Prognostic factors in patients with hepatocellular carcinoma treated by transcatheter arterial embolization

BACKGROUND: Transcatheter arterial embolization induces marked antitumor response in patients with hepatocellular carcinoma, but the survival benefit of transcatheter arterial embolization remains to be determined. This study investigated prognostic factors in patients with advanced hepatocellular carcinoma treated by transcatheter arterial embolization. METHODS: A total of 128 consecutive patients with non-resectable hepatocellular carcinoma, who had undergone transcatheter arterial embolization between May 1990 and August 1998, were analyzed to investigate prognostic factors. RESULTS: Median survival time and survival proportions at 1, 3 and 5 years were 3.3 years, 92.0, 54.6 and 23.4%, respectively. By multivariate analysis using the accelerated failure time model, age <60 years, hepatitis C virus antibody positivity, serum albumin >3.5 g/dl, absence of portal vein invasion and serum alpha-fetoprotein level <400 ng/ml were significantly associated with favorable survival. For clinical application, we also propose a prognostic equation with combination of specific prognostic factors, by which survival curves of each patient could be predicted directly. CONCLUSION: The findings of the current study may be helpful in predicting the life expectancy of hepatocellular carcinoma patients treated by transcatheter arterial embolization and in designing future clinical trials of transcatheter arterial embolization for hepatocellular carcinoma.     

132例原发性肝癌灌注化疗及栓塞治疗疗效观察

目的 探讨影响肝动脉灌注化疗＋栓塞治疗疗效的因素。方法 １９９３年１月￣１９９７年１０月,对１３２例不能切除的原发性肝癌行选择性插管灌注化疗及栓塞治疗５９７次,肝动脉灌注化疗＋栓塞者１２２例,单纯灌注化疗１０例。结果 １,２,３年生存率分别为８１．８％、３６．４％和１８．２％,疗效较治疗初期有显著提高。肿瘤分期、栓塞剂及其用量、侧支循环的形成以及肝动脉超选择性插管是影响疗效的主要因素。结论 合理施     

原发性肝癌的肝段动脉栓塞治疗

 本文报道50例肝癌肝段动脉栓塞治疗的1年、2年、3年、4年累积生存率分别83.8％, 65.4％, 42.9％, 24.5％, 总结分析了瘤周门脉碘油逆流的表现及临床价值, 本组病例门脉逆流出现率为64％, 作者认为肿瘤周围出现门脉碘油逆流是肿瘤碘油栓塞完全的标志之一, 可对肿瘤门脉供血起部分栓塞作用。     

A phase II trial of transcatheter arterial infusion chemotherapy with an epirubicin-Lipiodol emulsion for advanced hepatocellular carcinoma refractory to transcatheter arterial embolization

Introduction Transcatheter arterial embolization (TAE) has been recognized as an effective palliative treatment option for advanced hepatocellular carcinoma (HCC). However, no effective alternative treatments for TAE-refractory HCC have yet been established. The aim of this study was to evaluate the antitumor activity and toxicity of transcatheter arterial infusion chemotherapy using an epirubicin-Lipiodol emulsion in patients with TAE-refractory HCC. Methods Patients with TAE-refractory HCC were enrolled. A dose of 60 mg/m² epirubicin emulsified in Lipiodol and contrast medium was administered from the feeding artery of the HCC. Treatment was repeated every 4 to 12 weeks if there was no evidence of tumor progression or unacceptable toxicity. Results Twenty patients were enrolled in this trial. The median number of treatment courses was 1 (range 1–4). Among the enrolled patients, one (5%) achieved a partial response, and three (15%) showed a minor response. Five (25%) patients had no change and 11 (55%) showed progressive disease. The median survival time, 1-year survival rate and median progression-free survival time for the patients as a whole were 12.4 months, 52.6%, and 1.1 months, respectively. The main grade 3 and 4 toxicities were leukocytopenia (35%), neutropenia (65%), thrombocytopenia (30%), and elevations of the aspartate aminotransferase (45%) and alanine aminotransferase (35%) levels. These toxicities were generally brief and reversible. Conclusion Transcatheter arterial infusion chemotherapy with an epirubicin-Lipiodol emulsion appears to have only modest activity with moderate toxicity for treatment of patients with TAE-refractory HCC. These findings do not support its use in practice, and further studies with the same regimen in patients with TAE-refractory HCC are not recommended.     

