Publications by authors named "Tetsuo Taguchi"

40 Publications

Serum soluble CD26/DPP4 titer variation is a potential prognostic biomarker in cancer therapy with a humanized anti-CD26 antibody.

Biomark Res 2021 Mar 23;9(1):21. Epub 2021 Mar 23.

Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo, Japan.

Background: The phase I trial of the humanized anti-CD26 monoclonal antibody YS110 for CD26-expressing tumors was conducted recently. The present study identifies a potential prognostic biomarker for CD26-targeted therapy based on the phase I data.

Methods: Box and Whisker plot analysis, Scatter plot analysis, Peason product moment correlation/Spearman's rank-difference correlation, Bar graph analysis, and Receiver Operating Characteristics (ROC) were used to examine the correlation between sCD26 titer variation with YS110 administration and tumor volume change, RECIST criteria evaluation and progression free survival (PFS). Mechanism for serum sCD26 titer variation was confirmed by in vitro experimentation.

Results: Serum sCD26/DPP4 titer was reduced following YS110 administration and gradually recovered until the next infusion. Serum sCD26/DPP4 titer before the next infusion was sustained at lower levels in Stable Disease (SD) cases compared to Progressive Disease cases. ROC analysis defined the cut-off level of serum sCD26/DPP4 titer variation at day 29 pre/post for the clinical outcome of SD as tumor response or PFS. In vitro experimentation confirmed that YS110 addition reduced sCD26 production from CD26-expressing tumor and non-tumor cells.

Conclusions: Our study indicates that serum sCD26/DPP4 titer variation in the early phase of YS110 treatment is a predictive biomarker for evaluating therapeutic efficacy.
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http://dx.doi.org/10.1186/s40364-021-00273-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989014PMC
March 2021

[The New Year's Impression of Cancer Acting-How Cope with Cancer ?]

Authors:
Tetsuo Taguchi

Gan To Kagaku Ryoho 2019 Jan;46(1):1-4

Emeritus Professor of Osaka University.

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January 2019

The occurrence of severe rotavirus gastroenteritis in children under 3 years of age before and after the introduction of rotavirus vaccine: a prospective observational study in three pediatric clinics in Shibata City, Niigata Prefecture, Japan.

Jpn J Infect Dis 2014 ;67(4):304-6

Department of Pediatrics, Niigata University Medical and Dental Hospital.

The occurrence of severe rotavirus gastroenteritis (RVGE) in children under 3 years of age before and after the introduction of rotavirus vaccine was prospectively surveyed in three pediatric clinics in Shibata City, Niigata Prefecture, Japan, during the 2011 and 2012 RVGE epidemic seasons. In this observational study, a significantly lower occurrence of severe RVGE among severe gastroenteritis cases was observed in 2012. The incidence rate of severe RVGE among outpatients in 2012 was significantly lower than that in 2011. Despite the significant reduction in severe RVGE, the results must be interpreted with caution because the surveillance period is short and requires extension to conclude whether the reduction in the incidence of severe RVGE is a direct effect of rotavirus vaccination. Therefore, we will continue the survey to evaluate the impact of vaccination.
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http://dx.doi.org/10.7883/yoken.67.304DOI Listing
April 2015

Clinical utility of loop-mediated isothermal amplification for rapid diagnosis of Mycoplasma pneumoniae in children.

J Med Microbiol 2014 Feb 13;63(Pt 2):248-251. Epub 2013 Nov 13.

Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Loop-mediated isothermal amplification (LAMP) is a cost-effective and rapid method for identifying Mycoplasma pneumoniae (MP). We investigated the utility of the LAMP assay in diagnosing MP pneumonia among children in a clinical setting. In this prospective study, the cause of community-acquired pneumonia was evaluated in 111 patients for whom MP was the suspected pathogen. All participants were patients at a city hospital in Japan between April 2012 and September 2012. Throat swabs for the LAMP assay were obtained at admission, and paired serum samples to measure antibody titres to MP by particle agglutination were obtained at admission and during convalescence. Overall, 45 of 111 (41 %) patients had a fourfold or greater increase in MP titres and received a diagnosis of MP pneumonia. Among them, 43 (96 %) patients (median age, 9 years) were positive on the LAMP assay and had a fourfold or greater increase in MP titres. The median interval from fever onset to collection of throat swabs was 7 days (range, 4-10 days). As compared with paired serum titres, the LAMP assay enabled quicker diagnosis of MP (median interval, 13 vs. 7 days), thereby allowing early initiation of appropriate antimicrobial therapy.
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http://dx.doi.org/10.1099/jmm.0.068288-0DOI Listing
February 2014

[Induction chemotherapy for solid tumors].

Authors:
Tetsuo Taguchi

Gan To Kagaku Ryoho 2013 Jun;40(6):679-83

Osaka University,Osaka, Japan.

