Prodrug Of 5-fluorouracil Research Articles

959 FEASIBILITY OF BIOCHEMICAL MODULATION CHEMOTHERAPY WITH UFT, CISPLATIN, AND DEXAMETHASONE FOR DOCETAXEL-REFRACTORY PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (III)1 Apr 2013959 FEASIBILITY OF BIOCHEMICAL MODULATION CHEMOTHERAPY WITH UFT, CISPLATIN, AND DEXAMETHASONE FOR DOCETAXEL-REFRACTORY PROSTATE CANCER Katsuhiro Fukuta, Hiromichi Naruyama, Masahito Hirose, Hiroki Kubota, Noriyasu Kawai, Keiichi Tozawa, Kenjiro Kohri, and Kenjiro Kohri Katsuhiro FukutaKatsuhiro Fukuta yatomi, Japan More articles by this author , Hiromichi NaruyamaHiromichi Naruyama yatomi, Japan More articles by this author , Masahito HiroseMasahito Hirose yatomi, Japan More articles by this author , Hiroki KubotaHiroki Kubota yatomi, Japan More articles by this author , Noriyasu KawaiNoriyasu Kawai nagoya, Japan More articles by this author , Keiichi TozawaKeiichi Tozawa nagoya, Japan More articles by this author , Kenjiro KohriKenjiro Kohri nagoya, Japan More articles by this author , and Kenjiro KohriKenjiro Kohri nagoya, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.540AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Docetaxel-based systemic chemotherapy has been shown to be useful for the management of castration-resistant prostate cancer (CRPC). However, reports on drug therapy for docetaxel-refractory prostate cancer are scarce. We evaluated the effectiveness of UFT (a prodrug of 5-fluorouracil [5-FU]), cisplatin, plus dexamethasone in patients with docetaxel-refractory prostate cancer. METHODS Fifty-six patients with CRPC whose serum prostate-specific antigen (PSA) levels had increased on 3 consecutive measurements during docetaxel-based treatment were included in the analysis. Twenty-five patients received oral UFT and dexamethasone plus intravenous cisplatin (UFT-P therapy) and control group (thirty-five patients) were continued docetaxel therapy. PSA levels were measured once a month to evaluate the treatment response. UFT-P therapy related adverse events and overall survival were also assessed. RESULTS The average age was 72.4 years (range, 51-86 years). The mean initial PSA was 720 ng/ml (range, 1.84-9700). Forty-two patients had bone metastases (UFT group had twenty patients, and control group had thirty-five patients) and sixteen patients had lymph node metastases at the start of therapy. The previous treatment was full extraction in fifteen patients and radiotherapy in six patients. The mean observation periods was 592 days (range, 65-1380 days). During UFT-P therapy, PSA levels decreased in 14 of 25 patients (56%). PSA doubling time (PSADT) decreased in 7 of 11 patients, although their PSA levels were increasing. Including these latter patients, the response rate to UFT-P therapy was 84% (21 of 25 patients). The median survival of UFT-P group and control group (docetaxel continued) was 34 and 21 months, respectively. The median time to PSA progression of UFT-P group and control group were 14 and 6 months, respectively. The adverse events of UFT-P therapy were mild diarrhea (20%), general fatigue (100%), and anorexia (44%). However there were not pancytopenia, and adverse events were all grade 1. Treatment by UFT-P could be continued in all patients. Tumor shrinkage during UFT-P therapy was minimal on imaging studies, although hydronephrosis with lymph node metastasis improved in one patient. CONCLUSIONS Our results suggest that UFT-P therapy is effective against docetaxel-refractoly prostate cancer, with minimal adverse events. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e393 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Katsuhiro Fukuta yatomi, Japan More articles by this author Hiromichi Naruyama yatomi, Japan More articles by this author Masahito Hirose yatomi, Japan More articles by this author Hiroki Kubota yatomi, Japan More articles by this author Noriyasu Kawai nagoya, Japan More articles by this author Keiichi Tozawa nagoya, Japan More articles by this author Kenjiro Kohri nagoya, Japan More articles by this author Kenjiro Kohri nagoya, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The Advanced Generation of Oral 5-Fluorouracil Available in Europe – Teysuno® (S-1)

