients who underwent liver transplant following transarterial chemoembolization, the median transplant-free survival was 21.3 (95% CI
6 ▪ Outcomes of a 75-μm Drug-Eluting Embolic
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Figure 3. Kaplan-Meier curves of progression-free survival stratified according to BCLC staging. There was no significant difference in the progression-free survival between BCLC stages A and B (median 12.1 months) versus BCLC stages C and D (median 11 months).
17.7–25.6) months. OS was not affected by age, gender, pretransarterial chemoembolization AFP level, tumor size, tumor location, or PV invasion. OS was statistically higher in Child-Pugh A patients compared to Child-Pugh B and C patients (33.4 months vs 15.4 months, P ¼ .0004) (Fig 5, Table 4). OS was also higher in BCLC stages A and B patients compared with BCLC stages C and D patients (28.2 months vs 18.2 months, P ¼ .014) (Fig 6, Table 4). In particular, BCLC stage A patients had a median OS of 39.9 months and BCLC stage B patients had a median OS of 25.1 months. When the OS was stratified based on tumor response, there was a significant difference in the OS between the different categories of the modified Response Evaluation Criteria in Solid Tumors (P ¼ .016) (Fig E2 [available online on the article’s Supplemental Material page at www.jvir.org]), with patients who had CR showing the highest OS (39.9 months) and patients who had progressive disease showing the least OS (9.5 months). At the end of the follow-up period, 36 (33%) patients received curative therapy (liver transplantation, liver resection, or ablation). Ten (9.2%) patients were successfully bridged to liver transplantation, and 26 (23.8%) were successfully downstaged, of which 20 (18.3%) patients received ablation, 5 (4.6%) received liver transplantation, and 1 (0.9%) received liver resection (Table 6).
DISCUSSION Recent studies have suggested that smaller diameter DEE may have a superior therapeutic effect in the treatment of
Table 4. PFS and OS Based on Child-Pugh Classification and BCLC Staging PFS Months (95% CI)
OS P
Months (95% CI)
P
Child Pugh score A
12.1 (9.5–20.7)
B and C BCLC staging
10.1 (5.7–18.8)
A and B
12.1 (8.9–18.8)
C and D
11.0 (5.5–20.7)
.471 33.4 (22.6– 42.7) .0004 15.4 (8.7–21.5) .434 28.2 (22.6–42.7) .0136 18.2 (11.5–22.4)
OS ¼ overall survival; PFS ¼ progression-free survival.
HCC compared with larger diameter DEE (11,12). This may be due to occlusion of more distal vessels with smaller particle sizes, resulting in more localized chemotherapeutic delivery. Lee et al used 100- to 300-μm particles in an animal model and demonstrated increased penetration of liver tumors when compared with 300- to 500-μm particles, which were distributed at the periphery of the tumors (13). Distal embolization has been demonstrated with a 40-μm DEE by Tanaka et al in a rabbit tumor model with the deposition of the microspheres documented histologically inside the tumor (14). Similarly, Dreher et al (5) showed that microspheres 70–150 μm have a better penetration and distribution inside the tumor compared with larger embolics (15). The need for distal embolization at the level of intratumoral vessels is also apparent from the fact that therapeutic levels of
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Figure 4. Kaplan-Meier overall survival curve for all patients, with a median overall survival of 25.1 months.