Surgical treatment for solid malignancies, which is the gold standard for operable tumors, is being combined with nonsurgical modalities with an increasing frequency. Advanced cancers that are not curable by surgery alone are subjected to sophisticated multimodality regimens. Accordingly, the sequence and timing of integrated combined treatment modalities are essential. Traditionally, the common objective of induction chemotherapy has been to reduce the risk of distant disease recurrence. Administration of chemotherapy before other treatment has many theoretical advantages. Induction chemotherapy can result in tumor downstaging, thus increasing the rate of conservative surgery. In cases of more advanced disease, induction chemotherapy can render inoperable tumors resectable. Other advantages of induction chemotherapy include the ability to obtain information about tumor response, which can be used to study the biologic effects of chemotherapy and assess long-term disease-free survival(DFS)and overall survival(OS). Induction chemotherapy as a component of primary treatment has been shown in several studies and meta-analyses to decrease the incidence of metastatic disease. Currently, the terms induction, primary, preoperative, basal and neoadjuvant are all used to describe chemotherapy given as initial treatment. There are 2 methods of induction chemotherapy: intra-arterial induction chemotherapy and induction systemic chemotherapy. The clinical results of several trials of arterial infusion chemotherapy alone as induction chemotherapy for advanced cancer revealed that 20-30% higher response rates can be achieved. However, the benefits of prolonged survival rates and improved quality of life are not consistently realized. Induction arterial infusion chemotherapy did not gain enthusiastic support for several different malignancies. Induction systemic chemotherapy is mainly used in patients with stage II/III disease to improve surgical outcomes and increase the rate of breast-conserving surgery in the breast cancer case, although clinical studies have not revealed a significant improvement in DFS or OS. The favorable response rate and achievement of pathological complete response(pCR)have favorable effects on DFS in breast cancer patients. The available data suggest a minimal benefit for additional chemotherapy after surgery in patients with residual disease. New targets must be identified to develop non-cross-resistant agents for patients with residual disease after prior chemotherapy. New genomic and proteomic tools must be developed to identify predictive markers for response to primary systemic therapy that allow clinicians to develop more personalized therapy, new strategic options, and new biologic agents and avoid unnecessary regimens. The side effects of induction chemotherapy depend on the types of drugs, their doses, and the duration of treatment.
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June 2013

Clinical implications of interleukin-18 levels in pediatric patients with Mycoplasma pneumoniae pneumonia.

J Infect Chemother 2011 Dec 17;17(6):803-6. Epub 2011 Jun 17.

Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medicine and Dental Sciences, Asahimachi, Niigata 951-8510, Japan.

The immunological pathogenesis of Mycoplasma pneumoniae pneumonia is known to involve several cytokines. The serum levels of interleukin-18 (IL-18) were examined using enzyme-linked immunosorbent assay in 23 pediatric patients (median age 6 years; range 4-13 years; 14 girls and 9 boys) with M. pneumoniae pneumonia admitted to our hospital. Serum levels of IL-18 ranged from 22 to 1808 pg/ml with a mean of 543 pg/ml. We started steroid therapy in two cases with IL-18 values greater than 1000 pg/ml without being aware of IL-18 levels. Examination of associations between IL-18 levels determined by enzyme-linked immunosorbent assay and a routine laboratory test showed that levels of lactate dehydrogenase (LDH) and IL-18 were significantly correlated. To determine the appropriateness of steroid administration in M. pneumoniae pneumonia patients, serum LDH should be examined. Patients with elevated levels of LDH are likely to have significantly elevated IL-18 values (≥1000 pg/ml) and thus can be candidates for steroid therapy.
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http://dx.doi.org/10.1007/s10156-011-0265-7DOI Listing
December 2011

Irinotecan overcomes the resistance to 5-fluorouracil in human colon cancer xenografts by down-regulation of intratumoral thymidylate synthase.

Oncol Rep 2010 Oct;24(4):835-42

Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Kawauchi, Tokushima 771-0194, Japan.

To clarify the molecular interaction of irinotecan (CPT-11) and oxaliplatin (l-OHP) in combination with 5-fluorouracil (5-FU), the antitumor effects of CPT-11 and l-OHP combined with the oral 5-FU prodrug, S-1 composed by tegafur, gimeracil and potassium oteracil, were investigated on human colon cancer KM12C xenografts sensitive or resistant to 5-FU in nude mice. In parental KM12C tumor xenografts, combined treatment of CPT-11 with oral S-1 significantly augmented the antitumor activity compared with those of CPT-11 and S-1 alone. Interestingly, combined therapy of CPT-11 with S-1 was markedly effective with almost 90% of inhibition of tumor growth on 5-FU-resistant tumors (KM12C/ 5-FU), and its potency likely corresponded to that in parental tumors. In contrast, combined administration of l-OHP with S-1 did not shown an effect on KM12C/5-FU tumor xenografts. To investigate why only CPT-11 potentiated the anti-tumor activity in combination with 5-FU pro-drugs against 5-FU-resistant colon tumors, the activities or expression levels of thymidylate synthase (TS), ribonucleotide reductase (RNR) and other enzymes in 5-FU-metabolism in both tumors were measured following administration of CPT-11 and/or l-OHP. CPT-11, but not l-OHP, induced a decrease in activities and protein levels of TS and an increase in those of RNR in KM12C/5-FU tumors only, which was likely related to decreased expressions of several proteins in G1/S phase of the cells including CDK4, pRB, and E2F1 in these tumors. These findings suggest that CPT-11, but not l-OHP, would overcome the resistance to 5-FU in combination with 5-FU pro-drugs on 5-FU-resistant colon tumors.
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http://dx.doi.org/10.3892/or.2010.835DOI Listing
October 2010

Prophylactic cefdinir for pediatric cases of complicated urinary tract infection.

Pediatr Int 2011 Feb;53(1):57-61

Department of Pediatrics, Niigata Prefectural Shibata Hospital, Shibata-shi, Nigata, Japan.

Background: This study evaluated the effect of prophylactic cefdinir (3 mg/kg given once daily) for the prevention of recurrent and complicated urinary tract infections (UTI) in pediatric patients.

Methods: The study included 14 infants who were observed for at least 6 months following the first signs of infection (eight boys, six girls; mean age at admission [± SD]: 6.2 [± 7.4] months). Twelve patients had vesico-ureteric reflux (grade I, two; grade II, three; grade III, six; grade IV, one), and two patients had ureteropelvic junction stenosis.

Results: No patients discontinued medication due to diarrhea or other adverse drug reactions. The patients had a 6-month recurrence-free rate of 93% (13/14); only one patient had recurrent UTI. The mean urinary cefdinir concentration was 16.3 [± 11.7]µg/mL; there was considerable variability among individual measurements, even though the samples were collected at similar intervals after drug intake (mean 18.00 [± 2.63] h after dose). However, the lowest measured urinary cefdinir concentration (1.16 µg/mL) was sufficient to eradicate Escherichia coli, one of the most significant causes of UTI. Fecal cultures, obtained at monthly clinic visits during the observation period, indicated that the patients' E. coli strains were very sensitive to cefdinir. No patients were infected with Pseudomonas aeruginosa or other non-fermenting Gram-negative bacilli or fungi.

