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High serum des-gamma-carboxy prothrombin level predicts poor prognosis after radiofrequency ablation of hepatocellular carcinoma
Article first published online: 31 DEC 2008
Copyright © 2009 American Cancer Society
Volume 115, Issue 3, pages 571–580, 1 February 2009
How to Cite
Kobayashi, M., Ikeda, K., Kawamura, Y., Yatsuji, H., Hosaka, T., Sezaki, H., Akuta, N., Suzuki, F., Suzuki, Y., Saitoh, S., Arase, Y. and Kumada, H. (2009), High serum des-gamma-carboxy prothrombin level predicts poor prognosis after radiofrequency ablation of hepatocellular carcinoma. Cancer, 115: 571–580. doi: 10.1002/cncr.24031
- Issue published online: 20 JAN 2009
- Article first published online: 31 DEC 2008
- Manuscript Accepted: 25 AUG 2008
- Manuscript Revised: 6 AUG 2008
- Manuscript Received: 12 FEB 2008
- Japanese Ministry of Health, Labor, and Welfare, and the Okinaka Memorial Foundation of Toranomon Hospital
- hepatocellular carcinoma;
- prognostic factor
Currently, surgical resection is considered the first-line treatment for early stage hepatocellular carcinoma (HCC). Radiofrequency ablation (RFA) has been an alternative choice for unresectable HCC. However, RFA is expected to have similar therapeutic efficacy for early stage HCC with fewer invasions.
The authors retrospectively analyzed 199 patients who underwent surgery and 209 patients who underwent RFA for HCC with a maximum diameter of ≤3 cm and tumors numbering ≤3. All patients were complicated with Child-Pugh A cirrhosis.
The 3- and 5-year survival rates of the resection (90.3%, 79.0%, respectively) and RFA groups were similar (87.4%, 74.8). The 1- and 3-year tumor recurrence-free survival rates of the resection group (83.1%, 51.0%, respectively) were higher than in the RFA group (82.7%, 41.8%; P = .011). Multivariate analysis identified prothrombin time ≥80% (hazard ratio [HR], 2.72; 95% confidence interval [CI], 1.56-4.74; P < .001) as an independent prognostic factor for survival in the resection group. Des-gamma-carboxy prothrombin (DCP) <100 arbitrary units (AU)/L (HR, 5.49; CI, 2.23-13.5; P < .001) and platelet count ≥1.0 × 105 (HR, 2.70; CI, 1.24-5.88; P = .012) were significant markers in the RFA group. Among patients with DCP ≥100 AU/L, treatment procedure (HR, 1.26; CI, 1.04-1.53; P = .020) was a significant prognostic factor for survival.
High DCP levels reflect the biologic aggressiveness and progression of HCC tumors. In the aforementioned cases, we recommend surgical resection rather than RFA for such patients. Cancer 2009. © 2008 American Cancer Society.
Hepatocellular carcinoma (HCC) is the sixth most common malignancy and third most deadly carcinoma in the world.1 In Japan, HCC is ranked third among males and fifth among females as the leading causes of cancer death.2 Most patients with HCC are infected with either hepatitis B virus (HBV) or hepatitis C virus (HCV), and have complications stemming from underlying chronic liver disease. The importance of liver condition in the treatment of HCC should be clearly discerned.3
A maximum tumor diameter of ≤3 cm and tumors numbering ≤3 are good candidates for liver transplantation in patients with Child-Pugh class B and C.4, 5 However, patients with Child-Pugh class A conditions should be treated curatively.5, 6 Hepatectomy is currently recommended for patients with single asymptomatic HCC and extremely well-preserved liver function, who have neither clinically substantial portal hypertension nor abnormal bilirubin levels.6 However, resection is suitable for only 20% to 35% of patients with HCC because of poor hepatic reserve.7, 8 Radiofrequency ablation (RFA) was introduced as a minimally invasive therapy for such cirrhotic patients.9-13 RFA was the initial choice for unresectable HCC; however, 2 recent randomized controlled trials concluded that there were no substantial statistical survival differences between resection and RFA.9, 10 Although the results of these studies have not yet reached a worldwide consensus, some authors recommend RFA as a first-line therapy for such early stage HCC.11-13
Tumor staging and the decision between possible treatment options are conducted predominantly based on tumor size, number, vascular invasion, and extrahepatic metastasis evaluated by imaging analysis such as ultrasonography or dynamic computed tomography (CT). However, the malignant nature of the tumor as well as other characteristics are not generally considered.14, 15 Alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) are HCC-specific tumor markers. High levels of serum tumor markers often indicate HCC development in the liver. On the basis of histopathological analysis, serum AFP and DCP levels are also correlated with tumor differentiation, microscopic portal invasion, or intrahepatic metastasis.16, 17
This present study is an attempt to evoke discussion on treatment strategies for small HCC measuring ≤3 cm by comparing the long-term outcome of patients treated with either hepatectomy or RFA as the first-line treatment for HCC. AFP and DCP were also accounted as indicators in the decision-making and treatment procedure.
