gimeracil and Stomach-Neoplasms

The product Teysuno™ (S-1) contains tegafur, a prodrug of 5-fluorouracil (5-FU), and two modulators of 5-FU metabolism, gimeracil and oteracil. The main clinical study in this application was a randomized controlled study comparing S-1 plus cisplatin with 5-FU plus cisplatin. In this study, median overall survival times of 8.6 months and 7.9 months for S-1 plus cisplatin and 5-FU plus cisplatin, respectively, were observed (hazard ratio, 0.92; 95% confidence interval, 0.80-1.05). The Committee for Medicinal Products for Human Use of the European Medicines Agency concluded that S-1 in combination with cisplatin (75 mg/m²) was noninferior to 5-FU plus cisplatin (100 mg/m²) in patients with advanced gastric cancer and adopted a positive opinion recommending the marketing authorization for this product for the treatment of advanced gastric cancer when given in combination with cisplatin. The recommended dose of S-1 is 25 mg/m² (expressed as tegafur content) twice a day, for 21 consecutive days followed by 7 days rest (one treatment cycle), in combination with 75 mg/m² cisplatin i.v. administered on day 1. This treatment cycle is repeated every 4 weeks. The most common side effects reported in the pivotal study were anemia, neutropenia, vomiting, diarrhea, abdominal pain, weight decrease, anorexia, and fatigue. The objective of this paper is to summarize the scientific review of the application leading to approval in the EU. The full scientific assessment report and the summary of product characteristics are available on the European Medicines Agency website (http://www.ema.europa.eu).

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Drug Approval; European Union; Humans; Oxonic Acid; Practice Guidelines as Topic; Pyridines; Randomized Controlled Trials as Topic; Stomach Neoplasms; Tegafur; Treatment Outcome

Anlotinib hydrochloride is a multi-targeted receptor tyrosine kinase inhibitor that targets angiogenesis-related kinases and has already showed good safety and efficacy in some solid tumours. However, evidence on the safety and feasibility of anlotinib in patients with stage IV gastric cancer is scarce.. This study is a single-armed and single-centred clinical study being designed to include 150 patients of stage IV gastric cancer. The patients' demographics, pathological characteristics, test results of blood, biochemistry and tumour markers before and after medication, disease-free survival and overall survival will be collected and analysed. The primary and main efficacy outcomes are objective response rate, progression-free survival, disease control rate and overall survival. The secondary efficacy outcome is safety indicator including the incidence of adverse drug reactions and adverse events after administration.. Ethics approval has been obtained from the Ethics Committee at the First Affiliated Hospital (Xijing Hospital) of Fourth Military Medical University (KY20192111-F-1). The results of this study will be disseminated at several research conferences and as published articles in peer-reviewed journals.. ChiCTR1900026291 (registration date: 29 September 2019).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Oxonic Acid; Progression-Free Survival; Pyridines; Stomach Neoplasms; Tegafur; Treatment Outcome

S-1 is an oral fluoropyrimidine anticancer drug consisting of the 5-fluorouracil prodrug tegafur combined with gimeracil and oteracil. The purpose of this study was to evaluate the pharmacokinetic (PK), bioequivalence, and safety of a newly developed generic formulation of S-1 compared with the branded reference formulation, in Korean gastric cancer patients.. This was a single-center, randomized, open-label, single-dose, two-treatment, two-way crossover study. Eligible subjects were randomly assigned in a 1:1 ratio to receive the test formulation or reference formulation, followed by a one-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 hrs (predose), 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hrs after dosing in each period. The plasma concentrations of tegafur, 5-FU, gimeracil, and oteracil were analyzed using a validated liquid chromatography-tandem mass spectrometry method. The PK parameters were calculated using a non-compartmental method.. In total, 29 subjects completed the study. All of the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. No serious adverse events were reported during the study.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Chromatography, Liquid; Cross-Over Studies; Drug Compounding; Fluorouracil; Humans; Oxonic Acid; Pyridines; Republic of Korea; Stomach Neoplasms; Tandem Mass Spectrometry; Tegafur; Therapeutic Equivalency

