ORIGINAL ARTICLE HEPATOBILIARY TUMORS. Ann Surg Oncol (2014) 21: DOI /s - PDF

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Ann Surg Oncol (2014) 21: DOI /s ORIGINAL ARTICLE HEPATOBILIARY TUMORS Survival Advantage of Radiofrequency Ablation Over Transarterial Chemoembolization for Patients with
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Ann Surg Oncol (2014) 21: DOI /s ORIGINAL ARTICLE HEPATOBILIARY TUMORS Survival Advantage of Radiofrequency Ablation Over Transarterial Chemoembolization for Patients with Hepatocellular Carcinoma and Good Performance Status Within the Milan Criteria Po-Hong Liu, MD 1,4, Yun-Hsuan Lee, MD 1,4, Chia-Yang Hsu, MD, MPH 1,4,6, Yi-Hsiang Huang, MD, PhD 2,4, Yi-You Chiou, MD 1,5, Han-Chieh Lin, MD 1,4, and Teh-Ia Huo, MD 1,3,4 1 Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; 2 Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; 3 Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan; 4 Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 5 Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan; 6 Department of Biostatistics, University of California Los Angeles, Los Angeles, CA ABSTRACT Background. Performance status is closely linked with survival in patients with hepatocellular carcinoma (HCC). We evaluated the impact of performance status on patients with small HCC receiving radiofrequency ablation (RFA) versus transarterial chemoembolization (TACE). Methods. A total of 424 and 282 patients within the Milan criteria undergoing RFA and TACE, respectively, were analyzed. Patients were classified as performance status 0 (n =516) and performance status C1 (n=190) groups. A propensity-score matching analysis with preset caliper width was used. A total of 167 and 68 matched pairs were selected from patients with a performance status of 0 and C1, respectively. Results. Radiofrequency ablation provided significantly better long-term survival than TACE for patients within the Milan criteria (p \ 1). After being stratified by performance status and matched in the propensity model, the baseline characteristics were similar between the RFA and TACE groups for patients with a performance status of 0 or C1. RFA provided significantly better long-term survival than TACE in patients with a performance status of 0 in the propensity model (p \ 5); TACE was significantly associated with fold increased risk of mortality Ó Society of Surgical Oncology 2014 First Received: 4 April 2014; Published Online: 6 June 2014 T.-I. Huo, MD (95 % confidence interval ) by using the Cox proportional hazards model. TACE was not a significant prognostic predictor in patients with a performance status C1 in the propensity model. Conclusions. For HCC patients within the Milan criteria with a performance status of 0, RFA provides better longterm survival than TACE. RFA should be considered a priority treatment in inoperable HCC patients within the Milan criteria. Performance status is a feasible surrogate marker to enhance treatment allocation. Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, accounting for nearly 700,000 deaths annually. 1 According to the HCC management guidelines published by the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL), the therapeutic options for HCC are surgical resection (SR), liver transplantation, percutaneous ablation, transarterial chemoembolization (TACE) and targeted therapy. 2,3 In early-stage HCC, SR, percutaneous ablation, and liver transplantation are widely used treatment modalities that may provide 5-year survival rate up to 75 %. 4,5 Among various local ablation therapies, radiofrequency ablation (RFA) is considered the treatment of choice for small HCC. 6 Alternatively, for patients not suitable for curative treatments, TACE is an effective approach and can provide better local-regional tumor control and long-term survival compared with best supportive care alone. 