Conclusions: These results show that cefdinir given 3 mg/kg once daily is very effective and safe for preventing recurrent complicated UTI in infants.
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http://dx.doi.org/10.1111/j.1442-200X.2010.03190.xDOI Listing
February 2011

Phase I study of YM155, a novel survivin suppressant, in patients with advanced solid tumors.

Clin Cancer Res 2009 Jun 26;15(11):3872-80. Epub 2009 May 26.

Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.

Purpose: YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors.

Experimental Design: Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21-day cycles.

Results: Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m(2)/d. The MTD was determined to be 8.0 mg/m(2)/d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m(2)/d. The most common adverse reactions judged to be related to YM155 were urine microalbumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients.

Conclusions: YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m(2)/d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-1946DOI Listing
June 2009

Phase II study of a combination of S-1 and paclitaxel in patients with unresectable or metastatic gastric cancer.

Oncology 2008 10;74(1-2):37-41. Epub 2008 Jun 10.

Department of Clinical Oncology, Hiroshima University, Hiroshima, Japan.

Objectives: A phase II study of weekly paclitaxel combined with S-1, a novel oral fluoropyrimidine, was performed to evaluate the efficacy and tolerability in unresectable or metastatic gastric cancer.

Patients And Methods: Twenty-nine patients with unresectable and/or metastatic gastric cancer were enrolled in the study. Paclitaxel 50 mg/m(2) was administered on days 1 and 8. S-1 was administered orally at 40 mg/m(2) b.i.d. for 14 consecutive days, followed by a 1-week rest. The primary endpoint was the response rate. Secondary endpoints were safety and overall survival.

Results: The overall response rate in 29 patients was 48.3%, differentiated 36.4% and undifferentiated 55.6%. The median survival time was 13.9 months. Grade 3 or higher toxicity was observed in neutropenia (3.4%), diarrhea (3.4%), bilirubin (3.4%) and neuropathy (3.4%).

Conclusions: Combination chemotherapy of weekly paclitaxel and S-1 demonstrated tolerable toxicity and efficacy. This regimen will be one of the initial treatment options for unresectable or metastatic gastric cancer.
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http://dx.doi.org/10.1159/000138978DOI Listing
July 2008

Phase II study of a combination of irinotecan and S-1 in patients with advanced gastric cancer (OGSG0002).

Oncology 2007 12;73(1-2):65-71. Epub 2008 Mar 12.

Department of Gastrointestinal Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka,

Background/aims: To investigate the efficacy and safety of the combination therapy of irinotecan (CPT-11) plus S-1 in patients with advanced gastric cancer at the dose recommended by a previous phase I study.

Methods: A total of 23 patients received 80 mg/m(2) of CPT-11 on days 1 and 15, and S-1 at a dose level set on the basis of the body surface area (BSA): 40 (BSA <1.25 m(2)), 50 (BSA > or =1.25 to <1.5 m(2)) or 60 mg (BSA > or =1.5 m(2)) b.i.d. was given from days 1-21.

Results: The overall response rate was 47.8% (11 of 23, 95% confidence interval, CI: 27.4-68.2%). The median time to progression (TTP) was 210 days (95% CI: 145-322 days) and the median survival time was 394 days (95% CI: 241-484 days). The incidence of grade 3 or 4 hematological and non-hematological toxicity was 17.4 and 8.7%. The most common hematological toxicity was anemia and the most common non-hematological toxicity was diarrhea.

Conclusion: The combination therapy of CPT-11 and S-1 provided prolonged TTP with low toxicity, and the results warrant a further phase III study to define the efficacy in improvement of survival in patients with advanced gastric cancer.
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http://dx.doi.org/10.1159/000120630DOI Listing
April 2008

Multicenter phase II study of irinotecan plus bolus fluorouracil/l-leucovorin for metastasic colorectal cancer.

Anticancer Res 2007 Mar-Apr;27(2):1003-8

Department of Gastroenterogical Surgery, Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka 540-0006, Japan.

Unlabelled: Treatment of metastatic colorectal cancer remains inadequate.

Patients And Methods: In a multicentre Phase II study, irinotecan (100 mg/m2), 5-fluorouracil (5-FU) (500 mg/m2), and l-leucovorin (l-LV) (250 mg/m2) were administered on days 1, 8, and 15 of a five-week cycle. Forty-five patients were enrolled.

Results: The objective response rate was 26.7%. The median survival time was 21.8 months and the one-year survival rate was 73.3%. The median number of cycles was 4.0, with a median relative dose intensity of 83.3% for both irinotecan and 5-FU. Grade 3 or 4 haematological toxicities were anaemia in four patients, leukopaenia in six patients, and neutropaenia in 15 patients, while non-haematological toxicities were diarrhoea in three patients, and nausea, vomiting, anorexia and increased transaminases in two patients each. No treatment-related deaths occurred.

Conclusion: Irinotecan plus 5-FU/l-LV can be used to treat metastatic colorectal cancer on an outpatient basis.
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May 2007

[A randomized controlled study comparing uracil-tegafur (UFT)+tamoxifen (UFT+TAM therapy) with cyclophosphamide+adriamycin+5-fluorouracil (CAF therapy) for women with stage I , II, or IIIa breast cancer with four or more involved nodes in the adjuvant setting].

Gan To Kagaku Ryoho 2006 Oct;33(10):1423-9

Osaka Medical Center for Cancer and Cardiovascular Diseases.

