s-1-(combination) and Carcinoma--Hepatocellular

The most common sites of recurrence after liver transplantation for hepatocellular carcinoma (HCC) have been reported to be the liver, lung, bone, and adrenal glands, but there have also been many reports of cases of multiple recurrence. The prognosis after recurrence is poor, with reported median survival after recurrence of HCC ranging from 9 to 19 months. Here, we report a case of long-term survival after recurrence of pharyngeal metastasis following living-donor liver transplantation (LDLT) for HCC within the Milan criteria, by resection of the metastatic region and cervical lymph node dissection.. A 47-year-old man with a Model End-stage Liver Disease (MELD) score of 11 underwent LDLT for HCC within the Milan criteria for liver cirrhosis associated with hepatitis B virus infection, with his 48-year-old elder brother as the living donor. One year and 10 months after liver transplantation, he visited a nearby hospital with a chief complaint of discomfort on swallowing. A pedunculated polyp was found in the hypopharynx, and biopsy revealed HCC metastasis. We performed pharyngeal polypectomy. Two years later, cervical lymph node metastasis appeared, and neck lymph node dissection was performed. Although recurrence subsequently occurred three times in the grafted liver, the patient is still alive 12 years and 10 months after recurrence of pharyngeal metastasis. He is now a tumor-free outpatient taking sorafenib.. It is necessary to recognize that the nasopharyngeal region is a potential site of HCC metastasis. Prognostic improvement can be expected with close follow-up, early detection, and multidisciplinary treatment, including radical resection.

Topics: Allografts; Biopsy; Carcinoma, Hepatocellular; Catheter Ablation; Chemotherapy, Adjuvant; Drug Combinations; End Stage Liver Disease; Hepatectomy; Humans; Liver; Liver Neoplasms; Liver Transplantation; Living Donors; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Pharyngeal Neoplasms; Pharynx; Positron Emission Tomography Computed Tomography; Sorafenib; Tegafur; Treatment Outcome

A 57-year-old man was admitted to our hospital for hepatocellular carcinoma (HCC). He underwent right hepatectomy with preoperative adjuvant transcatheter arterial chemoembolization. A follow-up computed tomography scan revealed a single pulmonary metastasis. After 2 courses of S-1 administration, he underwent left lower lobectomy, and a pathological specimen taken at the time was diagnosed as pulmonary metastasis of HCC. Although adjuvant chemotherapy with S-1 resulted in relapse-free survival for 2 years after pulmonary resection, he was found to have recurrence of liver cancer and underwent partial hepatectomy. This case report suggests that surgical resection and S-1 administration would be a useful treatment option for hepatocellular carcinoma with distant metastasis.

Topics: Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Combined Modality Therapy; Drug Combinations; Hepatectomy; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Oxonic Acid; Tegafur

The prognosis for hepatocellular carcinoma with extrahepatic metastasis or vascular invasion is very poor. We treated a case successfully by combining chemotherapy and liver resection for hepatocellular carcinoma with multiple pulmonary metastases and vascular invasion. A 56-year-old man who complained of abdominal pain in his right side was transported to the hospital by ambulance. Because CT scan revealed the rupture of hepatocellular carcinoma, he underwent emergency transcatheter arterial embolization (TAE). A close examination revealed tumor thrombus in the inferior vena cava and posterior segment of the portal vein branch, with multiple pulmonary metastases. We conducted right hepatic lobectomy and removal of the inferior vena cava tumor thrombus. After the operation, pulmonary metastatic lesions gradually grew larger, so the oral administration of S-1 at 120 mg per day was started. At the end of the first course, the CT scan revealed that multiple pulmonary metastases were significantly reduced, and treatment was maintained until the end of 4 courses. A prolongation of survival could be expected by combining systemic chemotherapy and liver resection for advanced hepatocellular carcinoma such as the present case.

Topics: Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Combined Modality Therapy; Drug Combinations; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neovascularization, Pathologic; Oxonic Acid; Prognosis; Tegafur

Unresectable advanced hepatocellular carcinoma is a heterogeneous disease, for which sorafenib is the first targeted agent approved for first-line therapy, and treatment options for patients with sorafenib-refractory advanced hepatocellular carcinoma are limited. We assessed the efficacy and safety of S-1, a chemotherapeutic agent based on fluorouracil, in patients with sorafenib-refractory advanced hepatocellular carcinoma.. We did a randomised, double-blind, placebo-controlled, phase 3 study done at 57 sites in Japan. Patients with advanced hepatocellular carcinoma who were ineligible for surgical or local-regional therapy and judged refractory to sorafenib (ie, had progressed on sorafenib or had discontinued sorafenib because of adverse events) were randomly assigned (2:1) to receive oral S-1 (weight-banded 80 mg/m. Between Oct 26, 2009, and Aug 22, 2012, we screened 399 patients. 65 patients were excluded due to not meeting criteria (n=61), declining to participate (n=3), or other reasons (n=1). 334 patients were randomly assigned to receive either S-1 (n=223) or placebo (n=111). One patient in the S-1 group did not receive treatment, and was thus excluded from analyses. At data cutoff, median follow-up was 32·4 months (IQR 24·0-34·7) in the S-1 group and 32·9 months (23·7-39·5) in the placebo group. Median overall survival was 11·1 months (95% CI 9·7-13·1) in the S-1 group and 11·2 months (9·2-12·8) in the placebo group (hazard ratio 0·86, 95% CI 0·67-1·10; p=0·220). The most frequently reported adverse events were skin hyperpigmentation (123 [55%] of 222 patients in the S-1 group vs nine [8%] of 111 patients in the placebo group), decreased appetite (104 [47%] vs 21 [19%]), fatigue (102 [46%] vs 20 [18%]), diarrhoea (77 [35%] vs 14 [13%]), and increased blood bilirubin (77 [35%] vs 14 [13%]). Serious adverse events were reported in 90 (41%) of 222 patients in the S-1 group and 24 (22%) of 111 patients in the placebo group. Five treatment-related deaths were reported in the S-1 group.. S-1 did not prolong overall survival in patients with sorafenib-refractory advanced hepatocellular carcinoma. Further research is needed to identify subgroups of patients who might benefit from S-1.. Taiho Pharmaceuticals.

