Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma

Hepatocellular carcinoma （HCC） is one of the most common malignancies worldwide, including Japan. Although the development of imaging modalities has made the early diagnosis of HCC possible, surgically resectable cases are relatively uncommon because of hepatic function reserve and/or an advanced stage at presentation. Several modalities, such as transcatheter arterial chemoembolization, percutaneous ethanol injection, microwave coagulation therapy and radiofrequency ablation are reportedly useful in treating patients with non-resectable disease. However, unfortunately, many HCC patients have tumor recurrence. The overall prognosis of patients with HCC is very poor, and treatment of the advanced form is still problematic. In this article, we review the clinical efficacy and toxicity of enteric-coated tegafur/uracil in the treatment of patients with advanced non-resectable HCC.     

Complete disappearance of recurrent hepatocellular carcinoma with peritoneal dissemination and splenic metastasis: a unique clinical course after surgery

Spontaneous regression of hepatocellular carcinoma (HCC) is a rare phenomenon. We report a case of complete disappearance of intrahepatic, peritoneal and splenic metastases in HCC after hepatectomy using treatment with tegafur and uracil (UFT). The effect of UFT alone was not likely to have caused the disappearance of this tumour because HCC recurrence advance markedly within 5 months of surgery despite oral administration of UFT. This case demonstrates a unique postoperative clinical course that suggests spontaneous regression of HCC. This is the first case of complete disappearance of unresectable HCC with peritoneal seeding and splenic metastasis.     

Advanced hepatocellular carcinoma with distant metastases, successfully treated by a combination therapy of alpha-interferon and oral tegafur/uracil

We report a case of advanced hepatocellular carcinoma (HCC), successfully treated by a combination therapy of alpha-interferon (IFN-alpha) and tegafur/uracil (UFT). A 44-year-old Japanese man who underwent a partial hepatectomy for HCC developed tumor recurrence in the liver 10 months after surgery. Transcatheter arterial chemoembolization (TAE) was performed twice within 7 months, but was ineffective. Later, multiple metastatic lesions appeared in the liver, lung and spine. Following the third TAE, a combination therapy of IFN-alpha (10 x 10(6) units, i.m., t.i.w.) and UFT (300 mg, p.o.d.) was started. The treatment resulted in a fall in serum PIVKA-II (protein induced by vitamin K antagonism) levels from 906 mAU to normal levels and a complete resolution of all lung nodules within 6 months. At the latest follow up 24 months after the initiation of combination treatment, the patient was working full-time and showed no evidence of tumor relapse. A combination therapy of IFN-alpha and UFT may be promising for the treatment of advanced HCC.     

Improved survival for hepatocellular carcinoma with portal vein tumor thrombosis treated by intra-arterial chemotherapy combining etoposide, carboplatin, epirubicin and pharmacokinetic modulating chemotherapy by 5-FU and enteric-coated tegafur/uracil: A p

AIM: To investigate the poor prognosis of HCC with PVTT, we evaluated the efficacy by a new combination chemotherapy for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT).METHODS: From 2002 to 2007, a total of 10 consecutive patients with Stage IVA HCC accompanied by PVTT were studied prospectively to examine the efficacy of treatment by intra-arterial infusion of a chemotherapeutic agents consisting of etoposide, carboplatin, epirubicin and pharmacokinetic modulating chemotherapy by 5-FU and enteric-coated tegafur/uracil.RESULTS: The mean course of chemotherapy was 14.4 (range, 9-21) mo. One patient showed complete response (CR) with disappearance of HCC and PVTT after treatment, and the two patients showed partialresponse (PR), response rate (CR + PR/All cases 30%).The median survival time after the therapy was 457.2 d. The one-year survival rate was 70%. Adverse reactions were tolerable.CONCLUSION: Although the prognosis of most patients with Stage IVA HCC by PVTT is poor, our combination chemotherapy may induces long-term survival and is an effective treatment and produced anti-tumor activity with tolerable adverse effects in patients for advanced Stage IVA HCC accompanied by PVTT.     