We performed a controlled study to compare the response to cyclophosphamide (CPA), adriamycin (ADM), and fluorouracil (5-FU) (CAF therapy) with that to uracil-tegafur (UFT) plus tamoxifen (TAM) (UFT+TAM therapy), when given as postoperative adjuvant therapy to women with breast cancer. The patients were registered from September 1991 through February 1995 at 51 institutions in the Kinki district of Japan. All patients had stage I, II, or IIIa breast cancer with four or more lymph-node metastases and underwent mastectomy. CAF therapy and UFT+TAM therapy were started within 4 weeks after surgery. CAF therapy consisted of CPA (100 mg/day) on days 1 to 14, followed by 2 weeks of rest, plus ADM (20 mg/m(2)/day) on days 1 and 8 and 5-FU (300 mg/m(2)/day) on days 1 and 8. A total of 6 courses were delivered. UFT+TAM therapy consisted of 3 years of UFT (400 mg/day) plus TAM (20 mg/day), given daily. CAF therapy and UFT+TAM therapy were each assigned to 82 patients. The 5-year survival rate was significantly higher in the UFT+TAM group (82.1%) than in the CAF group (66.2%; p=0.04, logrank test). The 5-year relapse-free survival rate was higher in the UFT+TAM group (61.8%) than in the CAF group (46.3%; p=0.07, logrank test). As for adverse events, the rates of leukopenia, anorexia, nausea and vomiting, general malaise, and hair loss were lower in the UFT+TAM group than in the CAF group. These results suggest that long-term treatment with UFT+TAM may be a useful alternative adjuvant therapy for the management of breast cancer, especially in elderly patients.
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October 2006

[Pharmacokinetics of S-1].

Gan To Kagaku Ryoho 2006 Jun;33 Suppl 1:27-35

Dept of Surgery (Section 1), Sapporo Medical University, Japan.

S-1 is an attractive oral fluorouracil antitumor drug, which is being called "a self-rescuing drug". This novel oral fluoropyrimidine is combined with three pharmacological agents: tegafur (FT) which is a prodrug of 5-fluorouracil (5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) activity, and potassium oxonate (Oxo) which reduces gastrointestinal toxicity. Phase I and an early phase II clinical trials were performed about ten years ago, and these results had already been introduced to the Journal "Clinical Cancer Research Vol. 5, pages 2000-2005, 1999". The data of this article in this journal was referred from the results of the figures and tables based on the above trial. Most of the authors in this article have contributed on that pharmacokinetics study and published the above manuscripts. In that study, the pharmacokinetics of 5-FU, intact FT, CDHP and Oxo after administration of the standard dose of S-1 had been performed. These studies were carried out at two hospitals, Department of Surgery (Section 1) Sapporo Medical University and Chemotherapy Cancer Center, Cancer Institute Hospital and Japanese Foundation for Cancer Research (Ohtsuka). The number of patients accepted for this trial is twelve, 5 patients with gastric cancer, 4 with colorectal cancer and 3 with breast cancer. Single administration trial was referred to all patients, but consecutive administration trial was limited to ten patients. The results of plasma concentration, Cmax, Tmax, AUC0-14, and T1/2 of 5-FU, FT, CDHP, and Oxo were ascertained in details. It was a surprise that the indicated data was very similar to that of the intravenous 5-FU continuous infusion. Therefore, the low dose administration of 5-FU (FT) as S-1 may result in good antitumor effects with minimum adverse effects to the patients.
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June 2006

[Timeline from discovery of 5-FU to development of an oral anticancer agent S-1 and its drug concept].

Gan To Kagaku Ryoho 2006 Jun;33 Suppl 1:4-18

Kitasato Institute for Life Science, Kitasato University.

C. Heidelberger et al left great gifts to us. Approximately 50 years have elapsed since their discovery of 5-FU in 1957 before eventually elucidating the mechanisms by which the drug exerts its pharmacological actions and provokes its adverse reactions. Namely, 5-FU is a typical antimetabolite with strong time dependency, and continuous venous infusion(CVI) is considered to be its optimal regimen. The following facts may be mentioned to explain why such a long period of time has been spent to reach this level of research: 1) 5-FU, when administered to the living individual, is mostly inactivated by hepatic catabolic enzymes without delay and is then excreted in the urine, thus making it difficult to precisely analyze the relationship of blood 5-FU concentrations with concentration persistence, anticancer activity, and adverse reactions; and 2) unlike other anticancer agents, an antimetabolite 5-FU separately generates metabolites which show anticancer activity and adverse reactions, as well as metabolites which show adverse reactions only. For the last 30 years, we paid attention especially to 5-FU among chemotherapeutic agents for cancer and have sought for a long-lasting therapeutic modality which maintains quality of life of the patient and patient compliance by considering the balancing between its effects and adverse reactions. Consequently, we concretized an innovative therapeutic drug, TS-1 (S-1). We have a long history of research before developing S-1, which is represented by a series of investigations consisting in the developments of Futrafur (FT)--an oral anticancer agent of a 5-FU derivative (prodrug)-in 1970 subsequent to the above discovery of 5-FU, of UFT(FT: Ura=1 : 4) in 1976, and of S-1 in 1999. To date, we took the initiative in the world to devise S-1, the first self-rescuing concept(SRC)-based anticancer agent with dual actions, i.e., enhancement of pharmacological actions of 5-FU and reduction of its adverse reactions, by making use of the biochemical and enzymological properties of 5-FU and by combining FT, which is gradually converted to 5-FU in the body, with a 5-FU's effect-enhancing substance and a 5-FU's adverse reaction-reducing substance. S-1 is an oral anticancer agent in capsule, in which the following 2 modulators for 5-FU are combined to FT: one is CDHP(5-chloro-2,4-dihydroxypyridine) which increases blood concentrations and enhances pharmacological actions of 5-FU by potently inhibiting the degradation of 5-FU; and another is Oxo(potassium oxonate) which is localized in the mucosa of the gastrointestinal (GI) tract after oral administration and reduces GI toxicities provoked by 5-FU. S-1 is an oral anticancer agent in which these 3 components, FT, CDHP, and Oxo, are combined at a molar ratio of 1 : 0.4 : 1. Our conception to develop an SRC-based therapeutic drug and the preclinical concepts validated by numerous basic studies were demonstrated also in the clinical trials. In January 1999, S-1 was approved for the treatment of advanced and recurrent gastric cancers through the priority review system. From 2001 to 2005, S-1 was approved for the treatment of head and neck cancer, colon cancer, non-small cell lung cancer, and breast cancer. S-1 has been applied to acquire its expanded indications for the treatment of pancreatic cancer and biliary tract cancer. We are confident that the combined regimen of S-1 with other anticancer agents and with other therapeutic modalities will contribute to the routine medical practice of cancer treatment in the future.
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June 2006