Effectiveness of Lipiodol in transcatheter arterial embolization of hepatocellular carcinoma

The effectiveness of Lipiodol (iodized oil) in transcatheter arterial embolization (TAE) of hepatocellular carcinoma (HCC) was retrospectively evaluated using statistical analysis. A total of 343 HCC patients who underwent TAE at 5 institutions between 1984 and 1989 were divided into 2 groups: the GS-TAE group underwent TAE with Gelfoam sponge alone, whereas the LP-TAE group was given Lipiodol (LP) immediately before GS-TAE. The statisticalT value calculated for the LP-TAE group showed that the administration of LP, the tumor size, intrahepatic metastasis, portal vein infiltration, and serum total bilirubin and alpha-fetoprotein levels significantly (P<0.01) affected=" the=" patients'=" survival.=" both=" the=" cumulative=" survival=" determined=" using=" the=" kaplan-meier=" model=" and=" the=" cumulative=" hazard=" calculated=" using=" cox's=" proportional=" hazard=" model=" differed=" significantly=">P<0.01) between=" the=" gs-tae=" group=" and=" the=" lp-tae=" group=" (log-rank=" test).=" these=" results=" confirmed=" the=" effectiveness=" of=" lp=" used=" in=" combination=" with=" gelfoam=" sponge=" for=" tae=" of=">Presented at the Second International Symposium on Treatment of Liver Cancer. Taipei, 3–4 February 1991     

Clinicopathological study on combination therapy consisting of arterial infusion of lipiodol-dissolved SMANCS and transcatheter arterial embolization for hepatocellular carcinoma

Combination therapy (LpTAE) consisting of arterial infusion of a lipophilic anticancer drug, SMANCS, dissolved in an oily lymphographic agent, lipiodol (LPD), and transcatheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) was studied with special reference to the pathological findings. A total of 32 patients were subjected to surgical resection after LpTAE. The pattern of LPD deposition in the tumor was examined by CT scan (Lipiodol CT, LpCT) at 7 days and/or 1 month after LpTAE. The resected materials were examined radiographically with soft X-rays and histologically. LPD was deposited in tiny daughter nodules with a diameter of less than 5 mm and in tumor thrombi as well as in the main tumors, which showed necrotic change. Part of the LPD flowed out from the main tumor via the drainage vein and was deposited in the capsular invasion, resulting in necrosis. LPD accumulated almost exclusively within the blood spaces of trabecular-type HCC, creating a pattern corresponding to a cast of the tumor vessels, which showed prominent necrossi. On the other hand, LPD was not deposited in scirrhous, compact, or well-differentiated HCC, which showed little or no necrosis. It was demonstrated that LpCT images, which accurately depicted the existence and the extent of LPD deposition and necrosis in peutic effect. Our findings indicate that LpTAE and LpCT are valuable for the diagnosis and treatment of HCC and should play a central role in systemic therapeutic approaches to this disease.Presented at the Second International Symposium on Treatment of Liver Cancer. Taipei, 3–4 February 1991     

经导管肝动脉和B超引导下经细针门静脉双重化疗栓塞治疗原发性肝癌

目的　研究经导管肝动脉化疗栓塞 (TACE)联合B超引导下经细针门静脉化疗栓塞(PVE)治疗原发性肝癌的疗效。方法　原发性肝癌 2 0 9例 ,其中TACE 10 4例 ,TACE +PVE 10 5例。结果　TACE组和TACE +PVE组总有效率 (CR +PR)分别为 37.5 %和 5 7.2 % ,差异有显著性 (P <0 .0 1)。门静脉癌栓消失 +缩小率分别为 2 2 .2 %和 6 8.8% ,差异有显著性 (P <0 .0 1)。 1,2 ,3年生存率TACE组分别为 6 5 .1%、36 .3%和 2 0 .5 % ;TACE +PVE组分别为 95 .6 %、5 9.6 %和 39.1% ,两组差异有显著性 (P <0 .0 5 )。结论　经导管肝动脉和B超引导下经细针门静脉双重化疗栓塞治疗原发性肝癌疗效优于单纯TACE。B超引导下经细针PVE操作简便 ,并发症少 ,值得临床推广使用。     

Anticoagulant-induced pseudothrombocytopenia occurring after transcatheter arterial embolization for hepatocellular carcinoma

Pseudothrombocytopenia (PTCP) is the in vitro phenomenon of anticoagulant-activated platelet agglutination that results in spuriously low platelet counts. We report the case of a 65-year-old man with EDTA- and sodium citrate-dependent PTCP occurring after transcatheter arterial embolization (TAE) for hepatocellular carcinoma (HCC) due to hepatitis C cirrhosis. Invasion of the portal and hepatic veins by HCC formed severe trans-tumoral arterio-venous shunts that were effectively treated by TAE. Two days after the therapy, PTCP was seen on blood count and continued for 4 months. The patient received unnecessary treatment for disseminated intravascular coagulation (DIC) until the diagnosis of PTCP was established. PTCP is a rare complication but should be considered after TAE for HCC; lack of recognition may lead the physician to misdiagnosis and patient mismanagement.     