The European Society for Medical Oncology 15th World Congress of Gastrointestinal Cancer satellite symposium was held in Barcelona to discuss the oral fluoropyrimidine S-1. S-1 is a combination of three pharmacological compounds: tegafur, gimeracil and oteracil potassium. Tegafur is a prodrug of 5-fluorouracil (5-FU), an oral fluoropyrimidine, and has been developed as a replacement for infusional 5-FU therapy. S-1-based chemotherapy has become first-line treatment for unresectable advanced gastric cancer in Japan. It has also shown efficacy in the treatment of colorectal cancer, and a recent Japanese phase III clinical trial in pancreatic cancer showed that adjuvant treatment with S-1 substantially increases overall survival rates compared with treatment with the standard post-operative drug gemcitabin. Following a clinical trial in Western patients, S-1 has been approved in Europe and offers a tolerable and convenient treatment regimen with a tolerable safety profile.

Quantitative determination of capecitabine and its six metabolites in human plasma using liquid chromatography coupled to electrospray tandem mass spectrometry

Capecitabine is the oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The purpose of this study was to quantify capecitabine and its metabolites including 5′-deoxy-5-fluorocytidine (5′-dFCR), 5′-deoxy-5-fluorouridine (5′-dFUR), 5-FU, dihydro-5-fluorouracil (FUH2), α-fluoro-ureidopropionic acid (FUPA) and fluoro-β-alanine (FBAL) in human plasma using liquid chromatography coupled to electrospray tandem mass spectrometry. To this end two individual assays were developed: one for the simultaneous quantification of capecitabine, 5′-dFCR and 5′-dFUR using reversed phase chromatography and gradient elution, and one assay for 5-FU, FUH2, FUPA and FBAL using hydrophilic interaction chromatography and isocratic elution. Both assays were fully validated according to current FDA guidelines. Total run time for the capecitabine assay was 9.0min, and of the 5-FU assay 5.0min. Analyte extraction was performed by protein precipitation. Stable labeled isotopes for each of the analytes were used as internal standards. The linear ranges of the analytes were 50–6000ng/mL for the capecitabine assay and 50–5000ng/mL for the 5-FU assay. Validation results demonstrate that capecitabine and its metabolites can be rapidly, accurately, precisely and robustly quantified in human plasma with the presented methods. Both assays are currently in extensive use in support of pharmacokinetic studies in patients treated with capecitabine or 5-FU.

Comparative bioavailability study of capecitabine tablets of 500 mg in metastatic breast cancer and colorectal cancer patients under fed condition

Capecitabine (oral prodrug of 5-fluorouracil) is the first-line treatment for the metastatic breast and colorectal cancer. The objective of the study was to determine the bioequivalence between the test product (capecitabine tablets 500 mg) of Dr. Reddy’s Laboratories Limited relative to that of reference product XELODA® (capecitabine) 500 mg tablets of Roche Registration Inc. in patients of metastatic breast or colorectal cancer stabilized with twice daily dosing of capecitabine monotherapy. This was an open-label, randomized, single dose, two-way cross-over bioequivalence study under fed conditions. The subjects received either of the treatments (test or reference) 30 min after consumption of a high fat, high calorie breakfast as a single morning dose of 2000 mg on two separate days (days 1 and 2) based on their body surface area. Blood samples were collected up to 10 h post-dose and analyzed for capecitabine using the validated liquid chromatographic mass spectrometric (LC-MS/MS) method. The least squa...

5′-Deoxy-5-Fluorouridine: Characterisation, Crystal Structure and Molecular Conformations Determined from X-Ray Powder Data

The title compound [systematic name: 1-[(1R,2R,3S,4R)-2,3-dihydroxy-4-methyltetrahydrofuranyl]-5-fluoropyrimidine-2,4(1H,3H)-dione], C9H11FN2O5, is a prodrug of 5-fluorouracil used as a cytostatic in cancer therapy. Its crystal structure was determined from laboratory X-ray powder diffraction data. The compound crystallises in the triclinic space group P1 with two molecules in the asymmetric unit. These symmetrically independent molecules differ in their hydrogen-bond patterns, the pseudorotational angles P of their furanosyl fragments as well as their N-glycosidic torsion angles χ. The crystal structure of 5′-deoxy-5-fluorouridine, 1-[(1R,2R,3S,4R)-2,3-dihydroxy-4-methyltetrahydrofuranyl]-5-fluoropyrimidine-2,4(1H,3H)-dione], C9H11FN2O5, a prodrug of 5-fluorouracil used as a cytostatic in cancer therapy, was determined from laboratory X-ray powder diffraction data. The compound crystallises in the triclinic space group P1 with two symmetrically independent molecules differing in their hydrogen-bond patterns, the pseudorotational angles P of their furanosyl fragments as well as their N-glycosidic torsion angles χ.