MATERIALS AND METHODS
A total of 1057 patients were admitted to the Department of Hepatology, Toranomon Hospital between 1995 and 2006 for the treatment of initially developed HCC. The major background liver disease was HCV (767 patients, 72.6%), followed by HBV (196 patients, 18.5%), HCV + HBV (8 patients, 0.8%), alcoholic liver diseases (habitual drinking of ethanol at >80 g/day, 48 patients, 4.5%), primary biliary cirrhosis (4 patients, 0.4%), autoimmune hepatitis (2 patients, 0.2%), and cryptogenic liver disease (42 patients, 4.0%). Treatment of HCC included surgical resection in 281 patients, local ablation therapy in 398 patients (RFA, 267 patients; microwave coagulation, 47 patients; ethanol injection, 84 patients), and transarterial chemoembolization in 378 patients. Among these patients, we included patients with Child-Pugh A cirrhosis and HCC measuring ≤3 cm in diameter and numbering ≤3 tumors who were treated radically by either surgical resection or RFA. Table 1 summarizes the profile of the 199 patients who received resection and 209 patients who received RFA. HBV-related liver diseases were more common among patients who underwent resection, who were younger (62 vs 67 years; P < .001) than patients with RFA. The maximum tumor diameter was larger in the resection group than in the RFA group (20 vs 18 mm; P < .001). With regard to laboratory tests, serum albumin level, platelet count, and prothrombin time (%) were higher among patients in the resection group, whereas serum aspartate aminotransferase (AST) levels were higher among patients in the RFA group. None of the patients in either group had tumor invasion of the major portal branch or extrahepatic metastasis. Our institution does not require informed consent for retrospective analysis.
|Factors||Resection Group (n = 199)||RFA Group (n = 209)||P|
|Age, y*||62 (29-80)||67 (38-87)||<.001|
|HBV:HCV:HBV + HCV:others||60:121:3:15||22:176:1:10||<.001|
|Habitual alcohol intake, yes:no||29:170||9:200|
|Diameter of HCC, mm*||20 (9-30)||18 (8-30)||<.001|
|No. of HCC, 1:2:3||168:22:9||169:29:11|
|Tumor vascularity, present:absent||185:14||156:53|
|Albumin, g/dL*||3.7 (2.8-4.7)||3.6 (2.6-4.4)||<.001|
|Bilirubin, mg/dL*||1.0 (0.3-2.4)||1.0 (0.2-2.4)||NS|
|AST, IU/L*||43 (13-386)||55 (17-208)||<.001|
|Platelets, ×104/mm3*||13.1 (4.0-27.2)||10.5 (2.7-25.3)||<.001|
|Prothrombin time, %*||92 (62-115)||88 (57-125)||.006|
|AFP, ng/mL*||22 (1-7960)||18 (2-1490)||NS|
|DCP, AU/L*||20 (<10-1650)||17 (<10-1370)||NS|
Diagnosis of HCC
Diagnosis of HCC was predominantly based on image analysis. If a hepatic nodular lesion was found on screening ultrasonography, the patient underwent dynamic CT and/or dynamic magnetic resonance imaging (MRI). Furthermore, when a liver nodule showed hyperattenuation in the arterial phase of dynamic study and washout in portal or delayed phase, or showed typical hypervascular staining on digital subtraction angiography, the nodule was diagnosed as HCC. According to the American Association for the Study of Liver Disease guidelines, we obtained at least 2 dynamic imaging images before treatment.5 When the nodule did not appear in the abovementioned typical imaging features, a fine needle aspiration biopsy was carried out followed by histological examination and diagnosis.