肝癌肝动脉栓塞化疗术并发碘油肺栓塞的临床观察

探讨肝癌肝动脉栓塞化疗术并发碘油肺栓塞的发病机制、临床表现、治疗方法及预防措施。分析肝癌行TACE术后发生碘油肺栓塞7例患者的术前肝脏CT、术中DSA检查、术中所用的碘油量及化疗药物剂量、术中术后的临床表现、辅助检查及临床治疗情况。患者出现不同程度的咳嗽、咯血、呼吸困难和低氧血症,胸片可见片状密度增高影。给予吸氧、扩张支气管、必要时呼吸机辅助呼吸及其他支持治疗后好转。随访观察20d～2个月,复查胸片正常。7例病例病灶直径约>10cm,存在肝动脉-肝静脉瘘的5例,碘油用量>20mL的5例。初步研究结果提示,碘油肺栓塞常发生在巨块型肝癌,且多存在肝动脉-肝静脉瘘,碘油用量多>20mL,术中正确处理可减少此类并发症的发生。     

Arterial chemotherapy and transcatheter arterial embolization therapy for non-resectable hepatocellular carcinoma

An assessment was made on the therapeutic effects of arterial chemotherapy and transcatheter arterial embolization (TAE) therapy on 378 cases with non-resectable hepatocellular carcinoma (HCC). For the 191 cases who had undergone arterial chemotherapy, 22% had a 1-year survival rate, 8.9% survived for 2 years, and 4.0% for 3 years. Of these, for the 128 cases who were compatible with our criteria for patient selection, the three survival rates were 31.4%, 12.2% and 5.9% respectively. However, for the other 63 cases, who were incompatible with our criteria, the 1-year survival rate was 1.6% and it was worse for the cases who had received supportive care alone. For the cases who had undergone arterial chemotherapy, the highest survival rates were obtained by the alternate administration of different anticancer agents, and the three survival rates were 39.0%, 13.1% and 4.9% respectively. For the 187 cases who had undergone TAE therapy, the 1-year survival rate was 66.2%, the 2-year survival rate 36.5%, and the 3-year survival rate 21.9%. For the 124 cases with a tumor progression rate of less than 20% in the liver (E1), the survival rates were 77.8%, 50.1% and 30.8% respectively. The peripheral venous drug concentrations of mitomycin C and adriamycin were lower, but were maintained for a longer period in TAE therapy than in arterial chemotherapy. These results suggest that consideration of the criteria for patient selection and the alternate administration of anticancer agents are necessary in arterial chemotherapy, and that the best therapeutic effects can be obtained by TAE therapy combined with chemotherapy for cases of non-resectable HCC because of the chemotherapeutic and ischemic effects on the tumors.     

Evaluation of the therapeutic effect of transcatheter arterial embolization for hepatocellular carcinoma

Transcatheter arterial embolization (TAE) has been widely performed for patients with hepatocellular carcinoma (HCC). However, the method of evaluating the therapeutic effect of TAE has not been established. We examined the rate of necrotic area to whole tumor (TN) by CT, the tumor regression rate (TR) and the reduction rate in serum alpha-fetoprotein (AFP) levels in patients with HCC who received hepatic resection within 3 months after TAE. In the evaluation of TN, the lipiodol accumulation in tumor was regarded as being necrotic. Rates of necrotic area, which were also examined pathologically (PN) in resected tumors, were compared with TN, TR and AFP reduction rates, respectively. Eighty-eight patients were enrolled in this study, and there was a significant positive correlation between TN and PN (r = 0.80, p < 0.001). Although TR significantly correlated to PN (p = 0.001), the correlation coefficient between them was low (r = 0.34). The correlation coefficients between AFP reduction rate and PN was 0.76 (p < 0.001) in 26 patients (30%) with an AFP level >/=200 ng/ml before TAE. The evaluation method using lipiodol accumulation in CT is the most useful for assessing the therapeutic effect of TAE, particularly when a sufficiently long interval exists between TAE and the evaluation, because of the highest correlation coefficient between TN and PN, and the availability of TN for all patients. The reduction rate in serum AFP levels was also useful in patients with AFP levels >200 ng/ml before treatment.     