7 3836 P. Liu et al. The Milan criteria (a single tumor B5 cm or three or fewer nodules B3 cm in diameter, with no extrahepatic spread or vascular invasion) are used to define early-stage HCC and are utilized as the reference system for liver transplantation. 4 Patients with HCC within the Milan criteria may receive SR, liver transplantation, or RFA as the primary curative treatment. 2,3 However, candidates of liver transplantation far outnumber liver donors by a significant margin. 8 Moreover, liver functional reserve, tumor location, and tumor number may limit the possibilities of SR and local ablation. TACE thus remains the only plausible treatment for patients with unresectable HCC not eligible for liver transplantation and RFA. Recent studies reported satisfactory results with TACE for small HCC with compensated liver function. 9,10 However, the long-term survival of HCC patients within the Milan criteria receiving TACE as their primary treatment remains largely undetermined due to insufficient clinical evidence. The performance status scale developed by the Eastern Cooperative Oncology Group (ECOG) measures how daily living ability is affected by the disease, and is extensively used by clinicians to evaluate functional status in cancer patients. 11 Performance status scale is a major predictor of survival in HCC and is specifically included in the Barcelona Clinic Liver Cancer (BCLC) staging system as an important parameter for treatment allocation. 2,12,13 A recent large-scale study suggested that performance status plays a crucial role in determining treatment outcomes independent of treatment strategy. 14 Until now, very few studies specifically compared the long-term survival of RFA versus TACE when used as the primary treatment for HCC within the Milan criteria. This study aimed to investigate the impact of performance status on long-term survival in a large cohort of HCC patients within the Milan criteria who received RFA and TACE as their initial treatment. Patients receiving RFA or TACE had discrete prognostic characteristics, including severity of cirrhosis, tumor burden, and general performance status. A propensity-score matching analysis was utilized in order to generate matched groups of HCC patients and to minimize potential bias inherent to a retrospective, non-randomized study. PATIENTS AND METHODS Patients We retrospectively analyzed 3,007 patients with HCC admitted to the Taipei Veterans General Hospital in more than a decade (from 2002 to 2013). Patients within the Milan criteria who received RFA or TACE as their primary treatment were identified and formed the basis of this study. Comprehensive baseline information, including patient demographics, etiology of underlying liver disease, characteristics of tumor(s), serum biochemistry, tumor staging, severity and complication of cirrhosis, and performance status, was recorded at the time of diagnosis. The survival of patients was inspected every 3 4 months until death or dropout from the follow-up program. This study was approved by the Institutional Review Board and complies with the standards of the Declaration of Helsinki and current ethical guidelines. Diagnosis and Definitions The diagnosis of HCC was histologically confirmed or based on the findings of typical radiological features in a four-phase, multidetector, contrast-enhanced computed tomography (CT) scan or dynamic magnetic resonance imaging (MRI). 2,15 Alcoholism was diagnosed in patients with consumption of alcohol at least 40 g daily for 5 years or more. 16 The Child Turcotte Pugh (CTP) classification was used to define the severity of cirrhosis. Total tumor volume (TTV) was calculated as the sum of all tumor nodule volumes, and each tumor volume was calculated as 4/ (maximum radius of the tumor in centimeters) 3, as previously described. 17 Performance status was assessed at the time of diagnosis by using the ECOG performance scale ranging from 0 (asymptomatic) to 4 (confined to bed). 14 The Cancer of the Liver Italian Program (CLIP) classification was used to define staging. 