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Dihydropyrimidinase (DHP, EC 3.5.2.2), encoded by the gene DPYS, is the second enzyme in the catabolic pathway of pyrimidine and of fluoropyrimidine drugs such as 5-fluorouracil, which are commonly used in anticancer treatment; DHP catalyzes the hydrolytic ring opening of dihydrouracil and dihydro-5-fluorouracil. DPYS mutations are known to contribute to interindividual variations in the toxicity of fluoropyrimidine drugs, but the functional characterization of DHP allelic variants remains inadequate. In this study, in vitro analysis was performed on 22 allelic variants of DHP by transiently expressing wild-type DHP and 21 DHP variants in 293FT cells and characterizing their enzymatic activities by using dihydrouracil and dihydro-5-fluorouracil as substrates. DHP expression levels and oligomeric forms were determined using immunoblotting and blue native PAGE, respectively, and the stability of the DHP variants was assessed by examining the proteins in variant-transfected cells treated with cycloheximide or bortezomib. Moreover, three kinetic parameters, K m , V max , and intrinsic clearance (V max /K m ), for the hydrolysis of dihydrouracil and dihydro-5-fluorouracil were determined. We found that 5/21 variants showed significantly decreased intrinsic clearance as compared to wild-type DHP, and that 9/21 variants were expressed at low levels and were inactive due to proteasome-mediated degradation. The band patterns observed in the immunoblotting of blue native gels corresponded to DHP activity, and, notably, 18/21 DHP variants exhibited decreased or null enzymatic activity and these variants also showed a drastically reduced ability to form large oligomers. Thus, detection of DPYS genetic polymorphisms might facilitate the prediction severe adverse effects of fluoropyrimidine-based treatments., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The article discusses research on adjuvant chemotherapy for advanced gastric cancer with S-1, a combination of tegafur, gimeracil and oteracil. It references a study by S. Sakuramoto et al published in a 2007 issue of the "New England Journal of Medicine." According to the study, patients treated with S-1 have higher overall survival and relapse-free rates.

Interactions between phenytoin and the fluoropyrimidine derivatives, 5 fluorouracil (5FU) and capecitabine, are not commonly documented or widely recognised. As more people with significant medical comorbidities are now being considered for chemotherapy, it is increasingly likely that people receiving phenytoin will be prescribed treatment with fluoropyrimidines. We present two cases of clinical phenytoin toxicity occurring after starting treatment with 5-fluorouracil/folinic acid (5FU/FA) and a third who developed clinical phenytoin toxicity after starting capecitabine (an orally administered prodrug of fluorouracil). [ABSTRACT FROM AUTHOR]

Chemotherapy for multiple primary cancers is challenging. We describe a case of synchronous duodenal cancer with lung cancer harboring an epidermal growth factor receptor (EGFR) mutation treated with erlotinib and S-1, an oral fluoropyrimidine agent. A 78-year-old woman with advanced EGFR-mutated lung adenocarcinoma was simultaneously diagnosed with duodenal adenocarcinoma. After the treatment with erlotinib, the lung cancer responded well, but her duodenal cancer showed no response. S-1 was added to erlotinib, and the duodenal cancer demonstrated a good response with tolerable toxicities. The concurrent use of erlotinib and S-1 was safe and efficacious for synchronous lung cancer harboring an EGFR mutation and duodenal cancer.