P-0146 Toxicity of Capecitabine - Limiting Factor of Treatment

ABSTRACT Introduction Capecitabine (Xeloda) is a prodrug of 5-fluorouracil, orally chemotherapeutic drug, and is widely administered in certain advanced malignancies such as breast cancer, colorectal cancer and gastric cancer. It is used in adjuvant and also in palliative care. The most frequent side effects are associated with capecitabine treatment involve palmar and plantar erythrodysesthesia (hand-foot syndrome), gastrointestinal toxicity (diarrhoea, vomiting), haematology toxicity (neutropenia, thrombocytopenia, anemia). Serious toxicity is not common, but in the some cases it can induced reduction of the dose or discontinuation of capecitabine. Methods In our retrospective analysis we included 288 patients treated with capecitabine from January 2007 to December 2011. 69 patients of this group were excluded due to missing data. The data from 219 patients, 126 men and 93 women were analysed. 178 patients were treated for colorectal cancer, 38 patients breast cancer, 3 patients gastric cancer. We used capecitabine in monotherapy or in combination regiments due to standard given by diagnosis in adjuvant or in paliative care. Results We observed some toxicity in 196 cases, included 67 cases of haematology toxicity (various types or grades), 58 cases of hand-foot syndrome, 42 cases of gastrointestinal toxicity (diarrhoea, vomiting, dyspeptic syndrome), 10 cases of neurotoxicity, 8 cases of cardiotoxicity (serious arrhythmia, acute cardiac infarct, angina pectoris), 4 cases of elevation of the hepatic transaminases and 4 cases of mucositis. Serious life-threatening pancytopenia was occurred in 3 cases, the patients had to be hospitalized in the intensive care unit, one of them died early due to toxicity of capecitabine (serious pancytopenia). The reduction of dose was necessary in 75 cases and in 50 cases was therapy stopped due to unacceptable toxicity during the therapy. Conclusion In 63% of cases in our group the toxicity caused to dose reduction or discontinuation of the treatment. Capecitabine is cytotoxic drug with a large spectrum of toxicities, mostly good manageable, but rarely (in 1.5% of our group) can caused to life- threatening of patients.

Postoperation chemotherapy with S1 and docetaxel in curatively resected gastric cancer of stage III (POST trial).

TPS4142 Background: Complete surgical resections remains the only chance for cure in patients with gastric cancer, but approximately from 40% to 80% of patients still have recurrences and most patients ultimately die from their disease. The recent adjuvant trials in gastric cancer showed significantly improved survival in patients with adjuvant chemotherapy than those with surgery alone. However, further studies need for the effect of adjuvant chemotherapy following D2 dissected gastric cancer patients, especially in advanced gastric cancer. S-1 is an oral anticancer drug, a prodrug of fluorouracil, very effective in gastric cancer. Docetaxel is the first drug that showed survival benefits when added to the two drugs in advanced gastric cancer patients. And docetaxel is also synergistic anti-cancer effect with S-1 in advanced gastric cancer. Base on this background, the aim of this study is to detect a significant increase in 3 –year disease free survival (DFS) of adjuvant chemotherapy with docetaxel and S-1(DS) relative to those with S-1 and cisplatin (SP) in patients with stage III gastric cancer Methods: This study is an open-label, phase 3, randomized controlled trial, multicenter in South Korea. Patients with stage III (AJCC 7th edition) gastric cancer who had had curative D2 gastrectomy is randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of intravenous docetaxel (35 mg/m2 on day 1 and 8 of each cycle) plus oral S-1 (35 mg/m2 twice daily on days 1 to 14 of each cycle) for 6 months (DS) or chemotherapy of eight 3-week cycles of oral S1 plus intravenous cisplatin (60 mg/m2). After satisfying the screening criteria, patients have been randomized to the SD or SP arm in a 1:1 ratio. The randomization is stratified by institution and stage of disease (IIIA vs. IIIB vs. IIIC). The each stratum has been randomized by using the method of randomly permuted block. The primary endpoint is 3 year DFS, will analyze by intention to treat. A total of 290 patients will be enrolled, 67 patients have been treated to day, with continuing accrual. The trial is registered at ClinicalTrials.gov (NCT01283217).