To observe the efficacy and safety of chemotherapy regimens oxaliplatin combined with capecitabine (CAPOX) or oxaliplatin combined with tegafur, gimeracil and oteracil potassium capsules (S-1)(SOX), and to investigate the value of expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) proteins in tumor tissue for predicting the efficacy of CAPOX and SOX regimens in advanced gastric cancer patients.. A total of 107 newly-diagnosed, stage Ⅲc/Ⅳ gastric cancer patients (no surgical indication, ECOG performance scores 0-2 and expected survival time ≥3 months) were recruited with 101 patients evaluated. The patients were randomly divided into two groups. One was study group in which the patients received CAPOX regimen. The other was control group received SOX regimen. Each patient received four cycles, at least two cycles chemotherapy every three weeks and followed up until death or lost. Tumor biopsies were obtained by gastroscopy for immunohistochemical examination of the expression of TP and DPD proteins before chemotherapy. Response rate (ORR), overall survival (OS) and time to tumor progression (TTP) of the patients were assessed.. The objective response rate (ORR) of the study and control groups was 49.0% (5/51) vs. 46.0% (23/50), respectively (P>0.05). The overall survival (OS) was 357.36±24.69 days in the study group and 349.87±22.63 days in the control group, and the time-to-progression (TTP) was 216.75±19.32 days in the study group and 220.54±18.47 days in the control group (P>0.05 for both). Stratified analysis showed that the ORR of TP-positive patients in the study group was significantly higher than that in the control group (72.0 % vs. 41.7 %, P=0.032). There was no significant difference in ORR between the TP-negative patients in the study and control groups (26.9% vs. 50.0%, P=0.087), while the ORR of DPD-positive patients in the control group was significantly higher than that of the study group (51.9% vs. 34.6%, P=0.046). There was no significant difference in the ORR between DPD-negative patients in the study and control groups (64.0% vs. 39.1%, P=0.084). The follow-up showed that the OS (378.42±22.56 days) and TTP (271.77±24.92 days) in the TP-positive patients of the study group were significantly longer than those of the control group (OS: 326.57±19.84 days, and TTP: 229.13±22.68 days)( P<0.05). The OS was 371.25±23.97 days and TTP was 264.66±21.36 days in the DPD-positive patients of control group, significantly longer than those of the study group (OS: 334.73±21.47days, and TTP: 208.58±20.70 days) (P<0.05). But there was no significant difference in the OS and TTP between the TP- and DPD-negative patients in the two groups (P>0.05). In respect of adverse events, both the rates of hematological and non-hematological toxicities were low and similar between the two groups (P>0.05), and well-tolerated by the patients.. Both CAPOX and SOX regimens are effective chemotherapeutic protocols in treatment of patients with advanced gastric cancer. The expression levels of TP and DPD in tumor tissue can be used as a predictive factor for the efficacy of capecitabine or tegafur, gimeracil and oteracil potassium capsules combined with oxaliplatin regimens. CAPOX chemotherapy regimen is more suitable for the TP-positive gastric cancer patients, and SOX regimen is more suitable for the DPS-positive gastric cancer patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Capsules; Dihydrouracil Dehydrogenase (NADP); Disease Progression; Humans; Neoplasm Proteins; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur; Thymidine Phosphorylase

S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and postoperative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. The pharmacokinetics of tegafur, 5-fluorouracil, and CDHP were analyzed by noncompartmental analysis (NCA) methods and by modeling. In modeling analysis, CHDP concentrations were incorporated in the model as a time-varying covariate that inhibits the clearance of 5-fluorouracil following an inhibitory Emax model. In NCA, the pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seem to be too small to have any clinical implication.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Drug Combinations; Female; Gastrectomy; Humans; Male; Middle Aged; Models, Biological; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur

To determine the clinical toxicities and antitumor effects of a chemotherapy regimen of FTQ, a compound preparation of tegafur, the drug prototype of 5-furacil (5-FU), gimeracil (CDHP), a decomposition inhibitor of 5-FU, oteracil potassium, phosphorylation inhibitor of 5-FU, and combined with cisplatin in patients with inoperable locally or metastatic advanced gastric cancer.. 119 patients with inoperable locally or metastatic advanced gastric cancer admitted in 10 hospitals in China were divided into 2 groups: FTQ group (n = 59), undergoing a 3-week regime, i.e. oral use of 80 mg x m(-2) x d(-1) for 14 d and then discontinuance for 1 week and intravenous drip cisplatin 75 mg/m2 on days 1-3; and control group (n = 60) undergoing a 3-week regimen including oral use of tegafur 800 mg x m(-2) x d(-1) tid for 14 d and then discontinuance for 1 week and intravenous drip of cisplatin 75 mg/m2 on days 1-3. The curative was evaluated after at least after 2 regimens.. There were 102 patients in the per-protocol population. The overall response rate of the FTQ group was 28. 3% (15/53), significantly higher than that of the control group (4.1%, 2/49, P = 0.004). The clinical improvement of the FTQ group was 50.9%, significantly higher than that of the control group (24.5%, P = 0.006). The main toxicities occurred in bone marrow and the digestive tract. The leucopenia and thrombocytopenia rates of the FTQ group were 47.45% and 32.22% respectively, both similar to those of the control group. There were no differences in the incidence rate of digestive canal side reaction between these 2 groups .. The regimen of FTQ combined with cisplatin is generally well-tolerated and has substantial antitumor activity.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Fluorouracil; Humans; Middle Aged; Oxonic Acid; Pyridines; Single-Blind Method; Stomach Neoplasms; Tegafur; Treatment Outcome

The effect of gastrectomy on pharmacokinetics after S-1 administration was investigated.. A dose of 40 mg/m(2) of S-1 was administered orally twice daily for 7 days (80 mg/m(2)/day) preoperatively in ten patients with resectable gastric cancer, and the same dose of S-1 was administered for 28 consecutive days after gastrectomy. Plasma concentrations of tegafur, gimeracil, and oteracil potassium, all the components of S-1, and 5-FU were measured on pre- and postoperative days. Concentrations of 5-FU in tumor and normal tissues were also determined.. At day 4 from the initial preoperative administration of S-1, the AUC of 5-FU was 1,055 +/- 304 ng h/ml. At day 18, day 28, and day 42 after gastrectomy, it was 1,012 +/- 331, 1,070 +/- 403, and 946 +/- 226 ng h/ml, respectively. No significant differences for plasma 5-FU were observed between pre- and postoperative days. In the resected tumor tissues, concentrations of 5-FU were 242 +/- 83 ng/g around 4.5 h and 91.7 +/- 37.0 ng/g around 20 h after the final administration, respectively.. Gastrectomy does not affect on pharmacokinetics of 5-FU derived from S-1 regardless of partial or total gastrectomy, indicating that S-1 can be a useful drug in postoperative adjuvant chemotherapy for gastric cancer.