Aim: This prospective randomized study compared the survival of patients with stage IB-IIIA gastric cancer treated with surgery alone or surgery followed by adjuvant chemotherapy., Patients and Methods: Patients with pathological stage IB-IIIA disease were randomly assigned to the following groups: surgery alone (n=116), or surgery followed by adjuvant chemotherapy with 5-fluorouracil, doxifluridine, or uracil-tegafur for 12 months (n=113)., Results: The overall survival rate was 86.1% in the adjuvant group and 78.5% in the surgery-alone group. The overall survival rate did not significantly differ between the adjuvant-chemotherapy and surgery-only groups (p=0.163). In the subgroup analyses, patients with stage II disease and those receiving uracil-tegafur treatment in the adjuvant group showed significantly better prognosis than those in the surgery-alone group (p=0.036 and 0.005, respectively)., Conclusion: This study did not find a significant survival benefit to be associated with adjuvant chemotherapy with fluoropyrimidines in patients with stage IB-IIIA gastric cancer. However, it may be effective for patients with stage II disease. Additionally, uracil-tegafur is a promising agent for adjuvant chemotherapy of gastric cancer if S-1 is not available because of its toxicity., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Trifluridine/tipiracil (TAS-102) is a new oral combination therapy approved by the US Food and Drug Administration for the treatment of patients with metastatic colorectal cancer who are refractory to or intolerant of standard chemotherapy. This agent consists of a thymidine-based nucleoside analogue (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil), which is included to reduce the degradative breakdown of trifluridine. In the phase III Randomized, double-blind, phase III Study of TAS-102 plus best supportive care [BSC] versus placebo plus BSC in patients with metastatic colorectal cancer [CRC] refractory to standard chemotherapies (RECOURSE) trial, trifluridine/tipiracil showed significant improvement in overall survival compared with placebo. Trifluridine/tipiracil is administered at a 35 mg/m 2 dose orally twice daily in a 28-day cycle consisting of 5 treatment days/2 rest days for 2 weeks followed by a rest period of 2 weeks. Because trifluridine/tipiracil is a completely oral chemotherapy regimen, patient adherence to treatment is an important consideration. It is also critical to have strategies in place for managing toxicities, because side effects might have a negative effect on patient adherence. The most frequent adverse events reported in patients with metastatic colorectal cancer receiving trifluridine/tipiracil in the phase III RECOURSE trial were myelosuppression, nausea/vomiting, diarrhea, decreased appetite, and fatigue. In this review we aim to provide clinicians with practical recommendations for facilitating patient adherence to oral chemotherapy, managing trifluridine/tipiracil dosing, and address the most common adverse events in patients who receive trifluridine/tipiracil therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The optimal treatment strategy for biliary tract cancer (BTC) after curative-intent resection remains controversial. The purpose of this study was to evaluate the efficacy of fluoropyrimidine-based adjuvant chemotherapy for BTC patients undergoing microscopically margin-negative (R0) resection., Methods: We retrospectively analyzed the clinical data of BTC patients who underwent curative-intent R0 resection. Patients were eligible if they received either fluoropyrimidine-based adjuvant chemotherapy or observation after R0 resection., Results: A total of 153 patients were included. In the entire patient cohort, no significant differences were observed in 5-year overall survival (OS) rates (48.4% vs. 39.6%, P = 0.439) or 3-year recurrence-free survival (RFS) rates (49.1% vs. 39.5%, P = 0.299) between patients who received fluoropyrimidine-based adjuvant chemotherapy or observation. However, for patients with stages II and III BTC, chemotherapy significantly improved 5-year OS rate (52.4% vs. 35.6%, P = 0.002) and 3-year RFS rate (55.5% vs. 39.1%, P = 0.021) compared with observation., Conclusion: Fluoropyrimidine-based adjuvant chemotherapy may prolong the survival of patients with stages II and III BTC after R0 resection.

Background: Disseminated intravascular coagulation (DIC) is a rare complication of advanced gastric cancer (AGC). Despite reports of the efficacy of chemotherapy for AGC with DIC, little is known of platinum-based doublet therapy., Patients and Methods: We conducted a single-institute, retrospective chart review of 500 consecutive chemotherapy-naïve patients with advanced gastric adenocarcinoma (recurrent or metastatic) from November 2010 to November 2015., Results: Six patients were diagnosed with AGC with DIC (1.2%); five (1.0%; 3 men, 2 women) received platinum-based doublet chemotherapy. All patients exhibited improved DIC and thrombocytopenia and survived for >100 days (range=114-313) with no therapy-related mortality. Grade ≥3 adverse effects included neutropenia, anemia, hyponatremia, catheter-related infection and diarrhea (maximum: 2 patients each)., Conclusion: Fluoropyrimidine plus platinum combination therapy was effective against DIC and yielded acceptable survival outcomes. Combination chemotherapy should be considered as a primary therapy for AGC with DIC., (Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