Method of Treatment
Physicians and surgeons usually discuss together the preferred choice of therapy in individual patients. Hepatic resection was performed under intraoperative ultrasonographic monitoring and guidance. For small and superficial HCCs, arterial and portal vein clamping at hepatic hilum was not usually performed to maintain liver perfusion.
RFA was performed using 3 different devices: the radiofrequency interstitial tumor ablation system (RITA, RITA Medical Systems Inc., Mountain View, Calif), the cool-tip system (Tyco Healthcare Group LP, Burlington, Vt), and the radiofrequency tumor coagulation system (RTC system, Boston-Scientific Japan Co., Tokyo, Japan). In the first 2 systems, treatment procedures were performed according to the protocol advised by the manufacturer. However, treatment using the RTC system was performed by adopting the “stepwise hook extension technique.”18 The needle was inserted into the tumor percutaneously under ultrasonographic guidance. Because the HCC nodule could not be observed by ultrasonography in 6 cases, the needle was inserted under CT assistance. In the case of RFA, dynamic CT was performed 1 to 3 days after therapy, and the ablated area was evaluated. The goal of treatment was to obtain a necrotic area larger than the original tumor size, with a surrounding treatment margin of ≥5 mm in all directions. When this was not achieved or a residual tumor was found, additional ablation was considered. Of 206 total patients, total ablation session was required once in 149 (71.3%) patients, twice in 47 (22.5%) patients, and 3 times or more in 13 patients (6.2%).
Measurement of Serum AFP and DCP
Serum AFP level was measured by chemiluminescent enzyme immunoassay (CLEIA) using a commercial assay kit (Lumipulse Prestoll AFP, Fujirebio Inc., Tokyo, Japan). DCP level was measured by CLEIA (Lumipulse PIVKA II Eisai, Eisai, Tokyo, Japan).
Physicians examined the patients every 4 weeks after treatment, and liver function tests and tumor markers were also measured once every month. After completion of HCC eradication, recurrence was surveyed with contrast enhancement 3-phase CT every 3 months. Local tumor progression was defined as tumor recurrence adjacent to the resected or ablated area.
Differences in background features and laboratory data between resection and RFA groups were analyzed by the chi-square test and Mann-Whitney U test. Survival and recurrence-free survival were analyzed using the Kaplan-Meier technique, and differences in curves were tested using the log-rank test. Independent risk factors associated with survival and recurrence-free survival were studied using stepwise Cox regression analysis.19 Potential risk factors for survival and recurrence-free survival included the following 14 variables: age, sex, etiology of background liver disease, amount of alcohol intake, serum albumin, bilirubin, AST, platelet count, prothrombin time, AFP, DCP, diameter of the HCC, tumor multiplicity, and tumor vascularity evaluated by dynamic CT or dynamic MRI. A probability of less than .05 was considered significant. Data analysis was performed using SPSS statistical software version 10 (SPSS Inc., Chicago, Ill).
Survival and Recurrence-free Survival Rates
During the median follow-up of 3.3 years (range, 0.1-12.2 years), 112 (56.3%) of 199 patients in the resection group and 120 (57.4%) of 209 patients in the RFA group developed HCC recurrence. HCC recurrences mainly occurred in other sites in the liver. However, in the RFA group, local tumor progression, defined as HCC recurrence adjacent to the treated site, was seen in 18 (8.6%) of 209 patients, but noted in only 1 patient of the resected group. The cumulative local tumor progression rate in the RFA group was 2.7%, 11.3%, and 12.5% at 1, 3, and 5 years, respectively. The tumors were treated with surgical resection in 2 patients, additional tumor ablation in 8 patients, and transcatheter chemoembolization in the remaining 8 patients.
Exactly 64 patients of the resection group and 31 patients of the RFA group died during the follow-up. The cause of death among patients in the resection group was tumor progression in 51, hepatic failure in 10, gastrointestinal bleeding in 1, and other causes in 2. Uniformly, the cause of death in the RFA group was tumor progression in 16, hepatic failure in 13, gastrointestinal bleeding in 1, and other causes in 1. The cumulative survival rates for the resection group at 1, 3, 5, and 7 years were 96.9%, 90.3%, 79.0%, and 61.5%, whereas those for the RFA group were 99.0%, 87.4%, 74.8%, and 65.4%, respectively. The overall survival rates were not significantly different between the 2 groups.