Topics: Administration, Oral; Aged; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Drug Combinations; Female; Fluorouracil; Gastrectomy; Humans; Male; Middle Aged; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur

Doxifluridine (DF), an oral 5-FU prodrug, has been used for various solid cancers due to its efficacy and low toxicity. We aim to evaluate the effect of DF as adjuvant monotherapy in advanced gastric cancer.. We retrospectively reviewed the clinical data of 263 patients with advanced gastric cancer who underwent curative gastrectomy between January 2010 and December 2013 at our institute. Since previous randomized control trials have confirmed the efficacy of S-1 as adjuvant chemotherapy in advanced gastric cancer, we analyzed the oncologic effect and patient compliance of the DF group compared to the S-1 group. After propensity score matching, 48 patients were included in each group.. There was no significant difference in 5-year overall survival (OS) and 5-year disease-free survival (DFS) between DF and S-1 groups (5-year OS; 77.1% vs 75.0%; p = 0.729, 5-year DFS; 76.6% vs 73.9%; p = 0.748). The completion rates of the DF and S-1 groups were 60.4% and 72.9%, respectively (p = 0.194). The mean relative dose intensity of the DF and S-1 groups were 76.2% and 84.2%, respectively (p = 0.195). After multivariate analysis, the chemotherapy regimen was not a risk factor for OS and DFS, whereas relative dose intensity and pathologic stage were independent prognostic factors.. There was no significant difference in the oncologic effect and patient compliance between DF and S-1 groups. DF could be an alternative option for adjuvant chemotherapy in advanced gastric cancer. In addition, we confirmed that relative dose intensity is an important independent prognostic factor for survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Gastrectomy; Humans; Neoplasm Staging; Oxonic Acid; Propensity Score; Retrospective Studies; Stomach Neoplasms; Tegafur

For the past 20 years, S-1 has been used in the treatment of many types of cancer. However, the clinical importance of myocardial dysfunction attributed to S-1 remains to be unclear. Thus, in this study, we report on a patient with myocardial dysfunction associated with S-1.S-1 postoperative chemotherapy for gastric cancer was included as a treatment for a 65-year-old man. On day 8, S-1 treatment was discontinued after the patient developed an oral ulcer. He was then admitted to the hospital because of diarrhea caused by S-1. At approximately the same time, he developed dyspnea, and his chest X-rays revealed perihilar vascular engorgement and cardiac enlargement. Although his brain natriuretic peptide was 595.8 pg/mL, troponin I and creatine phosphokinase were unremarkable. Electrocardiograms showed no change in atrial fibrillations or new ST-T wave change. As per his transthoracic echocardiogram, noted were expansion of the left ventricle, global hypokinesis, and reduced left ventricular ejection fraction (approximately 40%). The patient was then diagnosed with S-1-related myocardial dysfunction. Furosemide, human atrial natriuretic peptide, dobutamine, enalapril, spironolactone, and bisoprolol were administered. Thirteen days after being diagnosed with heart failure, his symptoms disappeared, his echocardiogram showed that the left ventricular ejection fraction had increased to 65%, and the cardiothoracic ratio improved to 47% according to his chest X-rays.S-1-related myocardial dysfunction may be reversible, as it can improve after approximately 2 weeks.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cardiotoxicity; Drug Combinations; Humans; Male; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur

Topics: Animals; Dog Diseases; Dogs; Drug Combinations; Oxonic Acid; Pilot Projects; Pyridines; Silicates; Stomach Neoplasms; Tegafur; Titanium

Adjuvant chemotherapy has changed the paradigm in resectable gastric cancer. S-1 is an oral chemotherapeutic with promising efficacy in Asia. However, comparisons with close observation or platinum-based doublets post D2 gastrectomy have been less reported, notably on real-world experiences.. We retrospectively evaluated patients with D2-dissected stage IB-III gastric cancer who received S-1 (S-1, n = 67), platinum-based doublets (P, n = 145) and surgery with close observation (OBS, n = 221) from Jan 2008 to Oct 2018. A propensity score matching was used to compare for recurrence-free (RFS) and overall survivals (OS) in patients who had a locally-advanced disease (T3-4 or lymph node-positive). Adverse reactions, dosage, and associated factors for S-1 are also discussed.. In a median follow-up time of 51.9 months, adjuvant S-1 monotherapy was associated with an intermediate survival as compared with P and OBS (median RFS/OS: S-1 vs. P, 20.9/35.8 vs. 31.2/50.5 months, HR = 1.76/2.14, p = 0.021/0.008; S-1 vs. OBS, 24.4/40.2 vs. 20.7/27.0 months, HR = 0.62/0.55, p = 0.041/0.024). The survival differences were more prominent in patients with N2-3 diseases. S-1 was well-tolerated with a relative dose intensity of 73.6%, a median duration of 8.3 months and associated with less adverse reactions as compared with P. S-1 monotherapy was selected by physicians based on age, lymph node stage, serum carcinoembryonic antigen and disease stage.. Adjuvant S-1 correlated with intermediate survival outcomes between OBS and P but conferred fewer adverse reactions as compared with P. Patients with a moderate risk of recurrence had comparable survivals when treated with S-1 while platinum-based doublets were favored in advanced cases. The study provides additional information about adjuvant S-1 in patients with selected risk of recurrence.