F10 is a novel polymeric fluoropyrimidine drug candidate with strong anticancer activity in multiple preclinical models. F10 has strong potential for impacting cancer treatment because it displays high cytotoxicity toward proliferating malignant cells with minimal systemic toxicities thus providing an improved therapeutic window relative to traditional fluoropyrimidine drugs, such as 5-fluorouracil. F10 has a unique mechanism that involves dual targeting of thymidylate synthase and Top1. In this review, the authors provide an overview of the studies that revealed the novel aspects of F10's cytotoxic mechanism and summarize results obtained in preclinical models of acute myeloid leukemia, acute lymphocytic leukemia, glioblastoma and prostate cancer that demonstrate the strong potential of F10 to improve treatment outcomes., Competing Interests: Financial & competing interests disclosure The authors advise Salzburg Therapeutics, which is involved in commercialization of F10 for cancer treatment and are inventors on issued patents and pending patent applications filed by Wake Innovations. The authors are grateful for support from the Wake Forest Baptist Comprehensive Cancer Center P30 CA012197. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Fluoropyrimidine (FU) and platinum-based chemotherapies are greatly complicated by their associated toxicities. This umbrella systematic review synthesized all systematic reviews that investigated associations between germline variations and toxicity, with the aim of informing personalized medicine. Systematic reviews are important in pharmacogenetics where false positives are common. Four systematic reviews were identified for FU-induced toxicity and three for platinum. Polymorphisms of DPYD and TYMS, but not MTHFR, were statistically significantly associated with FU-induced toxicity (although only DPYD had clinical significance). For platinum, GSTP1 was found to not be associated with toxicity. This umbrella systematic review has synthesized the best available evidence on the pharmacogenetics of FU and platinum toxicity. It provides a useful reference for clinicians and identifies important research gaps.

Approximately half of the colorectal cancer (CRC) patients develop metastatic disease. Fluoropyrimidine-based chemotherapy forms the backbone of treatment in these patients. However, the response to this therapy varies between individuals. Therefore, an important challenge in CRC research is to identify biomarkers that are predictive of this response. In this study, we explored the potential of miRNAs, and the miRNA producing protein Dicer, as biomarkers that can predict chemo-sensitivity to fluoropyrimidine chemotherapy in patients with metastatic colorectal cancer (mCRC). We analyzed the levels of 22 miRNAs and the Dicer protein in primary tumors from patients with mCRC who were treated with first-line capecitabine monotherapy within the CAIRO trial of the Dutch Colorectal Cancer Group. Correlation between the expression status of miRNAs or Dicer in primary tumors and the progression free survival (PFS) were investigated. Patients with low expression of miR-143 in their primary tumor had increased median PFS compared to those with high expression of miR-143. Furthermore, FXYD3, an ion transport regulator and a putative target of miR-143, also showed an association with PFS. These findings warrant further studies to investigate the relationship between miR-143, FXYD3 and fluoropyrimidines, and the clinical utility of miR-143 as biomarker.

Advanced neuroendocrine tumors are incurable, and most patients will succumb to the disease. Chemotherapies with cytotoxic agents such as streptozocin, 5-fluorouracil, or temozolomide have been frequently used as drug therapies for neuroendocrine tumors. Streptozocin, which is the only approved cytotoxic agent available for the treatment of this disease in many countries, has been considered a key agent for the treatment of advanced neuroendocrine tumors based on the results of phase III studies. However, the widespread acceptance of streptozocin-based chemotherapy for this indication has been limited by concerns regarding toxicity. Recent prospective and retrospective studies showed the promising activity of a temozolomide-based regimen, although an adequate prospective controlled study defining the role of temozolomide in the treatment of neuroendocrine tumors is lacking. The promising activity of cytotoxic agents awaits confirmation; solid evidence-based recommendations and treatment decisions are needed for the optimal use of chemotherapy against this disease., (© 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

This is a prospective randomized trial performed to compare the efficacy of concurrent chemoradiotherapy (CCRT) + S-1 (oral fluoropyrimidine) with that of CCRT + cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma. A total of 105 eligible patients were randomly assigned to receive CCRT with S-1 (S-1 arm, n=50) or cisplatin weekly (control arm, n=55). Patients in the S-1 arm received CCRT plus S-1 (40-60 mg, twice daily for 4 consecutive weeks. Patients in the control arm received standard CCRT with weekly cisplatin. All the patients were included in an intention-to-treat survival analysis. Our results demonstrated that the S-1 and control arms did not differ significantly in terms of complete response, partial response, progression-free survival or overall survival (all P-values >0.05). However, the two arms varied significantly regarding certain grade 3-4 toxicities, including leukopenia, 5.5 vs. 22.0% (P=0.013); mucositis, 20.0 vs. 46.0% (P=0.004); dermatitis, 15.5 vs. 32.7% (P=0.011); and nausea, 9.1 vs. 41.6% (P<0.001) for the S-1 and control arms, respectively. In conclusion, CCRT with S-1 was found to be similar in efficacy but superior in terms of toxicity compared to the standard CCRT with weekly cisplatin.