doxorubicin (0.55–6.80 M) extend up to 600 μm from the surface of the embolics, and proximity of the microsphere to the neoplastic cells is essential, therefore necessitating the use of DEE <300 μm (16). Pharmaceutical research continues to focus on the development of smaller DEE. The efficacy and safety of the tested 75-μm DEE is not well-studied clinically. To the authors’ knowledge, the only study investigating the 75-μm DEE in humans thus far was performed by Malagari et al (17), and included 52 patients. They used 40-μm DEEs for tumors <6 cm in diameter, 75-μm DEEs for tumors 6–10 cm in diameter, and 100-μm DEEs for tumors >10 cm in diameter, resulting in a CR, OR, and DC rates of 13.72%, 57.69%, and 98.08%, respectively, after the first transarterial chemoembolization treatments. The CR, OR, and DC rates in the current study were comparable to those seen in the Malagari et al study (17). Regarding safety, there is concern that smaller particle size would result in extrahepatic toxicity resulting from passage via small collateral hepatic vessels (18); however, in the current study, mild systemic adverse effects of doxorubicin were observed, which is consistent with results published with larger diameter DEE (19,20). Grade 3 and 4 adverse events reported the current study, were also comparable to previously published data ranging from 2.9% to 6.6% (20,21). There was no 30-day mortality or tumor rupture observed. Concern for hepatobiliary injury is a common reservation regarding the use of DEE with a size <100 μm (22,23) and is thought to be a result of ischemia of the hypertrophied
Table 5. Estimated OS Patients (n)
Death (n)
Censored (n)
Estimated OS rate, %
6-mo OS rate
109
9
1
91.71
12-mo OS rate
99
17
6
75.47
18-mo OS rate
76
8
11
66.9
24-mo OS rate
57
13
8
50.49
OS ¼ overall survival.
peribiliary capillary plexus seen in cirrhotic patients (4,9), and also nontarget embolization of healthy liver tissue (6,24). The hepatobiliary injuries of 11.9% in the current study are in the lower range of the existing literature (6,9) and were mostly asymptomatic biloma (69%) that required no intervention. The drivers behind the difference in the reported hepatobiliary injuries might be due to the difference in the technique of transarterial chemoembolization, in which large number of patients underwent lobar transarterial chemoembolization (6). In comparison, most of the patients in this study received DEE-transarterial chemoembolization with very selective catheter approach, making it less likely to cause nontarget embolization and less likely to cause widespread embolization of the peribiliary capillary plexus. The difference might also be due to the type of DEE used in this study, which offers tight
8 ▪ Outcomes of a 75-μm Drug-Eluting Embolic
Aal et al ▪ JVIR
Figure 5. Kaplan-Meier curves of overall survival stratified according to Child-Pugh score. There was a significant difference in the overall survival between Child-Pugh A (median 33.4 months) versus Child-Pugh B and C (median 15.4 months).
Figure 6. Kaplan-Meier curves of overall survival stratified according to BCLC staging. There was a significant difference in the overall survival between BCLC stages A and B (median 28.2 months) versus BCLC stages C and D (median 18.2 months).
calibration (75 ± 15 μm) with shrinkage of 9% after loading with doxorubicin, compared with 20%–24% seen in other products (25). The change in size following drug loading
resulting in more variability in size might cause embolization of the nontarget liver tissue with more effect on the peribiliary capillary plexus.
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Table 6. Subsequent Curative Therapy after First DEBTransarterial Chemoembolization Subsequent potentially curative therapy No. of patients (%) after DEB-transarterial chemoembolization Ablation
20 (18.3)
Resection
1 (0.9)
Liver transplantation (downstaged)
5 (4.6)
Liver transplantation (bridged)
10 (9.2)
Total
36 (33%)
DEB ¼ drug-eluting beads.
This study is not without limitations. It is retrospective in nature; hence, selection bias is an inherent limitation. The study does not offer direct comparison between small- and large-diameter DEE. In the absence of head-to-head comparisons between different DEE particle sizes in the present population, there is no guarantee that the DEE particle size contributes to outcomes. The present experience includes 1 formulation of small DEE particles, and conclusions cannot be drawn about small DEE particles in general. Another limitation is the lack of stratification by baseline patient or tumor characteristics, which could have helped to identify subgroups of patients who would gain the most benefit from transarterial chemoembolization with small DEE particles. The study offers limited long-term data on safety and outcomes and further follow-up will provide more information on these DEE particles. The present study reports experiences in a single center that, despite suggesting relative consistency in technique of DEE-transarterial chemoembolization between patients, some patients underwent bland embolization following DEE-transarterial chemoembolization using different sizes of embolics, which does not provide uniformity in the technique and might affect the results of the study. In addition, DEE-transarterial chemoembolization techniques are likely to vary among centers and so the results of this study cannot be generalized; however, the present cohort, including a broad range of patients, provides reliable findings and offers a reasonable safety and survival outcome data. In conclusion, this study adds more to the existing literature on the safety and efficacy of the tested 75 μm DEE in the treatment of HCC not eligible for surgical resection, ablation, or liver transplant. The tested DEE shows lower incidence of significant adverse events and hepatobiliary injuries compared with the published literature, which might be related to the technique of transarterial chemoembolization. Within the limitations of this retrospective study, the tested DEE demonstrated promising radiologic response and survival rates.