Improved survival for hepatocellular carcinoma with portal vein tumor thrombosis treated by intra-arterial chemotherapy combining etoposide, carboplatin, epirubicin and pharmacokinetic modulating chemotherapy by 5-FU and enteric-coated tegafur/uracil： A pilot study

AIM： To investigate the poor prognosis of HCC with PVTT, we evaluated the efficacy by a new combination chemotherapy for advanced hepatocellular carcinoma （HCC） with portal vein tumor thrombus （PVTT）.
METHODS： From 2002 to 2007, a total of 10 consecutive patients with Stage IVA HCC accompanied by PVTT were studied prospectively to examine the efficacy of treatment by intra-arterial infusion of a chemotherapeutic agents consisting of etoposide, carboplatin, epirubicin and pharmacokinetic modulating chemotherapy by 5-FU and enteric-coated tegafur/uracil.
RESULTS： The mean course of chemotherapy was 14.4 （range, 9-21） too. One patient showed complete response （CR） with disappearance of HCC and PVI-F after treatment, and the two patients showed partial response （PR）, response rate （CR ＋ PR/All cases 30%）. The median survival time after the therapy was 457.2 d. The one-year survival rate was 70%. Adverse reactions were tolerable.
CONCLUSION： Although the prognosis of most patients with Stage IVA HCC by PVTT is poor, our combination chemotherapy may induces long-term survival and is an effective treatment and produced anti-tumor activity with tolerable adverse effects in patients for advanced Stage IVA HCC accompanied by PVTT.     

Complete remission of multiple hepatocellular carcinomas associated with hepatitis C virus-related, decompensated liver cirrhosis by oral administration of enteric-coated tegafur/uracil

We report a case of complete remission of multiple hepatocellular carcinomas after oral administration of enteric-coated tegafur/uracil. A 77-yr-old woman was diagnosed as having recurrent hepatocellular carcinoma associated with decompensated liver cirrhosis. We administered enteric-coated tegafur/uracil to this patient. After 1 month of oral administration, there was a decrease in tumor markers. An image analysis showed disappearance of hepatocellular carcinoma. No recurrence of the hepatocellular carcinoma was recognized for 18 months up to the time of the patient's death, which was due to massive bleeding from a hemorrhagic rectal ulcer. At autopsy, the tumor lesion had necrotized. Oral administration of enteric-coated granules containing tegafur/uracil may provide an effective treatment for hepatocellular carcinoma.     

Hepatic artery infusion chemotherapy for advanced hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common cancers worldwide. Surgery, percutaneous ablation and liver transplantation are the only curative treatment modalities for HCC. However, the majority of patients have unresectable disease at diagnosis. Therefore, effective treatment options for patients with advanced HCC are required. In advanced HCC, according to current international guidelines, sorafenib, a molecular targeted agent, is the standard treatment. However, alternative treatment modalities are required because of the low response rates and unsuitability of molecular agents in real practice. In various treatment modalities, mostly in Asia, hepatic arterial infusion chemotherapy(HAIC) has been applied to advanced HCC with a view to increasing the therapeutic efficacy. HAIC provides direct drug delivery into the tumor feeding vessels and also minimizes systemic toxicities through a greater first-pass effect in the liver. However, the sample sizes of studies on HAIC have been small and large randomized trials are still lacking. In this article, we describe the treatment efficacy of HAIC for advanced stage HCC and discuss future therapeutic possibilities.     

Role of adjuvant treatment in liver transplantation for advanced hepatocellular carcinoma

