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"A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the THYMIDYLATE SYNTHETASE conversion of deoxyuridylic acid to thymidylic acid." (MeSH 2013)

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Web Resources: Fluorouracil
Latest Research Publications

Web Resources: Fluorouracil (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Maemura K, Mataki Y, Kurahara H, et al.
Gemcitabine and S-1 Induction Chemotherapy Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancers.
Anticancer Res. 2017; 37(1):233-237 [PubMed] Related Publications
BACKGROUND: Gemcitabine and S-1 are drugs commonly used for treating locally advanced pancreatic cancer (LAPC). However, the safety and efficacy of combination of these agents for induction chemotherapy (IC) followed by chemoradiotherapy are not well-defined.
PATIENTS AND METHODS: Fifteen patients with LAPC (IC-CRT group) were treated with gemcitabine and S-1 IC, followed by S-1 chemoradiotherapy. The clinical outcomes were compared to a cohort of 38 patients who received chemoradiotherapy alone (CRT group).
RESULTS: Disease control rates in the CRT and IC-CRT groups were 84% and 93%, respectively (p=0.024). The median time of disease progression was 10.8 and 15.4 months in the CRT and IC-CRT group, respectively (p=0.043). The median overall survival time was longer in the IC-CRT group compared to CRT (23.4 vs. 17.3 months), but this increase was not statistically significant.
CONCLUSION: Gemcitabine and S-1 combination chemotherapy, followed by CRT, is a promising IC regimen for treating LAPC.

Park M, Sundaramoorthy P, Sim JJ, et al.
Synergistically Anti-metastatic Effect of 5-Flourouracil on Colorectal Cancer Cells via Calcium-mediated Focal Adhesion Kinase Proteolysis.
Anticancer Res. 2017; 37(1):103-114 [PubMed] Related Publications
AIM: To investigate the possibility of enhancing an anti-metastatic effect of 5-fluorouracil (5-FU) on colorectal cancer (CRC) cells by combining it with continuous calcium supplementation.
MATERIALS AND METHODS: Optimal doses of 5-FU with/without lactate salt (CaLa) were determined via clonogenicity and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays using human CRC cells cultured on normal or low-attachment plates. Invasion and migration assays confirmed the enhanced anti-metastatic effect of combining 5-FU and CaLa. Western blot analysis for elements of the focal adhesion kinase (FAK) signaling cascade and epithelial-mesenchymal transition (EMT) markers was used to investigate the underlying mechanism.
RESULTS: 5-FU (2.5 μM) had no antitumor activity against unanchored CRC cells, while it significantly suppressed anchorage-dependent cell proliferation. In contrast, treatment with CaLa (2.5 mM), alone and in combination with 5-FU, exerted antitumor activity against both anchored and unanchored CRC cells via calcium-mediated FAK proteolysis and inhibition of EMT markers, such as vimentin and SNAIL.
CONCLUSION: Calcium supplementation represents a method of enhancing the potency of existing antitumor agents such as 5-FU, augmenting their clinical effectiveness.

Roberto M, Romiti A, Botticelli A, et al.
Evaluation of 5-fluorouracil degradation rate and Pharmacogenetic profiling to predict toxicity following adjuvant Capecitabine.
Eur J Clin Pharmacol. 2017; 73(2):157-164 [PubMed] Related Publications
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(6) cells/min) and ultra-rapid (>2.1 ng/mL/10(6) 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(6) 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.