ACKNOWLEDGMENTS This work was funded by a research grant from Boston Scientific.
REFERENCES 1. Llovet JM. Update treatment approach to hepatocellular carcinoma. J Gastroenterol 2005; 40:225–235. 2. Nicolini A, Martinetti L, Crespi S, Maggioni M, Sangiovanni A. Transarterial chemoembolization with epirubicin-eluting beads versus transarterial embolization before liver transplantation for hepatocellular carcinoma. J Vasc Interv Radiol 2010; 21:327–332. 3. Padia SA, Shivaram G, Bastawrous S, et al. Safety and efficacy of drugeluting bead chemoembolization for hepatocellular carcinoma: comparison of small-versus medium-size particles. J Vasc Interv Radiol 2013; 24: 301–306. 4. Joskin J, de Baere T, Auperin A, et al. Predisposing factors of liver necrosis after transcatheter arterial chemoembolization in liver metastases from neuroendocrine tumor. Cardiovasc Intervent Radiol 2015; 38: 372–380. 5. Dreher MR, Sharma KV, Woods DL, et al. Radiopaque drug-eluting beads for transcatheter embolotherapy: experimental study of drug penetration and coverage in swine. J Vasc Interv Radiol 2012; 23:257–264. 6. Deipolyi A, Oklu R, Al-Ansari S, et al. Safety and efficacy of 70–150μm and 100–300μm drug-eluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2015; 26:516–522. 7. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology 2011; 53:1020. 8. Lencioni R, Llovet JM. Medified (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30:52–60. 9. Odisio BC, Ashton A, Yan Y, et al. Transarterial hepatic chemoembolization with 70–150 μm drug-eluting beads: assessment of clinical safety and liver toxicity profile. J Vasc Interv Radiol 2015; 26:965–971. 10. U.S. Department of Health and Human Services, National Institutes of Health, and National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.03 2010. 11. Malagari K, Chatzimichael K, Alexopoulou E, et al. Transarterial chemoembolization of unresectable hepatocellular carcinoma with drug eluting beads: results of an open-label study of 62 patients. Cardiovasc Intervent Radiol 2008; 31:269–280. 12. Lencioni R, de Baere T, Burrel M, et al. Transcatheter treatment of hepatocellular carcinoma with doxorubicin-loaded DC beads (DEBDOX): technical recommendations. Cardiovasc Intervent Radiol 2012; 35: 980–985. 13. Malagari K, Pomoni M, Moschouris H, et al. Chemoembolization of hepatocellular carcinoma with Hepasphere 30–60 lm. Safety and efficacy study. Cardiovasc Intervent Radiol 2014; 37:165–175. 14. Lee KH, Liapi E, Ventura VP, et al. Evaluation of different calibrated spherical polyvinyl alcohol microspheres in transcatheter arterial chemoembolization: VX2 tumor model in rabbit liver. J Vasc Interv Radiol 2008; 19:1065–1069. 15. Tanaka T, Nishiofuku H, Hukuoka Y, et al. Pharmacokinetics and antitumor efficacy of chemoembolization using 40 lm irinotecan-loaded microspheres in a rabbit liver tumor model. J Vasc Interv Radiol 2014; 25: 1037–1044. 16. Guiu B, Schmitt A, Reinhardt S, et al. Idarubicin-loaded ONCOZENE drugeluting embolic agents for chemoembolization of hepatocellular carcinoma: in vitro loading and release and in vivo pharmacokinetics. J Vasc Interv Radiol 2015; 26:262–270. 17. Namur J, Wassef M, Millot JM, Lewis AL, Manfait M, Laurent A. Drugeluting beads for liver embolization: concentration of doxorubicin in tissue and in beads in a pig model. J Vasc Interv Radiol 2010; 21:259–267. 18. Malagari K, Kiakidis T, Pomoni M, et al. Pharmacokinetics, safety, and efficacy of chemoembolization with doxorubicin-loaded tightly calibrated small microspheres in patients with hepatocellular carcinoma. Cardiovasc Intervent Radiol 2016; 39:1379–1391. 19. Malagari K, Pomoni M, Spyridopoulos TN, et al. Safety profile of sequential transcatheter chemoembolization with DC Bead™: results of 237 hepatocellular carcinoma (HCC) patients. Cardiovasc Intervent Radiol 2011; 34:774–785. 20. Song MJ, Chun HJ, Song DS, et al. Comparative study between doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. J Hepatol 2012; 57:1244–1250. 21. Sacco R, Bargellini I, Bertini M, et al. Conventional versus doxorubicineluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2011; 22:1545–1552.