The results of liver transplantation for advanced hepatocellular carcinoma have been disappointing because of high recurrence rates, leading to low long-term survival; this indication remains controversial in an era of organ shortage. To continue to offer this treatment possibility, efforts were made to reduce recurrence and improve survival. The first approach is to maintain a strict selection policy excluding patients with extraheptic disease. The second approach is to test the efficacy of perioperative adjuvant therapies in patients selected for transplantation. The reasons for recurrence include: (1) undetected preoperative micrometastases, (2) intraoperative dissemination by surgical manipulation, and (3) acceleration of tumor growth by immunosuppression. Preoperative treatment, which may include systemic chemotherapy or arterial chemoembolization, seems necessary to limit tumor progression during the waiting period. Systemic chemotherapy has been tested pre-, intra-, and postoperatively. It is considered essential postoperatively and should be used as soon as possible after surgery (i.e., in the 1st postoperative week). Several teams have performed pilot studies that included rather limited numbers of patients, and the results were compared with those for historic controls. Published results show that chemoembolization creates tumor necrosis in most instances. This is efficient in limiting tumor progression but the effect on recurrence and survival is unknown. All authors who used postoperative chemotherapy reported improved survival over controls, with 50%—60% 3-year survival and up to 50% 5-year survival. However, recent results suggest that late recurrence may occur. Chemotherapy was usually well tolerated, although leukopenia, sometimes severe, was observed in most patients. The use of granulocyte colony-stimulating factor seems useful to overcome this problem. Perioperative adjuvant treatments seem to prolong survival in patients undergoing liver transplantation for advanced hepatocellular carcinoma, but delayed recurrence remains possible. Further studies are necessary; these should ideally be multicentric, prospective, and randomized.     

Skin toxicities and survival in advanced hepatocellular carcinoma patients treated with sorafenib

Aim: Sorafenib is the first small molecule with significant clinical activity for advanced hepatocellular carcinoma (HCC). However, intolerable adverse events are sometimes observed. On the other hand, it has been reported that some toxicities of molecular targeted drugs, such as skin toxicities and arterial hypertension, are correlated with good clinical outcomes in other cancers. Methods: We identified the correlations between adverse events and prognosis for sorafenib therapy in all patients with HCC treated at the institutions of the Saga Liver Cancer Study Group. The toxicities were assessed using the Common Terminology Criteria for Adverse Events version 4.0. Results: Ninety‐four patients received sorafenib until August 2010. The overall incidence of treatment‐related adverse events was 98% of patients. Skin toxicities, including palmar‐plantar erythrodysesthesia syndrome, rash, pruritus and alopecia, were the most common adverse events and were observed in 58 patients (62%). Hypertension was observed in 23 patients (24%). The median survival time was 12.5 months among the total patients. The patients with skin toxicities showed significantly longer survival than the patients without these toxicities (hazard ratio, 0.449; 95% confidence interval, 0.256–0.786; P = 0.005). Hypertension had no correlation with survival. Skin toxicities were also significant prognostic factors in a multivariate analysis (hazard ratio, 0.522; 95% confidence interval, 0.274–0.997; P = 0.049), along with Child–Pugh class and α‐fetoprotein level. The median development time for skin toxicities was 21 days. Conclusion: Skin toxicities occur commonly at the early phase in patients treated with sorafenib, and could be a promising surrogate marker for the treatment outcome.     

Efficacy of splenectomy for hypersplenic patients with advanced hepatocellular carcinoma

Aim: Chemotherapy for advanced hepatocellular carcinoma (HCC) patients with hypersplenism is generally unsatisfactory, as a lower-dose therapy is usually administered. Splenectomy may represent a better approach to overcoming the complication due to hypersplenism in patients with advanced HCC. This retrospective study was conducted to evaluate whether HCC patients who undergo splenectomy show improved prognosis. Methods: We examined 34 HCC patients. Twenty-two had thrombocytopenia and/or leucopenia and underwent laparoscopic splenectomy. The completion rate of full-dose drug regimens, the response rate, the toxicity of chemotherapy and the cumulative survival rate were compared between the splenectomy and non-splenectomy groups. Results: The response rate and the cumulative survival rate in the splenectomy group were significantly better than that in the non-splenectomy group. Conclusions: Splenectomy is an efficient method for advanced HCC patients with hypersplenism treated by chemotherapy.     

Prognostic determinants for survival after resection/ablation of a large hepatocellular carcinoma

Background:

Liver resection of large hepatocellular carcinomas (HCC), measuring at least 10 cm remains a controversial debate. Multiple studies on HCCs treated with surgical resection and/or ablation had shown variable results with 5-year survival rates ranging from 0% to 54.0%. The aim of this study was to evaluate the survival of patients with HCCs measuring at least 10 cm and to identify the potential prognostic variables affecting the outcome.