The tumor recurrence-free survival rates for the resection group at 1, 3, 5, and 7 years were 83.1%, 51.0%, 36.8%, and 23.3%, and for the RFA group were 82.7%, 41.8%, 17.0%, and 5.8%, respectively (Fig. 1). The recurrence-free survival rate was higher in the resection group than in the RFA group (P = .011).
Factors Associated With Survival in Patients in the Resection Group
Among 199 patients treated with surgical resection, factors associated with survival were evaluated by both univariate and multivariate analysis (Table 2). Single tumor, serum albumin >3.8 g/dL, and prothrombin time >80% were significant by Kaplan-Meier analysis, whereas factors such as age, sex, etiology of background liver disease, amount of alcohol intake, bilirubin, AST, platelet count, AFP, DCP, diameter of the HCC, and tumor vascularity were not significantly related to patients' survival. In a multivariate analysis using the Cox proportional hazard model, prothrombin time >80 % (hazard ratio [HR], 2.72; 95% confidence interval [CI], 1.56-4.74; P < .001) was the independent prognostic factor for survival.
|Variable||No.||% 5-Year Survival Rate||Hazard Ratio (95% CI)||P|
|No. of tumors||.012|
|Prothrombin time (%)||.003|
|Prothrombin time, %, ≥80/<80||2.72 (1.56-4.74)||<.001|
Factors Associated With Survival in Patients in the RFA Group
We also evaluated the factors associated with the survival of 209 patients treated with RFA (Table 3). Platelet count ≥1.0 × 105 and DCP <100 arbitrary units (AU)/L were significant in univariate analysis, whereas 12 other variables were not associated with survival. Multivariate analysis identified DCP <100 AU/L (HR, 5.49; 95% CI, 2.23-13.5; P < .001) and platelet count ≥1.0 × 105 (HR, 2.70; 95% CI, 1.24-5.88; P = .012) as significant and independent determinants of survival.
|Variable||No.||% 5-Year Survival Rate||Hazard Ratio (95% CI)||P|
|DCP, AU/L, <100/≥100||5.49 (2.23-13.5)||<.001|
|Platelets, ×104/mm3, ≥10/<1||2.70 (1.24-5.88)||.012|
Factors Associated With Recurrence-free Survival in Patients in the Resection Group
Next, we evaluated the factors associated with recurrence-free survival in patients treated with surgical resection (Table 4). Presence of a single tumor, serum albumin ≥3.8 g/dL, platelet count ≥1.0 × 105, and prothrombin time ≥80% were significant in the univariate analysis, whereas 10 other variables were not significant factors for recurrence-free survival. In multivariate analysis, single tumor (HR, 2.39; 95% CI, 1.51-3.80; P < .001), serum albumin ≥3.8 g/dL (HR, 1.54; 95% CI, 1.02-2.32; P = .040), and platelet count ≥1.0 × 105 (HR, 1.47; 95% CI, 1.03-2.12; P = .036) were independent prognostic factors for recurrence-free survival.
|Variable||No.||% 3-Year Survival Rate||Hazard Ratio (95% CI)||P|
|No. of tumors||<.001|
|Prothrombin time, %||.009|
|No. of tumors, single/multiple||2.39 (1.51-3.80)||<.001|
|Albumin, g/dL, ≥3.8/<3.8||1.54 (1.02-2.32)||.040|
|Platelets, ×104/mm3, ≥10/<10||1.47 (1.03-2.12)||.036|
Factors Associated With Recurrence-free Survival in Patients in the RFA Group
Factors associated with recurrence-free survival were evaluated in patients treated by RFA. The 3-year recurrence-free survival rate was 44.7% in 185 patients with DCP <100AU/L, whereas it was 0.0% in 13 patients with DCP ≥100 AU/L. Univariate and multivariate analysis identified only DCP <100 AU/L (HR, 6.82; 95% CI, 3.49-13.3; P < .001) as a significant determinant of recurrence-free survival.
