Transarterial bland versus chemoembolization for hepatocellular carcinoma: rethinking a gold standard

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Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.JournalofSurgicalResearch.com

Transarterial bland versus chemoembolization for hepatocellular carcinoma: rethinking a gold standard Nader N. Massarweh, MD, MPH,a,b,* Jessica A. Davila, PhD,a,c Hashem B. El-Serag, MD, MPH,a,c,d Zhigang Duan, MD, MS,a Sarah Temple, BA,a Sarah May, MS,a Yvonne H. Sada, MD, MPH,a,e and Daniel A. Anaya, MD f a

Veteran Affairs HSR&D Center for Innovations in Quality, Effectiveness and Safety (IQUEST), Michael E DeBakey VA Medical Center, Houston, Texas b Michael E DeBakey Department of Surgery, Division of Surgical Oncology, Baylor College of Medicine, Houston, Texas c Department of Medicine, Division of Health Services Research, Baylor College of Medicine, Houston, Texas d Department of Medicine, Division of Gastroenterology, Baylor College of Medicine, Houston, Texas e Department of Medicine, Division of Medical Oncology, Baylor College of Medicine, Houston, Texas f Section of Hepatobiliary Tumors, Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida

article info

abstract

Article history:

Background: Transarterial chemoembolization (TACE) is the most common procedure for

Received 20 July 2015

the treatment of hepatocellular carcinoma (HCC). However, HCC is generally considered

Received in revised form

chemoresistant and data demonstrating the superiority of TACE over bland embolization

25 August 2015

(TAE) are lacking.

Accepted 25 September 2015

Materials and methods: A nationwide, retrospective cohort study of HCC patients treated

Available online 3 October 2015

with first-line TACE or TAE within the Veterans Affairs health care system (2005e2012) was performed. The primary outcome was overall survival. Risk of death by treatment type

Keywords:

(TACE or TAE) was evaluated using multivariate (adjusted for age, presence of cirrhosis,

Hepatocellular carcinoma

Barcelona Clinic Liver Cancer stage, and Charlson comorbidity score) and propensity score-

Transarterial chemoembolization

adjusted Cox regression.

Transarterial embolization

Results: The cohort included 405 patients treated with first-line transarterial embolization. Among these patients, 32 (7.9%) underwent TAE. Most of the patients (76.8%) had intermediate or advanced stage at presentation. Similar proportions of patients (TACE 53.3% versus TAE 43.7%; P ¼ 0.30) received more than one embolization procedure. There was no difference in median survival (20.1 versus 23.1 mo, respectively; log-rank P ¼ 0.84). Compared to TACE, there was no difference in risk of death associated with TAE after multivariate (hazard ratio [HR] 0.92; 95% CI, 0.61e1.37) and propensity score adjustment (HR ¼ 0.86; 95% CI ¼ 0.58e1.29).

* Corresponding author. Michael E DeBakey VA Medical Center, 2002 Holcombe Blvd (OCL 112), Houston, TX 77030. Tel.: þ1 713 794 8780; fax: þ1 713 794 7352. E-mail address: [email protected] (N.N. Massarweh). 0022-4804/$ e see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jss.2015.09.034

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Conclusions: There is no clear benefit associated with chemotherapy infusion over bland embolization for HCC treatment. Given the rising incidence of HCC in the United States and considering the added costs associated with TACE compared to TAE, future work comparing these competing management strategies is needed. Published by Elsevier Inc.

1.

