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Evaluation of combined therapy with transarterial
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&Evaluation of combined
with transarterial chemoembolization and percutaneous ethanol injection for large carcinomaFAN Wei-jun，GAO Fei，GU Yang-kui，HUANG Jin-hua，LI You-he, LI Wen-quan，LU Lian-weiWeijun Fan，Gao Fei，Gu Yangkui，Jinhua Huang，Wenquan Li， Department of Imaging and Interventional Radiology，Cancer Center，Sun Yat-sen University，China，510060Correspondence to：Jinhua Huang , Department of Imaging and Interventional Radiology，Cancer Center，Sun Yat-sen University，ChinaTel：86-20-& Fax：86-20-[Abstract]Objective To assess the effects of combined transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) in patients with large hepatocellular carcinoma (HCC) .Methods A total of 63 patients with large unresectable HCC was treated with TACE followed by PEI. The largest dimension of the tumours ranged from 5.3 cm to 17.8 cm. Survival rates, acute effects, toxicity and prognostic factors were analysed. Follow-up ranged from 3 months to 62 months. Results The cumulative survival rates at 1, 3 and 5 years were 59.4%, 28.4% and 15.8% respectively (median survival is 27.7 months). A reduction of tumor area greater than 50%, was achieved in 48.6% of cases. In 86.9% of the cases with increased a-feto protein (AFP) values, AFP level underwent a reduction of more than 75%. The
therapy was generally well tolerated. Only two patient died from variceal bleeding associated with therapy. The Cox proportional hazards model showed that the number of tumours，the tumor margin and the ethanol dose were independent prognostic factors. Conclusion The results indicate that combined TACE with PEI is a promising therapeutic approach for large unresectable HCC.[Key words] Hepa CE Combination therapy0.IntroductionHepatocellular carcinoma (HCC) is one of the most common malignancies in the world, responsible for an estimated one million deaths annually. It has a poor prognosis due to its rapid infiltrating growth and complicating liver cirrhosis. Surgery is the only potential cure but the resection rate for HCC is only 10－30%. The remaining patients are subjected to various forms of non-surgical therapy. Transcatheter arterial chemoembolization (TACE) has become one of the most popular forms of non-surgical treatment, with good results in reducing tumor size in HCC and improving survival[1－4]. However, tumor cells remain viable in and around the capsule, which is supplied by both arterial and portal blood, and these cells are often responsible for later recurrence and spread [5, 6].Further treatment is needed to eradicate residual tumor cells. We used TACE combined with PEI for 63 patients with large HCC and retrospectively evaluated the effects of this combination therapy and the prognostic factors.1.Materials and methods1.1. PatientsFrom November 2001 to January 2007, 63 consecutive patients with large unresectable HCC were enrolled in this study. In all patients, the diagnosis of HCC was made on the basis of histologic or angiographic findings combined with a rise in the serum levels of -fetoprotein (AFP). In 41 patients (65.1%) the diagnosis of HCC was confirmed by histologic examination. Diagnosis in the remaining 22 patients was made on the basis of characteristic findings on ultrasound, CT and angiography, and of high serum a-feto protein (AFP) levels. The enrolling criteria for this study were as follows: (1) lesion detectable on ultrasound and CT; (2) tumor/liver volume ratio not above 0.7:1; (3) level of serum transaminase under 80 IU/L; and (4) no evidence of extrahepatic metastasis or ascites. Patients who had ascites, extrahepatic metastasis, severe cirrhosis (class C according to Child's classification), or Karnofsky performance score ,70 were excluded.1.2. MethodsTACE was performed in the following processes: a 5.0 French