Topics: Aged; Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Diarrhea; Double-Blind Method; Drug Combinations; Fatigue; Feeding and Eating Disorders; Female; Humans; Hyperbilirubinemia; Hyperpigmentation; Liver Neoplasms; Male; Middle Aged; Oxonic Acid; Survival Analysis; Tegafur

Sorafenib is the sole molecular-targeted agent showing a survival benefit in patients with advanced hepatocellular carcinoma (HCC). We evaluated the tolerability and effectiveness of a combination of S-1 with sorafenib in patients with advanced HCC.. S-1 was administered during days 1-14 and sorafenib was administered every day. This treatment was repeated every 21 days. In phase I, we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). The dose of each drug was planned as follows: cohort 1: S-1 48 mg/m(2)/day and sorafenib 400 mg/day, cohort 2a: S-1 48 mg/m(2)/day and sorafenib 800 mg/day, cohort 2b: S-1 64 mg/m(2)/day and sorafenib 400 mg/day, cohort 3: S-1 64 mg/m(2)/day and sorafenib 800 mg/day, and cohort 4: S-1 80 mg/m(2)/day and sorafenib 800 mg/day. In phase II, the patients were treated at the MTD to evaluate safety and efficacy.. Nineteen patients were enrolled in phase I. One of the six patients in cohort 1 and one of the six patients in cohort 3 experienced DLT. None of the three patients in cohort 2a experienced DLT and three of the four patients in cohort 4 experienced DLT. Therefore, cohort 3 was considered the MTD. Subsequently, 26 patients were enrolled in phase II. The most common grade 3/4 toxicities were an increase of aspartate aminotransferase (38.5 %), thrombocytopenia (23.1 %), neutropenia (19.2 %), hyperbilirubinemia (15.4 %), an increase of alanine aminotransferase (15.4 %), hyponatremia (11.5 %), rash (11.5 %), and hypophosphatemia (11.5 %). Sudden death occurred in one patient (3.8 %). A patient (3.8 %) had a partial response, 15 (57.7 %) had stable disease, and 10 (38.5 %) had progressive disease. The median times to progression and overall survival were 2.4 and 10.5 months, respectively.. The MTD of S-1 and sorafenib in patients with advanced HCC was 64 mg/m(2)/day and 800 mg/day, respectively. This dose/regimen demonstrated substantial clinical activity among patients with advanced HCC.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Combinations; Female; Humans; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Niacinamide; Oxonic Acid; Phenylurea Compounds; Prospective Studies; Sorafenib; Tegafur

In Japan, transarterial infusion chemotherapy using cisplatin (CDDP-TAI) is frequently used for advanced hepatocellular carcinoma (HCC). Moreover, oral chemotherapy with S-1, an oral fluoropyrimidine derivative, has also elicited promising responses in HCC patients. We determined the recommended dosage for CDDP-TAI plus S-1 combination therapy for advanced HCC.. Twelve Child-Pugh class A or B patients with advanced HCC who met the eligibility criteria were enrolled in this phase I trial. Patients received CDDP-TAI (infusion, day 1) plus S-1 (oral administration, days 1-21) every 5 weeks until disease progression.. Cisplatin (65 mg/m(2)) was administered with S-1 at 50 mg · m(-2) day-1 (level 1, 3 patients), 60 mg · m(-2) day-1 (level 2, 3 patients), or 80 mg · m(-2) day-1 (level 3, 6 patients). The total number of treatment courses was 25 (median, 2 courses/patient; range, 1-6 courses). Dose-limiting toxicity was not observed in any patient at any level; therefore, the recommended dosage for cisplatin and S-1 in combination was level 3. Grade 3 adverse events were elevated alanine aminotransferase levels (2 patients), elevated aspartate aminotransferase levels (2 patients), anemia (1 patient), and decreased platelet counts (1 patient). Median progression-free survival and overall survival were 73 days and 328 days, respectively. The disease control rate was 58% (7/12); 17% (2/12) of patients achieved partial response and 42% (5/12) achieved stable disease. CDDP-TAI plus S-1 is safe for the treatment of HCC.. The recommended dosage for further evaluation of this combination therapy in phase II studies is 65 mg/m(2) CDDP and 80 mg/m(2) S-1.. UMIN; number: UMIN000003113.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Disease-Free Survival; Drug Combinations; Female; Humans; Japan; Liver Neoplasms; Male; Middle Aged; Oxonic Acid; Tegafur; Treatment Outcome

We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-β, and S-1, an oral fluoropyrimidine, in patients with advanced hepatocellular carcinoma (HCC) based on its associated dose-limiting toxicity (DLT) frequency. We also determined the safety, tolerability, pharmacokinetics (PK), and efficacy of the combination treatment.. Patients without any prior systemic therapy received 400 mg/day TSU-68 orally and 80 mg/day (level 1) or 100 mg/day (level 2) S-1 for 4 or 2 weeks followed by a 2- or 1-week rest period (groups A and B, respectively). According to the treatment, patients progressed from level 1B to level 2A, then level 2B. Safety and response rates were assessed.. Eighteen patients were enrolled. Two patients at levels 1B and 2A but none at level 2B showed DLTs. The common adverse drug reactions were a decrease in hemoglobin levels, hypoalbuminemia, and anorexia, which were mild in severity (grades 1-2). PK data from levels 1B and 2A indicated that the area under the curve for TSU-68 and 5-fluorouracil was unlikely to be affected by the combination treatment. Response rate, disease control rate, median time to progression, and median overall survival were 27.8 %, 61.1 %, 5.3 months, and 12.8 months, respectively.. The recommended dose for advanced HCC should be 400 mg/day TSU-68 and 100 mg/day S-1 for 4 weeks followed by 2-week rest.

Topics: Administration, Oral; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Combinations; Female; Humans; Indoles; Liver Neoplasms; Male; Middle Aged; Oxindoles; Oxonic Acid; Propionates; Pyrroles; Tegafur; Treatment Outcome

Sorafenib is a multi-kinase inhibitor, which was approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). We conducted a phase 1 study of sorafenib plus S-1 in patients with advanced HCC.. We designed to escalate S-1 at 4 different dose levels with fixed dose of sorafenib. Four dose levels were as follows: level 1, D1-14 S-1 50 mg/m(2)/day + D1-21 sorafenib 400 mg bid; level 2, D1-14 S-1 60 mg/m(2)/day + D1-21 sorafenib 400 mg bid; level 3,, D1-14 S-1 70 mg/m(2)/day + D1-21 sorafenib 400 mg bid; level 4, D1-14 S-1 80 mg/m(2)/day + D1-21 sorafenib 400 mg bid. The treatment was repeated every 3 weeks.. From August 2009 to July 2010, 20 patients with advanced HCC were enrolled. The median age was 48 years (range, 29-74). Eighteen (90%) patients had hepatitis B viral infection and 19 (95%) patients were rated as Child-Pugh class A. The dose-limiting toxicities were grade 4 infection and thrombocytopenia. After a median follow-up duration of 8.6 months (range, 3.7-14.2 months), median PFS was 3.9 months (95% CI, 0.8-7.0 months) and median OS was 10.4 months (95% CI, 0-22.4 months). In pharmacokinetic analysis, there was no statistically significant drug interaction between sorafenib and S-1.. The combination of sorafenib and S-1 showed tolerable toxicity profile and modest clinical efficacy in patients with advanced HCC. The recommended dose of sorafenib and S-1 was 400 mg twice daily and 40 mg/m(2) twice daily, respectively.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Hepatocellular; Drug Combinations; Female; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Niacinamide; Oxonic Acid; Phenylurea Compounds; Pyridines; Sorafenib; Tegafur; Treatment Outcome

S-1, an oral fluoropyrimidine derivative, has been shown to be clinically effective against various solid tumors, and preclinical studies have demonstrated activity against hepatocellular carcinoma. We conducted a phase I/II study in patients with advanced hepatocellular carcinoma to examine the pharmacokinetics, recommended dose, safety and efficacy of S-1. In phase I, the administered dose of S-1 was approximately 64 mg/m(2) per day in three patients (level 1) and approximately 80 mg/m(2) per day in six patients (level 2). There was no dose-limiting toxicity at level 1, but two patients had dose-limiting toxicity at level 2 (grade 3 anorexia and grade 2 rash requiring eight or more consecutive days of rest). The recommended dose was finally estimated to be 80 mg/m(2) per day. There were no significant differences in the pharmacokinetics of S-1 between patients with Child-Pugh A and those with B. In phase II, five of 23 patients (21.7%) had partial responses. The median progression-free survival and overall survival were 3.7 and 16.6 months, respectively. The most common toxicities of grade 3 or 4 were elevated serum aspartate aminotransferase levels, hypochromia and thrombocytopenia. In conclusion, S-1 showed an acceptable toxicity profile and promising antitumor activity for hepatocellular carcinoma, warranting further evaluation in randomized clinical trials.