Methods:

Retrospective analysis was performed on the prospectively updated HCC database. A total of 44 patients with tumours measuring 10 cm or more were ‘curatively’ treated with surgical resection with or without ablation. Patient demographics, clinical, surgical, pathology and survival data were collected and analysed.

Results:

Thirty-one patients received surgical resection alone. Thirteen other patients were treated with a combination of surgical resection and ablation. The median follow-up duration was 14.5 months. The overall median survival at 1, 3 and 5 years were 66.4%, 38.1% and 27.8%, respectively. The median time to tumour recurrence was 10.7 months and the 1, 3 and 5-year disease-free survival were 49.6%, 23.9% and 19.1%, respectively.Univariate analysis demonstrated cirrhosis, microvascular invasion, poor tumour differentiation and ethnicity to adversely affect survival. For overall survival, only cirrhosis, poor tumour differentiation and ethnicity were significant on multivariate analysis. Portal vein tumour thrombus, microvascular invasion and ethnicity were identified on univariate analysis to significantly affect disease-free survival.

Conclusion:

Surgical treatment offers good survival to patients with large HCCs (≥10 cm). Both cirrhosis and poor tumour differentiation are independent variables prognostic of adverse survival.     

Cyberknife treatment for advanced or terminal stage hepatocellular carcinoma

AIM: To investigate the safety and efficacy of the Cyberknife treatment for patients with advanced or terminal stage hepatocellular carcinoma(HCC).METHODS: Patients with HCC with extrahepatic metastasis or vascular or bile duct invasion were enrolled between May 2011 and June 2015. The Cyberknife was used to treat each lesion. Treatment response scores were based on Response Evaluation Criteria in Solid Tumors v1.1. The trends of tumor markers,including alpha fetoprotein(AFP) and proteins induced by vitamin K absence Ⅱ(PIVKA Ⅱ) were assessed. Prognostic factors for tumor response and tumor markers were evaluated with Fisher's exact test and a logistic regression model. Survival was evaluated with the Kaplan-Meier method and multivariate analysis was performed using the Cox proportional hazards model.RESULTS: Sixty-five patients with 95 lesions were enrolled. Based on the Barcelona Clinic Liver Cancer classification,all patients were either in the advanced or terminal stage of the disease. The target lesions were as follows: 52 were bone metastasis; 9,lung metastasis; 7,brain metastasis; 9,portal vein invasion;4,hepatic vein invasion; 4,bile duct invasion; and 10 other lesion types. The response rate and disease control rate were 34% and 53%,respectively. None of the clinical factors correlated significantly with tumor response. Fiducial marker implantation was associated with better control of both AFP(HR = 0.152; 95%CI: 0.026-0.887; P = 0.036) and PIVKA Ⅱ(HR = 0.035; 95%CI: 0.003-0.342; P = 0.004). The median survival time was 9 mo(95%CI: 5-15 mo). Terminal stage disease(HR = 9.809; 95%CI: 2.589-37.17,P 0.001) and an AFP of more than 400 ng/m L(HR = 2.548; 95%CI: 1.070-6.068,P = 0.035) were associated with worse survival. A radiation dose higher than 30 Gy(HR = 0.274; 95%CI: 0.093-0.7541,P = 0.012) was associated with better survival. In the 52 cases of bone metastasis,36 patients(69%) achieved pain relief. One patient had cerebral bleeding and another patient had an esophageal ulcer after treatment.CONCLUSION: The Cyberknife can be safely administered to patients with advanced or terminal stage HCC. High AFP levels were associated with worse survival,but a higher radiation dose improved the survival.     