Release mechanism studies on TFu nanoparticles-in-microparticles system

This study was aimed at developing a nanoparticles-in-microparticles delivery system for N3-O-toluyl-5-fluorouracil (TFu), a new and potential antitumor prodrug of 5-fluorouracil (5-Fu), and intended to improve the release properties, bioavailability and therapeutic efficacy. TFu nanoparticles-in-microparticles system (TFu-NiMS), was prepared by ionotropic gelation technique, and the formulation and manufacture parameters were optimized concerning the drug encapsulation efficiency. TFu-NiMS was characterized according to particle size, zeta potential, drug entrapment efficiency, drug loading and physical stability, respectively. The effects of various factors on drug release and in vitro release characteristics of TFu from NiMS were investigated and the release mechanisms were also explored. The optimum formulation was found to be relatively uniform in size (350.5±12.6nm) with a positive zeta potential (13.4±0.9mV). The drug entrapment efficiency and loading were (75.58±3.25%) and (10.19±0.24%), respectively. The in vitro release behavior of TFu from NiMS followed the Weibull or Ritger–Peppas kinetic equation and could be better expressed by the following equations: lnln[1/(1−Q/100)]=0.5577lnt−0.3377, r=0.9768 and lnQ=0.5059lnt+3.881, r=0.9759, respectively. TFu-NiMS presented controlled release properties in comparison with TFu solutions and the release properties of TFu from NiMS were fit a combination of diffusion controlled drug release and matrix dissolution mechanism. The TFu-NiMS were valued to develop as a practical preparation for oral or i.v. administration.

A phase I study of S-1 in combination with sorafenib in metastatic renal cell carcinoma (mRCC).

447 Background: S-1 is an oral anticancer agent combining tegafur, a prodrug of 5-fluorouracil, with 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The purpose of this study was to confirm the recommended dose (RD) and maximum tolerated dose (MTD) of S-1 in combination with sorafenib, a small molecular inhibitor of several tyrosine protein kinase, in Japanese patients with mRCC. We assessed dose-limiting toxicities (DLTs) and pharmacokinetic interactions during the first cycle of treatment. Methods: Eligible patients had a histologically confirmed diagnosis of clear cell or papillary mRCC, measurable lesions, a history of no previous treatment or not more than 1 regimen of cytokine treatment, an ECOG performance status of 0 or 1, prior nephrectomy, and adequate organ functions. In this study, four dose levels were prepared, and the starting dose was set at Level 1B. S-1 was administered on days 1 to 28, and sorafenib was given on days 1 to 42 as one cycle. The MTD was assessed using a “3 + 3” dose escalation design and was defined as the highest dose level for which the incidence of DLTs was less than 33%. Results: Between August 2009 and March 2010, 9 patients were enrolled. Two DLTs occurred in patients assigned to level 2, which was the full therapeutic dose of each agent. Therefore, the MTD was not confirmed, but the RD was determined to be level 2. Although renal clearance affected the pharmacokinetics of S-1, there were no obvious drug interactions between S-1 and sorafenib. Details are shown in the Table. Conclusions: This combination therapy can be administered with acceptable tolerability, no overlapping toxicity, and no drug interactions. The RD for phase II studies was fixed at level 2, and a phase II study is ongoing. [Table: see text]

A phase II study of S-1 for the treatment of cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal cell carcinoma: Updated results.