Topics: Aged; Antimetabolites, Antineoplastic; Area Under Curve; Carcinoma, Hepatocellular; Disease-Free Survival; Drug Combinations; Female; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Oxonic Acid; Tegafur

We report here a rare case of a patient with recurrent intrahepatic cholangiocarcinoma that was treated with simple S-1 chemotherapy, who is still alive 6 years later. A liver tumor was identified in segments 5 to 6 in a 60-year-old male asymptomatic hepatitis B carrier. The tumor was diagnosed as hepatocellular carcinoma by MRI and CT. However, following its resection by extended posterior segmentectomy of the liver, pathological findings identified it as an intrahepatic cholangiocarcinoma. The surgical margin was cancer-negative. No additional adjuvant chemotherapy was administered because of the patient 's impaired renal function. When tumor recurrence was found by MRI 30 months later, an additional liver resection was planned but a laparotomy was eventually performed. This was because intraoperative findings revealed Glissonian sheath invasion with involvement of the umbilical portion. S-1 treatment(100mg/body/day)was started. Although the dose had to be reduced(mostly 75mg/body/day)due to hyperbilirubinemia and there were some interruptions in the regimen, in total of 42 g of S-1 was administered. The patient is currently still alive, 6 years after the detection of the tumor recurrence. This represents a rare case in patients with intrahepatic cholangiocarcinoma.

Topics: Antimetabolites, Antineoplastic; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Cholangiocarcinoma; Diagnosis, Differential; Drug Combinations; Hepatectomy; Humans; Male; Middle Aged; Oxonic Acid; Recurrence; Tegafur; Time Factors

We report here an experience treating a patient who developed gastric cancer at the same time as a multifocal intrahepatic recurrence of hepatocellular carcinoma (HCC). The patient was a 76-year-old woman who underwent partial liver resection after diagnosis of HCC in August 2008. Histopathological examination revealed moderately differentiated hepatocellular carcinoma and stage III pathology. Six months following surgery, an upper gastrointestinal endoscopy revealed a typeIIa+IIc gastric tumor in the angle of the stomach, which was pathologically diagnosed as adenocarcinoma(por2/sig) in the biopsy. Simultaneously, abdominal CT scan revealed multifocal intrahepatic recurrence of HCC, so Lip-TACE as performed. Eight days after TACE, S-1 (80 mg/body) was initiated. About one month after TACE, abdominal CT scan revealed multiple new hepat- ic lesions. The patient was repeatedly treated with a combination of Lip-TACE on day 1 and S-1 80 mg/body/day, administered on days 8 to 35 for 28 days, followed by a 7 day interval as 1 course. After 5 courses of medication of S-1, liver function had deteriorated and thrombocytopenia occurred. Although there was no progression of gastric cancer, medication of S-1 was discontinued. Lip-TACE was performed nine times. About one year after the initial TACE, the patient was admitted to our hospital in order to control ascites, 3 days after admission, she suffered a cerebral infarction and died 3 days later.

Topics: Aged; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Drug Combinations; Fatal Outcome; Female; Hepatectomy; Humans; Liver Neoplasms; Oxonic Acid; Recurrence; Stomach Neoplasms; Tegafur

Sorafenib and conventional systemic cytotoxicity chemotherapy are currently being used in parallel for the patients with advanced hepatocellular carcinoma (HCC). While sorafenib has been proven to improve the prognosis in patients with this malignant disease, however, the outcome of other newly developed systemic chemotherapeutic regimens remains controversial. We evaluated the outcome and safety of patients treated with the SOX regimen (oxaliplatin + S-1) and those treated with sorafenib in a single-center cohort. This retrospective study involved a total of 46 patients with advanced HCC, 22 of which were treated with SOX regimen (oxaliplatin [130 mg/m2] on day 1 and S-1 [80 mg/m2/day] on day 1-14, every 3 weeks), and 24 were daily treated with sorafenib (400 mg, b.i.d.). The median progression-free survival was 3.6 months (95% confidence interval [CI], 1.7 to 5.6) with SOX and 1.7 months (95% CI, 1.5 to 1.9) with sorafenib, respectively (P = 0.444). The median overall survival in SOX and sorafenib group was 7.6 months (95% CI, 4.3 to 10.9) and 4.7 months (95% CI, 2.7 to 7.3), respectively (P = 0.246). Response rate was 22.2% with SOX and 5.6% with sorafenib, respectively (P = 0.154). The frequent side effects in SOX-treated patients were thrombocytopenia, elevation of transaminase levels and neuropathy, whereas hand-foot syndrome, diarrhea and pruritus were common in sorafenib-treated patients. These preliminary results suggest that the SOX regimen may serve as an effective treatment for patients with advanced HCC, and the treatment-related toxicities were generally well-tolerated.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Disease-Free Survival; Drug Combinations; Female; Humans; Liver Neoplasms; Male; Middle Aged; Niacinamide; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Phenylurea Compounds; Sorafenib; Tegafur; Treatment Outcome

Sorafenib and S-1 (one mixed formulation containing 5-FU prodrug and dihydropyrimidine dehydrogenase inhibitor) were two effective agents against hepatocellular carcinoma (HCC), but whether they had synergistic effects remained unclear. The present study aimed at evaluating their synergistic effects against HCC and its mechanisms.. Inhibitory effects of sorafenib, 5-FU and their combination on HCC cells PLC/PRF/5 and SK-HEP-1 were evaluated. Expressions of transcription factor E2F-1 and its downstream thymidylate synthetase (TS) in the treated cells were determined using real-time PCR and Western blot. In vivo anti-tumoral efficacy of S-1 plus sorafenib on HCC was evaluated in NOD/SCID mice. E2F-1 and TS expressions in tumors were determined by immunohistochemical staining.. Sorafenib inhibited growth of HCC cells in dose-dependent manner, with IC50 of 5.4 ± 0.3 μmol/L for PLC/PRF/5 and 5.3 ± 0.5 μmol/L for SK-HEP-1. Sorafenib (1 μmol/L) enhanced inhibitory efficacy of 5-FU on HCC cells in vitro, dropping IC50 of 5-FU from 167.7 ± 12.1 to 105.4 ± 8.4 μmol/L for PLC/PRF/5 and 115 ± 10.2 to 82 ± 7.4 μmol/L for SK-HEP-1 (both p < 0.01). Sorafenib downregulated E2F-1 and TS expressions on HCC cells, and its combination with 5-FU yielded a synergistic downregulation of TS expression on HCC cells. In NOD/SCID mice with subcutaneously inoculated HCC, sorafenib combined with S-1 yielded greater inhibition on tumor growth and remarkable TS suppression when compared with sorafenib or S-1 alone (all p < 0.05).. Sorafenib enhanced therapeutic efficacy of 5-FU/S-1 against HCC through downregulation of E2F-1 and TS expressions. Sorafenib combined with S-1 might represent as valuable therapeutic regimen against HCC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Dose-Response Relationship, Drug; Down-Regulation; Drug Combinations; Drug Synergism; E2F1 Transcription Factor; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Liver Neoplasms; Male; Mice; Mice, Inbred NOD; Mice, SCID; Niacinamide; Oxonic Acid; Phenylurea Compounds; Real-Time Polymerase Chain Reaction; Sorafenib; Tegafur; Thymidylate Synthase