catheter(Terumo, Tokyo,Japan) was inserted into the femoral artery by the seldinger method. Celiac angiography and selective hepatic arterial angiography were routinely performed to observe the tumorous blood-supply, distribution of hepatic arteries and collateral circulation routes. Then, the tip of the cathter was placed at the feeding artery of the tumor, and embolization was performed using emulsionized mixture of lipiodol ultra-fluide（Guerbet, France），Perarubicin(50mg/m2) and DDP(80mg/m2). The maximum dose of embolization was based on the size of the tumor，blood supply and hepatic function of the patient. When the tumor was filling well with emulsifier，the embolization ended.Ethanol ablations were performed using an ethanol solution (99% concentration, mixed with& lipiodol，9：1 of volume ratio) slowly injected into the tumor through a 15-cm 21 gauge Chiba needle (Cook, Bloomington, IN) guided by CT scan. The number of needle, the amount of ethanol injected per procedure and the number of procedures for the entire treatment, were planned depending on the volume of the tumor and the CT scan monitoring of the extent of the transient high-density zones induced by ethanol diffusion. The procedure was considered as complete when the entire targeted tumor became high-density. The number of pass required per tumor was 2 to 5. The amount of ethanol injected per procedure and per tumor was 3 to 20 ml (mean 8.2ml, SD: 8.2±3.4 ml) and per patient 5 to 40 ml (mean 20.5ml, SD: 30.5±6.6 ml). The standard protocol for a 5.0-6.0 cm diameter HCC schedule is 3 procedures (1 procedure every 1.5 weeks).1.3.Prognostic factorsFactors thought to influence survival were selected and then classified to obtain survival rates using the Kaplan–Meier method. The significance of the differences was evaluated by the log-rank test with univariate analysis. The following prognostic factors were tested: sex, age, number of lesions, tumor size, tumor extention, tumor margin ,AFP, portal thrombosis, ascites, Child grade, Okuda stage, TACE times, PEI times and the total ethanol dose. Variables with possible prognostic significance were selected, and two to four classes of each variable were identified (Table 1).With each factor related to the survival rate used as variables,stepwise multiplevariate analysis was performed. Multiple regression analysis based on the Cox proportional-hazard model was applied to calculate the relative-risk ratio between each factor and the survival rate.2.Results2.1.Recent results,survival and prognostic factorsA reduction of tumor area greater than 50%, was achieved in 48.6% of cases. In 86.9% of the cases with increased a-feto protein (AFP) values, AFP level underwent a reduction of more than 75%.At the end of this study, 11 patients remained alive, and 52 patients had succumbed. The survival curve for all patients is shown in Figure 1. Overall survival rates at one, three, and five years were 54.0%, 31.7% and 17.5%, respectively (median survival 27.7 months).&Univariate analysis indicated that 11 factors significantly influence survival. Sex, age and TACE times were not significant(p&0.05) (Table 3).The Cox proportional hazards model showed that only the number of tumors, tumor margin and the total ethanol dose were independent factors predicting survival(Table 4).For the 43 patients with a solitary lesion, the overall survival rates at one, three, and five years were 58.1%, 39.5% and 23.3%, respectively, and were 45.0%, 15.0% and 5.0%, respectively for the 20 patients with multiple lesions. Mean survival of patients with a solitary lesion was significantly longer (p = 0.0145) than that of patients with multiple lesions(Figure 2). For patients with clear tumor margin (n = 28), the 1 , 3 , and 5-year survival rates were 89.3%, 53.6%, and 39.3%, respectively, and these figures were significantly higher (p = 0.0052) than those of patients without clear tumor margin (n = 35), who had survival