Introduction

The incidence of hepatocellular carcinoma (HCC) has risen over the last 2 decades, and it is a leading cause of cancerrelated mortality [1,2]. HCC management is often complicated by the severity of the patient’s underlying liver disease. Less than 20% of HCC patients present with disease that is amenable to curative therapy with resection, local ablation, or transplantation [3]. Among those who are not candidates for curative treatment, transarterial chemoembolization (TACE) has long been a mainstay of HCC management and is the most commonly used intervention in this setting [4]. The success of TACE in eliciting disease response is predicated on the tumor’s blood supply being predominantly derived from the hepatic artery. Therefore, the procedure involves selective angiographic access to the feeding artery, occlusion of the vessel through embolization, and concurrent infusion of chemotherapeutic agents. However, HCC is known to be a chemoresistant tumor [5]. Furthermore, the benefit of chemotherapy infusion as a part of this procedure has never been well evaluated. Although TACE and bland embolization (TAE) have been compared in several randomized controlled trials (RCTs), none were designed to specifically evaluate differences in survival and, as such, no study has demonstrated a clear survival benefit associated with the former [6e10]. An evaluation of the benefits of TACE compared to TAE is important for two main reasons. First, there are attendant complications associated with embolization procedures, and it is unclear whether these are related to the embolization itself, to the chemotherapy infusion or both. Second, there are additional costs associated with TACE. Therefore, given the current attention on cancer-related health care cost containment, as well as the frequency with which TACE is performed, identification of opportunities for cost savings in the treatment of an increasingly common cancer would be beneficial. In this context, our present study sought to compare first-line TACE and TAE on a random sample of HCC patients treated in the largest integrated health system in the United States with the hypothesis that chemotherapy infusion during transarterial embolization for HCC is not associated with a survival benefit when compared to bland embolization.

2.

Methods

2.1.

Data and study setting

This was an observational cohort study of patients diagnosed with HCC treated across the Veterans Affairs (VA) health care system nationally from 2005 through 2012. The VA is the largest integrated health system in the United States with

one of the oldest electronic medical records (EMR) as well as numerous other administrative data sources that can be used for clinical investigation. Both administrative data files (MedSAS Outpatient and Inpatient files as well as the VA Vital Status File) and data abstracted from the EMR were used. Patients with HCC were identified from VA administrative files as described below. The remainder of the patient information ascertained for this study was collected from the VA Compensation and Pension Records Interchange system, which includes medical record information for all VA patients nationwide. This study was approved by the Baylor College of Medicine Institutional Review Board and the Michael E DeBakey VA Research & Development committee.

2.2.

Study subjects

A thorough description of this data set has been previously published [11]. Patients who were actively using VA health care with at least two International Classification of Diseases, ninth revision, Clinical Modification diagnosis codes consistent with an initial HCC diagnosis (155.0) in the absence of a concurrent diagnosis code for intrahepatic cholangiocarcinoma (155.1) were identified from VA administrative files (n ¼ 10,695). A random, computer-generated sample of these patients was then selected for chart review to both confirm the diagnosis and extract relevant clinical data. Of the 1500 patients with confirmed incident HCC, those undergoing embolization procedures were identified using either International Classification of Diseases, ninth revision, Clinical Modification or Common Procedural Terminology procedure codes, as described previously [11]. Receipt of chemotherapy infusion during the embolization procedure (TACE versus TAE) was ascertained through detailed chart review. The cohort was further restricted to treatment naı¨ve patients treated with first-line arterial embolization.

2.3.

Variables

Demographic, clinical, and laboratory data were ascertained through detailed manual abstraction of the EMR demographic data and included age, sex, and race. Clinical data included Eastern Cooperative Oncology Group performance status, Model for End-Stage Liver Disease (MELD) score, Child-Pugh classification, Barcelona Clinic Liver Cancer (BCLC) HCC stage, presence of cirrhosis (defined as evidence of cirrhosis on prediagnosis biopsy, imaging features suggestive of cirrhosis, or abnormal laboratory values on 2 of 3 laboratory values [Albumin <3.0; platelet count <200,000; INR >1.1]) within 6 mo before and/or 4 wk after diagnosis, the Deyo modification of the Charlson comorbidity index, and tumor characteristics (stage, size, and number of lesions).

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Dates of embolization procedures and other treatment related information were also ascertained through review of the EMR. Date of death was collected from VA administrative files.

2.4.

