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doi:10.1111/jgh.12669
H E PAT O L O G Y
Impact of renal insufficiency on patients with hepatocellular carcinoma undergoing radiofrequency ablation Chuan-Fu Chen,* Po-Hong Liu,†,‡ Yun-Hsuan Lee,†,‡ Ya-Ju Tsai,§ Chia-Yang Hsu,†,‡,¶ Yi-Hsiang Huang,‡,** Yi-You Chiou†,†† and Teh-Ia Huo‡,‡‡ *Division of Gastroenterology, Wei Gong Memorial Hospital, Miaoli, †Faculty of Medicine, Institutes of **Clinical Medicine and ‡‡Pharmacology, National Yang-Ming University School of Medicine, and Departments of ‡Medicine and ††Radiology, Taipei Veterans General Hospital, Taipei, Taiwan; and §Queen of Angels Hospice, Arcadia, and ¶Department of Biostatistics, UCLA, Los Angeles, California, USA
Key words hepatocellular carcinoma, liver cirrhosis, radiofrequency ablation, renal insufficiency, Taipei Integrated Scoring System. Accepted for publication 18 June 2014. Correspondence Dr Teh-Ia Huo, Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, no. 201, Sec. 2, Shipai Rd., Taipei 11217, Taiwan. Email: [email protected] Disclosure: There are no conflicts of interests in all authors. Financial Funding: This study was supported by the grants from Wei Gong Memorial Hospital, Miaoli, Taiwan (103-I-002) and Taipei Veterans General Hospital, Taipei, Taiwan (V103C-008).
Abstract Background and Aim: Renal insufficiency (RI) is commonly seen in patients with hepatocellular carcinoma (HCC). We aimed to investigate the impact of RI on the long-term survival of HCC patients undergoing radiofrequency ablation (RFA) and to determine the optimal staging strategy for these patients. Methods: RI was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2. A total of 123 and 344 patients with and without RI undergoing RFA, respectively, were enrolled. A one-to-one propensity score matching analysis with preset caliper width was performed. The prognostic ability of four currently used staging systems was compared by the Akaike information criterion (AIC). Results: HCC patients with RI undergoing RFA were older (P < 0.001) and had significantly different baseline characteristics. Of all patients, RI was significantly associated with a decreased long-term survival (P = 0.03). After matching in the propensity model, the baseline characteristics were similar between patients with (n = 92) and without (n = 92) RI. In the propensity model, RI was not significantly associated with a shortened survival (P = 0.273). In the Cox multivariate analysis, Child-Turcotte-Pugh class B or C was identified as the only independent predictor of poor prognosis. Among patients with RI undergoing RFA, the Taipei Integrated Scoring (TIS) system provided the highest homogeneity and lowest AIC value among the currently used staging systems. Conclusions: The long-term survival of HCC patients undergoing RFA is not affected by RI. The TIS staging system may provide a better prognostic prediction for HCC patients with RI undergoing RFA.
Introduction Hepatocellular carcinoma (HCC) is one of the most common malignant neoplasms 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 Liver (EASL), the therapeutic options for HCC are surgical resection (SR), liver transplantation, percutaneous ablation, transarterial chemoembolization (TACE), and targeted therapy.2,3 For patients with early stage HCC, SR, percutaneous ablation, and liver transplantation are widely accepted treatment modalities.4,5 Among various local ablative therapies, radiofrequency ablation (RFA) is considered the treatment of choice for small HCC and can provide long-term survival up to 60%.6 Renal insufficiency (RI) is defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 according to Kidney 192
Disease Improving Global Outcomes guidelines.7 Nearly one quarter of HCC patients suffered from RI at the time of diagnosis.8 Patients with HCC often have preexisting liver cirrhosis due to hepatitis B, hepatitis C, or alcoholism.9 Notably, cirrhosis may predispose to the occurrence of diabetes mellitus and renal dysfunction.10 More importantly, cirrhosis is associated with splanchnic vascular dilatation and subsequent deficiency of effective blood volume and renal hypoperfusion.11 These mechanisms contribute to the high prevalence of RI in patients with HCC. For patients with HCC and coexisting RI, angiographic procedure such as TACE may be unappealing since the risks of contrastinduced nephropathy are unacceptably high.12,13 Percutaneous treatment is therefore a feasible treatment option for HCC patients with RI. However, the impact of RI on long-term survival of HCC patients receiving RFA has not been clearly delineated. To further complicate this issue is that the prevalence of chronic kidney disease is nearly 12% in Taiwan.14 Moreover, Taiwan has the
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highest prevalence and second highest incidence of end-stage renal disease in the world.15 As such, the prognostic impact of RI on HCC could be even more prominent. Several cancer staging systems, including Barcelona Clinics of Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Japan Integrated Scoring (JIS) and Taipei Integrated Scoring (TIS) system, are used for prognostic prediction. However, the predictive accuracy in HCC patients with RI undergoing RFA has not been evaluated. This study aimed to examine the impact of RI on the long-term survival of HCC patients undergoing RFA as the primary treatment. A one-to-one propensity score matching analysis was utilized to reduce confounding factors inherent to this retrospective study. The prognostic accuracy between different staging systems was compared to determine the most optimal model in these patients.