18 Treatment RFA was performed using the standard procedure. 6 Under ultrasound guidance, the tumor(s) was ablated by using a 17-gauge, cooled-tip electrode with the Cool-Tip Radiofrequency System (Radionics, Burlington, MA, USA). The ablation was performed in automatic impedance control mode in which the current output was automatically adjusted. Post-RFA sonography was performed immediately to confirm that there was no definite hemorrhage or hematoma. Transarterial chemoembolization was performed in patients who were not eligible or unwilling to receive SR, RFA, and liver transplantation, and with adequate liver function reserve and no signs of distant metastases or main portal trunk thrombosis. 19 The Seldinger s technique of arterial embolization was administered as the standard TACE procedure. After tumor stain was identified, infusion of a mixture of mg adriamycin (Carlo Erba, Milan, Italy) and 5 10 ml lipiodol (Laboratoire Guerbet, Villepinte, France) was performed after the artery supplying the tumor was catheterized with a three-french catheter superselectively. Sufficient amounts of emulsion and 2- to 3-mm strips of Gelfoam (Upjohn, Kalamazoo, MI, USA) were delivered to the tumor area until complete flow stagnation was achieved. Performance Status in HCC Within the Milan Criteria 3837 Propensity-Score Matching Analysis To investigate the association between treatment and outcome in an observational, non-randomized study, a propensity-score matching analysis without replacement was used in an attempt to reduce bias in patient selection and to generate a matched pair of patients to compare the long-term survival associated with RFA or TACE. 20,21 Possible variables associated with treatment selection, including age, sex, serum biochemistries, etiology of HCC, CTP score, CLIP score, tumor number, and TTV, were comprehensively included in the generation of propensity score. Binary logistic regression with the selected variables was used to generate a continuous propensity score from 0 to 1 to estimate the probability that a patient would undergo TACE or RFA. A nearest-neighbor match between the RFA and TACE groups was used to select patients into subsequent analyses and was stratified by performance status. A caliper width equal to of the standard deviation of the logit of the propensity score was chosen for superior performance in the estimation of treatment effects. 22 Statistics The Chi-square test and two-tailed Fisher s exact test were used to compare categorical data. The Mann Whitney U test was used to compare continuous variables between the two groups. The comparison of survival distribution was performed by the Kaplan Meier method with log-rank test. To analyze the significance of prognostic predictors, continuous variables were split by the median values and were treated as dichotomous covariates. Prognostic factors that were possibly linked to survival, including age, sex, etiology of liver disease, severity of liver cirrhosis, size and number of tumor nodules, serum biochemistries, performance status, treatment modalities, and cancer staging were included in survival analysis. Factors that were significant in the univariate survival analysis were introduced into the multivariate Cox proportional hazards model to determine the adjusted hazard ratios (HR) and 95 % confidence intervals (CI). A p value less than 5 was considered statistically significant. All statistical analyses were conducted with SPSS for Windows version 19 (IBM Corporation, Armonk, NY, USA). RESULTS Identification of Study Patients A total of 424 and 282 HCC patients within the Milan criteria who received RFA and TACE, respectively, as the primary treatment were identified. A total of 319 and 105 patients in the RFA group had a performance status of 0 All Patients and C1, respectively, whereas 197 and 85 patients in the TACE group had a performance status of 0 and C1, respectively. Overall, patients receiving RFA had significantly better long-term survival when