Prognostic factors in patients with advanced hepatocellular carcinoma receiving hepatic arterial infusion chemotherapy

Background The prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor. We aimed to clarify the prognostic factors in patients with advanced HCC receiving hepatic arterial infusion chemotherapy (HAIC).Methods Forty-four HCC patients were treated with HAIC, using low-dose cisplatin (CDDP) and 5-fluorouracil (5-FU) with/without leucovorin (or isovorin). Of these 44 patients, 15 received low-dose CDDP and 5-FU, and 29 received low-dose CDDP, 5-FU, and leucovorin or isovorin. Prognostic factors were evaluated by univariate and multivariate analyses of patient and disease characteristics.Results Of all patients, 5 and 12 patients respectively, exhibited a complete response (CR) and a partial response (PR) (response rate, 38%). The response rate (48.3%) in the low-dose CDDP and 5-FU with leucovorin/isovorin group was significantly better than that (20%) in the low-dose CDDP and 5-FU group (P = 0.002). The 1-, 2-, 3-, and 5-year cumulative survival rates of the 44 patients were 39%, 18%, 12%, and 9%, respectively. The regimen using low-dose CDDP and 5-FU with leucovorin/isovorin tended to improve survival rates (P = 0.097). Univariate and multivariate analyses showed the same variables—the Child-Pugh score (P = 0.013, P = 0.018), -fetoprotein (AFP) level (P = 0.010, P = 0.009), and therapeutic effect after HAIC (P = 0.003, P = 0.01), respectively, to be significant prognostic factors.Conclusions Patients who had advanced HCC with favorable hepatic reserve capacity and a lower AFP level were suitable candidates for HAIC. Moreover, the regimen using low-dose CDDP and 5-FU with leucovorin/isovorin may be suitable for advanced HCC patients, because of the improvement in the response rate and survival compared with the low-dose CDDP and 5-FU regimen without leucovorin/isovorin.     

Phase II study of hepatic arterial infusion of a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma.

Aim: Intra-arterial cisplatin appears to have high therapeutic efficacy, but this has not been studied in detail. Accordingly, we developed a fine-powder cisplatin formulation and tested it in advanced hepatocellular carcinoma (HCC) patients in an open-label, uncontrolled study in which 27 institutions participated. Methods: The patients in this study had inoperable advanced HCC without extrahepatic metastases. All received two infusions of high-concentration cisplatin (1.43 mg/mL) via the hepatic artery at a dose of 65 mg/m(2), with an intervening 4-6 week interval. Results: Cisplatin efficacy and safety were assessed in 80 patients. We found partial responses in 27 cases, no change in 37, and progressive disease in 11 (five were not evaluated). The overall response rate was 33.8%. The 1-year survival rate was 67.5% and the 2-year survival rate was 50.8%. Severe adverse effects (>/=grade 3) included anorexia in 22.5%, vomiting in 6.3%, abdominal pain in 1.3%, thrombocytopenia in 25%, neutropenia in 13%, leukopenia in 1.3%, hypochromia in 1.3%, elevated serum aspartate aminotransferase in 32.5%, elevated serum alanine aminotransferase in 11.3%, elevated serum bilirubin in 3.8%, decreased serum albumin in 1.3%, elevated serum alkaline phosphatase in 1.3%, elevated gamma-glutamyltranspeptidase in 3.8%, and elevated serum creatinine in 2.5%. Death from myocardial infarction occurred as an incidental event in one case, and no other life-threatening, adverse events were observed. Conclusion: Although intra-arterial cisplatin has substantial local and systemic toxicity, high therapeutic efficacy suggests the potential usefulness of this agent in the treatment of advanced HCC.     

Palliative chemotherapy for patients with recurrent hepatocellular carcinoma after liver transplantation

Background and Aim:  The majority of patients with post-transplantation recurrence of hepatocellular carcinoma (HCC) have extrahepatic metastases and multifocal lesions. Therefore, they have few treatment options and may not be amenable for local therapy. The safety and efficacy of palliative chemotherapy in this population has not been reported.
Methods:  We retrospectively analyzed 24 patients who received palliative chemotherapy for recurrent HCC after liver transplantation between January 2000 and December 2006 at the Seoul National University Hospital.
Results:  The mean age of patients was 55 years (range 42–70 years). The most commonly used chemotherapeutic regimens were 5-fluorouracil (5-FU)/cisplatin ( n  = 9), which was followed by capecitabine/cisplatin ( n  = 4), 5-FU/mitomycin ( n  = 3), 5-FU/oxaliplatin ( n  = 1), S-1 ( n  = 1), capecitabine ( n  = 1), gemcitabine/oxaliplatin ( n  = 1), gemcitabine/cisplatin ( n  = 1), 5-FU/interferon ( n  = 1) and sorafenib ( n  = 2). The Grade 3/4 hematological toxicity was neutropenia (29.1%), thrombocytopenia (20.9%) and anemia (20.9%). There were no cases of neutropenic fever or bleeding events. The Grade 3/4 non-hematological toxicity included elevation of liver transaminase (8.4%) and jaundice (16.7%). No patient showed an objective response and four patients (16.7%) demonstrated stable disease. The median time to progression was 7.0 weeks (95% CI 5.8–8.2) and the median overall survival was 16.6 weeks (95% CI 10.1–23.1).
Conclusion:  Palliative chemotherapy can be delivered to patients with recurrent HCC after liver transplantation with tolerable toxicity. However, the efficacy to date is not satisfactory. Therefore, more effective systemic chemotherapy is needed for this group of patients.     