Patients and methods Patients. We retrospectively analyzed patients with the diagnosis of HCC and admitted to Taipei Veterans General Hospital in more than a decade’s period from 2002 to 2013. A total of 467 patients receiving RFA as the 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 complies with the standards of the Declaration of Helsinki and current ethical guidelines. Diagnosis and definitions. The diagnosis of HCC was based on typical radiological features of contrast enhancement pattern in a four-phase multidetector contrast-enhanced computed tomography scan or dynamic magnetic resonance imaging.2,16 If the lesion did not show typical radiological features, biopsy was mandatory for establishment of HCC diagnosis. Alcoholism was diagnosed in patients with consumption of alcohol at least 40 g daily for 5 years or more.17 The Child-Turcotte-Pugh (CTP) classification was used to define the severity of cirrhosis. The performance status was assessed by using the Eastern Cooperative Oncology Group performance scale ranging from 0 (asymptomatic) to 4 (confined to bed).18 Total tumor volume (TTV) was calculated based on the mathematical equations as previously described.19 The BCLC, CLIP, JIS, and TIS staging systems were used to define clinical HCC staging.19–22 The eGFR was calculated using the reexpressed modification of diet in renal disease (MDRD) formula.23
eGFR (mL / min /1.73 m 2 ) = 175 × [creatinine (mg / dL)]−1.154 × [age (years)]−0.203 × 0.742 (if female) All patients in this study were ethnically Taiwanese. The serum creatinine level used in the reexpressed MDRD formula was the level recorded when the diagnosis of HCC was confirmed. Treatment. RFA was performed using the standard procedure.24 Under ultrasound guidance, the tumor(s) was/were ablated
Radiofrequency ablation in renal insufficiency
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. Propensity score matching analysis. To investigate the association between treatment and outcome in an observational, nonrandomized study, a propensity score matching analysis was used to reduce bias in patient selection and to generate a matched pairs of patients with and without RI to compare their long-term survival.25,26 Possible variables associated with the presence of RI, including age, gender, serum biochemistries, CTP classification, clinical staging, 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. A nearestneighbor match between patients with and without RI was used to select patients into subsequent analyses. A caliper width equal to 0.2 of the standard deviation of the logit of the propensity score was chosen for superior performance in the estimation of treatment effects.27 Statistics. The Chi-square test and two-tailed Fisher exact test were used to compare categorical data. The Mann–Whitney U-test was used to compare continuous variables between 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, gender, 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). The overall predictive accuracy of BCLC, CLIP, JIS, and TIS staging system was compared. Homogeneity (differences in survival among patients in the same stage within each system) was measured by likelihood ratio χ2 which was generated by the Cox proportional hazards model. AIC was calculated to reveal how the staging systems affected patient survival.28 A P value less than 0.05 was considered statistically significant. All statistical analyses were conducted with SPSS for Windows version 19 (IBM, NY, USA).
Results Characteristics and survival of patients receiving RFA. One hundred twenty-three and 344 HCC patients with and without RI, respectively, received RFA as their primary treatment. The baseline demographics of these patients are shown in Table 1; part of these patients had been analyzed in our previous studies.4,8,18 Patients with RI undergoing RFA were significantly older (P < 0.001). In addition, patients with RI were associated
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Table 1 Comparison of baseline demographics between patients with and without renal insufficiency undergoing radiofrequency ablation Variables
Without RI (n = 344)
With RI (n = 123)
P-value
Age (years), mean ± SD Male, n (%) Positive for HBsAg, n (%) Positive for anti-HCV, n (%) Alcoholism, n (%) Serum biochemistry (mean ± SD) Albumin (g/dL) Bilirubin (mg/dL) BUN (mg/dL) Creatinine (mg/dL) INR of PT ALT (U/L) Sodium (mmol/L) eGFR (mL/min/1.73 m2) AFP (ng/mL, mean ± SD) Performance status 0/1/2/3–4 (%) CTP class A/B/C (%) CTP score (mean ± SD) Tumor number (1/2/≥ 3), % TTV (cm3, mean ± SD) CLIP 0/1/2–6 (%)
64 ± 11 229 (67) 175 (51) 136 (40) 64 (19)
73 ± 9 78 (63) 44 (36) 58 (47) 10 (8)
< 0.001 0.580 0.004 0.166 0.006
3.7 ± 0.6 1.2 ± 1.1 14 ± 4 0.9 ± 0.2 1.1 ± 0.1 70 ± 61 139 ± 6 86.3 ± 21.0 281 ± 2000 74/17/8/1 81/17/2 5.8 ± 1.2 80/15/5 19 ± 102 60/32/8
3.8 ± 0.6 0.9 ± 1.0 27 ± 13 1.9 ± 1.6 1.0 ± 0.1 51 ± 34 139 ± 4 43.0 ± 14.8 617 ± 2142 75/11/11/3 87/11/2 5.6 ± 1.2 70/20/10 20 ± 34 50/38/12
0.232 < 0.001 < 0.001 < 0.001 < 0.001 0.001 0.229 < 0.001 0.049 0.196 0.207 0.099 0.004 0.034 0.316
AFP, α-fetoprotein; ALT, alanine transaminase; BUN, blood urea nitrogen; CLIP, Cancer of the Liver Italian Program; CTP, Child-Turcotte-Pugh; eGFR, estimated glomerular filtration rate; HCV, hepatitis C; INR, international normalized ratio; PT, prothrombin time; RI, renal insufficiency; SD, standard deviation; TTV, total tumor volume.
Figure 1 Comparison of survival between hepatocellular carcinoma (HCC) patients with and without renal insufficiency (RI) undergoing radiofrequency ablation (RFA). Patients with RI had significantly better long-term survival than patients with RI (P = 0.03).