rates of 25.7% at one year, 14.3% at three years, and 0 at five years(Figure 3). Mean 1 , 3 , and 5-year survival rates were estimated to be 0, 0, and 0 respectively, for the 2 patients who received 10-30 ml o 33.3%, 16.7%, and 0, respectively, for the 9 patients who received 30-60 ml o 51.7%, 31.0%, and 16.1%, respectively, for the 29 patients who received 60-90 ml o and 73.9%, 43.5%, and 26.1%, respectively, for the 23 patients who received over 90 ml of totol ethanol dose, and statistically significant difference was found between high dose group and low dose group(p &0.0001) (Figure 4).2.2.Side effectsFever, abdominal pain, nausea and vomiting occurred in most of the patients after TACE and PEI. These symptoms were self-limited in almost all of the patients, lasting less than 1 week. A slight increase in serum bilirubin (37 cases), an elevation of serum transaminase (59 cases), ascites (6 cases), leukopaenia (15 cases) and thrombocytopaenia (11 cases) were associated with the combination therapy. These side effects were transitory or easily controlled with medication in most of the patients. Two patients died because of variceal bleeding associated with therapy.Table 1. Variables and classes considered at univeriate and multivariate analyses(number of patients in parenthesis)Variables&&classes&&&A&B&C&DSex&M(52)&F(11)&&Age(years)&&55(36)&&55(27)&&No.of lesions&solitary(43)&multiple(20)&&Tumor size(cm)&5-10(41)&&10(22)&&Tumor extention&1 lobe(46)&2 lobe(17)&&Tumor margin&clear(28)&not clear(35)&&AFP&&400(22)&&400(41)&&Portal thrombosis&absent(51)&present(12)&&Ascites&absent(56)&present(7)&&Child grade&A(38)&B(25)&&Okuda stage&I(29)&II(34)&&TACE(number of times)&1(11)&2(26)&3(20)&4(6)PEI(number of times)&1(3)&2(6)&3(31)&&4(23)Totol ethanol dose &10-30(2)&-60(9)&-90(29)&&90(23)Table 2. All factors affecting survival in the univariate analysisVariables&Class&Survival(%)&&&p-value&&1 year&3 year&5 year&Sex&A&27(51.9)&16(30.8)&9(17.3)&&B&7(63.6)&4(36.4)&2(18.2)&0.924﹡Age(years)&A&21(58.3)&11(30.6)&5(13.9)&&B&13(48.1)&9(33.3)&6(22.2)&0.223﹡No.of lesions&A&25(58.1)&17(39.5)&10(23.3)&&B&9(45.0)&3(15.0)&1(5.0)&0.0145﹡Tumor size&A&28(68.3)&18(43.9)&11(26.8)&&B&6(27.3)&2(9.1)&0(0)&0.0041﹡Tumor extention&A&29(63.0)&18(39.1)&11(23.9)&&B&5(29.4)&2(11.8)&0(0)&0.0054﹡Tumor margin&A&25(89.3)&15(53.6)&11(39.3)&&B&9(25.7)&5(14.3)&0(0)&0.0052﹡AFP&A&16(72.7)&10(45.5)&9(40.9)&&B&18(43.9)&10(24.4)&2(4.9)&0.0030﹡Portal thrombosis&A&31(60.8)&18(35.3)&11(21.6)&&B&3(25.0)&2(16.7)&0(0)&0.0111﹡Ascites&A&32(57.1)&19(33.9)&11(19.6)&&B&2(28.6)&1(14.3)&0(0)&0.0115﹡Child grade&A&28(73.7)&17(44.7)&11(28.9)&&B&6(24.0)&3(12.0)&0(0)&0.0132﹡Okuda stage&A&22(75.9)&14(48.3)&10(34.5)&&B&12(35.3)&6(17.6)&1(2.9)&0.0150﹡TACE(number of times)&A&3(27.2)&2(18.2)&1(9.1)&&B&13(50.0)&7(26.9)&3(11.5)&&C&13(65.0)&8(40.0)&5(25.0)&&D&5(83.3)&3(50.0)&2(33.3)&0.1719﹡﹡PEI(number of times)&A&1(33.3)&0(0)&0(0)&&B&2(33.3)&1(16.7)&0(0)&&C&16(48.5)&10(32.3)&5(16.1)&&D&15(65.2)&9(39.1)&6(26.1)&&0.0001﹡﹡Totol ethanol dose&A&0(0)&0(0)&0(0)&&B&2(33.3)&1(16.7)&0(0)&&C&15(51.7)&9(31.0)&5(16.1)&&D&17(73.9)&10(43.5)&6(26.1)&&0.0001﹡﹡﹡p-value,B vs A; ﹡﹡p-value,D vs A.Table 3. Significant factors predicting survival, tested by the Cox proportional hazards modelVariables&Class&Hazard ratio&p-valueNo. of lesions&Multiple vs solitary lesion&2.626&0.0006Tumor margin&Not clear vs clear&2.439&0.0004Totol ethanol dose&30-60ml vs 10-30ml60-90ml vs 10-30ml&90ml vs 10-30ml&0.3860.2020.116&0.00010.00010.0001&Figure 1. Overall cumulative survival curve for 63 hepatocellular carcinoma patients receiving combined therapy with TACE and PEI.&Figure 2. Cumulative survival curves for patients according to number of lesions.&Figure 3. Cumulative survival curves for patients according to tumor margin.