Analysis

Descriptive statistics were applied to evaluate differences in categorical and continuous variables between groups. The primary outcome of interest was overall survival. Survival was defined as time from initial diagnosis to death or end of study follow-up. The KaplaneMeier method and log-rank test were applied to evaluate unadjusted survival. The association between treatment type and risk of death was further evaluated using multivariate Cox regression and propensity scoreadjusted modeling. Hazard ratios (HR) and their 95% confidence intervals (CI) were calculated. The multivariate model adjusted for clinically relevant variables including age, Charlson comorbidity index, BCLC stage, and presence of cirrhosis. Propensity scores for receipt of TAE were calculated using logistic regression models which included age, BCLC stage, presence of cirrhosis, uni/bilobar distribution, total bilirubin, and creatinine. All analyses were performed using SAS, version 9.3, (SAS Institute). All statistical comparisons were two sided with P values considered significant at P < 0.05.

3.

Results

3.1.

Baseline demographic and clinical characteristics

A total of 405 patients met eligibility criteria and were included in the study. Median age was 60.6 years (interquartile range, 56.4e65.9), 61.2% were white, and 47.7% had a comorbidity score 3. Approximately 8% (n ¼ 32) underwent TAE, and the remainder were treated with TACE. There were no clear geographic or hospital-specific preferences for use of TAE. Specifically, there were four geographic regions within the VA during the study time period (west, central, south, and east). The 32 TAE procedures were distributed across all four regions and performed at 12 different institutions. Table 1 provides demographic, clinical, and tumor-related information stratified by treatment group. No significant differences were observed between patients treated with TACE and TAE in regard to age (median age, 60.7 [56.4e66.3] versus 58.7 [54.8e62.1], P ¼ 0.17), burden of comorbid conditions (Charlson 3, 47.2% versus 53.1%, P ¼ 0.42), severity of underlying liver disease (no significant differences in presence of Cirrhosis, MELD, or Child-Pugh class; P > 0.05), or BCLC stage distribution (P ¼ 0.18). The only notable significant difference was with regard to performance statusda higher proportion patients treated with TAE had a poor Eastern Cooperative Oncology Group performance status than those treated with TACE (17.2 versus 34.4%, P ¼ 0.02).

3.2.

Procedural data

Table 2 describes clinical information related to the embolization procedures. We observed no difference in the proportions of patients who received more than one

embolization procedure (TACE 53.4% versus TAE 43.8%; P ¼ 0.30). As compared to those treated with TAE, those treated with TACE had significantly greater utilization overall of other associated treatments subsequent to the embolization (52.3% versus 34.4%, P ¼ 0.05). However, there were no significant differences observed based on the specific type of other treatment provided. The incidence of postprocedural mortality within 30 d was also not significantly different between treatment groups.

3.3.

Primary outcomedoverall survival

Median follow-up for the entire cohort was 20.2 mo (range, 10e39.2). Figure 1 demonstrates unadjusted overall survival stratified by treatment type. There was no difference in median survival between groups (20.1 versus 23.1 mo; logrank P ¼ 0.84). Similarly, there was no difference in 1-, 3and 5-y overall survival for patients treated with TACE as compared to those treated with TAE (1-y, 69.7% versus 65.6%; 3-y, 28.9% versus 31.3%; and 5-y, 13.8% versus 14.6%, respectively). A forest plot demonstrating the risk of death associated with these competing management strategies is provided in Figure 2. As compared to TACE, there was no difference in the risk of death associated with TAE after multivariate (hazard ratio [HR] ¼ 0.92; 95% CI, 0.61e1.37, P ¼ 0.68) and propensity score adjustment (HR 0.86; 95% CI, 0.58e1.29, P ¼ 0.47). After multivariate analysis, BCLC stage was the primary predictor of survivaldpatients with stage BCLC C and D had a higher risk of death as compared to those with early disease (BCLC stages 0eA) (HR ¼ 1.51 [95% CI, 1.12e2.04] for BCLC C and 3.21 [2.1e4.91] for BCLC D) (Table 3).

4.