compared with the TACE group (p =01; Fig. 1); the 1- and 3-year estimated survival rates in the RFA and TACE groups were 89 versus 84 % and 71 versus 59 %, respectively. Of these patients, 167 pairs of patients with a performance status of 0 and 68 pairs of patients with a performance status of C1 were identified by the propensity-score matching analysis to compare the therapeutic efficacy. Characteristics and Survival of Patients with a Performance Status of 0 RFA (n = 424) TACE (n = 282) p=01 RFA TACE FIG. 1 Comparison of survival between HCC patients within the Milan criteria undergoing RFA or TACE. Patients receiving RFA had significantly better long-term survival than patients receiving TACE (p =01). HCC hepatocellular carcinoma, RFA radiofrequency ablation, TACE transarterial chemoembolization A total of 319 and 197 patients with a performance status of 0 received RFA and TACE, respectively (Table 1). Patients in the RFA group had fewer tumor nodules, smaller TTV, better CTP score, and lower CLIP score (all p \ 5). Patients with a performance status of 0 undergoing RFA had significantly better long-term survival than patients receiving TACE (p \ 01; Fig. 2a); the 1- and 3-year estimated survival rates in the RFA and TACE groups were 93 versus 87 % and 77 versus 63 %, respectively. 3838 P. Liu et al. TABLE 1 Comparison of baseline demographics between patients undergoing radiofrequency ablation and transarterial chemoembolization stratified by performance status Performance status = 0 Performance status C 1 RFA (n = 319) TACE (n = 197) p value RFA (n = 105) TACE (n = 85) p value Age [years; mean ± SD] 66 ± ± ± ± Male [n (%)] 206 (65) 135 (69) (69) 57 (67) 76 Positive for HBsAg [n (%)] 145 (46) 87 (44) (51) 32 (38) 81 Positive for anti-hcv [n (%)] 140 (44) 95 (48) (35) 39 (46) Alcoholism [n (%)] 40 (13) 21 (11) (28) 17 (20) 38 Serum biochemistry [mean ± SD] Albumin (g/dl) 3.9 ± ± ± 3.4 ± 96 Bilirubin (mg/dl) 0.9 ± ± ± ± Creatinine (mg/dl) 1.1 ± 0.9 ± ± ± INR of PT 1.1 ± ± ± 1.2 ± 61 ALT (U/L) 67 ± ± ± ± Sodium (mmol/l) 139 ± ± ± ± AFP [ng/ml; mean ± SD] 314 ± 1, ± 19, ± ± 3, Performance status 0/1/2/3 4 (%) 100/0/0/0 100/0/0/0 00 0/60/32/8 0/61/32/7 92 CTP class A/B/C (%) 89/11/0 86/14/ /31/7 61/34/5 11 CTP score [mean ± SD] 5.5 ± 5.6 ± ± ± Tumor number 1/2/3 (%) 84/12/4 68/19/13 \01 75/19/6 68/15/17 53 TTV [cm 3 ; mean ± SD] 9.4 ± ± 15.4 \ ± ± CLIP 0/1/2/3 6 (%) 69/27/4/0 45/44/11/0 \01 37/45/12/6 33/44/17/ AFP a-fetoprotein, ALT alanine transaminase, CLIP Cancer of the Liver Italian Program, CTP Child Turcotte Pugh, HBsAg hepatitis B surface antigen, HCV hepatitis C, INR international normalized ratio, PT prothrombin time, RFA radiofrequency ablation, SD standard deviation, TACE transarterial chemoembolization, TTV total tumor volume Characteristics and Survival of Patients with a Performance Status C1 A total of 105 and 85 patients with a performance status C1 underwent RFA and TACE, respectively (Table 1). The two groups of patients were similar in baseline demographics, serum biochemistries, and tumor characteristics. Patients with a performance status C1 undergoing RFA had similar long-term survival when compared with their TACE counterpart (p =12; Fig. 2b); the 1- and 3-year estimated survival rates in the RFA and TACE groups were 78 versus 76 % and 38 versus 47 %, respectively. Characteristics and Survival of Patients with a Performance Status of 0 in the Propensity Model A total of 167 pairs of patients with a performance status of 0 were identified in the propensity model. There were no significant baseline differences in patients with a performance status of 0 receiving RFA or TACE in the propensity model (Table 2). The RFA group had significantly better long-term survival than the TACE group (p =06; Fig. 2c); the 1- and 3-year estimated survival rates in patients receiving RFA and TACE were 90 versus 89 % and 77 versus 62 %, respectively. In the univariate survival analysis, TACE, CLIP score C1, CTP class B or C, and serum