Background: Intracellular Zn(2+) levels decrease during prostate cancer progression and agents that modulate intracellular Zn(2+) are cytotoxic to prostate cancer cells by an incompletely described mechanism. F10 is a new polymeric fluoropyrimidine drug-candidate that displays strong activity with minimal systemic toxicity in pre-clinical models of prostate cancer and other malignancies. The effects of exogenous Zn(2+) or Zn(2+) chelation for enhancing F10 cytotoxicity are investigated as is the role of Omi/HtrA2, a serine protease that promotes apoptosis in response to cellular stress., Methods: To test the hypothesis that the pro-apoptotic effects of F10 could be enhanced by modulating intracellular Zn(2+) we investigated cell-permeable and cell-impermeable Zn(2+) chelators and exogenous Zn(2+) and evaluated cell viability and apoptosis in cellular models of castration-resistant prostate cancer (CRPC; PC3, C4-2). The role of Omi/HtrA2 for modulating apoptosis was evaluated by pharmacological inhibition and Western blotting., Results: Exogenous Zn(2+) initially reduced prostate cancer cell viability but these effects were transitory and were ineffective at enhancing F10 cytotoxicity. The cell-permeable Zn(2+) -chelator tetrakis-(2-pyridylmethl) ethylenediamine (TPEN) induced apoptosis in prostate cancer cells and enhanced the pro-apoptotic effects of F10. The pro-apoptotic effects of Zn(2+) -chelation in combination with F10 treatment were enhanced by inhibiting Omi/HtrA2 implicating this serine protease as a novel target for prostate cancer treatment., Conclusions: Zn(2+) -chelation enhances the pro-apoptotic effects of F10 and may be useful for enhancing the effectiveness of F10 for treatment of advanced prostate cancer. The serine protease Omi/HtrA2 modulates Zn(2+) -dependent apoptosis in prostate cancer cells and represents a new target for treatment of CRPC. Prostate 75:360-369, 2015. © 2014 Wiley Periodicals, Inc., (© 2014 Wiley Periodicals, Inc.)

Since over 50 years, 5-fluorouracil (5-FU) is in use as backbone of chemotherapy treatment regimens for a wide range of cancers including colon, breast, and head and neck carcinomas. However, drug resistance and severe toxicities such as mucositis, diarrhea, neutropenia, and vomiting in up to 40% of treated patients often lead to dose limitation or treatment discontinuation. Because the oral bioavailability of 5-FU is unpredictable and highly variable, 5-FU is commonly administered intravenously. To overcome medical complications and inconvenience associated with intravenous administration, the oral prodrugs capecitabine and tegafur have been developed. Both fluoropyrimidines are metabolically converted intracellularly to 5-FU, which then needs metabolic activation to exert its damaging activity on RNA and DNA. The low response rates of 10-15% of 5-FU monotherapy can be improved by combination regimens of infusional 5-FU and leucovorin together with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), thereby increasing response rates to 30-40%. The impact of metabolizing enzymes in the development of fluoropyrimidine toxicity and resistance has been studied in great detail. In addition, membrane drug transporters, which are critical determinants of intracellular drug concentrations, may play a role in occurrence of toxicity and development of resistance against fluoropyrimidine-based therapy as well. This review therefore summarizes current knowledge on the role of drug transporters with particular focus on ATP-binding cassette transporters in fluoropyrimidine-based chemotherapy response., (© 2015 Elsevier Inc. All rights reserved.)

