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The present study aimed to prospectively clarify the prognostic effect of the expression of several genes that are known to modulate 5-fluorouracil effects in 63 patients who underwent curative resection for stage II/III colorectal cancer following adjuvant chemotherapy with oral fluoropyrimidines between 2008 and 2012. Thymidine phosphorylase (TP) expression in primary tumours was significantly lower in the recurrence group compared with the no-recurrence group (P=0.03), whereas, expression levels of genes that encoded thymidylate synthase, dihydropyrimidine dehydrogenase, folylpolyglutamate synthase, γ-glutamyl hydrolase and dihydrofolate reductase were not statistically different in tumours from the recurrence and no-recurrence groups. In the multivariate analysis using stepwise Cox proportional hazards regression, the following factors were significantly associated with shorter relapse-free survival following adjuvant chemotherapy with oral fluoropyrimidines: Venous invasion [present; hazard ratio (HR)=6.51; 95% confidence interval (CI): 1.55–27.4; P=0.01), Tumour-Node-Metastasis stage (3b; HR=6.18; 95% CI: 1.36–28.2; P=0.02) and TP expression (low; HR=9.61; 95% CI: 1.81–51.0; P=0.04). Patients with two or more risk characteristics had significantly shorter 5-year relapse-free survival compared with patients with one or no risk characteristics (55.8 vs. 91.8%; log-rank P=0.0006). We concluded that low TP expression is an independent predictive factor for poor prognosis in colorectal cancer. Therefore, determining TP expression may help to improve recurrence risk stratification in patients with stage II/III colorectal cancer following adjuvant chemotherapy with oral fluoropyrimidines. [ABSTRACT FROM AUTHOR]

Background: On account of the lack of predictive biomarkers of toxicity, we investigated whether polymorphisms of genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with outcomes of adjuvant capecitabine in patients with early stage gastrointestinal cancers. Methods: Genotyping of DPYD GIVS14A, MTHFR C677T and A1298C SNPs were performed by pyro-sequencing technology. PCR analysis was used for genotyping TYMS-TSER. We also evaluated the 5-FU degradation rate, which determines the amount of drug consumed by PBMC in a time unit. Association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. Results: One hundred forty-two patients with early stage colon (39%), rectal (28%), stomach (20%) and pancreatic (13%) cancer, treated with adjuvant capecitabine, were included in this retrospective analysis. Seventy and 20% of the patients suffered from at least one G1-4 and G3-4 adverse events, respectively. According to the 5-FU degradation rate, three and 13 patients were assigned as poor (<0.86 ng/mL/10 cells/min) and ultra-rapid (>2.1 ng/mL/10 cells/min) metabolizers, respectively. At a multivariate logistic regression analysis, an altered 5-FU degradation rate (values <0.86 or >2.10 ng/mL/10 cells/min) was associated with grade 3-4 adverse events (OR = 2.09, 95% CI: 1.14-3.82, P = 0.01). No correlation was reported between toxicity and gene polymorphisms except for hand-foot syndrome that was more frequent in the MTHFR 1298CC homozygous variant genotype (OR = 2.03, 95% CI 1.04-3.96, P = 0.03). Conclusions: 5-FU degradation rate may be regarded as possible predictive biomarker of capecitabine toxicity in early stage gastrointestinal cancer. [ABSTRACT FROM AUTHOR]

Gastric cancer remains one of the most important malignancies worldwide in terms of incidence and mortality. The treatment is based on the combination of local surgery and radiation therapy as well as systemic chemotherapy and targeted molecules. Fluoropyrimidines and particularly 5-fluorouracil (FU) represent still the backbone for gastric cancer chemotherapy and new molecular versions of this molecule have been brought to clinical practice in order to improve benefits and reduce adverse effects. S-1 is an oral prodrug of 5-FU, which has demonstrated high effectiveness for gastric cancer treatment and a favorable safety profile. Currently, there are geographic differences in the treatment of gastric cancer and in the use of S-1, which is a mainstay of gastric cancer management in Eastern countries, but is not part of the standard care in the rest of the world. In this review, we gathered data from phase I, II, and III trials of S-1 in gastric cancer, in order to define its real benefit-risk ratio and assess whether geographic differences in S-1 use are justified by unchangeable factors. [ABSTRACT FROM AUTHOR]