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with lower serum bilirubin level, higher serum α-fetoprotein (AFP) level, higher number of tumor nodules, and higher TTV when compared to patients without RI (all P < 0.05). There were no significant differences in sex, performance status, and CTP classification between patients with and without RI (all P > 0.05). The most frequent etiology of underlying liver disease was hepatitis B (51%) in patients without RI, while hepatitis C prevailed in patients with RI (47%). After a median follow-up duration of 32 months, 106 patients died. Patients with RI receiving RFA had significantly worse long-term survival when compared to patients without RI (P = 0.030, Fig. 1); the 1- and 3-year estimated survival rates in patients with RI and without RI were 97% versus 91% and 83% versus 72%, respectively. Characteristics and survival of patients receiving RFA in the propensity model. Among patients receiving RFA, 92 matched pairs of patients with and without RI were selected by using the propensity score analysis (Table 2). Patients with RI had significantly higher serum blood urea nitrogen and creatinine level, and a lower eGFR (all P < 0.001). Otherwise, there were no significant differences between age, sex, etiology of chronic liver disease, severity of cirrhosis, performance status, and serum AFP level between patients with and without RI (all P > 0.05). The long-term survival between patients with and without RI showed no significant difference (P = 0.273, Fig. 2);
Table 2 Comparison of baseline demographics between patients with and without renal insufficiency undergoing radiofrequency ablation in the propensity score model Variables
Without RI (n = 92)
With RI (n = 92)
P-value
Age (years), mean ± SD Male, n (%) Positive for HBsAg, n (%) Positive for anti-HCV, n (%) Alcoholism, n (%) Serum biochemistry (mean ± SD) Albumin (g/dL) Bilirubin (mg/dL) BUN (mg/dL) Creatinine (mg/dL) INR of PT ALT (U/L) Sodium (mmol/L) eGFR (mL/min/1.73 m2) AFP (ng/mL, mean ± SD) Performance status 0/1/2/3–4 (%) CTP class A/B/C (%) CTP score (mean ± SD) Tumor number (1/2/≥ 3), % TTV (cm3, mean ± SD) CLIP 0/1/2–6 (%)
71 ± 9 60 (65) 36 (39) 39 (42) 16 (17)
71 ± 10 64 (70) 40 (44) 42 (46) 9 (10)
0.792 0.637 0.653 0.767 0.196
3.8 ± 0.5 0.8 ± 0.7 15 ± 4 0.9 ± 0.2 1.0 ± 0.1 60 ± 41 139 ± 3 82.3 ± 22.0 168 ± 671 72/21/7/0 91/9/0 5.4 ± 0.8 75/22/3 15 ± 31 63/31/6
3.9 ± 0.6 1.0 ± 1.1 27 ± 14 2.0 ± 1.9 1.1 ± 0.1 53 ± 36 139 ± 4 43.2 ± 15.3 380 ± 1772 75/11/10/4 90/7/3 5.6 ± 1.3 73/17/10 18 ± 29 58/36/6
0.786 0.681 < 0.001 < 0.001 0.865 0.226 0.381 < 0.001 0.295 0.068 0.193 0.503 0.230 0.953 0.888
AFP, α-fetoprotein; ALT, alanine transaminase; BUN, blood urea nitrogen; CLIP, Cancer of the Liver Italian Program; CTP, Child-Turcotte-Pugh; eGFR, estimated glomerular filtration rate; HCV, hepatitis C; INR, international normalized ratio; PT, prothrombin time; RI, renal insufficiency; SD, standard deviation; TTV, total tumor volume.
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the 1- and 3-year estimated survival rates in patients with RI and without RI were 99% versus 93% and 86% versus 76%, respectively. In the adjusted Cox proportional hazards model, only CTP class B or C (HR: 6.330, 95% CI: 2.846–14.077; P < 0.001) was identified as the independent predictor of poor prognosis (Table 3).
Performance of the cancer staging system for patients with RI. There were no significant differences in long-term survival of HCC patients with RI undergoing RFA between different cancer stages of BCLC and JIS (Fig. 3a,c, both P > 0.05). Alternatively, patients with a more advanced CLIP and TIS staging systems were significantly associated with decreased long-term survival (Fig. 3b,d, both P < 0.01). The four clinical staging systems were validated with both homogeneity (likelihood ratio χ2) and AIC method (Table 4). The TIS system had the lowest AIC value, followed by the CLIP, BCLC, and lastly, JIS system. Consistently, the TIS system provided the highest homogeneity among the four staging models, followed by the CLIP, BCLC, and JIS system.
Discussion Figure 2 Comparison of survival between hepatocellular carcinoma (HCC) patients with and without renal insufficiency (RI) undergoing radiofrequency ablation (RFA) in the propensity model. The long-term survival between patients with and without RI were similar (P = 0.273).
Table 3
Although RFA has been widely used as the primary treatment for HCC with RI, very few data are available regarding the impact of RI of these patients. In this large, single-center, propensitymatched study, we investigated the long-term survival between HCC patients with and without RI receiving RFA and found that RI was not associated with an inferior long-term survival. Multivariate analysis revealed that cirrhosis-related factors are more important in determining the overall survival. We also demonstrated that the TIS staging system may provide better prognostic
Prognostic predictors of survival for patients undergoing radiofrequency ablation in the propensity score model All RFA patients selected in the propensity model n = 184
Age (< 73/≥ 73 years) Sex (male/female) Albumin (≥ 3.9/< 3.9 g/dL) Bilirubin (< 0.66/≥ 0.66 mg/dL) BUN (< 20/≥ 20 mg/dL) Creatinine (< 1.1/≥ 1.1 mg/dL) INR of PT (< 1.03/≥ 1.03) ALT (< 40/≥ 40 U/L) Sodium (< 140/≥ 140 mmol/L) AFP (< 13/≥ 13 ng/mL) CTP class (A/B-C) No. of tumor (single/multiple) TTV (< 7/≥ 7 cm3) CLIP score (0/1–6) RI (no/yes)
94/90 124/60 83/101 92/92 109/75 97/87 97/87 78/106 117/67 90/94 167/17 136/48 86/98 111/73 92/92
Univariate P-value 0.789 0.446 < 0.001 0.349 0.776 0.580 < 0.001 0.143 0.766 0.033 < 0.001 0.963 0.639 0.027 0.273
HR
Multivariate 95% CI
P-value
6.330
2.846–14.077
< 0.001
Each variable was dichotomized into two groups by the median value for survival prediction. The forepart of variables was set as the reference group in the multivariate analysis. AFP, α-fetoprotein; ALT, alanine transaminase; BUN, blood urea nitrogen; CI, confidence interval; CLIP, Cancer of the Liver Italian Program; CTP, Child-Turcotte-Pugh; HR, hazard ratio; INR, international normalized ratio; PT, prothrombin time; RFA, radiofrequency ablation, RI, renal insufficiency; TTV, total tumor volume.