Topics: Aged; Chemotherapy, Adjuvant; Drug Combinations; Humans; Middle Aged; Oxonic Acid; Propensity Score; Pyridines; Retrospective Studies; Stomach Neoplasms; Tegafur

Gastric cancer is one of the most common malignancies worldwide, with high morbidity and poor survival rate. Its prognosis remains unsatisfactory, with a 5-year survival rate of <30%. Studies have indicated that Huaier granules have good antitumor efficacy and safety in several solid malignant tumors. Recent studies have also found that Huaier polysaccharides can promote apoptosis in numerous tumor cells, although only few studies have focused on the effects of Huaier granules on gastric cancers and the mechanisms underlying their antitumor role. We retrospectively evaluated stage IIb gastric cancer patients at Xiangya Hospital, Central South University, through our outpatient system from January 2013 to December 2015. Fifty-four patients were in the Huaier+Tegafur Gimeracil Oteracil Potassium (TGOP) group and 72 in the TGOP group. Further, we conducted CCK8, colony formation, Annexin V-FITC/PI, Western blot, RT-PCR, and plasmid transfection assays to analyze the mechanism by which Huaier polysaccharides play an antitumor role. We confirmed that Huaier granules combined with Tegafur Gimeracil Oteracil Potassium could promote patient prognosis, with a better disease-free survival rate (51.32 ± 2.23 vs. 44.19 ± 2.26,

Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Complex Mixtures; Disease-Free Survival; Female; Humans; Inhibitor of Apoptosis Proteins; Male; Middle Aged; Neoplasm Proteins; Potassium; Prognosis; Pyridines; Retrospective Studies; Stomach; Stomach Neoplasms; Survival Rate; Tegafur; Trametes

Limited studies exist comparing clinical outcomes by adjuvant treatment for pT1N1 gastric cancer. This study compared the disease-free survival (DFS) of patients with pT1N1 gastric cancer according to the type of adjuvant treatment-surgery alone, chemotherapy (CTx), and chemoradiotherapy (CCRTx)-and evaluated risk factors for tumor recurrence.. Between 1995 and 2015, 738 patients underwent radical gastrectomy for pT1N1 gastric cancer and were divided into three groups: surgery alone (n = 355), CTx (n = 214), and CCRTx (n = 169). Chronological changes in adjuvant treatment type and chemotherapeutic regimens were evaluated and DFS was compared. Risk factors for tumor recurrence were analyzed.. The proportion of patients who underwent surgery alone was more than 50% until 2001, and the proportion of those who had either CTx or CCRTx was more than 50% from 2002 to 2011, after which the proportion who underwent surgery alone increased again. The main chemotherapeutic agent was 5-fluorouracil with leucovorin. The 5-year DFS was 96.5% in the surgery-alone group, 96.0% in the CTx group, and 95.8% in the CCRTx group (no significant difference). The various chemotherapeutic regimens did not show differences in DFS. In univariate and multivariate analyses, adjuvant CTx and CCRTx showed no beneficial effect with regard to tumor recurrence.. Because adjuvant CTx and CCRTx did not show any benefit with regard to tumor recurrence, these treatment strategies might be unnecessary for pT1N1 gastric cancer after gastrectomy. Further studies are necessary to reveal pT1N1 gastric cancer patient subgroups who might benefit from adjuvant treatments.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemoradiotherapy, Adjuvant; Chemotherapy, Adjuvant; Cisplatin; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gastrectomy; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Oxaliplatin; Oxaloacetates; Oxonic Acid; Pyridines; Radiotherapy Dosage; Stomach Neoplasms; Tegafur

A 51-year-old woman underwent radical operation for a gastric cancer and adjuvant chemotherapy with tegafur, gimeracil, and oteracil potassium. Five and a half years later, screening chest computed tomography(CT)scan showed slight ground glass opacity(GGO)of the both lungs and they were regarded as inflammatory change. Several months later, she experienced a dry cough. CT scan showed aggravation of GGO, and she was refered to our hospital to investigate these lesions 6 years after operation. We performed a wedge resection of right middle lobe. A postoperative pathology revealed metastatic carcinomatous lymphangiosis of gastric cancer. Chemotherapy using capecitabine and oxaliplatin, and then docetaxel was performed and talc pleurodesis was done for the malignant pleural effusion. These treatments did not improve condition, and she died 7 months after lung operation. In conclusion, we need to consider GGO as the possibility of carcinomatous lymphangiosis in case of patient with gastric cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Carcinoma; Chemotherapy, Adjuvant; Docetaxel; Fatal Outcome; Female; Humans; Lung Neoplasms; Middle Aged; Oxaliplatin; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur; Tomography, X-Ray Computed