[Trend to adjuvant systemic treatment regimens for patients with early breast cancer--meeting highlights of St. Gallen Conference 2005].

Authors:
Tetsuo Taguchi

Gan To Kagaku Ryoho 2006 May;33(5):567-83

Osaka University.

The 9th International Expert Consensus Meeting on the Primary Therapy of Early Breast Cancer 2005, with 4166 participants from 78 countries, was held in January 2005 in St. Gallen, Switzerland. Its consensus recommendations were summarized in the Annals of Oncology (16:1569-1583, 2005), published on Sept. 7 that year. The Meeting made a fundamental change in the algorithm for selection of adjuvant systemic therapy for early breast cancer. Rather than the earlier approach commencing with risk assessment, the Panel affirmed that the first consideration was endocrine responsiveness. Three categories were acknowledged:endocrine responsive, endocrine non-responsive and tumors of uncertain endocrine responsiveness. The three categories were further divided according to menopausal status. Only then did the Panel divide patients into low-, intermediate-and high risk categories. It agreed that axillary lymph node involvement did not automatically define high risk. Intermediate risk included both node-negative disease (if some features of the primary tumor indicated elevated risk) and patients with one to three involved lymph nodes without additional high-risk features such as HER 2/neu gene over expression. The Panel recommended that patients be offered chemotherapy for endocrine non-responsive disease; endocrine therapy as the primary therapy for endocrine responsive disease, adding chemotherapy for some intermediate-and all high-risk groups in this category; and both chemotherapy and endocrine therapy for all patients in the uncertain endocrine response category except those in the low-risk group.
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May 2006

Prospective randomized trial of natural interferon-alpha versus natural interferon-alpha plus cimetidine in advanced renal cell carcinoma with pulmonary metastasis.

J Cancer Res Clin Oncol 2006 Aug 4;132(8):499-504. Epub 2006 Apr 4.

Department of Urology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537-8511, Japan.

Purpose: In a preliminary non-randomized study, combination therapy with natural (i.e. non-recombinant) interferon-alpha plus cimetidine obtained a high response rate in patients with advanced renal cell carcinoma. We conducted a prospective randomized phase III trial to determine whether combination therapy with natural interferon-alpha plus cimetidine is superior to natural interferon-alpha alone in patients with advanced renal cell carcinoma with pulmonary metastasis.

Methods: Patients received 5 million units (MU) natural interferon-alpha per day, five times a week, or the 5 MU natural interferon-alpha regimen plus a daily oral cimetidine. The primary and secondary end points were the response rate, and the time to progression (TTP), respectively.

Results: Between April 1998 and March 2002, 71 patients from 32 institutions were randomly assigned to the 2 treatment groups. One patient in each group did not receive any natural interferon-alpha whatsoever. Two patients in the natural interferon-alpha alone group stopped treatment: on day 9 and on day 10, respectively. In the intent-to-treat analysis, 1 complete response (CR), 4 partial responses (PRs), 16 no changes (NCs), and 12 progressive diseases (PDs) were observed among the 36 patients in the interferon-alpha alone group with a response rate of 13.9%. Of the 35 patients in the natural interferon-alpha plus cimetidine group, there were two CRs, 8 PRs, 13 NCs, and 11 PDs, yielding a response rate of 28.6% (P=0.13). TTP ranged from 9 to 845 days (median 112 days) in the natural interferon-alpha-alone group, and from 31 to 1,568 days (median 125 days) in the natural interferon-alpha plus cimetidine group (P=0.87).

Conclusions: Combined treatment with natural interferon-alpha plus cimetidine for advanced renal cell carcinoma did not result in a significant improvement in response rates or TTP compared to natural interferon-alpha therapy alone.
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http://dx.doi.org/10.1007/s00432-006-0095-7DOI Listing
August 2006

A pilot phase II study of capecitabine in advanced or recurrent breast cancer.

Breast Cancer 2006 ;13(1):49-57

Department of Clinical Research and Surgery, National Hospital Organization Shikoku Cancer Center.

Background: A pilot phase II study was conducted to evaluate the efficacy and safety of the Japanese intermittent regimen of capecitabine (Xeloda) in patients with advanced or recurrent breast cancer.

Methods: A total of 23 patients who had received no more than one prior chemotherapy regimen received oral 828 mg/m2 capecitabine twice daily for 3 weeks followed by a 1-week rest period. The response to capecitabine was evaluated in 22 patients (one patient ineligible).

Results: The overall response rate was 45.5% (95% CI, 24.4-67.8%), including 1 complete response (4.5%) and 9 patients with partial response (40.9%). A further 7 patients (31.8%) had stable disease. The median duration of response was 7.2 months (range, 3.0-15.8 months) and the median time to progression was 6.4 months (95% CI, 4.1-15.1 months). Treatment-related adverse events >or= grade 3 were observed in 7 patients (30.1%).