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(a)
(b)
(c)
(d)
Figure 3 Comparison of survival distributions in hepatocellular carcinoma (HCC) patients with renal insufficiency (RI) undergoing radiofrequency ablation (RFA) with different prognostic models: the Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Japan Integrated Scoring (JIS) system, and Taipei Integrated Scoring (TIS) system. There were no significant differences in long-term survival among patients with different stages of BCLC (P = 0.567, a) and JIS (P = 0.533, c). Alternatively, a more advanced cancer staging with CLIP (P = 0.005, b) and TIS (P < 0.001, d) was associated with a decreased long-term survival.
accuracy than the CLIP, BCLC, and JIS systems. Our results provide clinically relevant information regarding the selection of treatment modalities and assessment of the prognostic tool for HCC patients with RI undergoing RFA. In this study, patients with RI undergoing RFA had a poorer long-term prognosis compared with patients without RI in the 196
analysis outside the propensity score model. However, patients with RI were significantly older and had different baseline demographics including etiology of HCC, tumor characteristics, and serum biochemistries. The prognostic impact of RI could be erroneously confounded by these different baseline profiles. Propensity score matching analysis has been advocated to balance the
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Table 4 Comparison of common clinical staging systems among patients with renal insufficiency undergoing radiofrequency ablation
BCLC CLIP JIS TIS
Homogeneity (Likelihood ratio χ2)
Akaike information criterion
1.521 7.776 0.846 15.866
311.149 304.895 311.824 296.805
BCLC, Barcelona Clinics of Liver Cancer; CLIP, Cancer of the Liver Italian Program; JIS, Japan Integrated Scoring System; TIS, Taipei Integrated Scoring System.
covariates and to reduce biases between two patients groups.29 With similar baseline characteristics generated by propensity score matching, it is possible to properly inspect the impact of RI on patient survival. In the propensity model, the long-term prognosis was not significantly different between patients with and without RI. The Cox multivariate analysis confirmed that the long-term survival of patients undergoing RFA correlated with the severity of underlying liver cirrhosis but not the presence of RI. Patients with HCC frequently have coexisting liver cirrhosis, and are at increased risks of developing RI.30 Triggered by portal hypertension, reduction of systemic vascular resistance due to primary arterial vasodilatation in the splanchnic circulation is the primary mechanism of RI in cirrhotic patients.11 Patients with RI are also at increased risks of developing acute kidney injury following contrast medium injection during angiographic procedure.13 Therefore, it is not a common practice to treat HCC patients with RI by TACE.31 RFA is a widely accepted option in the management of surgically unresectable HCC.6 However, the feasibility of RFA for patients with RI is unclear, possibly due to increased bleeding tendency in these patients.32 This study shows that the long-term survival of HCC patients undergoing RFA was not affected by the presence of RI. Our finding is further supported by a study from Japan, where RFA had been performed safely and effectively in patients with end-stage renal disease.33 Notably, the prevalence of chronic kidney disease is high in general population in Taiwan, and up to one quarter of HCC patients suffered from RI at the time of diagnosis.8,14 For HCC patients with RI not suitable for surgical resection, RFA may be a feasible treatment option with proven efficacy and better safety profile. Therefore, the presence of RI should not preclude patients from active anticancer treatment such as RFA. In the Cox multivariate analysis, the only independent predictor of poor prognosis for patients undergoing RFA was CTP class B/C, with 6.3-fold increased mortality rate. However, many (83%) patients with RI receiving RFA still had preserved liver function (CTP class A). Patients undergoing RFA may need different assessment tool other than the CTP classification to represent the severity of cirrhosis. Taken together, our results imply that liver functional reserve, instead of RI per se, plays a major role in prognostic prediction. There has been intense debate on the optimal cancer staging system for HCC. It is unclear which staging system provides more accurate prognostic ability in patients with RI receiving RFA. It is also expected that different staging systems may be applied in different clinical settings. We specifically evaluated the perfor-
mance of four currently used staging systems in HCC patients with RI undergoing RFA treatment. In our analysis, we found that the CLIP and TIS staging system accurately discriminated the longterm survival in this patient group. The TIS system was associated with the lowest AIC value and highest homogeneity. Consistent with our previous findings, we demonstrated that the TIS staging system had a better discriminative ability when compared with BCLC, CLIP, and JIS staging systems.19 Since CTP classification system is included in all four staging systems, the main difference of the TIS over other staging systems is the incorporation of TTV in the scoring index. The efficacy of RFA highly correlates with tumor size. The complete tumor ablation rate may be up to 90% for HCC ≤ 3 cm, but the ablation rate drops to 20–45% for HCC > 5 cm.6 TTV should therefore be included in the clinical staging system for HCC in the RFA setting. There are a few limitations in this study. First, the retrospective nature made this study vulnerable to potential bias. Even with careful propensity score matching analysis with a predefined caliper, these biases still might not be completely avoided. Second, this single-center study was performed in the Asia-Pacific region, an endemic area with high prevalence of hepatitis B, and care must be taken when comparing the results from the Western countries with ours. Lastly, the calculation of TTV was based on the assumption that the tumor(s) was spherical, and the calculation of TTV might be inaccurate if the tumor(s) was irregularly shaped. In conclusion, our results suggest that for HCC patients undergoing RFA, the overall long-term survival was not compromised by the presence of RI. The TIS system is a better prognostic model compared with the CLIP, BCLC, and JIS staging systems in HCC patients with RI undergoing RFA. Our results may provide rationale for enhancing treatment allocation, improving accuracy of staging strategy, and refining study design in future clinical trials.
