Successful treatment for hepatocellular carcinoma with main portal vein tumor thrombi by 3-dimensional conformal radiation therapy combined with transarterial chemoembolization

In hepatocellular carcinoma (HCC), main portal vein (MPV) tumor thrombi are considered to indicate an advanced stage. Transarterial chemoembolization (TAE) is contraindicated in patients with MPV tumor thrombi because of the risk of hepatic functional deterioration. On the other hand, 3-dimensional conformal radiation therapy (3D-CRT) can focus a high dose of radiation on a small area and seems to be suitable for targeting tumor thrombi within the portal vein. Here, we describe 2 HCC cases with MPV tumor thrombi, who were successfully treated by 3D-CRT combined with TAE. In case 1, 3D-CRT successfully eliminated tumor thrombi within the MPV, and offered the opportunity of further TAE for intrahepatic tumor. The patient remained alive 5 months after the last TAE without liver function deterioration and without a viable HCC. In case 2, following this combined therapy, intrahepatic HCC and MPV tumor thrombi regressed. However, the MPV was not recanalized and subsequently liver function deteriorated. Fortunately, thrombi remaining within the MPV did not progress, and a collateral circulation developed around the MPV. This patient remained alive 12 months after treatment without a viable intrahepatic HCC. Therefore, although 3D-CRT combined with TAE cannot be routinely recommended because of anticipated hepatic functional deterioration, it can be cautiously considered for patients with MPV tumor thrombi.     

Complete response by a combination of 5-fluorouracil and interferon-alpha chemotherapy for lung metastasis of hepatocellular carcinoma after hepatic resection with portal and hepatic vein tumor thrombectomy.

A 75-year-old female was admitted to our hospital and diagnosed with hepatocellular carcinoma (HCC). Computed tomography (CT) revealed a liver tumor with tumor thrombi in the portal trunk and main hepatic vein, as well as small lung metastases. The patient had good liver function with no sign of hepatitis B or C infection. She underwent right trisectionectomy of the liver with tumor thrombectomy. Intrahepatic recurrence and progression of lung metastases were observed 4 months later. Intrahepatic recurrent tumors were treated with transcatheter arterial chemoembolization (TACE), and lung metastases were treated with systemic combination chemotherapy of 5-fluorouracil (5FU) and interferon-alpha (IFN-alpha). Computed tomography showed no viable lesions in the liver and lung 6 months after these treatments. The patient has been disease free for 18 months. Prognosis is poor for patients with hepatocellular carcinoma with portal vein tumor thrombus (PVVT) or extrahepatic metastasis. This systemic combination chemotherapy with 5-fluorouracil and interferon-alpha might be effective for patients with good liver function when intrahepatic lesions are well controlled by multidisciplinary treatments, including hepatic resection with tumor thrombectomy.     

Spontaneous ruptured hepatocellular carcinoma

The incidence of hepatocellular carcinoma (HCC) is rising worldwide. Spontaneous rupture of HCC occasionally occurs, and ruptured HCC with intraperitoneal hemorrhage is potentially life‐threatening. The most common symptom of ruptured HCC is acute abdominal pain. The tumor size in ruptured HCC is significantly greater than that in non‐ruptured HCC, and HCC protrudes beyond the original liver margin. In the acute phase, hemostasis is the primary concern and tumor treatment is secondary. Transcatheter arterial embolization (TAE) can effectively induce hemostasis. The hemostatic success rate of TAE ranges 53–100%. A one‐stage surgical operation is a treatment modality for selected patients. Conservative treatment is usually given to patients in a moribund state with inoperable tumors and thus has poor outcomes. Patients with severe ruptures of advanced HCC and poor liver function have high mortality rates. Liver failure occurs in 12–42% of patients during the acute phase. In the stable phase, tumor treatment, such as transarterial chemoembolization or hepatic resection should be concerned. The combination of acute hemorrhage and cancer in patients with ruptured HCC requires a two‐step therapeutic approach. TAE followed by elective hepatectomy is considered an effective strategy for patients with ruptured HCC.     

Successful treatment of advanced hepatocellular carcinoma by combined administration of 5-fluorouracil and pegylated interferon-α

We report a case of hepatocellular carcinoma (HCC) treated successfully by transarterial chemoembolization (TACE) followed by combination therapy of 5-fluorouracil (5-FU) and pegylated interferon-alpha (PEG-IFN-alpha). In the present case, the patient had massive and advanced HCC with a diameter of over 8 cm located in segment 7 (S7) of the liver. Furthermore, the tumor invaded into the major branch of the portal vein (Vp3). After TACE, combined administration of 5-FU and PEG-IFN-alpha was performed for 5 mo. HCC was totally eradicated and the serum levels of tumor markers were markedly decreased by the treatment. Although it has been reported that the combined use of conventional IFN-alpha and 5-FU showed striking effects on HCC in some cases, this case may suggest the more promising effect of PEG-IFN-alpha with a long-lasting effect, in the combined use with 5-FU for the treatment of massive advanced HCC.     

Hepatocarcinoma: considerations on surgical treatment in a personal series of 23 patients.

BACKGROUND/AIMS: Surgical treatment of primary liver tumors has undergone significant changes in recent years because of improved surgical and anesthesiological techniques and better pre- and post-operative care. We review our personal series from 1987-1995. METHODOLOGY: Of 31 cases of hepatocellular carcinoma (HCC) observed in the years 1987-1995, 23 underwent curative resective surgery for a total of 24 liver resections: 6 hepatectomies; 10 segmentectomies; 4 atypical subsegmentectomies; 2 extended resections, with excision of neoplastic thrombi within the portal vein; 1 orthotopic liver transplantation in another institution, and 1 limited segmental resection for tumor recurrence. In 7 recent cases, pre-operative transcatheter arterial chemoembolization (TAE) was used. RESULTS: The mean survival of the 13 patients that are known to be deceased is 27 months (range: 7-114 months). Perioperative mortality was nil. Actuarial 5-year survival rate is 27%. Pre-operative TAE was used in 7 patients: 4 out of 7 lesions were significantly reduced at computed tomography (CT) scan control 21 days following TAE, while in 3 the tumor size was unchanged. CONCLUSIONS: Liver surgery, even major resections, has become safe with no perioperative mortality in our series. In our experience, pre-operative TAE has often produced significant reduction of the mass, but its real efficacy is still the subject of debate. TAE and percutaneous ethanol injection (PET) should be evaluated as part of combined multimodality treatment in the therapy of large lesions previously considered inoperable.     

Radiation therapy for portal venous invasion by hepatocellular carcinoma

AIM: To clarify the efficacy and safety of three-dimensional conformal radiotherapy (3-D CRT) for this disease and to specify patient subgroups suitable for this treatment. METHODS: Fifty-two patients with HCC received PVI-targeted radiation therapy from January 1995 through December 2003. Portal venous invasion (PVI) was found in the second or lower order branches of the portal vein in 6 patients, in the first branch in 24 patients and in the main trunk in 22 patients. Child classifications of liver function before radiation therapy were A, B, and C for 19, 24 and 2 patients, respectively. All patients received three-dimensional conformal radiotherapy with a total dose ranging from 39 to 60 Gy (57.0 Gy in average). RESULTS: Overall survival rates at 1, 2, 3, 4, and 5 years were 45.1%, 25.3%, 15.2%, 10.1%, and 5.1%, respectively. Univariate analysis revealed that Child status, the number of tumor foci, tumor type, transcatheter arterial embolization (TAE) after radiation therapy were statistically significant prognostic factors. Multivariate analysis showed that the number of tumor foci and TAE after radiation therapy were statistically significant. CONCLUSION: The results of this study strongly suggest the efficacy of 3-D CRT as treatment for PVI in HCC. 3-D CRT is recommended in combination with post-radiation TAE for PVI of HCC with 5 tumor foci or less in the liver and with Child A liver function.     

Hepatocellular carcinoma with peritoneal dissemination which was regressed during vitamin K2 and vitamin E administration

A 65-year-old man with positive anti-hepatitis C antibody and chronic renal failure was diagnosed as having a ruptured hepatocellular carcinoma (HCC) based on computed tomography (CT). The patient underwent transcatheter arterial embolization (TAE) for the HCC. After one more session of TAE, the patient underwent surgery. But HCC seeding peritoneally was pointed out. Vitamin K2 and vitamin E were administered as a conservative treatment. Six months after starting vitamins K2 and E, the primary tumor did not increase in size and intraperitoneal dissemination disappeared on CT with a significant decrease of alpha-fetoprotein. Even though this is only one case, combination therapy of vitamin K2 and E may induce growth suppression of HCC.     

Study of repeated arterial infusion chemotherapy with a subcutaneously implanted reservoir for advanced hepatocellular carcinoma

We performed repeated arterial infusion chemotherapy (RAIC) in 114 advanced hepatocellular carcinoma (HCC) patients, using a subcutaneous reservoir implanted under ultrasonic guidance. In 60 patients, this was the initial therapy for the primary tumor and the other 54 patients being treated for recurrent tumor. One hundred and seventy-one patients with advanced HCC who had been treated by transcatheter arterial emblization (TAE) or single bolus arterial infusion chemotherapy before RAIC was available served as historical controls. In 97 patients, anticancer agents (4′-epidoxorubicin or acurarubicin) and Lipiodol emulsion were used, and in 17, anticancer agents alone were given. The response rates were 39.2% in the Lipiodol group and 17.6% in the non-Lipiodol group. The dose of Lipiodol and the degree of liver invasion were the most important factors influencing the response rate. The 1-, 2-, and 3-year survival rates were 55.0%, 30.9%, and 21.2%, respectively. The long-termsurvival was compared in relation to Child's classification and the presence or absence of portal vein tumor thrombosis (PVTT). In non-PVTT patients, the results of initial therapy and therapy for recurrence were similar, but recurrent Child's C patients showed a poorer prognosis. In PVTT patients, initial therapy had a better prognosis than treatment for recurrence, but initial Child's C patients had a poor long-termprognosis. During the observation period, no severe complications were encountered, but in Child's C patients, hepatic function sometimes deteriorated. Compared with the results in the 171 controls, RAIC was more useful for advanced HCC as initial therapy, and it was also beneficial for the treatment of recurrence after TAE.     

Hepatic arterial infusion of 5-fluorouracil in combination with subcutaneous interferon-alpha for advanced hepatocellular carcinoma

BACKGROUND/AIMS: Transcatheter arterial chemoinfusion (TACI) is the main therapeutic modality for advanced hepatocellular carcinoma (HCC) with portal thrombus. However, TACI is not sufficient to improve prognosis. In this study, we evaluated the response to hepatic arterial infusion of 5-fluorouracil (5-FU) in combination with subcutaneous interferon (IFN)-alpha in patients with advanced HCC. METHODOLOGY: Ten patients (men, 8; women, 2; mean age, 55-77) with advanced HCC were enrolled in this study. Hepatic arterial infusion of 5-FU (500 mg/24 hrs) was performed for 5 days on the first and second week. IFN-alpha (5 x 10(6) International Units) was subcutaneously administered three times a week for 4 weeks (1 therapeutic course). Response to therapy was evaluated by abdominal computed tomography at the end of two courses of therapy. Results: Seven patients received more than two courses of therapy. One patient (14%) showed complete response (CR). Four patients had stable disease (SD) (57%) and the remaining 2 patients had progressive disease (PD) (29%). Tumor markers decreased in all patients except 1 with PD. The 6-month survival rate was 40%. Therapy was discontinued in 3 patients due to severe adverse effects; all of these patients were over 70 years old, and had moderate liver dysfunction (Child-Pugh score of Grade B) before initiation of therapy. CONCLUSIONS: The goal of the therapy with hepatic arterial infusion of 5-FU in combination with subcutaneous IFN-alpha was attained in only 14% among our advanced HCC patients. The tumor completely disappeared in 1 patient, suggesting that this therapeutic modality may be of potential benefit in advanced HCC patients. However, this therapy should be performed with caution in patients with poor hepatic function (grade B or C of Child-Pugh score) and in those more than 70 years old.     

Rapidly growing hepatocellular carcinoma after direct-acting antiviral treatment of chronic hepatitis C

We report on a 62-year-old man with chronic hepatitis C who developed rapidly growing hepatocellular carcinoma (HCC) after achieving sustained virological response at post-treatment week 24 (SVR 24) by direct-acting antiviral (DAA) treatment. In 2008, he failed interferon therapy at 56 years of age. He received daclatasvir plus asunaprevir for 24 weeks after confirmation of no liver tumor by abdominal ultrasonography. He had no advanced liver fibrosis. Three months after initiation of DAA treatment, a liver tumor measuring 6 mm in diameter was detected by ultrasonography and confirmed with magnetic resonance imaging. After achieving SVR 24, the tumor increased in size to 16 mm. Two months later, a tumor biopsy was performed, and histology revealed moderately to poorly differentiated HCC. The patient’s alpha-fetoprotein (AFP) level was within the normal range, but the Lens culinaris agglutinin-reactive fraction of AFP level was elevated. The diameter of the tumor increased to 32 mm at 2 months after diagnosis. Lymph node metastasis in porta hepatis was found by positron emission tomography at 4 months after diagnosis. The patient received hepatic arterial infusion chemotherapy and radiation therapy, but died later. Careful monitoring is required during and after DAA treatment because HCC can grow fast even in patients with normal AFP and no advanced liver fibrosis.     

Recombinant interferon alfa 2b therapy in a patient with metastatic hepatocellular carcinoma

At present, there is no effective treatment of metastatic hepatocellular carcinoma (HCC). Systemic interferon alfa (IFN-alpha) was found to be of some use in patients with inoperable HCC in two randomized trials. We report a case in which metastatic HCC was cured by systemic IFN-alpha 2b in combination with surgery. A patient developed two bilateral pulmonary metastatic HCC nodules 5 months after the resection of the primary HCC. He was treated with systemic IFN-alpha 2b. One lesion completely disappeared. The other lesion showed an initial response but became resistant to the IFN-alpha 2b therapy after reduction in dosage because of the side effects. This was resected in view of the absence of new metastases after 9 months of IFN-alpha 2b therapy. He remained free from recurrence at 59 months of follow-up. A rare, but reversible, complication of retinal cotton wool spots caused by IFN-alpha 2b occurred in this patient. IFN-alpha 2b is partially effective in treating metastatic HCC. The time for its administration can also serve as an observation period, which is vital in deciding whether definitive surgical treatment of any residual lesions is indicated.     

综合序贯介入治疗原发性肝癌疗效分析

目的为进一步提高中晚期肝癌的治疗效果，采用综合序贯介入治疗，并对其疗效进行分析。方法３６例原发性肝癌，综合治疗组１６例，肝功能ＣｈｉｌｄＡ级１０例，Ｂ级６例。癌块＜５ｃｍ者１例，＞５ｃｍ者１５例，合并门脉癌栓者７例。肝动脉栓塞化疗（ＴＡＥ）组２０例，ＣｈｉｌｄＡ级及Ｂ级各１０例，癌块＜５ｃｍ者２例，＞５ｃｍ者１８例，门脉癌栓７例。ＴＡＥ组按常规行ＴＡＥ治疗。综合治疗组的措施是：ＴＡＥ．Ｂ超引导下门静脉栓塞化疗、无水乙醇肝内注射（ＰＥＩ）、Ｂ超引导下门脉癌栓的无水乙醇注射治疗、碘油及化疗药物肝内直接注射、其他措施有免疫制剂及９０Ｙ－玻璃微球肝内注射等，以上治疗序贯进行。结果随访时间３年，综合治疗组病程４～３４个月，最长生存湖３４个月（存活），半年生存率为８７．５％，一年生存率为５６．２％．ＴＡＥ组病程３－２９个月，最长生存期２９个月（死亡）。半年生存率为６０．０％，一年生存率为２０．４％。结论综合序贯治疗的半年及一年生存率均较单纯ＴＡＥ组显著延长，在改善肝癌预后上起重要作用。     

CASE REPORT: Haemothorax due to hepatocellular carcinoma rupture successfully controlled by transcatheter arterial embolization

A 64-year-old man was admitted to our hospital with multiple hepatocellular carcinoma (HCC) lesions in the liver and lung. On the seventh hospital day, a chest radiograph showed a marked increase in right pleural effusion. A thoracentesis revealed a haemothorax. Despite repeated pleural taps and blood transfusions, the patient's clinical status worsened and he developed severe dyspnoea. An inferior phrenic arteriography on the 19th hospital day showed a tumour growing over the diaphragm into the right thoracic cavity, suggesting a tumour rupture. A transcatheter arterial embolization (TAE) of the inferior phrenic artery successfully controlled the bleeding and improved the haemothorax. There was no rebleeding; however, the patient died of advanced HCC 3 months later. To our knowledge, this is the first case of a haemothorax secondary to a ruptured HCC that was treated successfully with TAE.     

α干扰素-对肝癌切除术后转移复发干预作用的实验研究

目的研究应用α干扰素(Interferon-α,IFN-α)对根治性切除术后肝癌转移复发的抑制作用,以及联合应用全反式维甲酸(all-trans retinoic acid,ATRA)是否与IFN-α的疗效有协同作用.方法在体外检测IFN-α和(或)ATRA对肝癌细胞株SMMC7721、BEL-7402、BEL-7405、MHCC97增殖的影响.44只裸鼠肝内原位接种裸鼠人肝癌转移模型LCI-D20肿瘤组织,于种植后第10天切除移植瘤,共分5组,分别为IFN-α治疗组(皮下注射,3×105U     

Impact of pre-operative transarterial embolization on the treatment of hepatocellular carcinoma with liver transplantation

AIM: To determine the effectiveness of pre-liver transplant (LT) transarterial embolization (TAE) in treating hepatocellular carcinoma (HCC) and the patient categories, which are likely to have a good outcome after LT. METHODS: Twenty-nine patients with hepatitis-related cirrhosis and unresectable HCC after LT were studied over a 7-year period. The patients were divided into two groups: group A patients (19/29) received pre-LT TAE, whereas group B (10/29) underwent LT without prior TAE. According to Milan criteria, group A patients were further subdivided into: group A1(12/19) who met the criteria, and group A2 (7/19) who did not. Patient survivals were compared. RESULTS: In the explanted liver, CT images correlated well with pathological specimens showing that TAE induced massive tumor necrosis (>85%) in 63.1% of patients in group A and all 7 patients in group A2 exhibited tumor downgrading that met Milan criteria. The overall 5-year actuarial survival rate was 80.6%. The TAE group had a better survival (84% at 5 years) than the non-TAE (75% at 4 years). The 3-year survival of group A2 (83%) was also higher than that of group A1(79%). Tumor necrosis >85% was associated with excellent survival of 100% at 3 years, which was significantly better than the others who showed <85% tumor necrosis (57.1% at 3 years) or who did not have TAE (75% at 3 years). CONCLUSION: TAE is an effective treatment for HCC before LT. Excellent long-term survival was achieved in patients that did not fit Milan criteria. Our results broadened and redefined the selection policy for LT among patients with HCC. Meticulous pre-LT TAE helps in further reducing the rate of dropout from waiting lists and should be considered for patients with advanced HCC.     

Liver atrophy after transcatheter arterial embolization and percutaneous ethanol injection therapy for a minute hepatocellular carcinoma.

A 63-year-old male patient with compensated cirrhosis underwent transcatheter arterial embolization (TAE) and percutaneous ethanol injection therapy (PEIT) for a minute hepatocellular carcinoma (HCC). Although the HCC was successfully treated, esophageal varices worsened and refractory ascites developed 3 months after the TAE and PEIT. Liver atrophy progressed rapidly compared to the natural course of liver cirrhosis.     

Uracil-tegafur as an adjuvant for hepatocellular carcinoma: a randomized trial

Frequent recurrence of hepatocellular carcinoma (HCC) after surgery remains a major clinical problem. This randomized controlled trial evaluated whether postoperative adjuvant therapy with oral uracil-tegafur (UFT) prevents recurrence of HCC. A total of 160 patients who underwent curative hepatic resection for HCC were randomly assigned to receive either 300 mg/day of UFT for 1 year after surgery (n = 79, UFT group) or surgery alone (n = 80, control group). The primary endpoint was recurrence-free survival, and the secondary endpoint was overall survival. Other study variables included liver function and type of recurrence. During a median follow-up of 4.8 years (range: 0.5-7.9), recurrence-free survival curves in the groups were similar (P = .87). Overall survival was slightly but not significantly worse in the UFT group than in the control group (P = .08). The rates of recurrence-free and overall survival at 5 years were 29% and 58%, respectively, in the UFT group, as compared with 29% and 73%, respectively, in the control group. The hazard ratio for recurrence in the UFT group, relative to the control, was 1.01 (95% confidence interval: 0.84-1.22, P = .87). The proportion of patients with advanced recurrence (i.e., multiple, extrahepatic, or associated with vascular invasion) was significantly higher in the UFT group (74%, 43 of 58 patients with recurrence) than in the control group (53%, 30 of 57) (P = .02). In conclusion, our results offer no evidence to support potential benefits of adjuvant chemotherapy with UFT after surgery in patients with HCC and suggest that such treatment may even worsen overall survival.     

Complete disappearance of pulmonary metastases in a case of hepatocellular carcinoma treated with docetaxel-based systemic chemotherapy

A case of the complete shrinkage of pulmonary metastases from multiple hepatocellular carcinomas (HCC) after administration of docetaxel, cisplatin and enteric-coated tegafur/uracil is reported. A 54-year-old Japanese man was diagnosed with recurrent multiple HCC associated with pulmonary metastases and compensated liver cirrhosis. Docetaxel, cisplatin and enteric-coated tegafur/uracil were given to this patient. After 2 months of treatment, there was a decrease in tumor markers and a shrinkage of the pulmonary metastases. Image analyses such as chest X-rays and chest computed tomography scans showed a disappearance of the pulmonary metastases, although the multiple HCC did not disappear completely. This was evaluated as a complete remission of metastatic lesions or a partial remission of primary lesions according to the World Health Organization criteria. No recurrence of pulmonary metastasis was seen for 10 months. This combination therapy was well-tolerated for lung cancer and could represent an effective treatment for pulmonary metastases from HCC.     

Prognosis following transcatheter arterial embolization for 121 patients with unresectable hepatocellular carcinoma with or without a history of treatment

AIM: To retrospectively evaluate the prognosis of patients with hepatocellular carcinoma (HCC) with or without a history of therapy for HCC following transcatheter arterial embolization (TAE). METHODS: One hundred and twenty-one patients with HCC treated with TAE from 1992 to 2004 in our hospital were enrolled in this study. Eighty-four patients had a history of treatment for HCC, while 37 did not. At the time of entry, patients with extra-hepatic metastasis, portal vein tumor thrombosis, or Child-Pugh class C were excluded. TAE was repeated when recurrence of HCC was diagnosed by elevated tumor markers, or ultrasonography or dynamic computed tomography findings. RESULTS: Tumor size was larger and the number of tumors was fewer in patients without past treatment (P<0.01). However, there were no differences in tumor node metastasis (TNM) stage or survival rate between the 2 groups. A bilobular tumor and high level of alpha-fetoprotein (AFP) (>100 ng/mL) were factors related to a poor prognosis in patients with a history of HCC. CONCLUSION: The prognosis following TAE is similar between HCC patients with and without past treatment. Early diagnosis of HCC or recurrent HCC and obtaining good local control against HCC before entry to a repeated TAE course can improve prognosis.     

A case of hepatocellular carcinoma with multiple lung, spleen, and remnant liver metastasis successfully treated by combination chemotherapy with the novel oral DPD-inhibiting chemotherapeutic drug S-1 and interferon-α

A 54-year-old man was admitted Osaka University Hospital for hepatocellular carcinoma (HCC) with portal vein thrombus and multiple intrahepatic metastases that extended to the bilateral lobes of the liver. He underwent multimodal therapy, including extended left lobectomy followed by intra-arterial 5-fluorourcil (5-FU) infusion chemotherapy combined with subcutaneous interferon-α (IFN-α) to treat the lesions in the residual liver. Seven months after the initial resection, recurrent tumors in the spleen, lung, and residual liver were detected by follow-up examination. We started a new regimen of per oral administration of S-1 and subcutaneous IFN-α injection, because the combined therapy with intra-arterial 5-FU infusion was not considered effective for distant metastases. After two cycles of S-1 and IFN-α, the metastatic tumor in the spleen and the recurrence in the residual liver had disappeared, and the diagnosis was complete remission with no adverse effect; the pulmonary metastasis showed a partial response, and was finally resected. This patient is still alive with no recurrence 32 months after initial hepatic resection. This outcome suggests that combination therapy with S-1 and IFN-α may be a promising treatment modality against advanced HCC with distant metastasis.