Survival and Recurrence-free Survival in Patients With DCP >100 AU/L
Figure 2 shows the cumulative survival rate, and Figure 3 shows the recurrence-free survival rate based on DCP levels. The survival rate and recurrence-free survival rate were associated with DCP in the RFA group, but they were not associated with DCP in the resection group. AFP >400 AU/L was associated with neither survival rate nor recurrence-free survival rate in either the resection or the RFA group. Therefore, 27 selected patients from the resection group and 13 from the RFA group whose DCP was ≥100 AU/L were examined to determine whether the overall survival rate was different between the resection and RFA groups. The backgrounds of the 2 groups based on treatment procedure are shown in Table 5. Treatment procedure (resection), age <65 years and serum albumin >3.8 g/dL were significant in the univariate analysis. Multivariate analysis revealed that treatment procedure (HR, 1.26; 95% CI, 1.04-1.53; P = .020) was a significant and independent determinant in the overall survival rate (Table 6).
|Factors||Resection Group, n = 27||RFA Group, n = 13||P|
|Age, y*||60 (35-73)||67 (50-78)||.006|
|Habitual alcohol intake, yes: no||3:24||2:11||NS|
|Diameter of HCC, mm*||22 (14-30)||22 (10-30)||NS|
|No. of HCC, single:multiple||26:1||9:4||.031|
|Tumor vascularity, present:absent||27:0||12:1||NS|
|Albumin, g/dL*||3.8 (3.3-4.3)||3.4 (2.6-4.1)||.003|
|Bilirubin, mg/dL*||0.9 (0.4-1.9)||0.9 (0.4-1.8)||NS|
|AST, IU/L*||38 (16-240)||49 (17-145)||NS|
|Platelets, ×104/mm3*||15.1 (6.0-24.5)||10.5 (4.5-24.6)||.025|
|Prothrombin time, %*||94 (79-112)||86 (73-110)||NS|
|Variable||No.||% 5-Year Survival Rate||Hazard Ratio (95% CI)||P|
|Resection or RFA||1.26 (1.04-1.53)|
Patients with HCC usually have a history of chronic liver disease, especially cirrhosis. Unfortunately, even when curative therapy is performed, tumor recurrence is frequent. For this reason, less invasive treatment procedures are needed to preserve liver function.
The Barcelona Clinic Liver Cancer (BCLC) guideline for the treatment of HCC recommends resection for patients with a single HCC and Child-Pugh A who have no other complications.5 The suggested option for RFA includes patients with multiple tumors and associated disease. However, in clinical practice, RFA is widely applied as a curative treatment for variable stages of HCC. Advances in imaging diagnosis have allowed identification of small HCC measuring <2 cm during the course of chronic liver disease.3 The use of RFA seems to be an excellent option for the aforementioned tumors.
In the present study, we focused on the malignant potential of HCC and examined 2 representative tumor markers of HCC. AFP has been used as a tumor marker for HCC worldwide, and is considered by some as a predictor of survival or recurrence after RFA.12 DCP is also useful as a prognostic factor in patients with HCC.20-22
In the present study, serum albumin levels and prothrombin time, which reflect liver function, were significantly associated with survival in patients who undergo resection similar to tumor multiplicity. Likewise, serum albumin level, platelet count, prothrombin time, and presence of multiple tumors were associated with recurrence-free survival. Alternatively, in RFA patients, in addition to platelet count, which indicates severity of portal hypertension, DCP levels were significant predictors of survival. Likewise, DCP levels were also significant predictors in recurrence-free survival. It is noteworthy that both survival and disease-free survival rates of patients who undergo RFA, but not resection, are correlated with DCP levels by multivariate analysis.
It is difficult to explain why DCP influenced survival and disease-free survival in the RFA group but not the resection group. We speculate that a high level of serum tumor marker reflects a high tumor malignant potential. Therefore, for a biologically aggressive tumor like HCC, resection is recommended over RFA because the radical nature of surgical resection may be superior to RFA.