Tan Q, Qin Q, Yang W, et al.
Combination of 125I brachytherapy and chemotherapy for unresectable recurrent breast cancer: A retrospective control study.
Medicine (Baltimore). 2016; 95(44):e5302 [PubMed] Related Publications
Recurrent breast cancer remains an incurable malignancy and cannot be removed by surgery in the majority of cases. This study aimed to explore the feasibility and efficacy of the combination of I brachytherapy and chemotherapy for the treatment of unresectable recurrent breast cancer. Patients with unresectable recurrent breast cancer treated between January 2011 and December 2014 with a combination of I brachytherapy and capecitabine or gemcitabine were evaluated and outcomes were compared with those of women treated with capecitabine or gemcitabine in conventional dose as a monotherapy. Of 61 patients evaluated, 28 received the combination treatment and 33 received capecitabine or gemcitabine monotherapy. The combination of I brachytherapy and chemotherapy resulted in a significant improvement in progression-free survival versus capecitabine or gemcitabine monotherapy (median, 17.8 vs 11.4 months; hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.23-0.84; P = 0.013). The objective response rate (ORR) was significantly higher with the combination (82.1%) than with monotherapy (54.5%; P = 0.022), and the rate of pain relief was higher in the combination arm (100% vs 73.6%; P = 0.038). There was no significant improvement for overall survival (median, 30.1 vs 27.2 months; HR, 0.82; 95% CI, 0.47-1.44; P = 0.496). There were no serious complications detected during the follow-up period, any grade toxicities were comparable between treatment arms. In conclusion, the combination of I brachytherapy and second-line chemotherapy is superior to chemotherapy alone and is an effective and safe therapy for unresectable recurrent breast cancer. However, further investigation and much larger scale randomized controlled trials with long-term follow-up are needed.

Koda K, Miyauchi H, Kosugi C, et al.
Tumor 5-FU-related mRNA Expression and Efficacy of Oral Fluoropyrimidines in Adjuvant Chemotherapy of Colorectal Cancer.
Anticancer Res. 2016; 36(10):5325-5331 [PubMed] Related Publications
BACKGROUND: It has not been elucidated whether the clinical efficacy of oral fluoropyrimidines for adjuvant chemotherapy of colorectal cancer varies with tumor biological characteristics.
PATIENTS AND METHODS: A multicenter randomized trial was performed comparing oral tegafur/gimeracil/oteracil (S-1) and uracil-tegafur/ leucovorin (UFT/LV) as adjuvant therapy for stage III colorectal cancer. Postoperative survival was compared based on the 5-FU-related mRNA levels in cancer tissues.
RESULTS: Among patients with tumor expressing dihydropyrimidine dehydrogenase (DPD) mRNA within the 66.7th percentile (lower 2/3) of all cases, overall survival (OS) was significantly better in the S-1 than in the UFT/LV group. In the S-1 group, patients with low DPD-expressing tumors had significantly better OS than those with highly expressing tumors. Patients with low thymidine synthase (TS)-expressing tumors had significantly better OS than those with highly expressing tumors.
CONCLUSION: The efficacy of oral fluoropyrimidines as adjuvant chemotherapy for colorectal cancer may be influenced by the level of 5-FU-related mRNA in cancer tissues.

Yawata K, Osada S, Tanahashi T, et al.
The Significant Role of Cyclin D1 in the Synergistic Growth-inhibitory Effect of Combined Therapy of Vandetanib with 5-Fluorouracil for Gastric Cancer.
Anticancer Res. 2016; 36(10):5215-5226 [PubMed] Related Publications
BACKGROUND: 5-Fluorouracil (5-FU) has been a mainstay of chemotherapy for gastric cancer. Vandetanib is a tyrosine kinase inhibitor with inhibitory activity against vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR). We investigated the combination effect of vandetanib with 5-FU on gastric cancer cells.
MATERIALS AND METHODS: Anticancer efficacy was assessed by 3-(4,5-dimethyl-2-tetrazolyl)-2,5-diphenyl-2H tetrazolium bromide assay of five gastric cancer cell lines, MKN1, MKN7, MKN45, MKN74, and TMK1. Signal expression was examined by western blot, and the cell-cycle distribution was assessed by flow cytometry. In vivo anticancer activity of vandetanib with/without 5-FU was tested in MKN74 cells on nude mice.
RESULTS: Vandetanib inhibited the growth of all cell lines. In MKN7 and MKN74 cells, the combination of 5-FU and vandetanib had synergistic effects, but effects were only additional against the other cell lines in vitro. Combination chemotherapy in vivo also significantly inhibited tumor growth compared to single use of each drug. Flow cytometry showed vandetanib increased the proportion in the G1 phase, and in MKN74, combination therapy increased the early S phase and caused bimodal peaks in the G1 phase. The level of expression of cyclin D1 was clearly strong in MKN7 and MKN74 in the natural state, and the expression of cyclin D1, E2 promoter binding factor 1 and thymidylate synthase (TYMS) was inhibited by vandetanib, but not in MKN1 cells. The synergistic effect disappeared in MKN7 and MKN74 cells in vitro when cyclin D1 was knocked-down by siRNA.
CONCLUSION: The synergistic effect of vandetanib with 5-FU is related to vandetanib-induced reduction of TYMS via down-regulation of cyclin D1. Hyperexpression of cyclin D1 might be a biomarker of the synergistic effect.