bilirubin level C0.9 mg/dl were associated with decreased long-term survival (all p \ 5; Table 3). In the adjusted Cox proportional hazards model, TACE (HR 1.641; 95 % CI ; p=22) and CLIP score C1 (HR 1.926; 95 % CI ; p=04) were identified as independent predictors of poor prognosis. Characteristics and Survival of Patients with a Performance Status C1 in the Propensity Model A total of 68 pairs of patients with a performance status of 0 were identified in the propensity model. There were no significant baseline differences in patients with a performance status C1 receiving RFA or TACE in the propensity model (Table 2). Patients with a performance status C1 receiving RFA or TACE in the propensity model had similar prognosis (p =13; Fig. 2d); the 1- and 3-year estimated survival rates in patients receiving RFA and TACE were 78 versus 73 % and 39 versus 43 %, respectively. In the univariate analysis, CTP class B or C, CLIP score C1 and serum albumin level \3.7 g/dl predicted Performance Status in HCC Within the Milan Criteria 3839 a PS=0 b PS 1 RFA (n = 319) TACE (n = 197) TACE (n = 85) p 01 RFA TACE RFA (n = 105) p=12 RFA 105 TACE c P S=0 d PS 1 RFA (n = 167) TACE (n = 167) TACE (n = 68) RFA (n = 68) RFA 167 TACE 167 Propensity Score Model p=06 FIG. 2 Comparison of survival between HCC patients within the Milan criteria undergoing RFA or TACE stratified by PS in all study patients and patients selected in the propensity model. Patients with a PS of 0 receiving RFA had significantly better long-term survival than patients undergoing TACE in all patients and in patients selected in the propensity score model [p \ 01 (a) and p = 01 (c), 1 4 RFA 68 TACE 68 Propensity Score Model p=13 respectively]. Alternatively, the long-term survival in patients with apsc 1 receiving RFA or TACE was similar [p =12 (b) and p=13 (d), respectively]. HCC hepatocellular carcinoma, RFA radiofrequency ablation, TACE transarterial chemoembolization, PS performance status decreased survival (all p \ 5; Table 3). In the adjusted Cox proportional hazards model, CTP class B or C (HR 2.456; 95 % CI ; p=02) was the only independent predictor of poor prognosis. DISCUSSION There has been insufficient information regarding the selection of treatment in patients with inoperable HCC 3840 P. Liu et al. TABLE 2 Comparison of baseline demographics between patients undergoing radiofrequency ablation and transarterial chemoembolization stratified by performance status in the propensity score model Propensity score model Performance status = 0 Performance status C 1 RFA (n = 167) TACE (n = 167) p value RFA (n = 68) TACE (n = 68) p value Age [years; mean ± SD] 68 ± ± ± ± Male [n (%)] 119 (71) 115 (69) (71) 45 (66) Positive for HBsAg [n (%)] 80 (48) 74 (44) (44) 29 (43) 00 Positive for anti-hcv [n (%)] 70 (42) 80 (48) (38) 28 (41) 61 Alcoholism [n (%)] 24 (14) 18 (11) (28) 13 (19) Serum biochemistry [mean ± SD] Albumin (g/dl) 3.8 ± ± ± 3.5 ± 91 Bilirubin (mg/dl) ± 1.1 ± ± ± 40 Creatinine (mg/dl) ± ± ± ± INR of PT 1.1 ± ± ± 1.1 ± ALT (U/L) 68 ± ± ± ± Sodium (mmol/l) 140 ± ± ± ± 3 53 AFP [ng/ml; mean ± SD] 160 ± 1, ± 20, ± 1, ± 2, Performance status 0/1/2/3 4 (%) 100/0/0/0 100/0/0/0 00 0/57/34/9 0/60/32/8 89 CTP class A/B/C (%) 87/13/0 86/14/ /31/6 65/32/ CTP score [mean ± SD] 5.6 ± ± ± ± Tumor number 1/2/3 (%) 74/18/8 71/19/ /19/9 73/15/ TTV [cm 3 ; mean ± SD] 13 ± ± ± ± CLIP 0/1/2/3 6 (%) 59/35/7/0 46/43/10/ /47/12/4 41/40/15/5 46 AFP a-fetoprotein, ALT alanine transaminase, CLIP Cancer of the Liver Italian Program, CTP Child Turcotte Pugh, HBsAg hepatitis B surface antigen, HCV hepatitis C, INR international normalized ratio, PT prothrombin time, RFA radiofrequency ablation, SD standard deviation, TACE transarterial chemoembolization, TTV total tumor volume within the Milan criteria. Performance status is tightly associated with long-term prognosis and may be useful in guiding treatment selection for HCC. 14 We investigated a
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