Discussion

For patients with HCC who are not candidates for transplantation or resection, TACE has long been a mainstay of treatment. The survival benefit of TACE over supportive care is not a matter of debate. However, HCC is considered a chemoresistant tumor [5]. As such, the value of chemotherapy infusion as a part of this procedure remains unclear. In this national VA cohort study, we did not find a significant difference in either overall median or long-term survival between patients treated with TACE compared to bland embolization. Furthermore, after multivariate and propensity score adjustment, there was no statistically significant difference in risk of overall death between treatment groups. There have been at least five randomized comparisons of TACE and other nonsurgical management strategies (either supportive care or TAE). Results from these trials clearly demonstrated a survival benefit for TACE over no intervention [8,12]. However, comparisons of TACE with TAE have demonstrated neither statistically significant nor clinically meaningful differences in survival [6e8,10,13]. Whereas providing important information on disease response, a major shortcoming of these RCTs was the choice of primary endpointdnone used overall or disease-specific survival for either the main study outcome or for sample size calculation. In fact, most of the trials recommended further evaluation of

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Table 1 e Demographic, clinical, tumor, and treatment characteristics for the cohort (n [ 405). Characteristic

Demographic characteristics Median age (IQR), y Age 65 y Male Race White Black Hispanic Other Clinical characteristics Charlson-Deyo score 0 1e2 3 ECOG performance status Good (score 0e1) Poor (score 2) Cirrhosis Child-Pugh class A B C BCLC stage 0/A B C D MELD score <10 10e19 20 Unknown Median AFP (IQR) Median bilirubin (IQR) Median creatinine (IQR) Median platelets (IQR)  1000 Tumor characteristics Tumor distribution Unilobar Bilobar Number of tumors Solitary Multifocal Median number of tumors (IQR) Median size largest tumor (IQR), cm Macroscopic vascular invasion

Type of embolization TACE (n ¼ 373)

TAE (n ¼ 32)

P value

60.7 (56.4e66.3) 108 (29.0%) 373 (100%)

58.7 (54.8e62.1) 4 (12.5%) 32 (100%)

0.17 0.05 0.23

233 83 50 7

(62.5%) (22.2%) (13.4%) (1.9%)

15 12 4 1

(46.9%) (37.5%) (12.5%) (3.1%) 0.42

62 (16.6%) 135 (36.2%) 176 (47.2%)

7 (21.9%) 8 (25.0%) 17 (53.1%)

309 (82.8%) 64 (17.2%) 326 (87.4%)

21 (65.6%) 11 (34.4%) 28 (87.5%)

217 (58.2%) 134 (35.9%) 22 (5.9%)

16 (50.0%) 15 (46.9%) 1 (3.1%)

87 136 119 31

7 7 16 2

0.02

0.99 0.43

0.18 (23.3) (36.5) (31.9) (8.3)

(21.9) (21.9) (50.0) (6.3) 0.05

186 (49.9) 162 (43.4) 7 (1.9) 18 (4.8) 19 (6.4e126.6) 1.1 (0.7e1.6) 1 (0.8e1.1) 119 (75e184)

9 (28.1) 20 (62.5) 2 (6.3) 1 (3.1) 28.3 (9.4e570) 1.5 (0.8e1.9) 1 (0.8e1.3) 107.5 (70e210.5)

0.81 0.07 0.62 0.99 0.87

273 (73.2) 100 (26.8)

23 (71.9) 9 (28.1)

139 (37.3) 234 (62.7) 3 (2.0e3.0) 3.2 (2.3e5.0) 13 (3.5)

9 (28.1) 23 (71.9) 2 (2.0e3.0) 3.4 (2.3e4.7) 3 (9.4)

0.3

0.75 0.91 0.10

IQR ¼ interquartile range, ECOG ¼ Eastern Cooperative Oncology Group, MELD ¼ model for end-stage liver disease score.