Six years after primary surgical treatment for gastric cancer, fluoro-deoxy-glucose positron emission tomography/computed tomography was performed in a 72-year-old man, and demonstrated an increased fluoro-deoxy-glucose uptake in the apex of the left ventricle. Magnetic resonance imaging also revealed a solitary small myocardial tumor. Under cardiopulmonary bypass, tumorectomy was performed with a macroscopically sufficient margin. Histopathologic examination showed adenocarcinoma with poor differentiation developed in the myocardium and pericardial fat; these findings were compatible with the previously resected gastric cancer. The postoperative course was uneventful; the patient has been alive for 29 months without any evidence of local recurrence or cardiac events.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Heart Neoplasms; Heart Ventricles; Humans; Magnetic Resonance Imaging; Male; Oxonic Acid; Positron Emission Tomography Computed Tomography; Pyridines; Radiopharmaceuticals; Remission Induction; Stomach Neoplasms; Tegafur

An 80-year-old Japanese woman with chronic renal failure was diagnosed with gastric cancer and 2 primary colon cancers. The colon cancers were treated with laparoscopic colectomy, but the gastric cancer metastasized to the liver with inoperable dissemination. After operative treatment of the colon cancers, 1 year of combination chemotherapy consisting of tegafur/gimeracil/oteracil (TS-1®) and nab-PTX was administered to treat the advanced gastric cancer. Tegafur is a well-known prodrug of 5-FU. Serum densitometry of 5-FU was performed to determine the correct dose of TS-1®. After completion of chemotherapy, no tumor was detected on gastroscopy or dynamic computed tomography. The patient was well with no recurrence 6 months after completion of chemotherapy. CDDP, CPT-11, 5-FU, PTX, and DTX are known chemotherapy agents for treating gastric cancer. Renal excretion is not involved in the metabolism of CPT-11, 5-FU, PTX, or DTX. These agents are metabolized in the liver. CPT-11 metabolism depends on individual hepatic enzymes. Therefore, we believe that nab-PTX and TS-1® are safe and effective agents for patients with chronic renal failure and advanced gastric cancer. Additionally, we also conclude that using serum densitometry of 5-FU to guide the administration of TS-1® can improve both safety and efficacy.

Topics: Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Kidney Failure, Chronic; Oxonic Acid; Paclitaxel; Pyridines; Stomach Neoplasms; Tegafur

Prognosis of patients with metastatic gastric cancer is abysmal, usually just a few months. S-1 is a peroral fluoropyrimidine antitumor drug. It is a fixed combination of three effective drugs - tegafur, gimeracil and oteracil potassium.. This is a case report of a 71-year-old man treated for local advanced and metastatic gastric carcinoma treated with combination of S-1 and cisplatin as a first line of therapy. Treatment response reached partial remission and lasted for six months. Treatment was very well tolerated, with no grade 3 and 4 toxicity. After progression, the patient was treated with further lines of therapy.. In the Czech Republic, experience with S-1 drug is very limited. Our case report showed a good treatment response and minimal toxicity of this treatment, in concordance with results of the study FLAGS.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Czech Republic; Drug Combinations; Humans; Male; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur; Treatment Outcome

Patients with advanced-stage gastric cancer and inoperable locoregional extension rarely survive more than a few months. Chemotherapy based on intravenous fluorouracil or oral capecitabine slightly prolongs overall survival. An oral fixed-dose combination of tegafur + gimeracil + oteracil (Teysuno degrees, Nordic) has been approved in the European Union for the treatment of advanced gastric cancer. Like capecitabine, tegafur is a metabolic precursor of fluorouracil. It is combined with gimeracil in order to increase its bioavailability and with oteracil to try to reduce its gastrointestinal toxicity. In two randomised, controlled but unblinded trials including 91 and 129 patients with advanced gastric cancer, there was no significant difference in median overall survival times between patients who received the tegafur + gimeracil + oteracil combination and those who received oral capecitabine alone (about 9 and 13 months, respectively). However, the study populations were too small to rule out a noteworthy difference in survival between the 2 treatments. Another randomised, unblinded trial compared tegafur + gimeracil + oteracil versus flurorouracil monotherapy in 1029 patients with gastric cancer, which was often metastastic. However, the dose of concomitantly administered cisplatin was lower in the tegafur group, therefore skewing the results. Median overall survival was about 8 months in both groups, and median progression-free survival was about 5 months. Neither outcome differed significantly between the 2 treatments. Compared to capecitabine, the tegafur + gimeracil + oteracil combination appears to cause fewer cases of severe palmoplantar dysaesthesia but more serious gastrointestinal disorders. Like capecitabine, the tegafur + gimeracil + oteracil combination is administered orally twice daily. In practice, when oral therapy is preferred for a patient with advanced gastric cancer, capecitabine is still the best option because it carries a lower risk of serious gastrointestinal adverse effects.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Deoxycytidine; Fluorouracil; Humans; Oxonic Acid; Pyridines; Randomized Controlled Trials as Topic; Stomach Neoplasms; Tegafur

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Combinations; Drug Interactions; Humans; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur

The study is to investigate the pharmacokinetics of S-1 capsule (tegafur, gimeracil and potassium oxonate capsule) in patients with advanced gastric cancer after single and multiple oral administration. Twelve patients with advanced gastric cancer were recruited to the study. The dose of S-1 for each patient was determined according to his/her body surface area (BSA). The dose for single administration was 60 mg every subject. The dose for multiple administration for one subject was as follows: 100 mg x d(-1) or 120 mg x d(-1), 28-days consecutive oral administration. The pharmacokinetic parameters of tegafur, 5-fluorouracil, gimeracil, potassium oxonate and uracil after single oral administration were as follows: (2,207 +/- 545), (220.0 +/- 68.2), (374.9 +/- 103.0), (110.5 +/- 100.8) and (831.1 +/- 199.9) ng x mL(-1) for Cmax; (11.8 +/- 3.8), (4.4 +/- 3.3), (7.8 +/- 5.1), (3.1 +/- 0.9) and (8.8 +/- 4.1) h for t1/2, respectively. After six days oral administration, the average steady state plasma concentrations (Cav) of tegafur, 5-fluorouracil, gimeracil, potassium oxonate and uracil were (2,425 +/- 1,172), (73.88 +/- 18.88), (162.6 +/- 70.8), (36.89 +/- 29.35) and (435.3 +/- 141.0) ng x mL(-1), respectively, and the degree of fluctuation (DF) were (1.0 +/- 0.2), (2.5 +/- 0.4), (3.1 +/- 0.8), (2.4 +/- 0.8) and (1.5 +/- 0.3), respectively. The cumulative urine excretion percentage of tegafur, 5-fluorouracil, gimeracil and potassium oxonate in urine within 48 h were (4.2 +/- 2.8) %, (4.7 +/- 1.6) %, (18.5 +/- 6.0) % and (1.7 +/- 1.2) %, repectively, after single oral administration of S-1. The results exhibited that tegafur had some drug accumulation observed, and gimeracil, potassium oxonate, 5-fluorouracil and uracil had no drug accumulation observed.

Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Capsules; Drug Combinations; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasm Staging; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur; Uracil

Scirrhous gastric carcinoma (SGC) carries the highest mortality because of a frequent metastasis to lymph node (LN). S1, a 5-fluorouracil (5-FU) analog, is clinically available for gastric cancer at an advanced stage. Fibroblast growth factor receptor 2 (FGFR2) is required for the proliferation of SGC. The objective of this study is to clarify the benefit of a combination of S1 and kinase inhibitors including FGFR2 inhibitor Ki23057 in gastric cancer. OCUM-2MLN and KATO-III were derived from SGC. MKN-7 and MKN-74 were derived from non-SGC. MTT assay was used to examine the growth-inhibitory activity of 5 small-synthetic molecules including Ki23057, Sunitinib, Glivec, Lapatinib or SU11274, in cells cultured with 5-FU. Combination effects of 5-FU with Ki23057 on proliferation, apoptosis and mRNA expression were examined. S1 and/or Ki23057 were administered to murine models of SGC created by the orthotopic inoculation of OCUM-2MLN cells. Ki23057 at 100 nM significantly (p < 0.01) inhibited the proliferation and decreased the phosphorylation of FGFR2 in SGC cells, but not in non-SGC. Ki23057 showed synergistic antitumor effects for SGC cells in combination with 5-FU using CalcuSyn analysis, but Sunitinib, Glivec, Lapatinib and SU11274 did not. The combination of Ki23057 and 5-FU decreased DPD expression and increased apoptosis rates and p21 expression level of SGC cells. The combined administration of S1 and Ki23057 significantly (p < 0.05) decreased orthotopic tumors as well as LN metastasis more effectively than S1 alone. These findings suggested that the combined treatment with 5-FU and Ki23057 produced synergistic antitumor effects and is therapeutically promising for SGC treatment.

Topics: Adenocarcinoma, Scirrhous; Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Division; Flow Cytometry; Fluorouracil; Indoles; Mice; Pyridines; Pyrroles; Receptor Protein-Tyrosine Kinases; Receptor, Fibroblast Growth Factor, Type 2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stomach Neoplasms; Sunitinib

Chemosensitivity tests have long been discussed but remain a topic of research. In this study, we investigated the correlation between the results of a chemosensitivity test for 5-fluorouracil and 5-chloro-2, 4-dihydroxypyridine and the clinical outcomes of gastric cancer patients treated with S-1, an oral fluoropyrimidine, as adjuvant chemotherapy.. For gastric cancer patients, we performed surgical treatment and a lymph node dissection of D2 or more. Afterwards, a chemosensitivity test for 5-fluorouracil and 5-chloro-2, 4-dihydroxypyridine was performed, using the collagen gel droplet embedded culture drug-sensitivity test (CD-DST), in surgical specimens. All the patients received postoperative adjuvant chemotherapy with S-1 for 1 year, and the overall survival (OS), relapse-free survival (RFS), and adverse events were investigated.. The chemosensitivity test was performed for 27 patients. The growth inhibition rate (IR) was 50% or more (high-sensitivity group) in 59.3% (16 cases) and it was under 50% (low-sensitivity group) in 40.7% (11 cases). The 3-year OS rate was 100% in the high-sensitivity group and 62.34% in the low-sensitivity group. The 3-year RFS rate was 83.33% in the high-sensitivity group and 24.24% in the low-sensitivity group. Thus, the 3-year OS rate and the 3-year RFS rate were higher in the high-sensitivity group than in the low-sensitivity group. No adverse events of grade 3 or greater severity were observed.. The results of the chemosensitivity test were correlated with the patient outcome. Therefore, such results might be useful for individualizing cancer chemotherapy and for determining future indications for postoperative adjuvant chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Drug Combinations; Female; Fluorouracil; Follow-Up Studies; Humans; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Oxonic Acid; Postoperative Care; Predictive Value of Tests; Pyridines; Stomach Neoplasms; Survival Analysis; Tegafur; Treatment Outcome