Effect of transcatheter arterial embolization on the boundary architecture of hepatocellular carcinoma

Daughter nodules and intrahepatic metastases are resistant to conventional transcatheter arterial embolization therapy. To clarify the mechanism of this resistance, the boundaries of hepatocellular carcinomas and their relationship to the blood supply were studied. The boundaries of the hepatocellular carcinomas studied were classified as one of five types: encapsulated, granulation, stromal, replacing, or sinusoidal. The granulation and stromal types had a capsule-like structure, but lacked the hyalinization which is the hallmark of a true tumor capsule. The granulation and stromal types could also be differentiated from the encapsulated type because of their different blood supplies and the differing effects of transcatheter arterial embolization. When barium sulfate was infused into the portal vein, it did not enter into encapsulated tumors, but it entered granulation and stromal type tumors. Small nodules such as daughter nodules and intrahepatic metastases do not have capsules, and so have a blood supply that makes them resistant to conventional transcatheter arterial embolization therapy.     

Evaluation of nontumorous tissue damage by transcatheter arterial embolization for hepatocellular carcinoma.

The serial changes in serum hepatic enzyme activities by transcatheter arterial embolization (TAE) were analyzed in 17 patients with hepatocellular carcinoma to estimate the contribution to the value by the damage of tumor or nontumorous hepatic cells. The serum levels of relatively tumor-specific fructose 1,6-diphosphate (FDP) aldolase were elevated after TAE in the cases of both superselective and nonsuperselective TAE that were performed from the segmental and the nonsegmental hepatic artery, respectively, but we found the marked elevation of FDP aldolase in the cases of the superselective TAE. In contrast, the non-tumor-specific fructose 1-phosphate (F1P) aldolase was markedly elevated only in the cases of nonsuperselective TAE. The total amount of FDP aldolase released by TAE correlated significantly with the integrated tumor tissue volume (P less than 0.005), whereas the total amount of F1P aldolase output correlated significantly with the integrated nontumorous tissue volume (P less than 0.005) as defined by lipiodol accumulation on computerized tomography scan. The consequent changes in the total nontumorous liver volumes after TAE were also analyzed by the follow-up computerized tomography scan. The nonsuperselective TAE caused the significant total nontumorous liver atrophy when compared with the superselective TAE. The progression of the total nontumorous liver atrophy correlated significantly with F1P aldolase output by TAE (P less than 0.001) but not with FDP aldolase output. These results suggest that the outputs of FDP and F1P aldolase are useful to estimate the degree of the tumorous and nontumorous tissue damage by TAE, respectively, and F1P aldolase output can be used to predict the progression of liver atrophy caused by TAE.     

Histologic assessment of resected hepatocellular carcinoma after transcatheter hepatic arterial embolization

Ten cases of large hepatocellular carcinoma (HCC) (largest diameter, 6.5-15 cm) were surgically resected from 3 to 19 days after transcatheter hepatic arterial embolization (TAE) for histologic assessment of the effectiveness. Another two patients, including one with a small HCC (3.5 X 3 X 3 cm) who died of complications, were also studied. The patients' ages ranged from 20 to 64 years, 11 were men and 1 was a woman, and all positive for serum hepatitis B surface antigen. All 11 cases with large HCC were symptomatic before the HCC was clinically diagnosed. Alpha-fetoprotein levels were elevated in ten cases but immediately dropped to normal levels after TAE and resection in eight cases. An effective massive tumor coagulative necrosis of 99% already occurred 3 days after TAE. A necrosis involving more than 95% of the whole tumor mass was demonstrated in eight cases: one was a large HCC taken from an autopsy specimen, and TAE was done three times. This strongly indicates the effectiveness of TAE on the destruction of HCC. However, the presence of viable residual tumors in 11 cases also strongly argues for the necessity for surgical resection whenever it is possible. The failure of a complete necrosis was related to the extracapsular extension, liver invasion, satellite nodules, and portal vein involvement, and probably related to collateral and portal vein blood supply.     

A pilot study of transcatheter arterial interferon embolization for patients with hepatocellular carcinoma