potential survival difference between TACE and TAE. However, to date, no such RCT has been performed. A metaanalysis on three of these trials demonstrated no difference in survival, but these results must be interpreted in the context of notable heterogeneity in the data [14]. There are two main reasons for further evaluation of TAE as a management strategy for HCC is important. First, there are recent, single-center series suggesting results after TAE may be at least as good as TACE [15e18]. Osuga et al. reported their results after TAE in 59 HCC patients and demonstrated

median overall survival to be 30 mo, radiographically stable disease in the vast majority (81%) of patients, and no major complications [15]. A shortcoming of this study was the lack of a TACE control group. However, when compared to outcomes for TACE from a population-level cohort of contemporary patients treated in the same setting, the results after TAE compared favorably [19]. In this regard, our study provides data from a contemporaneous comparison of TACE and TAE, with our results suggesting that bland embolization merits further evaluation in HCC management. Second, the

556

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Table 2 e Embolization procedure characteristics and postprocedure outcomes. Embolization characteristic

Type of embolization TACE (n ¼ 373)

Multiple embolization 199 procedures Mean number of procedures (SD) 2.2 Type of embolization chemotherapy No chemotherapy Single and/or multiagent 216 (traditional) Drug-eluting beads 100 Type of chemotherapy 57 infused unknown Procedures subsequent to the 195 embolization* Transplant 18 Resection 4 Ablation 44 Sorafenib 1 Other systemic therapy 43 Postprocedure outcome Postembolization death 9 within 30 d *

TAE (n ¼ 32)

P value

(53.4%)

14 (43.8%)

0.30

(1.7)

1.9 (1.4)

0.33

d (57.9%)

32 (100%) d

(26.8%) (15.3%)

d d

(52.3%)

11 (34.4%)

0.05

(4.8%) (1.1%) (11.8%) (0.3%) (11.5%)

0 0 3 (9.4%) 1 (3.1%) 2 (6.3%)

0.38 1 1 0.15 0.55

(2.4%)

1 (3.1%)

1.00

Treatments administered within 6 mo of embolization procedure.

association between chemotherapy infusion during TACE and postprocedural complications is an area requiring further investigation. Although we did not specifically evaluate postprocedural complications in this study, adverse events such as postembolization syndrome can occur in up to 80% of patients [20], with reports suggesting an association with

the chemotherapy infusion in addition to the embolization procedure itself [21]. Despite the relatively benign nature of such complications, they can have a substantial effect on postprocedure recovery and might impact long-term outcome [22]. There has been recent attention on the current costs of cancer care in the United States and worldwide with great emphasis placed on finding ways to provide high value care [23]. As different approaches to TACE have evolved, chemoembolization with drug-eluting beads (DEB) has become widely used [24]. Although, DEB was used in only a quarter of the patients in our cohort, we suspect this rate reflects the time frame of our study, and the actual rate in more recent years is substantially higher. Assuming there is truly no difference in survival between TACE and TAE, there is a clear opportunity for significant cost savings in the management of HCC by implementing a shift from TACE to TAE, particularly in the setting of the rising incidence of HCC [25], and that liver-directed therapiesdnamely TACEdrepresent the most frequently used therapy for these patients [4,26,27]. Given that the cost of DEB is estimated at US $1500 per vial and if DEB is assumed to be the dominant TACE strategy in current HCC management, a straightforward calculation using the most recent estimates of new HCC cases in the United States (n ¼ 30,640), [28] the rate at which HCC patients are treated with TACE (w56%) [26], and assuming each of these patients was to undergo two TACE procedures over the course of their treatment [14], reveals a potential cost savings of over US $50,000,000 by eliminating the cost of DEB alone. Although this would represent a relatively modest cost savings, this simple calculation neither accounts for other service-related costs associated with TACE [29,30] nor the costs associated with managing

100%

TACE

Proportion Surviving

80%

TAE

60%

40%

Log-rank = 0.84

20%

0%

0

12

24

36

48

Months Fig. 1 e Overall survival in HCC patients by embolization type (n [ 405).