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.

Topics: Adult; Antimetabolites, Antineoplastic; Brain Neoplasms; Carcinoma, Hepatocellular; Combined Modality Therapy; Drug Combinations; Hepatectomy; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Oxonic Acid; Tegafur

We describe our experience with a patient who had advanced hepatocellular carcinoma (HCC) that responded markedly to treatment with the oral fluoropyrimidine anticancer drug S-1 (120mg/day/body bid on day 1 through 28 followed by a 14-day recovery period). The patient was enrolled in a phase I / II study designed to evaluate the safety and efficacy of S-1 in patients with advanced HCC. The best overall efficacy was confirmed to be a partial response (PR). After a total of 6 courses of treatment given on an outpatient basis, the target lesion volume decreased by 73. 8%. With regard to adverse events, the patient did not develop Grade 3 or higher adverse drug reactions. Therefore, the patient continued outpatient treatment for a total of 6 courses. The duration of survival from the start of treatment until death was 820 days, suggesting that S-1 is moderately effective and well tolerated in patients with advanced HCC.

Topics: Aged; Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Drug Combinations; Fatal Outcome; Hepatitis C; Humans; Liver Neoplasms; Male; Neoplasm Staging; Oxonic Acid; Tegafur

A 59-year-old woman was admitted to our hospital for treatment of a right humerus fracture. The patient was diagnosed with hepatocellular carcinoma during work-up for hepatic dysfunction. A diffusely spreading tumor was observed from the right lobe to the medial segment of the liver, and a portal vein tumor thrombus filled the right branch of the portal vein and extended into the main trunk, accompanied by cavernous transformation (Vp4). A multidisciplinary treatment regimen including surgical intervention was planned because the patient desired aggressive treatment. Surgical intervention included a right hepatic trisegmentectomy and excision of the portal vein tumor thrombus. The patient experienced an uneventful postoperative course with no signs of hepatic failure and received transcatheter arterial chemoembolization for residual tumor in the hepatic S1 and S2 regions on post-operative day 15. Beginning at 2 months after the operation, the patient was given 3 courses of intraarterial 5-fluorouracil combined with subcutaneous interferon-α therapy. She tested negative for tumor markers at 3 months post-operatively and was noted to have no viable tumors on computed tomography scans at 5 months post-operatively. However, there was a rapid recurrence with deterioration of her general condition at 8 months after the operation, and she died of recurrence the following month. Hepatocellular carcinoma complicated by portal vein tumor thrombus has an unfavorable prognosis, but it was considered feasible to improve this patient's outcome by giving priority to active surgical resection of the tumors including the tumor thrombus, and by undertaking multidisciplinary therapeutic measures.

Topics: Carcinoma, Hepatocellular; Combined Modality Therapy; Drug Combinations; Fatal Outcome; Female; Hepatectomy; Humans; Interferon-alpha; Liver Neoplasms; Middle Aged; Oxonic Acid; Recurrence; Tegafur

Combination therapy with the oral fluoropyrimidine anticancer drug S1 and interferon is reportedly effective for the treatment of advanced hepatocellular carcinoma (HCC), but selection criteria for this therapy have not been clarified. In this study, we attempted to identify factors predicting the effectiveness of this combination therapy.. Pathological specimens of HCC were collected before treatment from 31 patients with advanced HCC who underwent S1+ pegylated-interferon (PEG-IFN) α-2b therapy between January 2007 and January 2009. In these pathological specimens, the expression levels of CD133, thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and interferon-receptor 2 (IFNR2) proteins were determined by Western blot assay. The presence or absence of p53 gene mutations was determined by direct sequencing. The relationships between these protein expression levels and the response rate (RR), progression-free survival (PFS), and overall survival (OS) were evaluated.. The CD133 protein expression level was significantly lower in the responder group than in the nonresponder group. Comparing the PFS and OS between high- and low-level CD133 expression groups (n = 13 and 18, respectively) revealed that both parameters were significantly prolonged in the latter group. The expression levels of TS, DPD, and IFNR2 protein and the presence of p53 gene mutations did not correlate with the RR.. CD133 was identified as a predictor of the therapeutic effect of S1+ PEG-IFN α-2b therapy against advanced HCC.

Topics: AC133 Antigen; Adult; Aged; Aged, 80 and over; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Hepatocellular; Dihydrouracil Dehydrogenase (NADP); Disease-Free Survival; Drug Combinations; Female; Genes, p53; Glycoproteins; Humans; Interferon alpha-2; Interferon-alpha; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Mutation; Oxonic Acid; Peptides; Polyethylene Glycols; Predictive Value of Tests; Receptors, Interferon; Recombinant Proteins; Survival Rate; Tegafur; Thymidylate Synthase; Treatment Outcome

Metronomic chemotherapy involves frequent, regular administration of cytotoxic drugs at nontoxic doses, usually without prolonged breaks. We investigated the therapeutic efficacies of metronomic S-1, an oral 5-fluorouracil prodrug, and vandetanib, an epidermal growth factor receptor and vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, in models of hepatocellular carcinoma (HCC).. We compared anti-HCC effects and toxicity in the six treatment groups: control (untreated), maximum tolerated dose (MTD) S-1, metronomic S-1, vandetanib, MTD S-1 with vandetanib, and metronomic S-1 with vandetanib. Tumor microvessel density (MVD) and tumor apoptosis were evaluated by immunohistochemistry. The expression of VEGF and thrombospondin-1, an endogenous inhibitor of angiogenesis, was analyzed by Western blot.. Metronomic S-1 significantly inhibited tumor growth, which was enhanced by combination with vandetanib. With respect to toxicities, MTD S-1 caused severe body weight loss and myelosuppression, whereas metronomic S-1 did not cause any overt toxicities. Moreover, metronomic S-1 or metronomic S-1 with vandetanib prolonged survival, the latter treatment providing the greatest benefit. Metronomic S-1 and metronomic S-1 with vandetanib decreased MVDs and increased apoptosis in tumor tissues. The expression of VEGF in tumor tissues was upregulated by vandetanib and metronomic S-1 with vandetanib, whereas the expression of thrombospondin-1 was upregulated by metronomic S-1 and metronomic S-1 with vandetanib.. Metronomic S-1 with an antiangiogenic agent seems to be an effective and safe therapeutic strategy for HCC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Drug Combinations; ErbB Receptors; Fluorouracil; Humans; Immunoenzyme Techniques; Lung Neoplasms; Male; Maximum Tolerated Dose; Mice; Mice, Inbred BALB C; Mice, Nude; Oxonic Acid; Piperidines; Quinazolines; Tegafur; Tumor Cells, Cultured