393 Background: S-1 is an oral anticancer agent combining tegafur, a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine and potassium oxonate. S-1 has shown efficacy for cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal-cell carcinoma (mRCC). We report the final results of a phase II study and evaluate 5-FU-related enzymes as a predictor of the response to S-1. Methods: 45 patients received S-1 at a dose of 40 mg/m2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR). The secondary endpoints of progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Formalin-fixed, paraffin-embedded specimens obtained by radical nephrectomy were used for mRNA expression assay, performed by reverse-transcriptase polymerase chain reaction. Results: 45 patients including 6 were progressed after TKI were enrolled from April 2006. 24 patients received more than 5 cycles, and 2 continued to receive S-1 as of October 2011. Two (4.4%) of the 45 patients had complete responses to S-1, 9 (20.0%) had partial responses, and 28 (62.8%) had stable disease. The final PFS and OS were 9.2 and 42.8 months, respectively, and the PFS of TKI refractory patients was approximately two times of final PFS (18.0 months). The most common grade 3-4 adverse events according to CTCAE v.3.0 were similar to the previous report except for hemoglobin decreased and fatigue. On mRNA expression analysis, the expression level of thymidylate synthase correlated with ORR and PFS. On the other hand, OS did not differ significantly between patients with low expression and those with high expression of 5-FU-related enzymes. Conclusions: S-1 is effective and well tolerated in patients with cytokine and/or TKI refractory mRCC. Moreover, long-term treatment with S-1 is safe in mRCC patients enabling long-term disease control, especially in TKI refractory patients. Clinical trial with large number of TKI refractory patients is warranted to determine the efficacy of S-1.

Significant Association between Hand-Foot Syndrome and Efficacy of Capecitabine in Patients with Metastatic Breast Cancer

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is a promising treatment for colorectal, breast and gastric cancers, but often causes hand-foot syndrome (HFS), the most common dose-limiting toxicity. The current study was conducted to investigate the relationship between HFS and efficacy of capecitabine in 98 patients with metastatic breast cancer. Possible associations between HFS and efficacy endpoints, including time-to-treatment failure (TTF), tumor response in metastatic lesions and changes in tumor markers, were investigated retrospectively using electronic medical records. The TTF of group with HFS of grade 1 and ≥2 was significantly longer than that of group with no HFS, respectively (hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.18-0.87 for group with grade 1; HR, 0.42, 95% CI, 0.19-0.90 for group with grade ≥2). Significantly higher disease control rates for the liver metastasis were observed in patients with HFS (grade 1 and greater) than in those without HFS (92.9 vs. 42.9%, p=0.009). Furthermore, prevention of increases in tumor marker levels (carcinoembryonic antigen (CEA), carbohydrate antigen 15-3 (CA15-3) and National Cancer Center-Stomach-439 (NCC-ST439)) was evident in patients with HFS. This study clearly showed a significant correlation between HFS and some efficacy markers of capecitabine therapy in patients with metastatic breast cancer, and suggests that early dose adjustment based on severity of HFS might improve efficacy. Studies are needed to explore predictive biomarkers for HFS/efficacy, so that capecitabine therapy can be further tailored to patient response.

The role of S-1 in the treatment of gastric cancer

The role of S-1 in the treatment of gastric cancer Mariela A Blum, Akihiro Suzuki, Takashi Taketa, Jaffer AjaniThe University of Texas, MD Anderson Cancer Center, Division of Gastrointestinal Oncology, Houston, TX, USAAbstract: Gastric cancer is a lethal disease and continues to be the second leading cause of cancer death worldwide. Surgical resection remains the main treatment for early stages with complete resection having the potential for a cure. Recent data suggest that surgery alone is inferior to surgery plus some form of adjunctive therapy. Unfortunately, most patients with gastric cancer are diagnosed in advanced stages, rendering palliative systemic therapy as the only choice of treatment. The most common chemotherapy combination as a first-line treatment in advanced gastric cancer (AGC) includes a platinum compound, a fluoroporyrimidine and a taxane (in the United States) or an antracycline (in Europe). Fluoropyrimidines have been the backbone in the chemotherapy regimens for the treatment of gastric cancer. There has been considerable interest in oral fluoropyrimidines. S-1 is a fourth-generation oral fluoropyrimidine that combines tegafur, which is a prodrug of 5-fluorouracil (5-FU), and two biochemical modulators: (1) 5-chloro-2,4-dihydroxypyridine, a powerful but reversible inhibitor of dihydropyrimidine dehydrogenase that prevents 5-FU degradation, and (2) potassium oxonate, which reduces gastrointestinal (GI) toxicity by inhibition of 5-FU phosphorylation in the GI mucosa. S-1 has produced an advantage in the postoperative setting in a large Phase III trial and has also been evaluated as a preoperative chemotherapy in gastric cancer, but in the preoperative setting, there are no completed Phase III clinical trials. Nonetheless, S-1 is considered, as a single agent, as the standard of care in Japan for the adjuvant treatment of resected gastric cancer and in combination with cisplatin in the advanced setting based on level 1 evidence in Phase III trials. S-1 is now widely available and has been approved in 27 European countries as a first-line treatment for AGC. S-1 is generally well tolerated with a low toxicity profile. It is a novel agent that provides a convenient and safe advantage over intravenous fluoropyrimidine in AGC.Keywords: tegafur, Ftorafur, FT, 5-FU, advanced gastric cancer