60

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557

Fig. 2 e Risk of death associated with embolization type.

postprocedural adverse events potentially attributable to the chemotherapy infusion. Clearly, this calculation does not take into account potentially lower costs associated with procedures using more traditional approaches to TACE (e.g., lipiodol embolization with direct infusion of chemotherapeutic agents). However, in current practice, traditional TACE is now performed in the minority of cases and elimination of the additional costs for these agents would still result in a

Table 3 e Multivariate Cox model to identify independent predictors of overall survival (n [ 405). Predictor

Hazard ratio

TAE (reference: TACE) Age increment in years Cirrhosis (reference: no cirrhosis) BCLC stage (reference: 0eA) Stage B Stage C Stage D Charlson comorbidity score 1e2 3

0.92 0.99 0.99

95% Confidence interval

P value

0.61e1.37 0.98e1.00 0.71e1.39

0.68 0.12 0.98

1.22 0.91e1.63 1.51 1.12e2.04 3.21 2.10e4.91 (reference: 0) 1.15 0.83e1.58 1.14 0.84e1.55

0.19 <0.01 <0.01 0.40 0.39

cost savings when compared to TAE. Future studies focused on comparing the efficacy of TACE versus TAE will need to incorporate cost analyses, because if oncologic outcomes for these two procedures are equivalent, cost containment alone should be a strong enough reason to support a shift from TACE to TAE when managing patients with HCC with transarterial therapies. There are important limitations to consider when interpreting these results. The reasons for which patients were treated with TAE instead of TACE are not known. Although multivariate and propensity score adjustment approaches were used to maximally balance relevant covariates in this cohort, there may still have been unmeasured selection bias. However, in our cohort, the bias appeared to favor TACE, with a higher proportion of these patients undergoing additional treatments after transarterial embolization. Despite this potential bias that would seemingly favor TACE, there was neither a statistically significant nor clinically meaningful difference in median or overall survival between the groups. Neither radiologic response rate nor progression-free survival was measured. Although the former was the primary endpoint in several previously published RCTs, this is a surrogate endpoint with the attendant shortcomings of such measures [31]. With regard to progression-free survival, we did not feel the observational nature of this study would allow robust and reliable ascertainment of this endpoint from

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radiology reports. For these reasons, we felt survival to be a more well-defined, meaningful, and appropriate primary endpoint for a comparison of these two modalities. There was variability in the agents used during TACE over the study period. However, this was likely representative of more global shifts in the field and changes in procedural technique over time. Finally, the number of patients treated with TAE in this cohort was relatively small. Thus, our study may have been underpowered to detect a statistically significant difference in survival. Yet, this is one of the largest studies examining utilization and comparing outcomes for TACE and TAE in a clinical practice setting and, even in the setting of a larger cohort, we would not consider the survival difference observed in this study to be clinically meaningful. Nonetheless, because this work was observational in nature, we believe our results further emphasize the need for a randomized trial designed to evaluate survival differences between these competing transarterial approaches. Our work suggests the need for better data comparing survival among HCC patients treated with transarterial embolization strategies. In light of the current lack of data to inform the benefit of TACE over TAE, as well as the incremental costs associated with TACE, additional level I data in this regard would be of great value. Given the rising incidence of this disease, finding ways to provide better tolerated and less costly approaches to the management of HCC patients would be equally timely and useful.

Acknowledgment This material is based on the work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, and the Center for Innovations in Quality, Effectiveness and Safety (CIN 13-413). Funding support had no role in the preparation, review, or approval of the article. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs and Baylor College of Medicine. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors would like to thank Diana Castillo for her assistance in preparing manuscript. Authors’ contributions: N.N.M., J.A.D., and D.A.A. conceived and designed the study. J.A.D., Z.D., and D.A.A. and S.T. and S.M. participated in data acquisition and provided analytic support. All authors provided support in the interpretation of results. N.N.M. prepared the manuscript. All authors assisted in the critical revision of the article. N.N.M. had final approval of the article. The authors had full access to all of the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis.

Disclosure The authors declare that they have no conflicts of interest.

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