Background: S-1, a novel oral fluoropyrimidine, has potent antitumor activity against non-small-cell lung cancer (NSCLC). Meanwhile, leucovorin enhances the efficacy of 5-fluorouracil by inhibiting thymidylate synthase. Therefore, this phase II clinical trial evaluated the safety and efficacy of S-1 plus leucovorin combination therapy for previously treated patients with NSCLC., Patients and Methods: Patients with stage IIIB or IV NSCLC were prospectively enrolled if they received 1 or 2 prior chemotherapy regimens. S-1 (40-60 mg) and leucovorin (25mg) were administered together orally twice per day for 7 consecutive days followed by 7 days of rest. This 2-week cycle was repeated for a maximum of 25 cycles until the onset of disease progression or unacceptable adverse events. Endpoints included objective tumor response, progression-free survival, overall survival, and safety., Results: Among 33 patients, 6 (18.2%), 14 (42.4%), and 11 (33.3%) had partial response, stable disease, and progressive disease, respectively. Median progression-free and overall survival times were 3.5 and 11.7 months, respectively. The common grade 3 toxicities included stomatitis (18.2%), anorexia (12.1%), and neutropenia (9.1%). One patient had pneumatosis cystoides intestinalis, and another experienced paralytic ileus. There were no treatment-related deaths., Conclusions: S-1 plus leucovorin combination therapy demonstrated promising efficacy and an acceptable toxicity profile in previously treated patients with NSCLC., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Chemotherapy remains of limited use for the treatment of prostate cancer with only one drug, docetaxel, demonstrating a modest survival advantage for treatment of late-stage disease. Data from the NCI 60 cell line screen indicated that the castration-resistant prostate cancer cell lines PC3 and DU145 were more sensitive than average to the novel polymeric fluoropyrimidine (FP), F10, despite displaying less than average sensitivity to the widely-used FP, 5FU. Here, we show that F10 treatment of PC3 xenografts results in a significant survival advantage (treatment to control ratio (T/C) days = 18; p < 0.001; n = 16) relative to control mice treated with saline. F10 (40 mg/kg/dose) was administered via jugular vein catheterization 3-times per week for five weeks. This aggressive dosing regimen was completed with no drug-induced weight loss and with no evidence of toxicity. F10 was also shown to sensitize PC3 cells to radiation and F10 was also shown to be a potent radiosensitizer of PC3 xenografts in vivo with F10 in combination with radiation resulting in significantly greater regression of PC3 xenografts than radiation alone. The results indicate that F10 in this pre-clinical setting is an effective chemotherapeutic agent and possesses significant radiosensitizing properties.

Aim: To determine the efficacy of adjuvant chemotherapy for gastric cancer in clinical practice, a retrospective analysis was conducted in a high-volume Chinese cancer center., Methods: Between November 1995 and June 2007, a total of 423 gastric or esophagogastric adenocarcinoma patients who did (Arm A, n = 300) or did not (Arm S, n = 123) receive radical gastrectomy followed by postoperative chemotherapy were enrolled in this retrospective analysis. In Arm A, monotherapy(fluoropyrimidines, n = 25), doublet (platinum/fluoropyrimidines, n = 164), or triplet regimens [docetaxel/cisplatin/5FU (DCF), or modified DCF, epirubicin/cisplatin/5FU (ECF) or modified ECF, etoposide/cisplatin/FU, n = 111] were administered. Disease-free survival (DFS) and overall survival (OS) were compared between the two arms. A subgroup analysis was carried out in Arm A. A multivariate analysis of prognostic factors was conducted., Results: Stage I, II and III cancers accounted for 9.7%, 35.7% and 54.6% of the cases, respectively, according to the American Joint Committee on Cancer (AJCC) staging system, 7(th) edition. Only 178 (42.1%) patients had more than 15 lymph nodes harvested. Hazard ratio estimates for Arm A compared with Arm S were 0.47 (P < 0.001) for OS and 0.59 (P < 0.001) for DFS. The 5-year OS rate was 52% in Arm A vs 36% in Arm S (P = 0.01); the adverse events in Arm A were mild and easily controlled. Ultimately, 73 patients (26.5%) who received doublet or triplet regimens switched to monotherapy with fluoropyrimidines. The OS and DFS did not differ between monotherapy and the combination regimens, however, both were statistically improved in the subgroup of patients who were switched to monotherapy with fluoropyrimidines after doublet or triplet regimens as well as patients who received ≥ 8 cycles of chemotherapy., Conclusion: In clinical practice, platinum/fluoropyrimidines with adequate treatment duration is recommended for stage II/III gastric cancer patients according to the 7(th) edition of the AJCC staging system after curative gastrectomy even with limited lymphadenectomy.