Tegafur/gimeracil/oteracil (S-1) approved for the treatment of advanced gastric cancer in adults when given in combination with cisplatin: a review comparing it with other fluoropyrimidine-based therapies

S-1 is a combination of three pharmacological compounds, namely tegafur, gimeracil, and oteracil potassium. Tegafur is a prodrug of 5-fluorouracil (5-FU), an oral fluoropyrimidine, and it has been developed as a replacement for infusional 5-FU therapy. S-1-based chemotherapy and the combination of S-1 and cisplatin are the most reasonable first-line standards for unresectable advanced gastric cancer in Japan. However, the application of S-1 for gastric cancer has been delayed in Western countries. One reason for this delay is that the pharmacokinetics of tegafur is affected by polymorphisms in cytochrome P-450 2A6, and consequently 5-FU concentrations in the plasma are more likely to be elevated in patients from Western countries. Although the dose of S-1 was reduced compared with the approved dose in Japan, a global Phase III study reported similar results regarding overall survival between S-1 plus cisplatin and infusional 5-FU plus cisplatin arms. Significant safety advantages were observed in the S-1 plus cisplatin arm compared with the infusional 5-FU plus cisplatin arm. S-1 plus cisplatin has become acceptable for Western countries, also, as a choice for unresectable advanced gastric cancer. Comparisons with capecitabine and combination of several targeting agents with S-1 are expected in the future.

The European Medicines Agency Review of Tegafur/Gimeracil/Oteracil (Teysuno™) for the Treatment of Advanced Gastric Cancer When Given in Combination with Cisplatin: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use (CHMP)

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).

Clinical Results of Definitive Chemoradiotherapy for Patients With Synchronous Head and Neck Squamous Cell Carcinoma and Esophageal Cancer

To assess the efficacy and toxicity of radical chemoradiotherapy for patients with synchronous head and neck squamous cell carcinoma (HNSCC) and esophageal cancer (EC). Thirty-four patients with synchronous HNSCC and EC were treated mainly with radical chemoradiotherapy at the same time. Median external radiation dose for HNSCC and EC was 70 Gy (range, 60-70.5 Gy), except for 2 patients with tongue cancer, who underwent brachytherapy and 60 Gy (range, 45-70 Gy), respectively. Thirty-one patients were treated with concurrent chemoradiotherapy with cisplatin and/or 5-fluorouracil or TS-1 (oral anticancer agent that combines tegafur, a metabolically activated prodrug of 5-fluorouracil, with 5-chloro-2, 4-dihydoroxypyridine, and potassium oxonate). Thirty-three patients completed the intended treatment. The response rate was 94%, with 26 complete responses (76%) and 6 partial responses (18%). At a median follow-up of 17.3 months, 2-year rates of overall survival, cause-specific survival, and disease-free survival were 44%, 52%, and 33%, respectively. Initial failure patterns were local failure in 14 patients (63%), regional progression in 3 patients (13%), and distant metastasis in 6 patients (27%). The most common acute toxicity was myelosuppression, with 8 patients experiencing grade 3-4 toxicity. Three patients experienced grade 3 mucositis and pharyngitis. No patients experienced late morbidity of grade 3 or higher. Definitive chemoradiotherapy for patients with synchronous HNSCC and EC is feasible with a low mortality rate and acceptable morbidity.