A 56-year-old man who was diagnosed with gastric cancer with multiple paraaortic lymph node metastases was treated with S-1 plus cisplatin. The spleen gradually enlarged during the therapeutic courses. After the 6th course of therapy, the primary gastric lesion and paraaortic lymphadenopathies disappeared. He underwent a curative resection, including a distal gastrectomy with regional and paraaortic lymph node dissections. Irregularly distributed congestion of the liver was noted during the surgery. Histological examinations revealed residual cancer cells in 3 regional lymph nodes and no cancer cells in the primary site and paraaortic lymph nodes. Hepatic sinusoidal obstruction syndrome (SOS) was also confirmed histologically. This is the first report of a case with SOS after S-1 plus cisplatin therapy. S-1 plus cisplatin therapy can cause SOS, although it is a promising preoperative chemotherapy for highly advanced gastric cancer. [ABSTRACT FROM AUTHOR]

Introduction: Neoadjuvant 5-FU-based chemoradiotherapy in resectable rectal cancer (RC) is a standard of treatment. The use of oral fluoropyrimidines and new agents such as oxaliplatin may improve efficacy and tolerance. Material and methods: Between 1999 and 2009, 126 RC patients with T3-T4 and/or N+ disease were given three successive protocols: UFT (32), UFT-oxaliplatin (75) and capecitabine-oxaliplatin (19), alongside 45 Gy of radiotherapy; with surgery 4-6 weeks after. Adjuvant treatment was given in all patients. The primary objective was pathologic complete response (pCR). Results: Preoperative therapy was well tolerated, with no toxic deaths and a 15% grade 3-4 toxicity rate. Eighty-five percent of patients received the full chemotherapy dose, 56% had an abdominoperineal resection, 6% reinterventions and 57% received the full adjuvant chemotherapy planned. The pCR rate was 13%. The downstaging rate was 80%; 8% had progression of disease. The relapse rate was 20%, with local relapse in 6%. By 5 years of followup, 92% of relapses had occurred. Median follow-up was 73 months, 5- and 10-year disease-free survival rates were 75% and 50%, and 5- and 10-year overall survival rates were 79% and 66% respectively. There was no benefit from the use of oxaliplatin regarding survival or pCR rates. Older patients had worse long-term outcomes. Conclusions: Neoadjuvant chemoradiotherapy with oral fluoropyrimidines and oxaliplatin is feasible and well tolerated. The risk of early progression is low. However, there was no added benefit with the use of oxaliplatin. There were no relapses in patients with pCR. The role of adjuvant chemotherapy is unclear. [ABSTRACT FROM AUTHOR]

Purpose: Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5-fluoropyrimidine (5-FU) catabolism. We examined whether tumor DPD expression is an effective marker in adjuvant therapy with oral fluoropyrimidines after curative resection of colorectal cancer. Methods: We studied 89 patients with stage II-III colorectal cancers who had undergone curative resections and received oral 5-FU-based adjuvant chemotherapy. The levels of DPD expression in tumor and normal colonic mucosa were measured by an enzyme-linked immunosorbent assay. In 53 tumor samples, DPD enzymatic activity was also analyzed in order to evaluate the relationship between DPD expression and enzymatic activity. Results: DPD expression significantly correlated with DPD enzymatic activity in these 53 tumors (r=0.56; P < 0.001). DPD expression in the tumors was significantly lower than in normal mucosa (47.1 ± 30.8 and 56.4± 18.5 U/mg protein, respectively; P < 0.05). We designated the cut-off value of tumor DPD as its median value (46.0 U/mg protein). Patients with low DPD expression had longer disease-free intervals than those with high DPD expression according to univariate analysis (P = 0.026). In a multivariate analysis, low DPD expression was significantly and independently associated with better survival. Conclusions: Tumor DPD expression is a useful marker for use with adjuvant chemotherapy with oral fluoropyrimidines after curative resection of colorectal cancer. [ABSTRACT FROM AUTHOR]