Park K, Kim KP, Park S, Chang HM
Comparison of gemcitabine plus cisplatin versus capecitabine plus cisplatin as first-line chemotherapy for advanced biliary tract cancer.
Asia Pac J Clin Oncol. 2017; 13(1):13-20 [PubMed] Related Publications
AIM: It remains unclear whether capecitabine combined with cisplatin would show similar effects compared with standard therapy using gemcitabine and cisplatin in advanced biliary tract cancer (BTC).
METHODS: Patients with advanced BTC who were treated with first-line chemotherapy at Asan Medical Center were retrospectively analyzed. All patients received either cisplatin followed by gemcitabine on days 1 and 8 every 3 weeks (GP group), or capecitabine on days 1-14 with cisplatin on day 1 every 3 weeks (XP group).
RESULTS: Of the 134 patients who met the inclusion criteria, 78 received XP and 56 were treated with GP. After a median follow-up of 26.2 months, the progression-free survival was 5.7 months for XP versus 4.1 months for GP (hazard ratio [HR] = 0.81, P = 0.31). The overall survival (OS) was 11.0 months for XP versus 9.8 months for GP (HR = 0.84, P = 0.36). In the multivariate analysis, there were no significant differences in PFS and OS between the two groups.
CONCLUSION: XP seems to be as effective as GP in patients with advanced BTC. The XP regimen is feasible and might offer increased convenience regarding the schedule of drug administration.

McHugh CI, Lawhorn-Crews JM, Modi D, et al.
Effects of capecitabine treatment on the uptake of thymidine analogs using exploratory PET imaging agents: (18)F-FAU, (18)F-FMAU, and (18)F-FLT.
Cancer Imaging. 2016; 16(1):34 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A principal goal for the use of positron emission tomography (PET) in oncology is for real-time evaluation of tumor response to chemotherapy. Given that many contemporary anti-neoplastic agents function by impairing cellular proliferation, it is of interest to develop imaging modalities to monitor these pathways. Here we examined the effect of capecitabine on the uptake of thymidine analogs used with PET: 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT), 1-(2'-deoxy-2'-[(18)F]fluoro-β-D-arabinofuranosyl) thymidine ((18)F-FMAU), and 1-(2'-deoxy-2'-[(18)F]fluoro-β-D-arabinofuranosyl) uracil ((18)F-FAU) in patients with advanced cancer.
METHODS: Fifteen patients were imaged, five with each imaging agent. Patients had been previously diagnosed with breast, colorectal, gastric, and esophageal cancers and had not received therapy for at least 4 weeks prior to the first scan, and had not been treated with any prior fluoropyrimidines. Subjects were imaged within a week before the start of capecitabine and on the second day of treatment, after the third dose of capecitabine. Tracer uptake was quantified by mean standard uptake value (SUVmean) and using kinetic analysis.
RESULTS: Patients imaged with (18)F-FLT showed variable changes in retention and two patients exhibited an increase in SUVmean of 172.3 and 89.9 %, while the other patients had changes ranging from +19.4 to -25.4 %. The average change in (18)F-FMAU retention was 0.2 % (range -24.4 to 23.1) and (18)F-FAU was -10.2 % (range -40.3 to 19.2). Observed changes correlated strongly with SUVmax but not kinetic measurements.
CONCLUSIONS: This pilot study demonstrates that patients treated with capecitabine can produce a marked increase in (18)F-FLT retention in some patients, which will require further study to determine if this flare is predictive of therapeutic response. (18)F-FAU and (18)F-FMAU showed little change, on average, after treatment.