According to previous reports, DCP is related to histological features of HCC.21, 22 Shirabe et al21 examined 218 HCC patients who underwent surgical resection for HCC and concluded that serum DCP level is a predictor of microvascular invasion. They identified microvascular invasion in 44% of their patients with DCP ≥100 AU/L, but in only 16% of patients with DCP <100 AU/L. Shimada et al22 examined explanted liver transplants and reported that serum DCP level is associated with vascular invasion and HCC recurrence. When we evaluated the relationship between clinicopathological features and serum DCP level in the resection group, microvascular invasion was found in 11 (44.0%) of 25 patients with DCP ≥100 AU/L, but in only 22 (13.6%) of 162 patients with DCP <100 AU/L, which was similar to the results in Shirabe et al.21
Unfortunately, in the RFA group, histological examination was performed only on nodules that showed atypical image findings. Moreover, it is sometimes difficult to judge microscopic vascular invasion in small specimens obtained by needle biopsy. However, we cannot deny the presence of microscopic vascular invasion in patients with high levels of tumor markers who have been treated with RFA. Furthermore, high levels of DCP are not only a marker of malignancy, but also indicate the biologic aggressiveness and progression of the HCC tumor. Hence, HCCs with high levels of DCP have greater chances of hypervascularity and early infiltration than do HCCs with lower levels of DCP.
In general, microscopic vascular invasion or intrahepatic metastasis is a poor prognostic factor for survival and recurrence-free survival even in patients who undergo surgical resection.23-25 Why was survival and recurrence-free survival not different among the resection group in our study? One of the reasons is that we included patients with an HCC of a maximum diameter of ≤3 cm. In contrast, most previous studies included HCC as large as 5 cm in diameter.23-25 The biological features of malignancy might be worse in such large tumors. We speculate that in HCC measuring ≤3 cm (median 2.0 cm), minimal microscopic vascular invasion or intrahepatic metastasis adjacent to the main tumor can be curatively resected by surgery, whereas these sometimes become incompletely necrotic even when a sufficient surrounding margin is obtained from treatment with RFA.
Analysis of factors associated with survival in patients with DCP of ≥100 AU/L showed that the type of treatment procedure (eg, hepatectomy) significantly influenced outcome. In contrast, no such relationship was found in patients with DCP of <100 AU/L. These results indicate that DCP is an important factor in selecting treatment procedure for patients with HCC measuring ≤3 cm and numbering ≤3 tumors.
In conclusion, DCP levels were significant predictors of both survival and recurrence-free survival in the RFA group. Hence, when the level of DCP is high, hepatic resection should be the treatment of choice even if the maximum tumor diameter is ≤3 cm and there are ≤3 tumors. If the level is low, RFA should be considered, because it is less invasive.
Because the current study was retrospective in nature, it has certain limitations and potential biases. The baseline characteristics of the 2 groups were quite different. Although we enrolled only Child-Pugh A patients, the resection group was younger and had better liver function. However, etiology of the liver disease was also different; the overall survival rates were not significantly based on etiology in either the resection or the RFA group. Therefore, we believe that the etiology of liver disease could be ignored in these patients. Our study did not uncover the reason for the high risk of mortality and tumor recurrence in patients in the RFA group with high levels of DCP. A cohort validation study is needed to confirm our results. In addition, clinicopathological and molecular analyses are also needed to define the biological significance of the biomarker.
Conflict of Interest Disclosures
Supported in part by a research grant from the Japanese Ministry of Health, Labor, and Welfare, and the Okinaka Memorial Foundation of Toranomon Hospital.
- 10Surgical resection versus percutaneous thermal ablation for early-stage hepatocellular carcinoma: a randomized clinical trial [in Chinese]. Zhonghua Yi Xue Za Zhi. 2006; 86: 801-805., , , et al.
- 15Liver Cancer Study Group of Japan. Classification of Primary Liver Cancer. First English Edition. Tokyo, Japan: Kanehara Press Co.; 1997.
- 19Regression models and life tables. J R Stat Soc. 1972; 34: 187-220..
- 24Liver resection for hepatocellular carcinoma in cirrhotics and noncirrhotics. Evaluation of clinicopathologic features and comparison of risk factors for long-term survival and tumour recurrence in a single centre. Aliment Pharmacol Ther. 2003; 17( suppl 2): 119-129., , , et al.
- 25Prognostic factors after hepatic resection for hepatocellular carcinoma with hepatitis C viral infection: univariate and multivariate analysis. Am J Gastroenterol. 2001; 96: 1243-1250., , , , .Direct Link: