Advanced liver fibrosis effects on the response to sofosbuvir-based antiviral therapies for chronic hepatitis C.

BACKGROUND: Sustained virological response (SVR) rates for the treatment of chronic hepatitis C virus (HCV)-infected patients have drastically improved with the use of direct-acting antiviral (DAA) therapies; however, a small minority of patients still fails to eradicate the virus. We analyzed factors associated with SVR in DAA therapy and the effect of age and liver fibrosis on treatment response. METHODS: Nine hundred and eighteen patients with chronic HCV infection were treated with 24 weeks of daclatasvir plus asunaprevir (DCV + ASV) or 12 weeks of sofosbuvir plus ledipasvir (SOF + LDV), ombitasvir, paritaprevir plus ritonavir (OMB + PTV + r) or sofosbuvir plus ribavirin (SOF + RBV). Multivariate logistic regression analysis was used to identify factors associated with SVR. The effect of age and liver fibrosis on SVR was analyzed. RESULTS: The overall SVR rate was 95.4% (876 of 918 patients), and rates by DAA regimen were 93.4%, 95.7%, 100%, and 95.0% in DCV + ASV-treated, SOF + LDV-treated, OMB + PTV + r-treated, and SOF + RBV-treated patients, respectively. Patients older than 75 years achieved a similar SVR rate with those aged 75 years or younger (96.4% and 94.8%, respectively). Multivariate logistic regression analysis identified absence of DAA therapy history (odds ratio [OR], 3.868 for presence; P = 0.002) and FIB-4 index of less than 3.25 (OR, 5.042 for ≥3.25; P = 0.001) as independent predictors for SVR. SVR rates were significantly lower in patients with FIB4 index of 3.25 or more compared with those with less than 3.25, especially in sofosbuvir-based therapies such as SOF + LDV-treated or SOF + RBV-treated patients. CONCLUSION: Both older and younger patients respond similarly to DAA therapy. Advanced liver fibrosis affects the virological response to sofosbuvir-based therapy.

Hepatic arterial infusion chemotherapy followed by sorafenib in patients with advanced hepatocellular carcinoma (HICS 55): an open label, non-comparative, phase II trial.

BACKGROUND: In patients with advanced hepatocellular carcinoma (HCC), evidence is unclear as to whether hepatic arterial infusion chemotherapy (HAIC) or sorafenib is superior. We performed a prospective, open-label, non-comparative phase II study to assess survival with HAIC or HAIC converted to sorafenib. METHODS: Fifty-five patients were prospectively enrolled. Patients received HAIC as a second course if they had complete response, partial response, or stable disease (SD) with an alpha fetoprotein (AFP) ratio < 1 or a des-γ-carboxy prothrombin (DCP) ratio < 1. Patients were switched to sorafenib if they had SD with an AFP ratio > 1 and a DCP ratio > 1 or disease progression. The primary endpoint was the 1-year survival rate. Secondary endpoints were the 2-year survival rate, HAIC response, survival rate among HAIC responders, progression-free survival, and adverse events. RESULTS: Of the 55 patients in the intent-to-treat population, the 1-year and 2-year survival rates were 64.0 and 48.3%, respectively. After the first course of HAIC, one (1.8%) patient showed complete response, 13 (23.6%) showed partial response, 30 (54.5%) had SD, and 10 (18.1%) patients had progressive disease. Twenty-three patients (41.8%) had SD with AFP ratios < 1 or DCP ratios < 1, and 7 (12.7%) had SD with AFP ratios > 1 and DCP ratios > 1. Thirty-seven patients (68.5%) were responders and 17 (30.9%) were non-responders to HAIC. In responders, the 1-year and 2-year survival rates were 78 and 62%, respectively. CONCLUSION: Given the results of this study, this protocol deserves consideration for patients with advanced HCC. This trial was registered prospectively from December 12. 2012 to September 1. 2016.

Pilot study of stereotactic body radiation therapy combined with transcatheter arterial chemoembolization for small hepatocellular carcinoma.

BACKGROUND/AIMS: We retrospectively evaluated the local tumor control and safety of transcatheter arterial chemoembolization (TACE) followed by stereotactic body radiation therapy (SBRT) for small hepatocellular carcinoma (HCC) in this pilot study. METHODOLOGY: Twenty-eight patients not for the indication of hepatectomy or ablation procedures were enrolled in this study. Eligible criteria was as followed: i) less than 3 hypervascular HCC nodules, each up to 30 mm in diameter; ii) not suitable for the hepatic resection or ablative therapy; iii) Child-Turcotte-Pugh (CTP) score < or = 7. SBRT was performed within 1-2 months after TACE. Treatment efficacy was evaluated, according to the Response Evaluation Criteria in Cancer of the Liver (RECICL). RESULTS: The median local tumor control time was not reached. The 1-year cumulative local tumor control rate was 96.3%. The median disease-free survival time was 18 months. The 1- year cumulative overall survival rate was 92.6%. One patient (3.6%) died due to intrahepatic ectopic multiple recurrence and systemic metastasis and one (3.6%) due to cerebral hemorrhage. No patients experienced severe acute hematologic or physical toxicity or radiation induced liver damage. CONCLUSIONS: Our study demonstrated SBRT combined with TACE is a safe and effective modality of the locoregional therapy for small primary HCC.

[A case report of hepatocellular carcinoma with metastases to the lip, stomach, and colorectum].

A 79-year-old man was diagnosed with hepatocellular carcinoma in 2000 and treated with partial hepatectomy. Intrahepatic carcinoma recurred with lung metastases 7 years later. Several transcatheter arterial chemoembolizations were performed to treat the recurrence, and a right lower lobectomy was performed for lung metastasis. Twelve years after the original carcinoma diagnosis, lip and lung metastases were detected, and he was hospitalized for radiotherapy of the lung metastasis; an oral molecular-targeting drug was initiated. During the therapy, hematochezia was observed, and a colonoscopy was performed. A submucosal lesion with a blood clot measuring approximately 4mm in diameter was found in the sigmoid colon, and endoscopic mucosal resection was performed. Furthermore, an elevated lesion with a 5-mm diameter recess was observed on upper gastrointestinal endoscopy. Both lesions were diagnosed histopathologically as hepatocellular carcinoma metastases.

Evaluation of the mRECIST and α-fetoprotein ratio for stratification of the prognosis of advanced-hepatocellular-carcinoma patients treated with sorafenib.

OBJECTIVE: To compare the assessment of response and prognosis of patients to sorafenib treatment by the Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP). METHODS: Sixty-six patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib were enrolled in this retrospective study. The response to treatment was evaluated by RECIST, mRECIST and changes in AFP and DCP. RESULTS: The median survival time of all patients was 8.6 months. The median time to radiological progression was 3.3 months. The response rates [complete response (CR) + partial response (PR)] by RECIST and mRECIST were 3.0 and 9.0%, respectively, while the disease control rates [CR + PR + stable disease (SD)] were 50 and 50%, respectively. Assessment by mRECIST of overall survival provided a better stratification of the patients according to the response to treatment (p = 0.009) than RECIST (p = 0.09). Assessment of overall survival by a change in AFP ratio of ≤ 1 at 8 weeks was better than that of >1 at 8 weeks (p = 0.002). The DCP ratio was not useful for assessment of overall survival. Multivariate analysis identified mRECIST response (CR + PR + SD; p = 0.001), AFP ratio at 8 weeks (≤ 1; p = 0.046) and Child-Pugh A before treatment (p = 0.012) as significant and independent determinants of survival. The combination of AFP ratio at 8 weeks, assessment by mRECIST and Child-Pugh score before treatment allows stratification of prognosis of patients treated with sorafenib. CONCLUSION: The combination of mRECIST and AFP ratio is useful for the assessment of prognosis of patients with advanced HCC treated with sorafenib.

Achievement of sustained viral response after switching treatment from pegylated interferon α-2b to α-2a and ribavirin in patients with recurrence of hepatitis C virus genotype 1 infection after liver transplantation: a case report.

We report a case in which sustained viral response was achieved after switching treatment from pegylated interferon (PEG-IFN) α-2b to α-2a and ribavirin (RBV) in patients with recurrence of hepatitis C virus (HCV) infection after living donor liver transplantation. The patient was a 62-year-old man with liver cirrhosis due to HCV genotype 1b infection. The patient had 8 amino acid (aa) substitutions in the interferon sensitivity-determining region, and had substitutions for mutant and wild-type at aa70 and aa91, respectively, in the core region. The patient had minor genotype (GG) IL28B single nucleotide polymorphisms (rs8099917). He had initially received interferon α-2b and RBV for 2 years, and later developed hepatocellular carcinoma (HCC). After surgical resection of HCC, he subsequently received PEG-IFN α-2b and RBV for 1.5 years, without undetectable viremia during the treatment course. Due to recurrence of HCC, the patient received a living donor liver transplantation. Later on, hepatitis C relapsed. For the management of relapse, he received another course of PEG-IFN α-2b and RBV. However, breakthrough viremia occurred. PEG-IFN was thus switched from α-2b to α-2a and RBV for another 17 months. The patient eventually achieved a sustained viral response.

Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma according to Child-Pugh classification.

BACKGROUND AND AIM: We compared the treatment response, survival, and safety to hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) according to Child-Pugh (CP) score. METHODS: The study subjects were 249 patients with advanced HCC and CP class A and B who had been treated with HAIC. Patients were grouped according to CP score (5/6, 7 and 8/9) and their tumor response, tolerance, and survival were assessed. RESULTS: The median survival time (MST) was 8.2, 9.7, 6.3, and 3.9 months for the whole group, patients with CP 5/6, 7 and 8/9, respectively (P < 0.0001). Complete response (CR) and partial response (PR) were seen in 11 and 57 patients, respectively, with an overall response rate of 27.3%. The response rate was higher in patients with CP score 5/6 and 7, than CP 8/9 (30.5%, 28.2%, 13.8%). The dropout rate was significantly higher in patients with CP score 8/9 than the other two (8.0%, 12.8%, 33.3%, respectively). The survival rate was significantly better in patients who achieved CR/PR than the others with CP score 5/6, 7. CP score 8/9 was an independent negative factor for response and survival. CONCLUSION: Advanced HCC patients with CP score of 5/6 and 7 showed a better response to HAIC and better prognosis than those with CP score 8/9.

Interleukin-28B single nucleotide polymorphism of donors and recipients can predict viral response to pegylated interferon/ribavirin therapy in patients with recurrent hepatitis C after living donor liver transplantation.

BACKGROUND AND AIM: Interleukin-28B (IL28B) single nucleotide polymorphism (SNP) influences viral response (VR) to interferon (IFN) therapy in patients with hepatitis C. We studied the relationship between VR and the IL28B polymorphism (rs8099917) in patients on long-term pegylated IFN plus ribavirin (PEGIFN/RBV) therapy for recurrent hepatitis C after living-donor liver transplantation (LDLT). METHODS: Thirty-five patients with recurrent hepatitis C after LDLT were treated with PEGIFN/RBV. We evaluated the effect of IL28B SNP on the outcome in 20 patients infected with hepatitis C virus genotype 1 who completed IFN therapy. RESULTS: The sustained VR (SVR) rate was 54% (19/35) for all patients; 46% (13/28) for genotype 1. The SVR rate of donors' TT group (major genotype) was higher than that of donors' TG+GG group (minor genotype) (73% vs 20%), while that of recipients' TT group was similar to that of recipients' TG+GG group (64% vs 50%). With regard to the combined effect of donors' and recipients' IL28B SNP, the SVR rates of TT:TT (donors':recipients'), TT:TG+GG, TG+GG:any group were 81%, 50%, and 20%, respectively. The VR rate of TT:TT, TT:TG+GG and TG+GG:any group at 12 weeks were 28%, 0%, and 0%; those at 48weeks were 70%, 50%, 20%, and those at the end of treatment were 100%, 50%, 20%, respectively. The multivariate analysis identified IL28B of donors:recipients (TT:TT) as the only independent determinant of SVR (odds ratio 15.0, P=0.035). CONCLUSION: Measurement of donors' and recipients' IL28B SNP can predict the response to PEGIFN/RBV therapy, and the donors' IL28B SNP might be a more significant predictor than that of the recipients.

[A case of advanced hepatocellular carcinoma with lung, brain and lymph node metastases recurred 8 years after hepatectomy successfully treated by operation, radiation and systemic chemotherapy using S-1/CDDP].

A 30-year-old man underwent a left lobectomy and S5/6 partial hepatectomy in August 2001 for hepatocellular carcinoma (HCC). A lung tumor was detected by positron emission tomography (PET-CT) 8 years after the surgery. In May 2010, he received pulmonary tumor resection and the histopathological findings revealed metastasis of HCC. However a metastatic brain tumor was detected by computed tomography (CT) in September 2010, therefore surgery and radiation therapy were subsequently performed. Thereafter, metastatic hilar lymph node appeared in December 2010, therefore we performed systemic chemotherapy using S-1/cisplatin combined with radiation therapy for the metastatic tumor. The tumor was markedly decreased and no shadow was detected by PET-CT. He has been followed up in the outpatient clinic with no recurrence.

Treatment strategy for early hepatocellular carcinomas: comparison of radiofrequency ablation with or without transcatheter arterial chemoembolization and surgical resection.

BACKGROUND: The preferred choice between surgical treatment and radiofrequency ablation (RFA) for the treatment of small resectable hepatocellular [corrected] carcinoma (HCC) has become a subject for debate. METHODS: We compared the results of hepatic resection (n = 199) with those of RFA (n = 87), of which 69 patients were treated with transcatheter arterial chemoembolization followed by RFA, for 286 patients with 3 or fewer nodules, none of which exceeded 3 cm in diameter at Hiroshima University Hospital. RESULTS: In subgroup analysis of single HCC with tumor size exceeding 2 cm in Child-Pugh class A, the disease-free survival time was significantly longer in the surgical resection group than in the RFA group (P = 0.048). In the subgroups of a single and multiple HCC with tumor size ≤2 cm in Child-Pugh class A, the overall and disease-free survival rates were almost the same for the surgical resection and RFA groups (P = 0.46 and 0.58, respectively, in single HCC, and P = 0.98 and 0.98, respectively, in multiple HCC). CONCLUSION: Surgical resection may provide better long-term disease-free survival than RFA in the subgroup of a single HCC exceeding 2 cm of Child-Pugh class A.

A first case of hepatic angiosarcoma treated with recombinant interleukin-2.

A 60 year-old woman was admitted to our hospital because of management of multiple liver tumors. According to image findings and liver biopsy, she was diagnosed as having epithelioid hemangioendothelioma of the liver accompanied by metastases in the spleen, lungs and bones. Based on the spread of the liver tumors and the extensive systemic metastases, she was considered inoperable. Instead, she received hepatic arterial infusion therapy using recombinant interleukin-2. However, she died due to liver failure about two months after admission. Autopsy revealed that the liver tumor was angiosarcoma. It is difficult to differentiate angiosarcoma from epithelioid hemangioendothelioma based on the image findings and pathological findings of percutaneous liver biopsy. Many cases are diagnosed as angiosarcoma at autopsy. There is no established effective treatment for hepatic angiosarcoma, because the tumor stage at the time of diagnosis is often progressive. To date, immunotherapy with recombinant interleukin-2 has been reported to be effective clinically for cutaneous angiosarcoma, such as of the scalp and facial skin. To our knowledge, there have been no reported cases of hepatic angiosarcoma treated with recombinant interleukin-2. Our case is important should recombinant interleukin-2 be considered effective for hepatic angiosarcoma in the future.

[Significant regression of a cavernous hepatic hemangioma to a sclerosed hemangioma over 12 years: a case study].

A sixties woman was found to have diagnosed by abdominal ultrasonography with a tumor in the left lobe of the liver and was referred to our institution in 1998. Abdominal magnetic resonance imaging (MRI) showed a typical, 70×45 mm cavernous hemangioma, which was followed up by annual MRI. In 2006, 8 years after the initial diagnosis, the MRI showed that the tumor had reduced to 30×15 mm. Although atypical of hemangioma, review of the annual observations indicated a diagnosis of regressive hemangioma, which also accorded with clinical observations. In 2009, a liver biopsy was performed by laparotomy during gastrectomy for gastric cancer. Pathological examination of the biopsy revealed sclerosed hemangioma tissue, confirming the diagnosis of regression of a cavernous hemangioma to a sclerosed hemangioma over 12 years.

Establishment of functional telomerase immortalized human hepatocytes and a hepatic stellate cell line for telomere-targeting anticancer drug development.

We previously reported that the telomere-targeting drug telomestatin induces apoptosis accompanied by G-tail reduction and dissociation of binding protein TRF2 from telomeres in cancer cell lines but not normal or human telomerase reverse transcriptase (hTERT)-immortalized cells. Because telomere-targeting drugs induce growth arrest in normal cells at higher doses, their development is dependent on the ability to predict toxicity before in vivo use, but no models for this are available. Here, we established two new cell lines, telomerase immortalized human fetal hepatocytes, Hc3716-hTERT, and telomerase immortalized hepatic stellate cells, NPC-hTERT. Examinations showed that Hc3716-hTERT maintained normal mammalian cell morphology, cell growth, albumin expression, and wild-type p53 responsiveness, whereas NPC-hTERT maintained hepatic stellate-like morphology, expression of hepatic stellate markers, alpha-smooth muscle actin, and secretion of type I collagen, an extracellular matrix protein. Given our finding that telomere G-tail length in Hc3716 cells was decreased in senescence and increased by hTERT infection, we next examined the effect of high-dose telomestatin-induced telomere dysfunction and G-tail shortening on cellular functions in Hc3716-hTERT cells. Interestingly, telomestatin decreased expression of cytochrome P450 (CYP) family members CYP3A3/4, CYP3A5, and CYP3A7, mRNA and induced albumin expression at both mRNA and protein levels. These gene expression responses to telomestatin were similar to those of the normal parental cell Hc3716. These established cell lines thus represent the first model for predicting the side-effects of telomere-targeting drugs in normal cells, and should be powerful tools in the development of these drugs.

Hypersensitivity reactions to transcatheter chemoembolization with cisplatin and Lipiodol suspension for unresectable hepatocellular carcinoma.

PURPOSE: To assess the predictors of hypersensitivity reaction to chemoembolization procedures with cisplatin and Lipiodol suspension for the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between February 2005 and December 2008, 434 patients with HCC were treated with chemoembolization with a cisplatin and Lipiodol suspension. This retrospective cohort study analyzed the incidence of hypersensitivity reactions as an adverse effect and their predictors by multivariate logistic regression analyses. RESULTS: In total, 847 chemoembolization procedures were carried out in 434 patients. The median number of procedures per patient was 2 (range, 1-12). Mean dose of cisplatin per chemoembolization session was 27 mg (range, 15.0-80.0 mg), and the median total dose of cisplatin per patient was 55 mg (range, 5.0-560.0 mg). Hypersensitivity reactions occurred in 14 patients (1.7%). The median number of chemoembolization procedures in these patients was 7 (range, 3-10). Mean dose of cisplatin per session was 22 mg (range, 9.2-35.7 mg), and the median total dose of cisplatin was 134 mg (range, 37-286 mg). On multivariate analysis, the only parameter that showed an independent association with hypersensitivity reactions was the performance of 3 or more than three chemoembolization procedures. CONCLUSIONS: Performance of more than three chemoembolization procedures with a cisplatin and Lipiodol suspension was found to be independently associated with hypersensitivity reactions. Patients undergoing repeated chemoembolization procedures with cisplatin and Lipiodol suspension may experience hypersensitivity reactions as an adverse effect.

Prolongation of interferon therapy for recurrent hepatitis C after living donor liver transplantation: analysis of predictive factors of sustained virological response, including amino acid sequence of the core and NS5A regions of hepatitis C virus.

OBJECTIVE: The aim of the present retrospective study was to evaluate the therapeutic efficacy and predictive factors of prolongation of treatment with peginterferon (PEGIFN) combined with ribavirin (RBV) for recurrent hepatitis C after living donor liver transplantation (LDLT). METHODS: Fifty-three patients underwent LDLT due to HCV-related end-stage liver disease. Sixteen patients were removed from the study as a result of early death (n=14), no recurrence of HCV (n=1) and refusal of antiviral therapy (n=1). Therapy is ongoing in another 10 patients. The remaining 27 patients were available to establish the efficacy of IFN therapy. HCV genotype was 1b in 24 patients. All patients with genotype 1b were treated with IFN therapy for at least 48 weeks after HCV RNA levels had become undetectable. Amino acid substitutions in the HCV core region and NS5A region were analyzed by direct sequencing before LDLT. RESULTS: The rate of sustained virological response (SVR) was 37.0% (10/27). SVR rate in patients with genotype 1 was 29.2% (7/24) and 100% (3/3) in patients with genotype 2. Most patients with genotype 1b whose HCV RNA reached undetectable levels achieved SVR (87.5%; 7/8). However, mutation of the HCV core region and number of ISDR mutations were not associated with SVR rate in LDLT in our study. CONCLUSIONS: Prolonged IFN therapy for more than 48 weeks after HCV RNA reached undetectable levels might prevent virological relapse of HCV.

Percutaneous radiofrequency ablation as first-line treatment for small hepatocellular carcinoma: results and prognostic factors on long-term follow up.

BACKGROUND AND AIMS: We evaluated the prognosis and associated factors in patients with small hepatocellular carcinoma (HCC; up to 3 nodules, each up to 3 cm in diameter) treated with percutaneous radiofrequency ablation (RFA) as first-line treatment. METHODS: Eighty-eight consecutive patients who underwent percutaneous RFA as first-line treatment were enrolled, among whom 70 who had hypervascular HCC nodules which were treated by a combination of transcatheter arterial chemoembolization and RFA. RFA was repeated until an ablative margin was obtained. RESULTS: The rate of local tumor progression at 1 and 3 years was 4.8% and 4.8%, respectively. The rate of overall survival at 3 and 5 years was 83.0% and 70.0%, and the rate of disease-free survival at 3 and 5 years was 34.0% and 24.0%, respectively. On multivariate analysis, age (< 70 years; hazard ratio [HR] = 2.341, 95% confidence interval [CI] = 1.101-4.977, P = 0.027) and indocyanine green retention rate at 15 min (< 15%; HR = 3.621, 95% CI = 1.086-12.079, P = 0.036) were statistically significant determinants of overall survival, while tumor number (solitary, HR = 2.465, 95% CI = 1.170-5.191, P = 0.018) was identified for disease-free survival. Overall survival of patients with early recurrence after RFA was significantly worse than that of patients with late recurrence. Tumor size was the only independent risk factor of early recurrence after RFA of HCC (tumor size > 2 cm; risk ratio [RR] = 4.629, 95% CI = 1.241-17.241, P = 0.023). CONCLUSION: Percutaneous RFA under the protocol reported here has the potential to provide local tumor control for small HCC. In addition to host factors, time interval from RFA to recurrence was an important determinant of prognosis.

Intra-arterial 5-fluorouracil/interferon combination therapy for hepatocellular carcinoma with portal vein tumor thrombosis and extrahepatic metastases.

BACKGROUND AND AIMS: We investigated the efficacy of intra-arterial 5-fluorouracil (5-FU) and systemic interferon (IFN)-alpha (5-FU-IFN) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis in the first branch or trunk (Vp3/4) and extrahepatic metastases. METHODS: We examined 17 HCC patients with Vp3/4 and extrahepatic metastases (meta group) and 31 HCC patients with Vp3/4 (non-meta group). Baseline intrahepatic tumor factors and the hepatic reserve were similar between groups. The extrahepatic metastases of the meta group were not considered prognostic factors. Following the administration of 5-FU/IFN to all patients, we compared the survival rates, response, time to progression (TTP), and safety between groups. RESULTS: For intrahepatic HCC, complete response, partial response, stable disease, progressive disease, and drop out were observed in no (0%), one (6%), seven (41%), nine (53%), and no (0%) patients of the meta group, and in five (16%), seven (23%), 13 (42%), five (16%) and one (3%) patient of the non-meta group, respectively. The response rate was significantly lower in the meta group (6% vs 39%, P = 0.018). The median TTP of intrahepatic HCC and the median survival time were significantly shorter in the meta group than in the non-meta group (1.6 vs 6.3 months, P = 0.0001, and 3.9 months vs 10.5 months, P < 0.0001, respectively). The multivariate analysis showed that the absence of extrahepatic metastases was a significant and independent determinant of both TTP of intrahepatic HCC (P < 0.001) and overall survival (P < 0.001). No patient died of extrahepatic HCC-related disease. CONCLUSIONS: The efficacy of 5-FU/IFN for advanced HCC with Vp3/4 and extrahepatic metastases was markedly limited.

Pilot study of systemic combination therapy with S-1, an oral fluoropyrimidine, and cisplatin for hepatocellular carcinoma with extrahepatic metastases.

BACKGROUND/AIMS: The aim of this pilot study was to elucidate the efficacy and safety of systemic combination therapy with S-1 and cisplatin (CDDP) for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. METHODOLOGY: Sixteen patients were enrolled in this pilot study. Two weeks of combination therapy represented one cycle, followed by two-to-four weeks rest. In each cycle, S-1 was administrated orally at 80-120 mg (depending on body surface area) every day and cisplatin was administrated intravenously at 60 mg/m2 on day 8. Response, overall survival and adverse effects were assessed. RESULT. No patient had intrahepatic HCC and all patients had a class A Child-Pugh score. Regarding overall response, 2 (13%), 0 (0%), 5 (31%), and 9 (56%) patients showed complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), respectively, giving an overall response rate of 13% (2/16). The overall survival rate at 12 months was 77%. With regard to NCI-CTC grade-3 adverse reactions, 2 (13%), 2 (13%), and 6 (38%) patients developed nausea, anorexia, and neutropenia, respectively. No grade-4 adverse reaction or toxicity-related death occurred. CONCLUSION; S-1/CDDP is a potentially safe and effective combination therapy for HCC patients with extrahepatic metastases.

Intra-arterial 5-fluorouracil/interferon combination therapy for advanced hepatocellular carcinoma with or without three-dimensional conformal radiotherapy for portal vein tumor thrombosis.

BACKGROUND: The aim of this study was to elucidate the efficacy of intra-arterial 5-fluorouracil (5-FU) and interferon (IFN) alpha combined with three-dimensional conformal radiotherapy (3D-CRT) for portal vein tumor thrombosis (PVTT). METHODS: The study groups were 16 HCC patients with PVTT treated with 5-FU/IFN combined with 3D-CRT (RT group) and 16 matched controls treated with 5-FU/IFN alone (non-RT group). We compared the survival rate, response, time to progression (TTP), portal hypertension-related events (PREs) and safety. RESULT: Complete response (CR) of PVTT, partial response (PR), stable disease (SD) and progressive disease (PR) were noted in three (19%), nine (56%), four (25%) and zero patients of the RT group, one (6%), three (19%), seven (44%) and five (31%) patients of the non-RT group, respectively. The objective response rate of PVTT was higher in the RT group (P = 0.012). The rate of PREs (variceal rupture, worsening of esophagogastric varices and emerging of uncontrollable ascites) was lower in the RT group than in the non-RT group (P = 0.0195). The median survival time of the RT group (7.5 months) was not significantly different from that of the non-RT group (7.9 months). RT-induced liver disease was not observed. CONCLUSION: 5-FU/IFN combination with 3D-CRT for PVTT improved the response rate of PVTT and reduced the incidence of portal hypertension-related events.

Successful treatment of pulmonary metastases associated with advanced hepatocellular carcinoma by systemic 5-fluorouracil combined with interferon-alpha in a hemodialysis patient.

A 54-year-old man maintained on hemodialysis had a relapse of multiple pulmonary metastases after multimodal therapy for primary hepatocellular carcinoma (HCC). He was treated with tegafur-uracil (UFT; 400 mg/day) and interferon alfa (IFN-alpha; 5 x 10(6) units three times per week) for 4 weeks. Following this he was treated with systemic 5-fluorouracil (5-FU; 1000 mg/day, 5 days per week) and cisplatin (CDDP; 10 mg/day, 5 days per week for 2 weeks). The response to the above treatments was inadequate; pulmonary metastasis deteriorated. Finally, we selected systemic chemotherapy of 5-FU (750 mg/day, 5 days per week) and recombinant IFN-alpha-2b (3 x 10(6) units three times per week) for 2 weeks. This therapy resulted in excellent shrinkage of pulmonary metastases, without severe adverse reactions. Hemodialysis was performed three times a week. We report a case of successful treatment of pulmonary metastases by systemic combination chemotherapy of 5-FU-IFN, previously unsuccessfully treated with UFT-IFN and 5-FU-CDDP in a patient on hemodialysis. Further studies are needed to select appropriate drugs with fluoropyrimidine-based systemic chemotherapy, and to analyze the pharmacokinetics of those agents in hemodialysis patients with HCC and extrahepatic metastases.