Conclusion: Intermittent capecitabine therapy (828 mg/m(2) twice daily for 3 weeks followed by a 1-week rest period) was shown to be effective and well tolerated as second-line treatment for advanced or recurrent breast cancer. The Japanese regimen is worthy of further study in larger numbers of patients in phase II / III clinical trials.
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http://dx.doi.org/10.2325/jbcs.13.49DOI Listing
May 2006

Phase I and pharmacokinetic study of S-1 combined with weekly paclitaxel in patients with advanced gastric cancer.

Oncology 2005 25;69(5):414-20. Epub 2005 Nov 25.

Department of Surgery, Osaka National Hospital, Japan.

Objective: A dose-escalation study of weekly paclitaxel combined with S-1, a novel oral fluoropyrimidine, was performed to determine the maximum tolerated dose (MTD), the recommended dose (RD) and the dose-limiting toxicities (DLTs) in advanced gastric cancer.

Patients And Methods: Twelve patients were enrolled. S-1 was given orally at a fixed dosage of 40 mg/m(2) b.i.d. for 14 consecutive days, followed by a 1-week rest. Paclitaxel was scheduled to be given intravenously on days 1 and 8 at a dose of 50, 60, 70 or 80 mg/m(2), depending on the DLTs. Treatment was repeated every 3 weeks. A pharmacokinetic study was conducted in an additional 5 patients on days 7 and 8 during the first course given at the RD.

Results: The MTD of paclitaxel was presumed to be 60 mg/m(2), because 50.0% of patients (2/4) developed DLTs (mainly grade 3 anorexia). DLT was observed in 1 out of 8 patients at a dose of 50 mg/m(2). Therefore, the RD of paclitaxel was estimated to be 50 mg/m(2). The preliminary response rate was 62.5% (5/8) at the RD. There were no significant pharmacokinetic interactions between S-1 and paclitaxel. An adequate plasma paclitaxel concentration for an antineoplastic effect was achieved with weekly doses of 50 mg/m(2).

Conclusion: Weekly paclitaxel combined with S-1 was demonstrated to exhibit a tolerable toxicity profile with therapeutic plasma concentration at the dose of 50 mg/m(2). This regimen could represent a novel and low toxic combination for advanced gastric cancer.
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http://dx.doi.org/10.1159/000089996DOI Listing
January 2006

[Clinical study of porous gelatin sphere (YM 670) in transcatheter arterial embolization].

Gan To Kagaku Ryoho 2005 Oct;32(10):1431-6

Dept. of Radiology, Osaka City University Medical School Hospital.

A clinical study on the use of porous gelatin particles(sterile gelatin embolization material, YM 670, Gelpart) in transcatheter arterial embolization (TAE) was performed in patients with hepatocellular carcinoma, and the efficacy (embolization,anti-tumor effect, recanalization and operationality) and safety (tolerability) were studied. An additive agent comprising porous gelatin particles and low osmolarity contrast media was administered peripherally through a catheter into the hepatic artery proper of 63 patients with hepatocellular carcinoma. Good hepatic arterial embolization was confirmed in all cases (embolization: 100%), and a tumor necrosis effect was obtained in most cases (35/62 patients, 56.5%). Moreover, operationality was assessed as "highly easy to use" or "easy to use" in all cases. Frequencies of adverse events in which a relationship to TAE was not excluded and abnormalities of clinical laboratory data were high at 71.4% and 9 8.4%, respectively. The most common adverse reactions were pyrexia, abdominal pain, queasiness and blood pressure increase;abnormalities in clinical laboratory data included hepatic function with increased AST (GOT), increased ALT (GPT), decreased cholinesterase, increased LDH and increased total bilirubin. These adverse reactions and abnormalities in clinical laboratory data, however, were transient and attributed to the TAE procedure itself, and no adverse reactions related to YM 670 as an embolic material were observed. In addition, with regard to tolerability (safety), the treatment was assessed as suitable for use in all the present cases.
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October 2005

Phase I study of S-1 combined with irinotecan (CPT-11) in patients with advanced gastric cancer (OGSG 0002).

Jpn J Clin Oncol 2005 Sep 1;35(9):520-5. Epub 2005 Sep 1.

Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan.

Objective: A dose-escalation study of irinotecan (CPT-11) combined with S-1, a novel oral fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD) and dose-limiting toxicities (DLTs) in advanced gastric cancer.

Methods: S-1 was administered orally at 80 mg/m(2)/day for 21 consecutive days followed by a 2 week rest. CPT-11 was given intravenously on days 1 and 15 of each course, at an initial dose of 40 mg/m(2)/day, stepping up to 60, 80, 100 or 120 mg/m(2)/day depending on the DLT. Courses were repeated every 5 weeks, unless disease progression or severe toxicity was observed. At a level of the RD, five patients were added to conduct a pharmacokinetic (PK) study.

Results: A total of 24 patients were entered in this study. The MTD of CPT-11 was considered to be 100 mg/m(2), because 50% of the patients (3/6) developed DLTs, diarrhea and rash. Therefore, the RD of CPT-11 was set at the dose immediately below 80 mg/m(2). The overall response rate (RR) by the criteria of the Japanese Research Society of Gastric Cancer was 58.3% (14/24) and the RR at the RD was 66.7% (6/9), suggesting promising clinical efficacy. There were no significant differences between the PK parameters of S-1 on days 10 and 15.

Conclusions: S-1 with CPT-11 can be combined safely without CPT-11 effect on S-1 PK data and holds promise as an effective regimen for advanced gastric cancer.
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http://dx.doi.org/10.1093/jjco/hyi148DOI Listing
September 2005

A Japanese phase I study of continuous oral capecitabine in patients with malignant solid tumors.

Int J Clin Oncol 2005 Feb;10(1):51-7

Department of Clinical Research and Surgery, National Hospital Organization Shikoku Cancer Center, Ehime, Japan.