The patient was a 54-year-old man. He was an HBV carrier, and hepatocellular carcinoma (HCC) was detected for the first time in 2000. An operation was performed, but HCC recurred. After repeating the operation and transarterial chemo-embolization (TACE) for the recurrent HCC, a tumor was found in January 2009 on the ventral side of the right kidney, and we thought it was a retroperitoneal metastasis of HCC or peritoneal dissemination. He was enrolled in a trial of systemic chemotherapy, called "S-1 monotherapy for extrahepatic metastasis of HCC", but the tumor seemed progressive. Since he showed no other lesion, he was indicated for surgical resection. Intraoperatively, the tumor was localized between the duodenum and the right kidney, and was covered by the retroperitoneum. Pathological examination of the resected specimen revealed retroperitoneal metastasis of HCC. Intrahepatic recurrence was detected 6 months after the resection. Therefore, he underwent TACE, and he is currently (1 year after surgery) alive without any extrahepatic metastasis. We describe herein this case because retroperitoneal metastasis of HCC is very rare.

Topics: Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Combined Modality Therapy; Drug Combinations; Hepatitis B virus; Humans; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Oxonic Acid; Recurrence; Retroperitoneal Neoplasms; Tegafur; Tomography, X-Ray Computed

A 77-year-old man was diagnosed as hepatocellular carcinoma, and was referred to our hospital. After he was treated by transcatheter chemoembolization, he underwent a left hepatic lobectomy of the liver and cholecystectomy. Serum AFP and PIVKA-II remarkably elevated 7 months after surgery, and CT scan revealed multiple metastatic nodules in bilateral lungs. The nodules were diagnosed as lung metastasis of HCC. Because the lesions grew larger, S-1/IFN was administered. Diagnostic imaging and tumor markers showed a marked improvement after 4 courses of S-1/IFN therapy, and he is still alive with good condition without recurrence and progression of tumors.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Combinations; Embolization, Therapeutic; Hepatectomy; Humans; Interferon-alpha; Liver Neoplasms; Lung Neoplasms; Male; Oxonic Acid; Recurrence; Remission Induction; Tegafur; Tomography, X-Ray Computed

A case of a 68-year-old man with hepatocellular carcinoma (HCC) is presented. He underwent partial liver resection for three times and transcatheter arterial chemoembolization (TACE) for three times. Follow-up CT revealed a recurrent hepatic surface mass with malignant extended into the inferior vena cava (IVC) and right atrium (RA). CT scan also revealed multiple metastatic nodules in bilateral lungs. The tumor thrombus into the RA and the hepatic surface mass were successfully treated with surgical resection. Pathological specimen allowed the diagnosis of poorly-differentiated HCC. Adjuvant chemotherapy with S-1 resulted in complete remission of lung metastases. Tumor markers showed a significant improvement after S-1 administration. This case report suggests that a surgical resection followed by S-1 administration would be effective for a patient with lung metastases and a tumor thrombus into IVC or RA.

Topics: Aged; Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Drug Combinations; Humans; Liver Neoplasms; Lung Neoplasms; Male; Neoadjuvant Therapy; Oxonic Acid; Recurrence; Tegafur; Tomography, X-Ray Computed

A 73-year-old woman was admitted to our hospital for hemorrhagic shock due to HCC rupture and treated by transcatheter arterial chemoembolization (TACE) in July 2007, followed by partial hepatic resection two months later. Multiple pulmonary and remnant liver metastases were detected by CT six months after the surgery. Since treatment with UFT for two months was not effective, the chemotherapy was changed to S-1 100 mg/body/day in June 2008. After S-1 treatment for three months, lung metastases remarkably diminished, as did the serum AFP level. Meanwhile, although the S-1 dose was gradually reduced to 50 mg/body/day due to adverse effects, pulmonary lesions and serum AFP level remained stationary for five months. While there is no established regimen for distant metastases of HCC, S-1 may be effective even at a reduced dose.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Combinations; Female; Humans; Liver Neoplasms; Lung Neoplasms; Oxonic Acid; Tegafur; Tomography, X-Ray Computed

The treatment for hepatocellular carcinoma with distant metastasis remains unclear. We experienced a successful case of S-1 chemotherapy for bilateral pulmonary recurrence of hepatocellular carcinoma following hepatectomy after gaining chemoresistance through pretreatment. A 62-year-old man underwent extended right hepatectomy for hepatocellular carcinoma occupying the whole right lobe. CT scan 15 months after hepatectomy revealed bilateral multiple pulmonary recurrence. Pharmacokinetic modulation chemotherapy (PMC) was performed after treatment of UFT, and stable disease status for 24 months was achieved. Pulmonary metastatic lesions gradually became larger, so oral administration of 100 mg per day of S-1 was followed by stable disease status for 9 months. The present case suggests that S-1 chemotherapy may be useful for hepatocellular carcinoma with distant metastasis.

Topics: Administration, Oral; Carcinoma, Hepatocellular; Drug Combinations; Hepatectomy; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Tegafur; Time Factors

Based on its potent inhibition of dihydropyrimidine dehydrogenase (DPD), S-1 is expected to be more active than other flouropyrimidines against tumors with higher DPD activity, such as hepatocellular carcinoma (HCC).. We retrospectively investigated the efficacy of S-1 and platinum in HCC. Patients received S-1 (80 mg/m(2)/day on days 1-14) with either cisplatin (60 mg/m(2) on day 1) or oxaliplatin (130 mg/m(2) on day 1) every 3 weeks. The primary end point was overall response rate.. Among the 21 HCC patients, 12 and 9 patients received S-1-based chemotherapy as a first-line and salvage treatment, respectively. Partial response was seen in 5 patients and stable disease in 6. The median time-to-progression was 4.0 months (95% confidence interval [CI], 2.4-5.6) and median overall survival was 14.0 months (95% CI, 6.7-21.3). Most patients were tolerable to chemotherapy and no grade 4 toxicity was observed. Tumors with lower DPD expression were more responsive to the therapy (response rate 60.0% in lower vs. 0.0% in higher DPD, p=0.045).. S-1 and platinum combination chemotherapy shows favorable efficacy and tolerability in advanced HCC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cisplatin; Drug Combinations; Female; Humans; Immunohistochemistry; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Retrospective Studies; Tegafur

A 54-year-old man was diagnosed as hepatitis B in 1987 and observed. In January 2007, he was detected a 7 cm mass in the posterior segment of the liver with inferior vena cava tumor thrombus (Vv3), a 4.5 cm mass and multiple small nodules in the liver by computed tomography. Moreover, his right pubic bone has solitary small osteolytic change in x-ray and abnormal up take on bone scintigram. We diagnosed it having a highly advanced hepatocellular carcinoma (HCC) with bone metastasis. We started to treat with multidisciplinary therapy. We performed Transarterial chemoembolization (TACE) twice for intrahepatic lesions and radiotherapy for bone metastasis. Interferon-α and S-1 combination therapy were performed for three months. A new lesion in the liver was appeared advanced slowly 16 months after the last TACE, and caused to increase PIVKA-II. He received TACE for this lesion. Three years after the diagnosis, and he is alive in good condition without a new extrahepatic metastasis. This case suggests that some patients with highly progressive HCC involving inferior vena cava tumor thrombus (Vv3) and bone metastasis can gain a long-term survival by multidisciplinary therapy including TACE and Interferon-α and S-1.