A 70-year-old woman who underwent proximal gastrectomy for gastric cancer (poorly-differentiated adenocarcinoma) of Stage IIIB at age 46 visited our hospital April 2004 because of exacerbated pain by movement in the buttocks since November 2003. She showed multiple bone metastasis by CT (computerized tomography). Pancreas cancer or gallbladder cancer was suspected by CT, and a high tumor marker score (CA19-9 18,625 U/mL, DUPAN-II 15,000 U/ mL elevations were acknowledged). Although her symptoms were severe with performance status (PS) 4, she was administered combination chemotherapy with gemcitabine and cisplatin. After 2 cycle therapy, her PS was improved to 2, but the tumor markers had elevated. So we changed the chemotherapy menu to S-1 and gemcitabine. Her tumor markers lowered and PS was improved to 1. There was a remarkable response to this chemotherapy, and the result of CT and bone scintigraphy suggested that her bone metastasis was improved. Because of hematologic relapse due to DIC at 1 year after the first treatment, she was readmitted to our hospital and later died. The autopsical result revealed recurrence of gastric cancer 23 years post-operatively.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Autopsy; Bone Marrow Neoplasms; Bone Neoplasms; Female; Gallbladder Neoplasms; Gastrectomy; Humans; Neoplasm Staging; Oxonic Acid; Pancreatic Neoplasms; Pyridines; Radionuclide Imaging; Stomach Neoplasms; Tegafur; Time Factors; Treatment Failure

The effect of gastrectomy on pharmacokinetics after S-1 administration was investigated in a total of 12 cases - nine in which partial gastrectomy was performed and three in which total gastrectomy was performed. A single oral dose of S-1, 50 mg as tegafur, was administered, serial peripheral blood samples were collected, and the concentrations of 5-fluorouracil (5-FU) and gimeracil (CDHP) were measured. The pre-operative S-1 dose was administered about 7 days before surgery and the post-operative dose was administered around post-operative hospital day 14. In the partial gastrectomy cases the maximum post-operative blood concentration (Cmax) of 5-FU and CDHP tended to be lower than before surgery, and the difference in 5-FU concentrations was significant. The area under the blood concentration-time curve (AUC0-8 h) for CDHP was significantly smaller post- than pre-operatively, but no significant difference was observed with regard to 5-FU. In the total gastrectomy cases the post-operative tmax of both 5-FU and CDHP was shorter than the pre-operative tmax, and no significant differences were observed between the pre- and post-operative AUC0-8 h values. Thus, the results of the present study showed that around post-operative hospital day 14, when total oral feeding had become possible after surgery for gastric cancer, the AUC0-8 h values of 5-FU and CDHP after S-1 administration were almost the same as before surgery and that gastrectomy had hardly any effect on the pharmacokinetics of S-1.

Topics: Administration, Oral; Aged; Antimetabolites, Antineoplastic; Drug Combinations; Female; Fluorouracil; Gastrectomy; Humans; Male; Middle Aged; Oxonic Acid; Pyridines; Stomach Neoplasms; Tegafur; Time Factors

The response of gastric cancer with peritoneal dissemination to systemic chemotherapy may be negatively affected by poor drug delivery due to the blood-peritoneal barrier. However, S-1 has been reported to be effective. We examined the pharmacokinetics of S-1 in 14 patients who had gastric cancer with peritoneal dissemination. S-1 was given from the morning of the day before surgery to the morning of surgery. Concentrations of 5-fluorouracil (5-FU) and gimeracil (CDHP) were measured in the serum, ascites, disseminated peritoneal nodes, and normal peritoneum. There was a strong correlation between 5-FU and CDHP concentrations in peritoneal tissues. The concentrations of 5-FU and CDHP in the serum were similar to those in ascites. The concentration of 5-FU was significantly higher in disseminated nodes than in the normal peritoneum. After administration of S-1 to gastric cancer patients with peritoneal dissemination, 5-FU and CDHP in the serum linearly pass through the peritoneum and enter the ascites. High concentrations of 5-FU selectively penetrate disseminated peritoneal cells.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Biological Availability; Drug Combinations; Female; Fluorouracil; Humans; Lymph Nodes; Male; Middle Aged; Oxonic Acid; Peritoneal Neoplasms; Peritoneum; Pyridines; Stomach Neoplasms; Tegafur

The optimum dose of TS-1 for the treatment of peritoneally disseminated gastric cancer in a patient with chronic renal failure undergoing chronic dialysis was estimated by monitoring the blood concentrations of 5-FU and gimeracil (CDHP) [therapeutic drug monitoring (TDM)] during administration of TS-1. Immediately after dialysis, 50 mg or 40 mg of TS-1, corresponding to 50% and 40% of the standard dose (100mg for this patient), respectively, was administered orally once a day every other day, and TDM was conducted. Compared with the pharmacokinetic parameters of 5-FU at the time of the initial administration of 50 mg or 40 mg of TS-1 and that of cancer patients with normal renal function, the AUC shown in the administration of 40 mg was equivalent to that observed with a single safe dose of 100 mg in patients with normal renal function. Based on this observation, the daily TS-1 dose was set at 40 mg in this patient, and TS-1 treatment was started after confirming the absence of the accumulation of 5-FU or CDHP during repeated administrations. In this treatment protocol, TS-1 was administered 11 times at a daily dose of 40 mg every other day immediately after dialysis, followed by a rest. This .administration schedule was defined as one course. Under these conditions, the patient was treated on an outpatient basis, and the treatment could be safely continued without the development of any severe adverse events, such as myelosuppression.