BACKGROUND: Systemic, high-dose interferon-alpha treatment given three times per week subcutaneously induces tumor regression in approximately 30% of patients with inoperable hepatocellular carcinoma (HCC). The objective of the current study was to determine the efficacy and safety of transcatheter arterial interferon embolization for the treatment of patients with inoperable HCC. METHODS: Eighteen patients with inoperable HCC were recruited to receive 3 different doses of interferon-alpha-2b (10 megaunits [MU]/m(2), 30 MU/m(2), or 50 MU/m(2)) at intervals of 8-12 weeks. Their tumor response, adverse events, and survival were monitored. RESULTS: In 14 patients with nondiffuse HCC, complete responses and partial responses (> 50% tumor reduction) were observed in 28.6% and 35.7% of patients, respectively. One of four patients with diffuse HCC had a partial response. Thirty-eight percent of patients had normalization of their alpha-fetoprotein level. The median ferritin level at the last follow-up was reduced significantly (765 pmol/L; range, 457-2720 pmol/L) compared with the baseline level (1980 pmol/L; range, 1100-3300 pmol/L; P = 0.011). The median survival was 15.9 months. Transient fever and rigor were the most common side effects observed. Five patients (27.8%) developed hypothyroidism. No significant liver decompensation was observed. CONCLUSIONS: This pilot study showed that transcatheter arterial interferon embolization was an effective method for the treatment of patients with inoperable HCC without significant hepatic toxicity.     

Radiotherapy for large hepatocellular carcinoma combined with transcatheter arterial embolization and percutaneous ethanol injection therapy.

This study was performed to determine the effect of radiotherapy (RT) combined with transcatheter arterial embolization (TAE) and percutaneous ethanol injection (PEI) on large HCC. Between 1988 and 1996, 102 patients with unresectable, biopsy proven HCC underwent uniform pretreatment assessment followed by TAE and PEI. Of the 102 patients, 68 (67%) had more than 2 lesions in the liver, and the largest tumor sizes in each patient ranged from 3 to 8 cm in diameter. Immediately after TAE and PEI, external beam RT (36 to 70 Gy) was administered to the largest tumors only in 44 patients. The cause-specific 5-year survival rate for all patients was 39.9%. The 3-year survival rate of the RT group was better than that of the no RT group (81.1% vs. 54.6%). The cumulative local control rates of the largest treated tumors were 53.2% in the RT group and 32.7% in the no RT, respectively (p=0.006). When the survival rate was compared between patients with and without local control in the RT group, that of patients with local control was significantly better than that with local recurrences (p=0.048). No deaths or major treatment related complications occurred. RT combined with TAE and PEI did not clearly show improvement of the survival, however, it effectively controlled large HCC, and demonstrated minimal toxicity. This treatment may represent therapeutic option for some patients with unresectable large HCC.     

Serum vascular endothelial growth factor in the course of transcatheter arterial embolization of hepatocellular carcinoma.

We previously reported that in vitro hypoxic condition enhanced VEGF level and its receptor expression in hepatic cancer cell line, HepG2. Transcatheter hepatic arterial embolization (TAE) therapy is one of the vasculo-occlusive and hypoxic challenges to hepatocellular carcinoma (HCC). Therefore, we examined the level of VEGF in sera of patients with HCC who underwent TAE during the course of the treatment. Thirty-eight patients with HCC and hepatitis C virus-positive cirrhosis were studied. Peripheral blood samples were taken before and 1, 3 and 7 days after TAE with informed consent. The serum levels of VEGF as well as hepatocyte growth factor (HGF), another hepatic remodeling factor, were measured. The molar ratio (BTR) of serum branched chain amino acid (BCAA) to tyrosine (Tyr), the serum levels of AST, ALT and LDH were also examined. Although the level of AST, ALT and LDH reached the peak value within 1 day after TAE, VEGF level increased significantly 7 days later. On the other hand, there were no significant alterations in the levels of HGF and BTR during the course of TAE. Although the level of HGF was significantly correlated with the level of VEGF before TAE, this correlation was no more observed after TAE. These data collectively suggest that VEGF may be secreted in response to clinical hypoxic intervention, TAE, independent of HGF or altered amino acid metabolism. VEGF may play a role as a sensitive marker for tumor ischemia.     

肝动脉灌注栓塞术治疗肝癌的临床分析

目的探讨肝动脉灌注栓塞术治疗肝癌的临床效果与安全性。方法选取50例肝癌患者作为研究组,所有患者行肝动脉灌注化疗后采取肿瘤血管末梢栓塞治疗;另选取经肝动脉灌注化疗的30例肝癌患者作为对照组,比较两组患者治疗后的瘤体客观反应率、甲胎蛋白(AFP)水平和生存率。结果研究组患者的生存率明显高于对照组,差异有统计学意义(P<0.05)。治疗后,研究组患者的AFP下降率和肿瘤缩小率明显高于对照组,差异有统计学意义(P<0.05)。研究组患者发热发生率为58.0%,消化道反应发生率为62.0%;对照组发热发生率为30.0%,消化道反应发生率为33.3%,研究组患者不良反应发生率明显高于对照组(P<0.05)。结论肝动脉灌注栓塞术治疗肝癌的疗效明显优于单纯肝动脉灌注化疗法,且不良反应较轻,值得临床推广应用。