Turkeli M, Aldemir MN, Bingol F, et al.
A morphometric study of the protective effect of cryotherapy on oral mucositis in cancer patients treated with 5-fluorouracil.
Biotech Histochem. 2016; 91(7):465-471 [PubMed] Related Publications
We investigated cytological changes in oral mucosa smears from patients treated with cryotherapy to determine whether cryotherapy prevented mucositis caused by 5-fluorouracil (5-FU) therapy. Patients with gastrointestinal malignancies were divided into four groups; control patients before 5-FU therapy, patients after 5-FU therapy without cryotherapy, patients with cryotherapy before 5-FU therapy and patients with cryotherapy after 5-FU therapy. Oral mucosa samples from all patients were assessed at the beginning and on day 14 of chemotherapy. We used exfoliative cytology to evaluate cellular changes in the oral mucosa that were caused by 5-FU. Smears from each patient were stained using the Papanicolaou method and analyzed using stereology. Smears were taken from each group before and after 5-FU infusion. We found that nuclear volume was decreased significantly in cells of the 5-FU therapy after cryotherapy patients compared to the 5-FU therapy before cryotherapy patients. We also found significantly decreased cytoplasmic volumes in the 5-FU therapy after cryotherapy patients compared to the 5-FU therapy before cryotherapy patients. The results of cytomorphometric estimations revealed that cryotherapy may be used to prevent damage to oral tissue and may decrease the frequency and duration of oral mucositis caused by 5-FU.

Jaferian S, Negahdari B, Eatemadi A
Colon cancer targeting using conjugates biomaterial 5-flurouracil.
Biomed Pharmacother. 2016; 84:780-788 [PubMed] Related Publications
There has been several research works on the development of an oral delivery system to deliver cytotoxic and chemo preventive agents directly at the targeted site of action with reduced unwanted side effects. The efficacy of the site-specific delivery system of a drug to colon has been proven to increase the drugs concentration at the target site, and thus requires a reduced dose of the drug with minimized side effects. This review includes discussion of the delivery systems of 5-FU using biodegradable materials and some significant outcomes in the pre-clinical development of 5-fluorouracil carriers for the colon cancer.

Naik MP, Mehta A, Abrol S, et al.
Topical 5% 5-fluorouracil in the treatment of multifocal basal cell carcinoma of the face: A novel chemotherapeutic approach.
Orbit. 2016; 35(6):352-354 [PubMed] Related Publications
To determine the safety and efficacy of topical 5-fluorouracil (5-FU) 5% ointment in treatment of non-syndromic multifocal basal cell carcinoma. A 55-year-old male patient, with 8 hours of daily sun exposure, having histologically proven and radiologically non-syndromic, multifocal basal cell carcinoma with involvement of 6 sites on the face, was treated with topical 5-FU 5% ointment twice daily over all sites except the site involving lid margin to prevent corneal toxicity. Left lid lesion underwent wide surgical excision with 5-mm clear margins and reconstruction with nasal septal mucoperichondrium and local skin mobilization. Pharmacologic effects first appeared at 4 weeks and by 8 weeks, the lesions had scabbed and had fallen off with no induration but residual mild perilesional erythema. Patient had post-op histopathological clear margins and recovered uneventfully. No recurrence in 6 months. A topical 5-FU 5% ointment represents a paradigm shift in the treatment of BCC from invasive and disfiguring options (surgery and chemoradiotherapy) to cheap, convenient, effective, non-invasive, non-disfiguring topical chemotherapy. Topical 5% 5-FU is a safe and effective modality of treatment of superficial spreading multifocal basal carcinoma, especially lesions larger than 10 mm, where margins cannot be identified clearly and recurrent lesions.

Patricia Rios-Ibarra C, Janeth Rodriguez-Silva C, Alonso Lopez-Chuken Y, et al.
Thymidylate synthase polymorphism in Mexican patients with colon cancer treated with 5-fluorouracil.
J BUON. 2016 Jul-Aug; 21(4):935-940 [PubMed] Related Publications
PURPOSE: We analyzed the genotype and allele frequency of variable number tandem repeats (VNTR)-thymidylate synthase (TS) and its relationship with the disease evolution in colon cancer patients.
METHODS: We selected 24 paraffin-embedded colon cancer tissue samples from Mexican patients who received a 5-fluorouracil (5-FU)-based chemotherapy regimen. Tumor tissue was digested with proteinase K and genomic DNA was isolated by the standard method with phenol-chloroform extraction. Polymerase chain reaction (PCR) was performed for TS genotyping of VNTR and the results were evaluated directly in a stained agarose gel.
RESULTS: The allele frequency of 2 repeats (2R) was greater (0.66) than 3R (0.34) in metastatic colon cancer (x(2)=10.24; p=0.001)) however, no difference in allelic distribution between 2R (0.54) and 3R (0.46) in non metastatic patients was observed (x(2)=0.640; p=0.424).
CONCLUSION: Our results suggest that Mexican patients with colon cancer present differences in the allelic distribution, the 2R allele being the most frequent.

Huang W, You L, Yang S, et al.
Metronomic S-1 chemotherapy plus transcatheter arterial chemoembolization (TACE): a promising treatment of hepatocellular carcinoma refractory to TACE.
J BUON. 2016 Jul-Aug; 21(4):909-916 [PubMed] Related Publications
PURPOSE: To assess the efficacy and safety of metronomic S-1 chemotherapy combination with transcatheter arterial chemoembolization (TACE) for the treatment of Barcelona Clinic Liver Cancer (BCLC) Stage B hepatocellular carcinoma (HCC) refractory to TACE.
METHODS: Twenty six patients met the eligibility criteria and were enrolled. TACE was performed on day 1, and metronomic S-1 chemotherapy on days 2-15. Tumor assessment was performed one month later. The primary endpoints were time to progression (TTP) and adverse events (AE).
RESULTS: Twenty six patients in total received 176 TACE interventions. There were 101 TACE interventions in 15 patients of metronomic S-1 chemotherapy plus TACE (TS) and 75 in 11 patients of TACE monotherapy (TM). Fifteen TS patients received a total of 55 cycles of treatment with S-1, with a median of 4 cycles (range 2-6). The total dose of S-1 was 6165 mg per day in 15 patients (average 120 mg, range 100-125). Median TTP and overall survival (OS) of TS group were 6 months (95% CI, 4.7-7.3) and 17 months (95% CI, 15.6-18.4), respectively, while for the TM group were 4 months (95% CI, 2.4-5.6) and 15 months (95% CI, 9.2-20.8), respectively. Though there were higher tumor response rate (RR) and disease control rates (DCRs) in patients with TS, no significant differences were detected. Both treatment approaches were tolerable with low grade AE.
CONCLUSIONS: In the present study, metronomic S-1 chemotherapy plus TACE in the present study was tolerable and associated with a better but not statistically significant TTP, RR and OS. It showed that metronomic S-1 chemotherapy plus TACE may be a promising treatment of BCLC Stage B HCC refractory to TACE.

Jin YY, Chen QJ, Xu K, et al.
Involvement of microRNA-141-3p in 5-fluorouracil and oxaliplatin chemo-resistance in esophageal cancer cells via regulation of PTEN.
Mol Cell Biochem. 2016; 422(1-2):161-170 [PubMed] Related Publications
microRNAs (miRNAs) act as a major regulator of acquired chemo-resistance in various types of cancer therapeutics. This study investigated the contribution of miRNAs in influencing multiple drug resistance in esophageal squamous cell carcinoma (ESCC). The sensitivity of four ESCC cell lines (EC109, EC9706, TE-1 and KYSE-150) to 5-fluorouracil (5-FU) and oxaliplatin (OX) was determined by MTT assay. A 5-FU and OX-resistant subline, EC9706R, was established by continuous exposure to stepwise increasing concentration of 5-FU and OX. Microarray technology was used to compare the differential expression of miRNAs between resistant cells and parental cells. Chemo-sensitivity assay was performed to evaluate drug response in EC9706R cells transfected with miRNA mimic or inhibitor. The direct targets of miRNA were identified by employing pathway analysis and then confirmed with luciferase assay. Sixty ESCC tissue samples and their paired adjacent normal tissues were collected to validate the expression of identified miRNA. Mouse models were further utilized to investigate the function of miRNA on acquired chemo-resistance. MicroRNA panel results indicated that a total of 12 miRNAs were differentially expressed and miR-141-3p was highly over expressed in resistant cells. Inhibition of miR-141-3p reversed acquired chemo-resistance in EC9706R cells by stimulating apoptosis. The expression of miR-141-3p was significantly increased in ESCC tissue samples compared to their matched distant normal tissues. In addition, the elevated miR-141-3p expression was found to be associated with ESCC differentiation status and TNM stage. Moreover, Phosphatase and tensin homolog (PTEN) was identified as direct target of miR-141-3p. Western blot exhibited altered protein levels of PTEN, Akt, and PI3k with miR-141-3p inhibitor. An inverse correlation between PTEN expression and miR-141-3p expression was also observed in tissue samples. EC9706R xenograft mouse model became sensitized to 5-FU and OX treatment following miR-141-3p inhibitor transfection in vivo. Our study demonstrated that miR-141-3p contributed to an acquired chemo-resistance through PTEN modulation both in vitro and in vivo.

Mahlberg R, Lorenzen S, Thuss-Patience P, et al.
New Perspectives in the Treatment of Advanced Gastric Cancer: S-1 as a Novel Oral 5-FU Therapy in Combination with Cisplatin.
Chemotherapy. 2017; 62(1):62-70 [PubMed] Related Publications
Oral fluoropyrimidines have been available for more than 10 years. Capecitabine is well established in treating solid tumors in Europe. S-1 (Teysuno®), an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, has not been available in non-Asia countries until recently. In Japan, S-1 in combination with cisplatin is the recommended first-line treatment in patients with gastric cancer. In Europe, the first trials with S-1 were disappointing due to high unacceptable incidences of adverse events. Pharmacokinetic studies showed differences in Asian and Caucasian patients; therefore, a new non-Asian study program was initiated, which led to the pivotal phase 3 trial First-Line Advanced Gastric Cancer Study (FLAGS). In FLAGS, 1,053 patients with advanced gastric cancer from 24 non-Asian countries were enrolled. S-1 plus cisplatin showed no overall survival (OS) benefit when compared to 5-FU plus cisplatin. The primary endpoint superior OS was not met but better tolerability was shown. A post hoc noninferiority OS and safety analysis showed that S-1 plus cisplatin has the same efficacy as 5-FU plus cisplatin but a more favorable safety profile. This led to the approval of S-1 in combination with cisplatin in gastric cancer in Europe in 2011. This article reviews the mode of action of S-1, pivotal study results from an EU point of view, and future perspectives.