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doi:10.1111/jgh.12669
H E PAT O L O G Y
Impact of renal insufficiency on patients with hepatocellular carcinoma undergoing radiofrequency ablation Chuan-Fu Chen,* Po-Hong Liu,†,‡ Yun-Hsuan Lee,†,‡ Ya-Ju Tsai,§ Chia-Yang Hsu,†,‡,¶ Yi-Hsiang Huang,‡,** Yi-You Chiou†,†† and Teh-Ia Huo‡,‡‡ *Division of Gastroenterology, Wei Gong Memorial Hospital, Miaoli, †Faculty of Medicine, Institutes of **Clinical Medicine and ‡‡Pharmacology, National Yang-Ming University School of Medicine, and Departments of ‡Medicine and ††Radiology, Taipei Veterans General Hospital, Taipei, Taiwan; and §Queen of Angels Hospice, Arcadia, and ¶Department of Biostatistics, UCLA, Los Angeles, California, USA
Key words hepatocellular carcinoma, liver cirrhosis, radiofrequency ablation, renal insufficiency, Taipei Integrated Scoring System. Accepted for publication 18 June 2014. Correspondence Dr Teh-Ia Huo, Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, no. 201, Sec. 2, Shipai Rd., Taipei 11217, Taiwan. Email: [email protected] Disclosure: There are no conflicts of interests in all authors. Financial Funding: This study was supported by the grants from Wei Gong Memorial Hospital, Miaoli, Taiwan (103-I-002) and Taipei Veterans General Hospital, Taipei, Taiwan (V103C-008).
Abstract Background and Aim: Renal insufficiency (RI) is commonly seen in patients with hepatocellular carcinoma (HCC). We aimed to investigate the impact of RI on the long-term survival of HCC patients undergoing radiofrequency ablation (RFA) and to determine the optimal staging strategy for these patients. Methods: RI was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2. A total of 123 and 344 patients with and without RI undergoing RFA, respectively, were enrolled. A one-to-one propensity score matching analysis with preset caliper width was performed. The prognostic ability of four currently used staging systems was compared by the Akaike information criterion (AIC). Results: HCC patients with RI undergoing RFA were older (P < 0.001) and had significantly different baseline characteristics. Of all patients, RI was significantly associated with a decreased long-term survival (P = 0.03). After matching in the propensity model, the baseline characteristics were similar between patients with (n = 92) and without (n = 92) RI. In the propensity model, RI was not significantly associated with a shortened survival (P = 0.273). In the Cox multivariate analysis, Child-Turcotte-Pugh class B or C was identified as the only independent predictor of poor prognosis. Among patients with RI undergoing RFA, the Taipei Integrated Scoring (TIS) system provided the highest homogeneity and lowest AIC value among the currently used staging systems. Conclusions: The long-term survival of HCC patients undergoing RFA is not affected by RI. The TIS staging system may provide a better prognostic prediction for HCC patients with RI undergoing RFA.
Introduction Hepatocellular carcinoma (HCC) is one of the most common malignant neoplasms 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 Liver (EASL), the therapeutic options for HCC are surgical resection (SR), liver transplantation, percutaneous ablation, transarterial chemoembolization (TACE), and targeted therapy.2,3 For patients with early stage HCC, SR, percutaneous ablation, and liver transplantation are widely accepted treatment modalities.4,5 Among various local ablative therapies, radiofrequency ablation (RFA) is considered the treatment of choice for small HCC and can provide long-term survival up to 60%.6 Renal insufficiency (RI) is defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 according to Kidney 192
Disease Improving Global Outcomes guidelines.7 Nearly one quarter of HCC patients suffered from RI at the time of diagnosis.8 Patients with HCC often have preexisting liver cirrhosis due to hepatitis B, hepatitis C, or alcoholism.9 Notably, cirrhosis may predispose to the occurrence of diabetes mellitus and renal dysfunction.10 More importantly, cirrhosis is associated with splanchnic vascular dilatation and subsequent deficiency of effective blood volume and renal hypoperfusion.11 These mechanisms contribute to the high prevalence of RI in patients with HCC. For patients with HCC and coexisting RI, angiographic procedure such as TACE may be unappealing since the risks of contrastinduced nephropathy are unacceptably high.12,13 Percutaneous treatment is therefore a feasible treatment option for HCC patients with RI. However, the impact of RI on long-term survival of HCC patients receiving RFA has not been clearly delineated. To further complicate this issue is that the prevalence of chronic kidney disease is nearly 12% in Taiwan.14 Moreover, Taiwan has the
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highest prevalence and second highest incidence of end-stage renal disease in the world.15 As such, the prognostic impact of RI on HCC could be even more prominent. Several cancer staging systems, including Barcelona Clinics of Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Japan Integrated Scoring (JIS) and Taipei Integrated Scoring (TIS) system, are used for prognostic prediction. However, the predictive accuracy in HCC patients with RI undergoing RFA has not been evaluated. This study aimed to examine the impact of RI on the long-term survival of HCC patients undergoing RFA as the primary treatment. A one-to-one propensity score matching analysis was utilized to reduce confounding factors inherent to this retrospective study. The prognostic accuracy between different staging systems was compared to determine the most optimal model in these patients.