Background: This study aimed to evaluate the tolerability and pharmacokinetics of capecitabine, given twice daily for 6 weeks without interruption, and to identify the maximum tolerated dose (MTD) and the suggested phase II schedule.

Methods: The initial dose of capecitabine was 251 mg/m2 twice daily, without interruption, and a dose escalation schedule was planned according to a modified Fibonacci scheme. Patients received oral capecitabine twice daily for at least 6 weeks unless grade 3 or 4 toxicity was observed. Blood and urine samples were collected for pharmocokinetic analysis on days 1 and 15.

Results: Sixteen patients with malignant solid tumors (seven breast, seven colorectal, and two gastric) were enrolled, all of whom were evaluable. Among 4 patients treated with capecitabine 1255 mg/m2 twice daily, one experienced grade 4 hemorrhagic gastric ulcer and one experienced grade 3 skin toxicity. Consequently, this dose was defined as the MTD, and gastrointestinal and cutaneous effects were identified as dose-limiting toxicities. There was no grade 3/4 diarrhea at any dose level. There was also no grade 4 hematologic toxicity at doses below the MTD, and there were no treatment-related deaths. Two patients with breast cancer had partial responses, at capecitabine doses of 502 mg/m2 and 1255 mg/m2, twice daily. Pharmacokinetic data show that high concentrations of doxifluridine (5'-DFUR) occur in tumor cells within 2 h after administration of capecitabine.

Conclusion: The MTD of continuous oral capecitabine over 6 weeks was 1255 mg/m2 twice daily. Because of the higher occurrence of skin disorders reported in this study with a continuous treatment regimen, an intermittent treatment regimen of 828 mg/m2, administered twice daily for 3 weeks, followed by a 1-week rest period, was recommended for phase II studies. This regimen is being evaluated in phase II studies in Japanese patients with gastric, colorectal, and breast cancers.
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http://dx.doi.org/10.1007/s10147-004-0460-yDOI Listing
February 2005

A phase II study of S-1 in patients with metastatic breast cancer--a Japanese trial by the S-1 Cooperative Study Group, Breast Cancer Working Group.

Breast Cancer 2004 ;11(2):194-202

Department of Clinical Research and Surgery, National Shikoku Cancer Center Hospital, Horinouchi 13, Matsuyama 790-0007, Japan.

Background: S-1 is a newly developed novel oral dihydrouracil dehydrogenase inhibiting fluoropyrimidine drug consisting of 1 M tegafur (FT), 0.4 M 5-chloro-2, 4-dihydroxypyrimidine (gimeracil), and 1 M potassium oxonate (oteracil), with efficient antitumor activity and low gastrointestinal toxicity which is widely used in Japan against advanced gastric, head and neck cancers. We investigated its clinical efficacy against metastatic breast cancer.

Methods: A non-blind phase II study was carried out to evaluate the efficacy and toxicity in metastatic breast cancer patients. Patients with measurable metastasis foci (n=111) were enrolled, and 108 patients were regarded as eligible. S-1 was administered orally at a standard dose of 80 mg/m2/day b.i.d. One course consisted of 28 consecutive days of administration followed by a 14-day rest, and courses were repeated up to six times.

Results: Among the eligible patients, 10 had a complete response and 35 had a partial response, with an overall response rate (CR+PR) of 41.7% (95% confidence interval: CI, 32.3-51.5%). The incidences of toxicity (> or =grade 3) were neutropenia 9.1%, anemia 0.9%, anorexia 3.6%, stomatitis 1.8%, nausea/vomiting 1.8%, diarrhea 0.9%, and fatigue 2.7%, however no treatment-related deaths were observed. The median survival time was 872 days (95% CI, 572-1,110 days). There was no difference in response rate or toxicity between the under 65-year-old group and the older group.

Conclusion: S-1 was demonstrated to have high efficacy with low gastrointestinal toxicity even in older patients and will be a promising new chemotherapy drug for metastatic breast cancer.
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http://dx.doi.org/10.1007/BF02968301DOI Listing
December 2004

A pilot phase II study of capecitabine in advanced or recurrent colorectal cancer.

Jpn J Clin Oncol 2004 Apr;34(4):195-201

Department of Surgery, Sapporo-Kosei General Hospital, Kita-3, Higashi-8, Chuo-ku, Sapporo, Hokkaido 060-0033, Japan.

Background: A pilot phase II study was conducted to evaluate the Japanese intermittent regimen of capecitabine in patients with advanced/recurrent colorectal cancer.

Methods: Twenty-two patients received oral capecitabine in a dose of 828 mg/m(2) twice daily for 3 weeks every 4 weeks.

Results: In the 20 patients evaluable for efficacy, the overall response rate was 25.0% (95% CI, 8.7-49.1%), rising to 33.0% in the subset of patients previously untreated for metastatic disease (n = 9). A further nine patients had stable disease. The median duration of response was 7.0 months. Five patients (22.7%) experienced grade 3/4 treatment-related adverse events, the most common being a bullous rash observed in two patients (9.1%).

Conclusions: The 3 weeks out of 4 intermittent regimen of capecitabine demonstrated good antitumor activity and tolerability in patients with advanced/refractory colorectal cancer, providing a clear rationale for conducting a larger phase II study in patients with advanced disease.
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http://dx.doi.org/10.1093/jjco/hyh034DOI Listing
April 2004

[A late phase II clinical study of S-1 in patients with progressed, refractory breast cancer].

Gan To Kagaku Ryoho 2004 Apr;31(4):539-47

Dept. of Clinical Research & Surgery, National Shikoku Cancer Center Hospital.