Topics: Antimetabolites, Antineoplastic; Bone Neoplasms; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Drug Combinations; Humans; Immunologic Factors; Interferon-alpha; Liver Neoplasms; Male; Middle Aged; Neoplastic Cells, Circulating; Oxonic Acid; Tegafur; Vena Cava, Inferior; Venous Thrombosis

To investigate the role of metronomic chemotherapy of S-1 on angiogenesis of hepatocellular carcinoma in animal model.. S-1 was dissolved in a 0.5% (w/v) HPMC solution. 30 LCI-D20 were randomly devided into five groups: control group(O), 10 mg * kg(-1) * d(-1) S-1 group (A), 1 mg * kg(-1) * d(-1) S-1 group (B), 0.5 mg * kg(-1) * d(-1) S-1 group (C) and 0.25 mg * kg(-1) * d S-1 group (D). 28 days after the treatment with 0.5% (w/v) HPMC solution, tumors in LCI-D20 mice were moved out. Tumor mass was measured and microvessel density (MVD) was used to evaluate angiogenesis in tumor. The cellular apoptosis was determined using flow cytometry. The expression of VEGF, bFGF and TSP-1 was measured by RT-PCR.. The mean tumor mass was 2.01, 0.38, 1.12, 1.38, 2.27 g in O, A, B, C, D group, respectively. The mean MVD was 39.57, 19.90, 5.93, 17.10, 29.53 in O, A, B, C, D respectively. The mean tumor cellular apoptosis rate was 4.08%, 44.37%, 31.73%, 19.83%, and 8.25% in O, A, B, C, D respectively. The expression of VEGF and bFGF in O group was highest, and A was slightly low, and C and D taked the third place, and B was the lowst; The expression of TSP-1 in B was highest, and C and D were slightly low, and A taked the third place, and O was the lowst.. Metronomic chemotherapy of S-1 destabilizes pre-existing tumor vasculature and inhibits ongoing angiogenesis.

Topics: Animals; Antimetabolites, Antineoplastic; Apoptosis; Carcinoma, Hepatocellular; Drug Combinations; Fibroblast Growth Factor 2; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Oxonic Acid; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tegafur; Vascular Endothelial Growth Factors

A57 -year-old man. Though chronic hepatitis C was pointed out before, it had been left untreated for about 5 years. He was hospitalized because many venereal diseases had been pointed out in the liver by abdomen ultrasonography. Results of close examination revealed stage IV B with bone metastases, and pulmonary metastases was diagnosed. After consultation, whole-body chemotherapy combining S-1 and PEG-IFN was attempted as of June 26, 2007. S-1 (80 mg/day) was then administered every day for two weeks with drug withdrawal for one week. PEG-IFNalpha-2a (180 microg)was administered once a week. We set three weeks as one course. The liver tumor was markedly reduced, and the pulmonary metastases were also reduced at the completion of 5 courses. The therapeutic effectiveness of this chemotherapy was confirmed by imaging test. The course was favorable, and whole-body chemotherapy was discontinued on January 29, 2008. At this writing in October of 2008, the course has been uneventful. This treatment method is a promising choice for whole-body chemotherapy for advanced hepatocarcinoma in the future. We have added some review of the literature, and the S-1+PEG-IFN combination chemotherapy is reported.

Topics: Angiography; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma, Hepatocellular; Drug Combinations; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Oxonic Acid; Polyethylene Glycols; Recombinant Proteins; Tegafur; Tomography, X-Ray Computed

We report a case of successful multimodal treatment for combined hepatocellular and cholangiocarcinoma with portal venous tumor thrombus. A 66-year-old man was diagnosed with hepatocellular carcinoma with Vp3 by abdominal enhanced CT. He underwent a complete tumor resection and following interferon and 5-FU combined intra-arterial chemotherapy as an adjuvant setting. The histological findings were consistent with combined hepatocellular and cholangiocarcinoma. At 9 months after the surgery, lymph node metastases were detected. Then we started an oral fluoropyrimidine anticancer agent S-1, because the recurrence was suspected to be originated from the cholangiocarcinoma component. Thereafter, sustained partial remission was achieved. In case of combined hepatocellular and cholangiocarcinoma, we need to create a treatment strategy against characteristics of both components.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Cholangiocarcinoma; Combined Modality Therapy; Drug Combinations; Fluorouracil; Hepatectomy; Humans; Interferons; Liver Neoplasms; Male; Neoplastic Cells, Circulating; Oxonic Acid; Tegafur

A 68-year-old man lost in unconscious and was diagnosed as ruptured hepatocellular carcinoma (HCC) in a local emergency hospital. He was treated by transcatheter arterial embolization, and further investigation revealed simultaneous cancer in rectum. He was referred to our institute, and admitted in June 2005. He underwent lateral segment and S8 partial resection of the liver, cholecystectomy, anterior resection of rectum, and D3 lymphadenectomy in August 2005. Multiple HCC recurrences in the remnant liver appeared in December 2005. He was subsequently treated with transcatheter chemoembolization four times. In May 2006, CT scan revealed multiple metastatic nodules in bilateral lungs with remarkably elevated serum AFP and PIVKA-II. The nodules were diagnosed as lung metastasis of the HCC. Because the lesions grew larger, S-1 was started in February 2007. Diagnostic imaging and tumor markers showed a marked improvement 2 months after S-1 administration, and no recurrence has been found since then. This case illustrates that S-1 may be an effective treatment for HCC with extrahepatic metastasis.