Patients and methods Patients. We retrospectively analyzed patients with the diagnosis of HCC and admitted to Taipei Veterans General Hospital in more than a decade’s period from 2002 to 2013. A total of 467 patients receiving RFA as the 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 complies with the standards of the Declaration of Helsinki and current ethical guidelines. Diagnosis and definitions. The diagnosis of HCC was based on typical radiological features of contrast enhancement pattern in a four-phase multidetector contrast-enhanced computed tomography scan or dynamic magnetic resonance imaging.2,16 If the lesion did not show typical radiological features, biopsy was mandatory for establishment of HCC diagnosis. Alcoholism was diagnosed in patients with consumption of alcohol at least 40 g daily for 5 years or more.17 The Child-Turcotte-Pugh (CTP) classification was used to define the severity of cirrhosis. The performance status was assessed by using the Eastern Cooperative Oncology Group performance scale ranging from 0 (asymptomatic) to 4 (confined to bed).18 Total tumor volume (TTV) was calculated based on the mathematical equations as previously described.19 The BCLC, CLIP, JIS, and TIS staging systems were used to define clinical HCC staging.19–22 The eGFR was calculated using the reexpressed modification of diet in renal disease (MDRD) formula.23
eGFR (mL / min /1.73 m 2 ) = 175 × [creatinine (mg / dL)]−1.154 × [age (years)]−0.203 × 0.742 (if female) All patients in this study were ethnically Taiwanese. The serum creatinine level used in the reexpressed MDRD formula was the level recorded when the diagnosis of HCC was confirmed. Treatment. RFA was performed using the standard procedure.24 Under ultrasound guidance, the tumor(s) was/were ablated
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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. Propensity score matching analysis. To investigate the association between treatment and outcome in an observational, nonrandomized study, a propensity score matching analysis was used to reduce bias in patient selection and to generate a matched pairs of patients with and without RI to compare their long-term survival.25,26 Possible variables associated with the presence of RI, including age, gender, serum biochemistries, CTP classification, clinical staging, 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. A nearestneighbor match between patients with and without RI was used to select patients into subsequent analyses. A caliper width equal to 0.2 of the standard deviation of the logit of the propensity score was chosen for superior performance in the estimation of treatment effects.27 Statistics. The Chi-square test and two-tailed Fisher exact test were used to compare categorical data. The Mann–Whitney U-test was used to compare continuous variables between 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, gender, 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). The overall predictive accuracy of BCLC, CLIP, JIS, and TIS staging system was compared. Homogeneity (differences in survival among patients in the same stage within each system) was measured by likelihood ratio χ2 which was generated by the Cox proportional hazards model. AIC was calculated to reveal how the staging systems affected patient survival.28 A P value less than 0.05 was considered statistically significant. All statistical analyses were conducted with SPSS for Windows version 19 (IBM, NY, USA).
Results Characteristics and survival of patients receiving RFA. One hundred twenty-three and 344 HCC patients with and without RI, respectively, received RFA as their primary treatment. The baseline demographics of these patients are shown in Table 1; part of these patients had been analyzed in our previous studies.4,8,18 Patients with RI undergoing RFA were significantly older (P < 0.001). In addition, patients with RI were associated
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Table 1 Comparison of baseline demographics between patients with and without renal insufficiency undergoing radiofrequency ablation Variables
Without RI (n = 344)
With RI (n = 123)
P-value
Age (years), mean ± SD Male, n (%) Positive for HBsAg, n (%) Positive for anti-HCV, n (%) Alcoholism, n (%) Serum biochemistry (mean ± SD) Albumin (g/dL) Bilirubin (mg/dL) BUN (mg/dL) Creatinine (mg/dL) INR of PT ALT (U/L) Sodium (mmol/L) eGFR (mL/min/1.73 m2) AFP (ng/mL, mean ± SD) Performance status 0/1/2/3–4 (%) CTP class A/B/C (%) CTP score (mean ± SD) Tumor number (1/2/≥ 3), % TTV (cm3, mean ± SD) CLIP 0/1/2–6 (%)
64 ± 11 229 (67) 175 (51) 136 (40) 64 (19)
73 ± 9 78 (63) 44 (36) 58 (47) 10 (8)
< 0.001 0.580 0.004 0.166 0.006
3.7 ± 0.6 1.2 ± 1.1 14 ± 4 0.9 ± 0.2 1.1 ± 0.1 70 ± 61 139 ± 6 86.3 ± 21.0 281 ± 2000 74/17/8/1 81/17/2 5.8 ± 1.2 80/15/5 19 ± 102 60/32/8
3.8 ± 0.6 0.9 ± 1.0 27 ± 13 1.9 ± 1.6 1.0 ± 0.1 51 ± 34 139 ± 4 43.0 ± 14.8 617 ± 2142 75/11/11/3 87/11/2 5.6 ± 1.2 70/20/10 20 ± 34 50/38/12
0.232 < 0.001 < 0.001 < 0.001 < 0.001 0.001 0.229 < 0.001 0.049 0.196 0.207 0.099 0.004 0.034 0.316
AFP, α-fetoprotein; ALT, alanine transaminase; BUN, blood urea nitrogen; CLIP, Cancer of the Liver Italian Program; CTP, Child-Turcotte-Pugh; eGFR, estimated glomerular filtration rate; HCV, hepatitis C; INR, international normalized ratio; PT, prothrombin time; RI, renal insufficiency; SD, standard deviation; TTV, total tumor volume.
Figure 1 Comparison of survival between hepatocellular carcinoma (HCC) patients with and without renal insufficiency (RI) undergoing radiofrequency ablation (RFA). Patients with RI had significantly better long-term survival than patients with RI (P = 0.03).