&Figure 4. Cumulative survival curves for patients according to PEI dose.3.DiscussionThe rationale for combination of TACE and PEI relies on the fact that after TACE tumor consistency is markedly decreased and intratumoral septa are usually irrupted, as a result of the necrotic phenomena induced by the procedure. These histopathologic changes make subsequent treatment with PEI easier, as they provide enhanced ethanol diffusion within the tumor.& Consequently, treatment with PEI is facilitated by the TACE-derived fibrous wall around the lesion, which favours a better retention of the injected ethanol within the tumor[7-9]. Moreover,. higher doses of ethanol than those used in conventional PEI can be injected, enabling complete and homogeneous perfusion even of large lesions In this research, mean 1 , 3 , and 5-year survival rates were estimated to be 0, 0, and 0 respectively,for the patients who received 10-30 ml o 33.3%, 16.7%, and 0, respectively, for the patients who received 30-60 ml o 51.7%, 31.0%, and 16.1%, respectively, for the patients who received 60-90 ml o and 73.9%, 43.5%, and 26.1%, respectively, for the patients who received over 90 ml of totol ethanol dose, and statistically significant difference was found between high dose group and low dose group(p &0.0001).Ethanol in PEI acts by diffusing within the cells, which causes immediate dehydration of cytoplasmic proteins with consequent coagulation necrosis followed by fibrosis, and by entering the circulation, which induces necrosis of endothelial cells and latelet aggregation with consequent thrombosis of small vessels followed by ischemia of the neoplastic tissues. Advantages for using PEI include[10-12]: no remarkable damage to the remaining parenchyma, relative safety, easy repetition when new lesions appear as in the majority of patients followed for 5 years, application anywhere due to its low cost and easy operation,and fairly good long-term results. PEI can be carried out either in patients with HCC who have poor hepatic function or in elderly patients (age & or = 70 years)[13,14].It is necessary to analyze prognostic factors in a large number of patients in sufficient detail and to evaluate the result of each method of treatment between groups with similar prognostic factors. Our study showed that only the number of tumors, tumor margin and the totol ethanol dose were independent factors predicting survival. Although various prognostic factors have been reported [15–17], no conclusion has been drawn as to which are significant. In this study, the significant factors for better prognosis included the number of tumors, tumor margin and the totol ethanol dose. The prognostic factors identified in this study suggested that, therapeutic results in patients with solitary tumors, clear tumor margin and a higher totol ethanol dose should be better than those in patients with multiple tumors, not clear tumor margin and a lower totol ethanol dose. Ebara et al. [18] and Vilana et al. [19] proposed tumors &30 mm in size and &3 in number as indications for PEI, mainly because of technical limitation such as the inability to inject an effective volume of ethanol into the whole area of the tumor. Our results suggested some tumors &50 mm in size were also indications for PEI because PEI performed in large HCC patients with solitary tumors, clear tumor margin and a higher totol ethanol dose after TACE can also get good therapeutic results.Long-term survival rates of PEI-treated patients are similar to those obtained in matched patients submitted to partial hepatectomy[20-22]. However, the long-term prognosis remainsdisappointed because of the high recurrent rate among patients with HCC after PEI, especially in those with multiple lesions, not clear margin, high levels of alphafetoprotein (AFP) and those without peritumoral capsule or with cirrhosis[23,24]. In fact, histological examination of HCC lesions after PEI reveals that viable tissue remains in portions isolated by septa or in extracapsular or intracapsular invasion. 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