Topics: Aged; Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Drug Combinations; Hepatectomy; Humans; Liver Neoplasms; Lung Neoplasms; Male; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Oxonic Acid; Rectal Neoplasms; Tegafur

There is no standard treatment for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. We assessed the efficiency and safety of the oral fluoropyrimidine anticancer drug S-1 combined with interferon alpha (IFN-alpha) for HCC patients with extrahepatic metastases.. Twenty-nine HCC patients with extrahepatic metastases received S-1/IFN. One cycle of combination therapy represented 2 weeks followed by 2-4 weeks of rest. In each cycle, S-1 was administrated orally at 80-120 mg (depending on body surface area) every day and IFN-alpha intramuscularly at 5 million units thrice weekly.. The overall response of 29 patients was complete response (CR) in 4 (14%), partial response (PR) in 1, stable disease in 4, progressive disease in 12, and dropout in 8 patients. Objective response (CR + PR) was 17%. The time to progression and survival rate were significantly higher in patients with lung metastases (n = 19) than in those with painful bone metastases (n = 7; p = 0.0058 and 0.0015). With regard to NCI-CTC grade 3 adverse reactions, 3 (10%), 3 (10%) and 2 (7%) patients developed anorexia, leukopenia, and neutropenia, respectively. No grade 4 adverse reaction or toxicity-related death occurred.. S-1/IFN is a potentially safe and suitable combination therapy for HCC patients with extrahepatic metastases, especially those with lung metastases.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Disease Progression; Drug Combinations; Female; Humans; Interferon-alpha; Liver Neoplasms; Male; Middle Aged; Oxonic Acid; Remission Induction; Retrospective Studies; Tegafur; Treatment Outcome

There are currently no effective treatments for patients with advanced hepatocellular carcinoma (HCC) with vascular invasion or extrahepatic metastases. We evaluated the efficacy and safety of combination therapy with S-1 and pegylated interferon (PEG-IFN)-alpha for advanced HCC.. A total of 22 patients received combination therapy with S-1 and PEG-IFN. One cycle of the combination therapy consists of oral S-1 (80 mg/m(2)) administration and subcutaneous PEG-IFN injection (PEG-IFN-alpha-2a 90 microg weekly or PEG-IFN-alpha-2b 50 microg weekly) for 4 weeks with 1- to 2-week intervals.. One patient was evaluated as complete response, 6 as partial response, 8 as stable disease, and 6 as progressive disease. One patient was not evaluable because therapy had to be discontinued as a result of jaundice. The median survival time was 15.3 months (95% CI: 4.4-26.2 months). The 1- and 2-year survival rates were 54.9 and 36.6%, respectively. The overall response rate was 31.8% and the disease control rate was 68.2%. Grade 3 neutropenia (18.2%), leukopenia (9.1%), anemia (9.1%), and thrombocytopenia (18.2%) were observed. Grade 4 toxicities were not observed.. Combination therapy with S-1 and PEG-IFN is effective and feasible, and is therefore a promising regimen for advanced HCC.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Disease Progression; Drug Combinations; Drug Therapy, Combination; Feasibility Studies; Female; Humans; Interferon alpha-2; Interferon-alpha; Liver Neoplasms; Male; Middle Aged; Oxonic Acid; Polyethylene Glycols; Recombinant Proteins; Survival Analysis; Tegafur; Treatment Outcome

To the authors' knowledge, there is no effective therapy for extrahepatic metastasis of hepatocellular carcinoma (HCC). In a pilot study, the results of combination therapy of S-1, a novel oral dehydropyrimidine dehydrogenase (DPD) inhibitor, and interferon-alpha (IFN-alpha) are reported for HCC patients with extrahepatic metastasis.. Twelve patients with extrahepatic metastasis of HCC were enrolled in the pilot study. S-1 was administered orally at a dose based on body surface area, twice daily after a meal, for 4 weeks. IFN-alpha was injected subcutaneously on Days 1, 3, and 5 of each week. One course consisted of consecutive administration for 28 days followed by 14 days rest.. An objective response was observed in 3 (25%) of 12 patients. The overall 1-year survival rate was 61.7%. Grade 3 leukocytopenia was observed in 1 patient (8.3%). No severe toxicity or treatment-related deaths were observed.. The combination therapy of S-1 and IFN-alpha appears to be highly efficacious, with low toxicity in patients with extrahepatic metastases of HCC. The combination chemotherapy of oral S-1 and subcutaneous IFN-alpha is a potentially promising treatment strategy for advanced HCC with extrahepatic metastasis.

Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Female; Follow-Up Studies; Humans; Immunologic Factors; Injections, Subcutaneous; Interferon-alpha; Leukopenia; Liver Neoplasms; Male; Middle Aged; Oxonic Acid; Pilot Projects; Remission Induction; Survival Rate; Tegafur; Thrombocytopenia

Advanced hepatocellular carcinoma (HCC) with distant metastases, in particular to the lung, has a poor prognosis. This study was undertaken to evaluate the effectiveness of TS-1 as chemotherapy in advanced HCC with lung metastases. Between January 2004 and October 2005, 8 patients with advanced HCC with lung metastasis were enrolled. All patients received systemic chemotherapy with TS-1. The drug was administered at a dose of 80 mg/m(2)/day for four weeks, followed by a two-week rest, repeated every six weeks until disease progression, unacceptable toxicity, or the patient's refusal. Median age of the patients was 59 years (range, 44 to 79 years). All patients were in Child-Pugh class A. A total of 22 cycles were administered to each patient (range, 1 to 5). No complete or partial responses were observed. There were two patients (25%) with decreasing tumor marker. Median progression-free survival was 79.5 days (range, 29 to 225). The median overall survival was 257 days (95% confidence interval, 191 to 323 days). TS-1 as chemotherapy was well tolerated when administered in the schedule used in this study. Some patients achieved stable disease and clinical benefits, though this regimen has limited activity in HCC with lung metastases. Randomized controlled trials are necessary to clarify survival benefits in patients with advanced HCC with lung metastasis.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Drug Administration Schedule; Drug Combinations; Female; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Oxonic Acid; Prognosis; Retrospective Studies; Survival Rate; Tegafur; Treatment Outcome

5-FU plus Cisplatin combination therapy had been employed against primary liver carcinomas for years. S-1 is a fourth-generation oral fluoropyrimidine and attracts considerable interest for the activity against gastric cancer. We herein examined the effect and adverse effects of S-1 plus Cisplatin combination therapy for primary liver carcinomas.. 4 patients with hepatocellular carcinoma (HCC) and 3 with cholangiocellular carcinoma (CCC) were employed for this study. They all had far-advanced diseases in and/or out of the liver at the time of the therapy initiation. They were 4 men and 3 women. Their ages were in the range of 42-73 (58 +/- 9.73, mean +/- SD) years old. The protocol of the therapy is a 3-week period of S-1 (70-80 mg/m2/day) oral administration combined with 2 intravenous administration of CDDP (20-35 mg/m2) during the period. With two weeks of intermission, the therapy was repeatedly performed 2-11 times for each patient.. Three patients had PR and 2 had NC response with the therapy. Two patients with HCC and pre-treatment with 5-FU had PD response. Although the patients developed leukopenia and thrombocytopenia, the therapy was well tolerable also in the outpatient basis.. S-1 plus Cisplatin combination therapy is a potential therapy for advanced primary liver carcinomas.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Drug Combinations; Female; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Oxonic Acid; Prognosis; Tegafur; Tomography, X-Ray Computed