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with lower serum bilirubin level, higher serum α-fetoprotein (AFP) level, higher number of tumor nodules, and higher TTV when compared to patients without RI (all P < 0.05). There were no significant differences in sex, performance status, and CTP classification between patients with and without RI (all P > 0.05). The most frequent etiology of underlying liver disease was hepatitis B (51%) in patients without RI, while hepatitis C prevailed in patients with RI (47%). After a median follow-up duration of 32 months, 106 patients died. Patients with RI receiving RFA had significantly worse long-term survival when compared to patients without RI (P = 0.030, Fig. 1); the 1- and 3-year estimated survival rates in patients with RI and without RI were 97% versus 91% and 83% versus 72%, respectively. Characteristics and survival of patients receiving RFA in the propensity model. Among patients receiving RFA, 92 matched pairs of patients with and without RI were selected by using the propensity score analysis (Table 2). Patients with RI had significantly higher serum blood urea nitrogen and creatinine level, and a lower eGFR (all P < 0.001). Otherwise, there were no significant differences between age, sex, etiology of chronic liver disease, severity of cirrhosis, performance status, and serum AFP level between patients with and without RI (all P > 0.05). The long-term survival between patients with and without RI showed no significant difference (P = 0.273, Fig. 2);
Table 2 Comparison of baseline demographics between patients with and without renal insufficiency undergoing radiofrequency ablation in the propensity score model Variables
Without RI (n = 92)
With RI (n = 92)
P-value
Age (years), mean ± SD Male, n (%) Positive for HBsAg, n (%) Positive for anti-HCV, n (%) Alcoholism, n (%) Serum biochemistry (mean ± SD) Albumin (g/dL) Bilirubin (mg/dL) BUN (mg/dL) Creatinine (mg/dL) INR of PT ALT (U/L) Sodium (mmol/L) eGFR (mL/min/1.73 m2) AFP (ng/mL, mean ± SD) Performance status 0/1/2/3–4 (%) CTP class A/B/C (%) CTP score (mean ± SD) Tumor number (1/2/≥ 3), % TTV (cm3, mean ± SD) CLIP 0/1/2–6 (%)
71 ± 9 60 (65) 36 (39) 39 (42) 16 (17)
71 ± 10 64 (70) 40 (44) 42 (46) 9 (10)
0.792 0.637 0.653 0.767 0.196
3.8 ± 0.5 0.8 ± 0.7 15 ± 4 0.9 ± 0.2 1.0 ± 0.1 60 ± 41 139 ± 3 82.3 ± 22.0 168 ± 671 72/21/7/0 91/9/0 5.4 ± 0.8 75/22/3 15 ± 31 63/31/6
3.9 ± 0.6 1.0 ± 1.1 27 ± 14 2.0 ± 1.9 1.1 ± 0.1 53 ± 36 139 ± 4 43.2 ± 15.3 380 ± 1772 75/11/10/4 90/7/3 5.6 ± 1.3 73/17/10 18 ± 29 58/36/6
0.786 0.681 < 0.001 < 0.001 0.865 0.226 0.381 < 0.001 0.295 0.068 0.193 0.503 0.230 0.953 0.888
AFP, α-fetoprotein; ALT, alanine transaminase; BUN, blood urea nitrogen; CLIP, Cancer of the Liver Italian Program; CTP, Child-Turcotte-Pugh; eGFR, estimated glomerular filtration rate; HCV, hepatitis C; INR, international normalized ratio; PT, prothrombin time; RI, renal insufficiency; SD, standard deviation; TTV, total tumor volume.
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the 1- and 3-year estimated survival rates in patients with RI and without RI were 99% versus 93% and 86% versus 76%, respectively. In the adjusted Cox proportional hazards model, only CTP class B or C (HR: 6.330, 95% CI: 2.846–14.077; P < 0.001) was identified as the independent predictor of poor prognosis (Table 3).
Performance of the cancer staging system for patients with RI. There were no significant differences in long-term survival of HCC patients with RI undergoing RFA between different cancer stages of BCLC and JIS (Fig. 3a,c, both P > 0.05). Alternatively, patients with a more advanced CLIP and TIS staging systems were significantly associated with decreased long-term survival (Fig. 3b,d, both P < 0.01). The four clinical staging systems were validated with both homogeneity (likelihood ratio χ2) and AIC method (Table 4). The TIS system had the lowest AIC value, followed by the CLIP, BCLC, and lastly, JIS system. Consistently, the TIS system provided the highest homogeneity among the four staging models, followed by the CLIP, BCLC, and JIS system.
Discussion Figure 2 Comparison of survival between hepatocellular carcinoma (HCC) patients with and without renal insufficiency (RI) undergoing radiofrequency ablation (RFA) in the propensity model. The long-term survival between patients with and without RI were similar (P = 0.273).
Table 3
Although RFA has been widely used as the primary treatment for HCC with RI, very few data are available regarding the impact of RI of these patients. In this large, single-center, propensitymatched study, we investigated the long-term survival between HCC patients with and without RI receiving RFA and found that RI was not associated with an inferior long-term survival. Multivariate analysis revealed that cirrhosis-related factors are more important in determining the overall survival. We also demonstrated that the TIS staging system may provide better prognostic
Prognostic predictors of survival for patients undergoing radiofrequency ablation in the propensity score model All RFA patients selected in the propensity model n = 184
Age (< 73/≥ 73 years) Sex (male/female) Albumin (≥ 3.9/< 3.9 g/dL) Bilirubin (< 0.66/≥ 0.66 mg/dL) BUN (< 20/≥ 20 mg/dL) Creatinine (< 1.1/≥ 1.1 mg/dL) INR of PT (< 1.03/≥ 1.03) ALT (< 40/≥ 40 U/L) Sodium (< 140/≥ 140 mmol/L) AFP (< 13/≥ 13 ng/mL) CTP class (A/B-C) No. of tumor (single/multiple) TTV (< 7/≥ 7 cm3) CLIP score (0/1–6) RI (no/yes)
94/90 124/60 83/101 92/92 109/75 97/87 97/87 78/106 117/67 90/94 167/17 136/48 86/98 111/73 92/92
Univariate P-value 0.789 0.446 < 0.001 0.349 0.776 0.580 < 0.001 0.143 0.766 0.033 < 0.001 0.963 0.639 0.027 0.273
HR
Multivariate 95% CI
P-value
6.330
2.846–14.077
< 0.001
Each variable was dichotomized into two groups by the median value for survival prediction. The forepart of variables was set as the reference group in the multivariate analysis. AFP, α-fetoprotein; ALT, alanine transaminase; BUN, blood urea nitrogen; CI, confidence interval; CLIP, Cancer of the Liver Italian Program; CTP, Child-Turcotte-Pugh; HR, hazard ratio; INR, international normalized ratio; PT, prothrombin time; RFA, radiofrequency ablation, RI, renal insufficiency; TTV, total tumor volume.