: Background and purposeChemoradiotherapy is increasingly used in the primary management of patients with loco-regionally advanced gastrointestinal (GI) cancer. Oral chemotherapy with uracil and tegafur (UFT) plus leucovorin (LV) may represent a convenient way of delivering protracted infusion of fluorouracil. Our goal was to evaluate the safety of UFT plus LV combined with radiation and determine the maximum-tolerated dose (MTD) and a recommended dose for further testing.: Patients and methodsPatients with inextirpable GI cancer received escalating doses of UFT (starting at 300 mg/m2/d with 50 mg/m2/d increments between consecutive cohorts) and fixed doses of LV (90 mg/d). UFT and LV were given 5 days per week concurrently with radiation to 50 Gy (2 Gy/fraction).: ResultsTwenty-five patients were treated, and 22 received the planned treatment. Three patients were withdrawn from treatment, two due to disease-progression and one due to toxicity. The MTD of UFT with radiation was 400 mg/m2/d with 90 mg/d of LV. Diarrhoea was the main dose limiting toxicity (DLT). Since some toxicity (3/12 DLTs) was seen in the expanded cohort at the level below, but none (0/9 DLT) at the starting level, the recommended dose chosen for further testing is 300–350 mg/m2/d depending upon the size of the target volume.: ConclusionConcomitant chemoradiation with oral UFT plus LV is feasible and well tolerated and should be further investigated since tumour responses were frequently seen. [Copyright &y& Elsevier]

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S-1 is a new oral fluorinated pyrimidine derivate, in which the oral 5-fluorouracil (5-FU) prodrug, tegafur, was combined with two 5-FU-modulating substances, 5-chloro-2,4-dihydroxypyridine (gimeracil), and potassium oxonate (oteracil), at a molar ratio of 1:0.4:1. The final mechanism of action is exerted by 5-FU. The present study is the first European phase II trial of S-1 in gastric cancer. The primary study objectives were the safety, toxicity and activity of S-1 in non-pretreated patients with gastric cancer. The secondary objective was the duration of response. Patients had to have histologically- or cytologically-verified metastatic or locally advanced, unresectable gastric cancer; S-1 was administered orally twice daily at 40, then 35 mg/m2 for 28 days every 5 weeks. The starting dose of 40 mg/m2 was found to be intolerable due to significant non-haematological toxicity, and this dose was rapidly reduced to 35 mg/m2 twice daily. Of the 7 patients enrolled at the 40 mg/m2 level, only 3 were evaluable. At 35 mg/m2, a response rate of 26.1% (95% Confidence Interval (CI) 12.0–45.1%) in 23 enrolled patients, and 31.6% (C.I. 14.7–53.0%) in 19 evaluable patients according to an independent radiology review, was found. The median duration of response at 35 mg/m2 (6 patients) was 223 days (range, 108–828 days), and of stable disease was 111 days (range 68–411 days). S-1 can be administered with an acceptable safety and toxicity in European patients at a dose of 35 mg/m2 days 1 – 28 every 5 weeks and is associated with a moderate response rate similar to the results achieved with other fluoropyrimidines. [Copyright &y& Elsevier]

Background: The purpose of this study is to evaluate the efficacy of postoperative adjuvant chemotherapy using uracil and tegafur (UFT) for colorectal cancer. Methods: In a multicenter trial among 43 institutions for patients who underwent curative resection of Dukes' B or C colorectal cancer, a surgery alone group (control group) and a treatment group (UFT group) to which UFT was administered at 400 mg/day for 2 years following surgery were compared. A total of 320 patients were registered between March 1991 and April 1994, and 289 of these patients were analyzed as a full-analysis set. Results: The 5-year disease-free survival rate was 75.7% in the UFT group and 60.1% in the control group, respectively, and the stratified log-rank test showed the statistical significance (P=0.0081). This difference was marked in rectal cancer (P=0.0016) and, in particular, the local recurrence was reduced. No significant difference was observed in the 5-year survival rate. The incidence of adverse reactions on administration of UFT was low, and there was no serious adverse reaction. Conclusion: It is suggested that the consecutive administration of UFT at 400 mg/day was an effective and highly safe therapeutic method as postoperative adjuvant chemotherapy for rectal cancer. [ABSTRACT FROM AUTHOR]