We previously identified five miRNAs (miR-1, miR-20a, miR-27a, miR-34a, and miR-423-5p) that are up-regulated in gastric cancer. The goal of this study was to investigate the value of these miRNAs as potential biomarkers for predicting chemosensitivity and prognosis in metastatic or recurrent gastric cancer patients who received first-line chemotherapy. A total of 82 patients with metastatic or recurrent GC receiving first-line chemotherapy were included in our study. The expression levels of the five miRNAs were evaluated using hydrolysis probe-based stem-loop quantitative reverse transcription polymerase chain reaction (qRT-PCR) in individual samples before first-line chemotherapy. Patients receiving first-line chemotherapy with fluoropyrimidine combined with oxaliplatin or paclitaxel were chosen for the chemosensitivity analysis. The relationships between expression of the five-miRNAs and clinicopathological parameters, response to chemotherapy and prognosis were analyzed statistically. Patients with higher miRNA1 expression levels tended to have a higher rate of liver metastasis, and higher miRNA34a expression levels occurred more frequently in males (P = 0.022). The expression of the remaining three miRNAs showed no obvious relationship to any of the clinicopathological features. The partial response rates of the patients with high miRNA1 expression and low miRNA1 expression were 11.1% and 23.1%, respectively (P = 0.048). Similar results were observed for miRNA27a (the partial response rate was 7.7% vs. 25.9%, P = 0.018). Patients with up-regulated miRNA27a expression had a significantly worse overall survival (OS) than patients with lower miRNA27a expression (P = 0.024). In patients with MRGC, miRNA27a is a potential biomarker for predicting resistance to fluoropyrimidine-based chemotherapy and a novel prognostic marker for gastric cancer., (© 2013 Wiley Periodicals, Inc.)

Aim: To evaluate the treatment outcomes of irinotecan monotherapy for patients with advanced biliary tract cancer refractory to gemcitabine, cisplatin, and oral fluoropyrimidine., Patients and Methods: Irinotecan (100 mg/m(2)) was administered intravenously on days 1, 8, and 15, repeated every four weeks., Results: Thirteen patients were enrolled. The dose intensity was only 55.0%. The response rate and disease control rate were 1/13 (7.7%) and 3/13 (23.1%), respectively. The median overall survival and time-to-progression were 6.7 months (95% confidence interval=3.0-10.4 months) and 1.8 months (95% confidence interval=1.6-3.9 months), respectively. Grade 3/4 adverse events included leukopenia (7/13), neutropenia (8/13), anemia (6/13), nausea (1/13), vomiting (1/13), anorexia (2/13), diarrhea (1/13), and constipation (1/13)., Conclusion: Irinotecan monotherapy had a modest antitumor effect even for patients who were refractory to gemcitabine, cisplatin, and oral fluoropyrimidine. However, this regimen was not fully tolerated as third-line or fourth-line therapy. Therefore, further evaluation of a modified irinotecan regimen is necessary.

Aim: To evaluate the chemotherapeutic outcomes and confirm the recent improvement of prognosis for unresectable biliary tract cancer., Methods: A total of 186 consecutive patients with unresectable biliary tract cancer, who had been treated with chemotherapy between 2000 and 2009 at five institutions in Japan, were retrospectively analyzed. These patients were divided into three groups based on the year beginning chemotherapy: Group A (2000-2003), Group B (2004-2006), and Group C (2007-2009). The data were fixed at the end of December 2011. Overall survival and time-to-progression were analyzed and compared chronologically., Results: No patient characteristics were significantly different among the three groups. The gallbladder was involved in about half of the patients in each group, and metastatic biliary tract cancer was present in three quarters of the enrollees. In Group A, 5-fluorouracil-based chemotherapies were primarily selected as first-line chemotherapy, and only 24% were treated with second-line chemotherapy. In Group B, gemcitabine or S-1 monotherapy was mainly introduced as first-line chemotherapy, and 51% of the patients who were refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with monotherapy. In Group C, the combination therapy with gemcitabine and S-1 was mainly chosen as first-line chemotherapy, and 53% of the patients refractory to first-line chemotherapy were treated with second-line chemotherapy mainly with combination therapy. The median time-to-progressions were 4.4 mo, 3.5 mo and 5.9 mo in Groups A, B and C, respectively (4.4 mo vs 3.5 mo vs 5.9 mo, P < 0.01). The median overall survivals were 7.1, 7.3, and 11.7 mo in Groups A, B and C (7.1 mo vs 7.3 mo vs 11.7 mo, P = 0.03). Induction rates of all three drugs (gemcitabine, platinum analogs, and fluoropyrimidine) in Groups A, B and C were 4%, 2% and 27% (4% vs 2% vs 27%, P < 0.01)., Conclusion: The prognosis of unresectable biliary tract cancer has improved recently. Using three effective drugs (gemcitabine, platinum analogs, and fluoropyrimidine) may improve the prognosis of this cancer.

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.