Topics: Adenocarcinoma; Adult; Antimetabolites, Antineoplastic; Area Under Curve; Drug Administration Schedule; Drug Combinations; Drug Monitoring; Fluorouracil; Gastrectomy; Humans; Kidney Failure, Chronic; Male; Oxonic Acid; Peritoneal Neoplasms; Pyridines; Renal Dialysis; Stomach Neoplasms; Tegafur

In a clinical study, a newly developed anticancer drug, TS-1 capsule, which contained tegafur (FT) and 5-chloro-2,4-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase, was orally administered to five gastric cancer patients (patients 1-5). The total area under the plasma FT concentration-time curve in patient 1 was four-fold higher than in other patients. Since cytochrome P450 2A6 (CYP2A6) has been reported to metabolize FT to yield 5-fluorouracil (5-FU), it was postulated that the poor metabolic phenotype of patient 1 was caused by mutations of the CYP2A6 gene. Thus, alleles for the CYP2A6 genes derived from patient 1 were completely sequenced. It was found that one allele was CYP2A6*4C, which was a whole deleted allele for the human CYP2A6 gene. The other allele was a novel mutant allele (CYP2A6*11) in which thymine at nucleotide 670 was changed to cytosine. The nucleotide change caused an amino acid change from serine at residue 224 to proline. To examine whether or not the amino acid change affected CYP2A6 activity, we expressed an intact or mutant CYP2A6 together with NADPH-P450 oxidoreductase in Escherichia coli, and compared the capacity of the wild and mutant enzymes to metabolize FT to 5-FU. The Vmax value for FT metabolism by the mutant CYP2A6 was approximately one-half of the value of the intact CYP2A6, although the Km values were nearly the same. From these results, we conclude that the poor metabolic phenotype of patient 1 was caused by the existence of the two mutant alleles, CYP2A6*4C and the new variant CYP2A6*11.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Coumarins; Cytochrome P-450 CYP2A6; DNA Primers; DNA, Neoplasm; Drug Combinations; Escherichia coli; Genotype; Humans; Kinetics; Middle Aged; Mixed Function Oxygenases; Mutagenesis, Site-Directed; Oxonic Acid; Polymerase Chain Reaction; Polymorphism, Genetic; Pyridines; Recombinant Proteins; Stomach Neoplasms; Tegafur; Transfection

TS-1(S-1) has been developed as a new oral anticancer drug based on the biological modulation of 5-fluorouracil. We treated a patient with highly advanced gastric carcinoma with a new combination chemotherapy of S-1 and low-dose cisplatin. Remarkable tumor reduction was observed after two cycles of this therapy in the primary tumor and metastatic lymph nodes, and the ascites disappeared. This was concluded to be a partial response. The only adverse effect was skin pigmentation of the fingers (grade 1), leading to early timing of operation after chemotherapy. The gastric tumor showed evident invasion to the serosa. Lymph nodes around the stomach were swollen. Peritoneal dissemination was also recognized in the omentum and mesocolon. Total gastrectomy with regional lymph node dissection was performed. Disseminated tumors were all resected. Histological examination showed that no tumor cells were detected in the gastric primary lesion, metastatic lymph nodes or disseminated peritoneal tumors, suggesting pathological complete remission. It was suggested that this regimen could be a potent combined therapy for the treatment of patients with highly advanced gastric carcinoma, and it could be useful as neoadjuvant chemotherapy. Further studies are necessary to evaluate the efficacy of this therapy.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Combinations; Gastrectomy; Gastroscopy; Humans; Male; Middle Aged; Neoadjuvant Therapy; Oxonic Acid; Peritoneal Neoplasms; Pyridines; Stomach Neoplasms; Tegafur; Tomography, X-Ray Computed; Treatment Outcome

The enhanced effects due to the combined use of oral administration of S-1 and intraperitoneal administration of Cisplatin (CDDP) were examined with gastric cancer xenografts (NUGC 4). S-1, a new anticancer drug, was daily administered at 10 mg/kg (qld x 5 x 3 weeks). 5-FU level in blood was 1 microgram/ml at two hours after the treatment. Antitumor activity was not found in mice with only the CDDP treatment. But antitumor activity by S-1 and daily low-dose (1 mg/kg) or intermittent treatment (5 mg/kg) of CDDP showed better results than daily S-1 treatment. The daily low-dose CDDP treatment showed similar efficacy to the intermittent administration at the same total dose, but the daily low-dose CDDP treatment was better in the light of toxicities. These results suggest that treatment with S-1 and daily low-dose CDDP was effective for gastric cancer.

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Drug Synergism; Humans; Infusions, Parenteral; Mice; Mice, Nude; Neoplasm Transplantation; Pyridines; Stomach Neoplasms; Transplantation, Heterologous