Impact of KRAS and BRAF Gene Mutations on Targeted Therapies in Colorectal Cancer

In Journal of Clinical Oncology, Price et al present an analysis of the predictive and prognostic impact of KRAS and BRAF gene mutations in patients with metastatic colorectal cancer. In this study, patients were randomly assigned to receive treatment with the fluorouracil prodrug capecitabine either alone or in combination with bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor-A (VEGF). The authors conclude that although KRAS mutations are not prognostic, patients with BRAF mutations have significantly worse survival. However, neither mutation was found to modulate outcome when bevacizumab was added to fluorouracil-based therapy. This Understanding the Pathway article provides an opportunity to gain a better understanding of the biology underlying K-Ras and B-Raf. Recurrent somatic mutations in KRAS and BRAF are found in colorectal carcinoma as well as other cancer types. Both of these genes encode proteins that are part of the mitogen-activated protein kinase (MAPK) pathway, a signaling cascade connecting receptors on the cell membrane (which receive external proliferative signals) to the downstream machinery regulating cellular growth. In the normal physiologic setting, this pathway is carefully regulated to prevent excessive cellular proliferation. However, this exquisite growth regulation is often bypassed in cancer through mutations within this pathway— mutations that either activate key signaling proteins (eg, Ras or Raf) or inactivate safeguard proteins that downregulate this signaling (eg, phosphatase and tensin homolog). Even a cursory inspection of the MAPK and intersecting pathways quickly reveals a who’s who of many commonly mutated genes in cancer (Fig 1). The proximal points of the pathway are the cell surface receptors, such as the epidermal growth factor receptor. On binding of ligand to the extracellular component of the receptor (by mitogens such as epidermal growth factor), the intracellular portion (which contains the kinase domain) becomes activated. The activated kinase adds phosphate groups to intracellular signaling proteins, thus activating the relevant downstream cascades. The phosphoinositide 3-kinase and MAPK pathways are among the most important signaling arms downstream of receptor tyrosine kinases. Within the MAPK pathway, cellular intermediates link the cell surface tyrosine kinase activity to Ras, a key hub of cellular activity and a classic oncoprotein. Proteins composing the Ras family (K-Ras, N-Ras, and H-Ras) all act in a similar fashion; they are guanosine triphosphatase (GTPase) proteins, the activity of which is governed by binding to GTP (active state) or by hydrolysis of GTP to guanosine diphosphate (GDP; inactive state). When activated, Ras proteins augment multiple downstream signaling pathways, including the MAPK pathway, which consists of a cascade of signaling, starting with Raf activation (Fig 1). Like Ras, Raf refers to a family of proteins (A-Raf, B-Raf, and C-Raf)—in this case, serine/threonine kinases whose signaling ultimately activates a transcriptional program regulating cell growth. RAS mutations are highly recurrent in human cancers. For example, KRAS mutations are seen in approximately 30% of colorectal PTEN PI3-K

Design, synthesis and in vitro drug release investigation of new potential 5-FU prodrugs

In order to identify new efficient prodrugs of 5-fluorouracil (5-FU) and to develop an original targeting approach using 2-fluoro-2-deoxyglucose (FDG) as a potential drug carrier, eight original 5-FU derivatives were synthesized: 5-FU was attached by the N1 position of the pyrimidinic ring to the C1 position of the FDG structure either by direct coupling ( 2a) or via various spacers ( 3, 6a– c, 10b and 19). A new sensitive high-performance liquid chromatography method was developed to simultaneously quantify 5-FU and its derivatives in human plasma and other relevant media at physiological temperatures. Half-lives were determined from the degradation profiles of these conjugates. Slow degradation of compounds 2a, 3, 10b and 19 was observed in vitro at 37 °C, but no 5-FU release was noticed. By contrast, the in vitro drug release profiles of compounds 6a– c followed pseudo-first-order kinetics, and 5-FU was found in all the media. The antiproliferative activity of the eight compounds was assessed in vitro by a fluorometric assay against two human solid cancer cell lines and one healthy cell line. A correlation was found between the activities of the compounds and their ability to release 5-FU efficiently.