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22. Cho KJ, Lunderquist A. Experimental hepatic artery embolization with Gelfoam powder. Microfil perfusion study of the rabbit liver. Invest Radiol 1983; 18:189–193. 23. Demachi H, Matsui O, Takashima T. Scanning electron microscopy of intrahepatic microvasculature casts following experimental hepatic artery embolization. Cardiovasc Intervent Radiol 1991; 14:158–162.
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24. Lencioni R, de Baere T, Soulen MC, et al. Lipiodol transarterial chemoembolization for hepatocellular carcinoma: a systematic review of efficacy and safety data. Hepatology 2016; 64:106–116. 25. de Baere T, Plotkin S, Yu R, Sutter A, Wu Y, Cruise GM. An in vitro evaluation of four types of drug-eluting microspheres loaded with doxorubicin. J Vasc Interv Radiol 2016; 27:1425–1431.
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Figure E1. Kaplan-Meier curves of progression-free survival stratified according to the tumor response by modified Response Evaluation Criteria in Solid Tumors showing significant difference in the progression-free survival between the different categories of modified Response Evaluation Criteria in Solid Tumors.
Figure E2. Kaplan-Meier curves of overall survival stratified according to the tumor response by modified Response Evaluation Criteria in Solid Tumors showing significant difference in the overall survival between the different categories of modified Response Evaluation Criteria in Solid Tumors.
10.e2 ▪ Outcomes of a 75-μm Drug-Eluting Embolic
Aal et al ▪ JVIR
Table E1. Radiologic Response at 1, 6, and 12 Months 1 Mo n ¼ 109
6 Mo n ¼ 86
12 Mo n ¼ 62
CR
25 (23%)
35 (41%)
36 (58%)
PR
47 (43%)
34 (39%)
13 (21%)
SD
26 (24%)
4 (5%)
1 (2%)
PD
11 (10%)
13 (15%)
12 (19%)
OR
72 (66%)
69 (80%)
49 (79%)
DC
98 (90%)
73 (85%)
50 (81%)
Radiologic Response
CR ¼ complete response; DC ¼ disease control; OR ¼ objective response; PD ¼ progressive disease; PR ¼ partial response; SD ¼ stable disease.
Table E2. Radiologic Response According to Tumor Location, Portal Vein Invasion, Tumor Size, and AFP Level CR
OR
DC
Tumor location Central
29.3%
Peripheral
19.4%
P ¼ .268
61.0%
P ¼ .254
70.2%
80.5%
P ¼ .014
95.5%
Portal vein invasion Yes
10.0%
No Tumor size, cm
24.2%
P ¼ .449
20.0%
P ¼ .003
70.7% P ¼ .044
60.0%
<3
34.3%
3–5
22.9%
70.8%
95.8%
>5
7.7%
46.2%
73.1%
74.3%
P ¼ .009
92.9% P ¼ .053
94.3%
P ¼ .009
AFP level 400
24.2%
>400
16.7%
P ¼ .759
71.4%
P ¼ .013
38.9%
AFP ¼ alpha fetoprotein; CR ¼ complete response; DC ¼ disease control; OR ¼ overall response.
92.3% 77.8%
P ¼ .082