Efficacy and safety of epirubicin and etoposide combination chemotherapy in advanced hepatocellular carcinoma: a retrospective analysis

Background and Aim: Systemic treatments of advanced hepatocellular carcinoma (AHCC) have offered marginal clinical benefits. Recently, Italian investigators reported that etoposide and epirubicin combination (EE) chemotherapy was highly active against AHCC, with a response rate of 39% and a median overall survival (OS) of 10 months. We report our efficacy and safety results of EE in clinical practice. Methods: Between December 1999 and October 2005, 35 patients with AHCC and fitting the preset eligibility criteria were treated with EE. Twenty‐eight patients (80%) had liver disease associated with hepatitis B virus (HBV) and 26 (74%) had a prior history of transarterial chemoembolization (TACE) using cisplatin. The EE chemotherapy consisted of epirubicin 40 mg/m² on day 1 and etoposide 120 mg/m² on days 1, 3 and 5 every 4 weeks. Results: A total of 102 chemotherapy cycles were administered, with a median of two cycles per patient (range one to eight cycles). Two patients had a partial response and nine had stable disease, with a tumor control rate of 32% (95% CI 17–48). The median progression‐free survival (PFS) was 2.1 months (95% CI 1.8–2.4) and the median OS was 6.4 months (95% CI 4.4–8.5). There was a tendency toward improved PFS in patients seronegative for HBsAg and peritoneal seeding (P = 0.06 and P = 0.054, respectively). Overall survival was significantly better in patients without HBsAg and Cancer Liver Italian Program (CLIP) score 0–1 (P = 0.024 and P = 0.033, respectively). The main toxicities were hematological events, including grade 3/4 neutropenia in 29% and febrile neutropenia in 11% of patients. Conclusion: Treatment with EE showed minimal antitumor activity with acceptable toxicity in HBV‐associated AHCC, especially in patients pretreated with TACE.     

替吉奥联合经肝动脉化疗栓塞治疗中晚期肝细胞癌的疗效观察

目的对比观察经肝动脉栓塞化疗(TACE)单用或联合替吉奥治疗中晚期肝细胞癌(HCC)的疗效。方法将2009年8月-2010年10月本院收治的无法手术切除的中晚期HCC患者60例随机分为2组,每组30例。治疗组采用TACE联合替吉奥口服,对照组仅行TACE。观察2组的有效率、疾病控制率、生存率以及不良反应情况。计数资料采用χ2检验;生存分析运用Logrank检验。结果有效率:治疗组63.3%,对照组33.3%,差异有统计学意义(χ2=5.406,P=0.020);疾病控制率:治疗组86.7%,对照组43.3%,差异有统计学意义(χ2=12.308,P=0.000)。1年生存率:治疗组77.3%,对照组51.5%,差异有统计学意义(χ2=4.593,P=0.032);2年生存率:治疗组34.8%,对照组10.4%,差异有统计学意义(χ2=4.812,P=0.028)。治疗组、对照组不良反应轻微,主要是恶心呕吐、腹泻和骨髓抑制,为1、2级,对症治疗可缓解,两组比较差异无统计学意义(P0.05)。结论替吉奥联合TACE术对中晚期HCC有一定的治疗价值,值得进一步探讨。