We have reported a remarkably high anti-tumor efficacy using intra arterial 5-FU infusion chemotherapy combined with subcutaneous interferon-alpha injection to treat advanced hepatocellular carcinoma (HCC) with portal vein thrombus. However, we have been confirming distant metastases along with a prognosis extension as hepatic lesions could possibly be controlled to a certain extent. Even though there has been no effective chemotherapy against hepatocellular carcinoma with distant metastases, we performed S-1 and interferon-alpha combination chemotherapy for the cases where good results were exhibited from interferon-alpha combined with arterial 5-FU infusion. As a result, we confirmed CR in the anti-tumor effect against distant metastases with no severe adverse effects. It was suggested that a combination therapy of S-1 and interferon-alpha may be one of the most effective treatment modalities against advanced HCC with distant metastases.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Administration Schedule; Drug Combinations; Humans; Interferon-alpha; Liver Neoplasms; Middle Aged; Neoplastic Cells, Circulating; Oxonic Acid; Remission Induction; Tegafur

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-alpha (IFN-alpha) 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-alpha 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-alpha, 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-alpha may be a promising treatment modality against advanced HCC with distant metastasis.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Drug Therapy, Combination; Follow-Up Studies; Hepatectomy; Humans; Immunologic Factors; Injections, Subcutaneous; Interferon-alpha; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Splenic Neoplasms; Tegafur; Tomography, X-Ray Computed

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma, Hepatocellular; Cisplatin; Drug Administration Schedule; Drug Combinations; Humans; Liver Neoplasms; Male; Middle Aged; Oxonic Acid; Pyridines; Tegafur

A 56-year-old male was admitted to our hospital for hepatoma with portal vein thrombus and multiple intrahepatic metastases. He underwent an extended left lobectomy and a partial resection of the liver in May 2002. After two weeks from the surgery, he received intra arterial 5-FU infusion chemotherapy combined with subcutaneous interferon-alpha injection to treat the lesions in the residual liver. Four months after the surgery, hepatic vein tumor thrombus appeared in the remnant liver and it extended to the inferior caval vein. And another 4 months later, multiple pulmonary metastases were detected with computed tomography and they grew rapidly in the view of their sizes and numbers. Because the combined therapy of 5-FU/interferon-alpha was not effective to distant metastases, we started a new regimen of oral administration of TS-1 and a subcutaneous interferon-alpha injection. After 1 treatment cool, hepatic vein thrombus was markedly reduced the size and vascularity in the CT. Multiple pulmonary metastases also decreased in their sizes and numbers. No adverse effect was seen during this treatment. It was suggested that a combination therapy of TS-1 and interferon-alpha may be one of the most effective treatment modalities against advanced HCC with distant metastasis.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Combined Modality Therapy; Drug Combinations; Hepatectomy; Humans; Infusions, Intra-Arterial; Injections, Subcutaneous; Interferon-alpha; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplastic Cells, Circulating; Oxonic Acid; Pneumonectomy; Pyridines; Tegafur; Thrombectomy; Vena Cava, Inferior

A 75-year-old man underwent distal gastrectomy for advanced gastric cancer with liver and lymph node metastases and synchronous hepatocellular carcinoma in April 2004. HAI with low-dose CDDP/TS-1 combination therapy was initiated after gastrectomy. Liver and lymph node metastases decreased significantly, with achievement of a partial response (PR) and a complete response (CR), respectively, and the hepatocellular carcinoma was reduced to 54.1% of its initial size after 3 sessions of this chemotherapy. These results suggested that combined chemotherapy with TS-1 and HAI with low-dose CDDP was not only useful for liver and lymph node metastases from gastric cancer, but for hepatocellular carcinoma as well.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Gastrectomy; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Neoplasms, Multiple Primary; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur

A standard treatment for hepatocellular carcinoma with extrahepatic metastasis is not established and chemotherapy is ineffective. We experienced a case of hepatocellular carcinoma with bone metastasis that responded to concurrent TS-1/low-dose cisplatin (CDDP) therapy and radiotherapy. A 58-year-old male patient with left iliac bone metastasis after 2 hepatectomies was admitted to our hospital. The titer of serum AFP and PIVKA-II showed an extremely high levels, 12,350.5 ng/ml and 993 mAU/ml, respectively. The uptake area was found at the left iliac bone by scintigraphy with 99mTc-HMDP. Treatment with TS-1/low-dose CDDP therapy and radiotherapy (36 Gy) was started concurrently. The chemotherapy regimen comprised daily oral administration of 100 mg of TS-1 for 21 days and CDDP 10 mg/body infusion (day 1-5, 8-12). An additional 2 courses of TS-1/low-dose CDDP therapy were repeated. After that, severe pain diminished and the titer of serum showed AFP and PIVKA-II had improved to within normal ranges. The uptake at the left iliac bone was found to have decreased by scintigraphy. Adverse events were grade 1 nausea and leucopenia. TS-1/low-dose CDDP therapy seems to be applicable for the treatment of hepatocellular carcinoma with bone metastasis.

Topics: alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biomarkers, Tumor; Bone Neoplasms; Carcinoma, Hepatocellular; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Hepatectomy; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Middle Aged; Oxonic Acid; Protein Precursors; Prothrombin; Pyridines; Tegafur

A 52-year-old male was admitted to our hospital with huge hepatoma of the right lobe. He underwent a right lobectomy of the liver in July 1999. After five months from the surgery, multiple recurrences in the liver and lung were revealed with Computed tomography (CT). TAE was performed for intrahepatic recurrence and a combination therapy, consisting of UFT and interferon-alpha, was started for pulmonary metastasis. Then 5-FU/CDDP/interferon-alpha therapy was given in 2001 and TS-1/interferon-beta therapy was given thereafter in 2002. Consequently, the patient survived for 31 months with no disturbance in quality of life. No intrahepatic recurrence was also detected during the survival period. It was suggested that a good prognosis may be expected, even in the HCC case with distant metastasis after hepatic resection, if the primary cite was curatively treated.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Drug Combinations; Fluorouracil; Hepatectomy; Humans; Interferon-alpha; Interferon-beta; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Pyridines; Tegafur; Time Factors; Uracil

A no change (NC) status could be maintained in a patient with remnant gastric cancer for more than 500 days with low-dose TS-1. The patient was a 68-year-old woman who was found to have remnant gastric cancer during an endoscopic examination in follow-up on an outpatient basis after surgery for hepatocellular carcinoma in our department. Surgery was rejected as a treatment option because of severe liver dysfunction, and the patient was started on oral TS-1 80 mg/day. Both AST and ALT levels increased immediately after the start of TS-1, and TS-1 was discontinued until these levels improved. It was resumed at 50 mg/day, and there were no subsequent adverse reactions. Endoscopic examination on day 69 after the start of TS-1 showed that a partial response (PR) had not been achieved, but the lesion had shrunk. Endoscopy on day 454 after the start of TS-1 showed it had been possible to maintain a similar state. This was a rare case in which it was possible to achieve prolonged same status with low-dose TS-1.

Topics: Adenocarcinoma; Administration, Oral; Aged; Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Drug Administration Schedule; Drug Combinations; Female; Humans; Liver Neoplasms; Neoplasm, Residual; Neoplasms, Multiple Primary; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur

Topics: Aged; Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Drug Combinations; Humans; Liver Neoplasms; Male; Oxonic Acid; Pyridines; Tegafur; Tomography, X-Ray Computed