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(a)
(b)
(c)
(d)
Figure 3 Comparison of survival distributions in hepatocellular carcinoma (HCC) patients with renal insufficiency (RI) undergoing radiofrequency ablation (RFA) with different prognostic models: the Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Japan Integrated Scoring (JIS) system, and Taipei Integrated Scoring (TIS) system. There were no significant differences in long-term survival among patients with different stages of BCLC (P = 0.567, a) and JIS (P = 0.533, c). Alternatively, a more advanced cancer staging with CLIP (P = 0.005, b) and TIS (P < 0.001, d) was associated with a decreased long-term survival.
accuracy than the CLIP, BCLC, and JIS systems. Our results provide clinically relevant information regarding the selection of treatment modalities and assessment of the prognostic tool for HCC patients with RI undergoing RFA. In this study, patients with RI undergoing RFA had a poorer long-term prognosis compared with patients without RI in the 196
analysis outside the propensity score model. However, patients with RI were significantly older and had different baseline demographics including etiology of HCC, tumor characteristics, and serum biochemistries. The prognostic impact of RI could be erroneously confounded by these different baseline profiles. Propensity score matching analysis has been advocated to balance the
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Table 4 Comparison of common clinical staging systems among patients with renal insufficiency undergoing radiofrequency ablation
BCLC CLIP JIS TIS
Homogeneity (Likelihood ratio χ2)
Akaike information criterion
1.521 7.776 0.846 15.866
311.149 304.895 311.824 296.805
BCLC, Barcelona Clinics of Liver Cancer; CLIP, Cancer of the Liver Italian Program; JIS, Japan Integrated Scoring System; TIS, Taipei Integrated Scoring System.
covariates and to reduce biases between two patients groups.29 With similar baseline characteristics generated by propensity score matching, it is possible to properly inspect the impact of RI on patient survival. In the propensity model, the long-term prognosis was not significantly different between patients with and without RI. The Cox multivariate analysis confirmed that the long-term survival of patients undergoing RFA correlated with the severity of underlying liver cirrhosis but not the presence of RI. Patients with HCC frequently have coexisting liver cirrhosis, and are at increased risks of developing RI.30 Triggered by portal hypertension, reduction of systemic vascular resistance due to primary arterial vasodilatation in the splanchnic circulation is the primary mechanism of RI in cirrhotic patients.11 Patients with RI are also at increased risks of developing acute kidney injury following contrast medium injection during angiographic procedure.13 Therefore, it is not a common practice to treat HCC patients with RI by TACE.31 RFA is a widely accepted option in the management of surgically unresectable HCC.6 However, the feasibility of RFA for patients with RI is unclear, possibly due to increased bleeding tendency in these patients.32 This study shows that the long-term survival of HCC patients undergoing RFA was not affected by the presence of RI. Our finding is further supported by a study from Japan, where RFA had been performed safely and effectively in patients with end-stage renal disease.33 Notably, the prevalence of chronic kidney disease is high in general population in Taiwan, and up to one quarter of HCC patients suffered from RI at the time of diagnosis.8,14 For HCC patients with RI not suitable for surgical resection, RFA may be a feasible treatment option with proven efficacy and better safety profile. Therefore, the presence of RI should not preclude patients from active anticancer treatment such as RFA. In the Cox multivariate analysis, the only independent predictor of poor prognosis for patients undergoing RFA was CTP class B/C, with 6.3-fold increased mortality rate. However, many (83%) patients with RI receiving RFA still had preserved liver function (CTP class A). Patients undergoing RFA may need different assessment tool other than the CTP classification to represent the severity of cirrhosis. Taken together, our results imply that liver functional reserve, instead of RI per se, plays a major role in prognostic prediction. There has been intense debate on the optimal cancer staging system for HCC. It is unclear which staging system provides more accurate prognostic ability in patients with RI receiving RFA. It is also expected that different staging systems may be applied in different clinical settings. We specifically evaluated the perfor-
mance of four currently used staging systems in HCC patients with RI undergoing RFA treatment. In our analysis, we found that the CLIP and TIS staging system accurately discriminated the longterm survival in this patient group. The TIS system was associated with the lowest AIC value and highest homogeneity. Consistent with our previous findings, we demonstrated that the TIS staging system had a better discriminative ability when compared with BCLC, CLIP, and JIS staging systems.19 Since CTP classification system is included in all four staging systems, the main difference of the TIS over other staging systems is the incorporation of TTV in the scoring index. The efficacy of RFA highly correlates with tumor size. The complete tumor ablation rate may be up to 90% for HCC ≤ 3 cm, but the ablation rate drops to 20–45% for HCC > 5 cm.6 TTV should therefore be included in the clinical staging system for HCC in the RFA setting. There are a few limitations in this study. First, the retrospective nature made this study vulnerable to potential bias. Even with careful propensity score matching analysis with a predefined caliper, these biases still might not be completely avoided. Second, this single-center study was performed in the Asia-Pacific region, an endemic area with high prevalence of hepatitis B, and care must be taken when comparing the results from the Western countries with ours. Lastly, the calculation of TTV was based on the assumption that the tumor(s) was spherical, and the calculation of TTV might be inaccurate if the tumor(s) was irregularly shaped. In conclusion, our results suggest that for HCC patients undergoing RFA, the overall long-term survival was not compromised by the presence of RI. The TIS system is a better prognostic model compared with the CLIP, BCLC, and JIS staging systems in HCC patients with RI undergoing RFA. Our results may provide rationale for enhancing treatment allocation, improving accuracy of staging strategy, and refining study design in future clinical trials.
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