A Polymorphism in the Cytidine Deaminase Promoter Predicts Severe Capecitabine-Induced Hand-Foot Syndrome

Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of capecitabine, an oral prodrug of 5-fluorouracil used in the standard treatment of breast and colorectal cancer. We investigated the association between grade 3 HFS and genetic variations in genes involved in capecitabine metabolism. We genotyped a total of 13 polymorphisms in the carboxylesterase 2 (CES2) gene, the cytidine deaminase (CDD) gene, the thymidine phosphorylase (TP) gene, the thymidylate synthase (TS) gene, and the dihydropyrimidine dehydrogenase (DPD) gene in 130 patients treated with capecitabine. We correlated these polymorphisms with susceptibility to HFS. We found an association of HFS appearance with rs532545 located in the promoter region of CDD (OR = 2.02, 95% CI = 1.02-3.99, P = 0.039). Because we found no association between the rs532545 genotype and CDD mRNA expression in Epstein-Barr virus lymphoblastoid cells, we explored additional genetic variations across the CDD promoter. We found an insertion, rs3215400, in linkage disequilibrium with rs532545 (D' = 0.92), which was more clearly associated with HFS (OR = 0.51, 95% CI = 0.27-0.95, P = 0.028) in patients and with total CDD gene expression (P = 0.004) in lymphoblastoid cells. In silico analysis suggested that this insertion might create a binding site for the transcriptional regulator E2F. Using a SNaPshot assay in lymphoblastoid cells, we observed a 5.7-fold increased allele-specific mRNA expression from the deleted allele. The deleted allele of rs3215400 shows an increased allele-specific expression and is significantly associated with an increased risk of capecitabine-induced HFS.

Are Cubilin (CUBN) Variants at the Heart of Urinary Albumin Excretion?

Oral capecitabine is a prodrug of 5-fluorouracil that has been used into the management of multiple cancers because of the convenience of administration and efficacy at least comparable with 5-fluorouracil. While cardiac complications associated with the use of 5-fluorouracil are well-documented, capecitabine-induced acute coronary syndrome has rarely been reported and often attributed to coronary vasospasm. We report a patient presented with acute coronary syndrome secondary to thrombotic coronary occlusion following treatment with oral capecitabine and intravenous oxaliplatin after resection of non-metastatic, node positive colon carcinoma. Capecitabine may induce acute coronary thrombotic occlusion in addition to coronary vasospasm.

Abstract P6-11-13: Phase I Study of Combined S-1 Plus Weekly Paclitaxel Therapy in Patients with Metastatic Breast Cancer

Abstract Introduction: S-1, a novel anticancer compound, contains tegafur, a prodrug of fluorouracil (FU), 5-chloro-2.4-dihydroxypyridine, which prevents FU degradation, and potassium oxonate, which prevents drug-induced diarrhea, has a broad spectrum of activity against gastric, colorectal, head & neck, and breast cancers. While combined S-1 with cisplatin or paclitaxel (PAC) therapy is feasible and highly active against gastrointestinal cancer, the feasibility in breast cancer patients has not yet been clarified. We conducted a phase I study of combined S-1 plus weekly PAC therapy (S-1/PAC) to determine the maximum tolerated dose (MTD), recommended dose (RD) and dose-limiting toxicities (DLT) in patients (pts) with HER2-negative, taxane-naïve metastatic breast cancer (MBC). Methods: S-1 was administered orally from day 1 through day 14 and PAC was administered intravenously on days 1, 8 and 15 of each 28-day cycle. Since S-1 is prescribed at the dose of 80mg/m2 in monotherapy, the primary dose levels (level 1) were set at 65 and 70mg/m2, respectively. The final dose (level 3) was set at 80mg/m2 for each drugs. DLT was defined over 2 cycles. Results: Ten MBC pts were enrolled in the study. No DLTs were documented. Although grade 1 or 2 adverse events were seen in all pts, no cases of febrile neutropenia or Gr 4 neutropenia were observed. Of the 8 evaluable pts, 3 pts achieved partial response and 4 pts had stable disease. Conclusion: Based on the results of this study, RD was determined to be 80mg/m2 for either drugs. We conclude that S-1/PAC was well-tolerated and highly active against HER2-negative MBC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-13.