The main purpose of the present review article is to shed light on the different 5-FU prodrugs by underlining their respective pharmacological features in terms of metabolic activation, DPD inhibition, pharmacokinetic profile and possibilities of biomodulation. Oral fluoropyrimidines differ particularly in their pharmacokinetic profile and especially in the delivery of circulating 5-FU. There are now possibilities to achieve pharmacomodulation of oral fluoropyrimidines, notably for tegafur/uracil (UFT®) and capecitabine. These applications open up the prospect of establishing significant novel treatment protocols based on drug combinations. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-FU) is an essential component of systemic chemotherapy for colorectal cancer (CRC) in the palliative and adjuvant settings. Over the past four decades, several modulation strategies including the implementation of 5-FU-based combination regimens and 5-FU pro-drugs have been developed and tested to increase the anti-tumor activity of 5-FU and to overcome the clinical resistance. Despite the encouraging progress in CRC therapy to date, the patients' response rates to therapy continue to remain low and the patients' benefit from 5-FU-based therapy is frequently compromised by the development of chemoresistance. Inter-individual differences in the treatment response in CRC patients may originate in the unique genetic and epigenetic make-up of each individual. The critical element in the current trend of personalized medicine is the proper comprehension of causes and mechanisms contributing to the low or lack of sensitivity of tumor tissue to 5-FU-based therapy. The identification and validation of predictive biomarkers for existing 5-FU-based and new targeted therapies for CRC treatment will likely improve patients' outcomes in the future. Herein we present a comprehensive review summarizing options of CRC treatment and the mechanisms of 5-FU action at the molecular level, including both anabolic and catabolic ways. The main part of this review comprises the currently known molecular mechanisms underlying the chemoresistance in CRC patients. We also focus on various 5-FU pro-drugs developed to increase the amount of circulating 5-FU and to limit toxicity. Finally, we propose future directions of personalized CRC therapy according to the latest published evidence. [ABSTRACT FROM AUTHOR]

Background: Capecitabine, an orally administered fluoropyrimidines, is widely used in the treatment of multiple malignancies. It has been extensively evaluated in patients with gastroesophageal carcinoma. Since recent reviews have discussed phase I/II trials (Cancer 107:221-231, 2006; Drugs 67:601-610, 2007), we focus on the impact of the results of the most current phase III trials using capectiabine in the treatment of advanced gastroesophageal cancers, primarily in the first-line setting., Methods: To find published phase III trials, Medline was searched for English-language clinical trials published from 1996 through June 2007 along with relevant abstracts presented at the American Society of Clinical Oncology, and meetings of the European Cancer Conference and European Society of Medical Oncology. Only representative trials were chosen for this manuscript., Results: The most frequently investigated combinations are capecitabine with taxanes, platinols, and camptothecins. Recent results of a large phase III trial (REAL-2) in untreated patients with gastroesophageal cancer suggest that capecitabine is a non-inferior substitute for intravenous 5-fluorouracil. These results of REAL-2 trial are substantiated by a smaller phase III trial. Previous analysis of multiple trials had suggested that capecitabine, when combined in doses lower than 1250 mg/m(2) twice daily, consistently resulted in lower frequency of Grade 3 or 4 toxic effects., Conclusions: Capecitabine provides much needed convenience to patients with gastroesophageal cancer. The recent data derived from two phase III trials confirm that capecitabine is a suitable substitute for intravenous 5-fluorouracil in patients whose swallowing is not greatly affected. Capecitabine remains a subject of further investigations in this group of patients with interest.