A late phase II clinical study of S-1 against advanced or refractory breast cancer was done by 37 institutes in Japan. S-1 was administered twice daily at 80, 100 or 120 mg/body/day consecutively for 28 days followed by 14 days of rest (1 course). Eighty-three patients were enrolled and 81 were eligible for the study. The response ratio was 42.0% with 6 CR and 28 PR and its 95% confidence interval for the response was 31.1 to 53.5%. The median survival period was 910 days (95% confidence interval was 493-1, 083 days). The observed major adverse reactions (> or = grade 2) were as follows: hematological toxicities: leukopenia 21.0% (17/81), neutropenia 28.4% (23/81), erythropenia 4.9% (4/81); gastrointestinal toxicities: anorexia 9.9% (8/81), nausea and vomiting 12.3% (10/81), diarrhea 8.6% (7/81), stomatitis 1.2% (1/81), and fatigue 8.6% (7/81). The severe adverse reactions (> or = grade 3) were as follows; hematological toxicities: neutropenia 8.6% (7/81), anorexia 4.9% (4/81), fatigue 3.7% (3/81), nausea and vomiting 1.2% (1/81), diarrhea 1.2% (1/81), stomatitis 1.2% (1/81). Grade 4 adverse reactions (neutropenia and fatigue) were observed only in 1 patient. The ratio without hospitalization was 87.7%. These results strongly suggest the superior efficacy and safety of S-1 against patients suffering from advanced, refractory breast cancer. Therefore, S-1 may be a new therapeutic agent to prolong the survival period of breast cancer patients due to its high antitumor activity and low toxicity.
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April 2004

[30th anniversary of the Japanese journal of cancer and chemotherapy publications].

Authors:
Tetsuo Taguchi

Gan To Kagaku Ryoho 2003 Oct;30(10):1412-5

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October 2003

[Development of marine-derived anti-cancer compounds].

Authors:
Tetsuo Taguchi

Gan To Kagaku Ryoho 2003 May;30(5):579-88

Osaka University.

The marine environment offers a rich source of natural products with potential therapeutic application. Marine organisms have evolved the enzymatic capability to produce potent chemical entities that make them promising sources of innovative cytotoxic compounds. Prominent in the identification and development of novel anti-cancer agents from marine sources is the Spanish biotechnology company, Pharma Mar, which currently has a large number of oncology products in late preclinical and clinical development. These include: Ecteinascidin-743 (ET-743), Aplidin, Kahalalide F and ES-285. Many of these innovative compounds have novel mechanisms of anti-tumor action that have yet to be fully elucidated.
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May 2003

Challenge and opportunities in the treatment of gastric cancer.

Gastric Cancer 2002 ;5 Suppl 1:1-3

Japan Society for Cancer Chemotherapy, 505, 1-18-35 Edobori, Nishi-ku, Osaka 550-0002, Japan.

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http://dx.doi.org/10.1007/s10120-002-0206-3DOI Listing
June 2003

Phase I study of docetaxel and cyclophosphamide in patients with advanced or recurrent breast cancer.

Breast Cancer 2003 ;10(2):140-8

Department of Surgery, Tokyo Women's Medical University Daini Hospital, 2-1-10 Nishiogu, Arakawa-ku, Tokyo 116-8567, Japan.

Background: A phase I clinical study of combination chemotherapy with docetaxel and cyclophosphamide (CPA) was performed to determine the maximum tolerated dose (MTD), the incidence and severity of toxicities and the pharmacokinetics in patients with advanced or recurrent breast cancer.

Methods: Docetaxel was administered by intravenous drip infusion over 60 minutes, followed by intravenous bolus injection of CPA every 3-4 weeks. The dosage of docetaxel/CPA was 40/200, 40/400, 50/400, or 60/400 mg/m(2)/day.

Results: Fifteen patients were enrolled and received a total of 33 cycles of the combined therapy. The dose limiting toxicities (DLTs) were leukopenia, neutropenia and thrombocytopenia. The MTD was estimated to be docetaxel 60 mg/m(2) in combination with CPA 400 mg/m(2) per day. Plasma clearance of both drugs was similar regardless of dose. The recommended doses of docetaxel/CPA for a phase Utrial are 50/400 mg/m(2)/day every 3-4 weeks.

Conclusion: The MTD of this combined therapy was docetaxel 60 mg/m(2) and CPA 400 mg/m(2). Neutropenia and leukopeina were common and severe. It is important to stress the need for modification of the dosing scheme.
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http://dx.doi.org/10.1007/BF02967639DOI Listing
November 2003

A pilot phase II study of capecitabine in advanced or recurrent gastric cancer.

Oncology 2003 ;64(3):232-6

Department of Gastroenterology, East Hospital, Kitasato University School of Medicine, 2-1-1 Asamizodai, Sagamihara City, Kanagawa 228-8520, Japan.

Objectives: To evaluate the efficacy and safety of capecitabine in patients with advanced or recurrent gastric cancer, we conducted a pilot phase II study in Japan.

Methods: Patients with advanced or recurrent gastric cancer were given oral capecitabine 828 mg/m(2) twice daily for 3 weeks, followed by 1 week of no treatment. Two or more cycles were administered. From July 1996 to December 1997, 32 patients were enrolled in the study. The response to capecitabine was evaluated in 31 patients, excluding 1 found to be ineligible.

Results: The overall response rate was 19.4% (6/31, 95% confidence interval: 7.5-37.5%). The median duration of response was 124.5 days, the median time to disease progression 85.0 days, and the median survival time 247.5 days. Drug-related adverse events of grade 3 or higher were infrequent: in 2 patients (6.3%) total bilirubin concentration increased, and 1 patient (3.1%) each had elevation of GOT, anemia, lymphopenia, increased creatinine, and hand-foot syndrome. No patient had gastrointestinal toxicity of grade 3 or higher.

Conclusion: Capecitabine was suggested to be safe and effective in the treatment of advanced or recurrent gastric cancer. Further phase II studies of capecitabine on a large scale are warranted.
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http://dx.doi.org/10.1159/000069313DOI Listing
May 2003
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