Danenberg PV, Gustavsson B, Johnston P, et al.
Folates as adjuvants to anticancer agents: Chemical rationale and mechanism of action.
Crit Rev Oncol Hematol. 2016; 106:118-31 [PubMed] Related Publications
Folates have been used with cytotoxic agents for decades and today they are used in hundreds of thousands of patients annually. Folate metabolism is complex. In the treatment of cancer with 5-fluorouracil, the administration of folates mechanistically leads to the formation of [6R]-5,10-methylene-tetrahydrofolate, and the increased concentration of this molecule leads to stabilization of the ternary complex comprising thymidylate synthase, 2'-deoxy-uridine-5'-monophosphate, and [6R]-5,10-methylene-tetrahydrofolate. The latter is the only natural folate that can bind directly in the ternary complex, with other folates requiring metabolic activation. Modulation of thymidylate synthase activity became central in the study of folate/cytotoxic combinations and, despite wide use, research into the folate component was neglected, leaving important questions unanswered. This article revisits the mechanisms of action of folates and evaluates commercially available folate derivatives in the light of current research. Better genomic insight and availability of new analytical techniques and stable folate compounds may open new avenues of research and therapy, ultimately bringing increased clinical benefit to patients.

Rachar V, Czejka M, Kitzmueller M, et al.
Assessment of Pharmacokinetic Interaction Between Capecitabine and Cetuximab in Metastatic Colorectal Cancer Patients.
Anticancer Res. 2016; 36(9):4715-23 [PubMed] Related Publications
AIM: This study focuses on the plasma disposition and metabolic activation of capecitabine (CCB) when administered alone or when combined with cetuximab (CTX).
PATIENTS AND METHODS: Twenty-four chemo-naïve patients with KRAS wild-type colorectal cancer were randomized into two arms and received either CCB alone (1,000 mg/m(2) bid p.o.), followed by CCB plus CTX (loading dose (LD)=400 mg/m(2) followed by 250 mg/m(2) weekly i.v. maintenance dose) (Arm A; n=12 patients (patients)) or CCB plus CTX followed by CCB alone (Arm B; n=12 patients). Plasma samples were collected from the cubital vein and CCB, 5'-desoxy-5-fluorocytidine (5'-DFCR) and 5'-desoxy-5 fluorouridine (5'-DFUR) were quantified by a sensitive, selective reversed phase high-performance liquid chromatography (HPLC) assay. Non-compartment pharmacokinetic parameters have been calculated by Phoenix WinNonlin.
RESULTS: No clinically relevant impact of CTX on CCB pharmacokinetic parameters and metabolic conversion could be detected in both arms after statistical evaluation (ANOVA).
CONCLUSION: From the pharmacokinetic point of view, co-administration of CTX to CCB seems to be safe.

Feng J, Xu J, Wang X, Zhao D
S-1 plus cisplatin with concurrent radiotherapy versus cisplatin alone with concurrent radiotherapy in Chinese patients with nonsmall-cell lung cancer: A multicentre randomized controlled trial.
Medicine (Baltimore). 2016; 95(36):e4557 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The aim of this study was to investigate the efficacy and safety of S-1 plus cisplatin combined with concurrent radiotherapy (SCCCR) versus cisplatin alone combined with concurrent radiotherapy (CCCR) in Chinese patients with unresectable stage III nonsmall-cell lung cancer (NSCLC).
METHODS: Between January 2012 and December 2014, 72 eligible Chinese patients with NSCLC were included and randomly divided into 2 groups, each having 36 patients. Patients in the SCCCR group received S-1 plus cisplatin with concurrent, radiotherapy. The other 36 patients in the CCCR group were administered cisplatin with concurrent radiotherapy. The primary outcome was the overall response rate. The secondary outcomes were overall survival (OS), progression-free survival (PFS), and adverse events.
RESULTS: The 3-year overall response rates for the SCCCR and CCCR groups were 60.1% and 53.3%, respectively (P = 0.041). The median OS was 35.1 (range, 6.5-47.2) months and 24.6 (range, 2.8-24.3) months for the SCCCR and CCCR groups, respectively (P = 0.016). The median PFS for the SCCCR and CCCR groups was 31.4 (range, 5.6-39.3) months and 22.3 (range, 2.4-36.5) months, respectively (P = 0.023). The toxicity profiles were similar for both groups.
CONCLUSION: The efficacy and safety of SCCCR was more encouraging compared to those of CCCR in Chinese NSCLC patients. In addition, the toxicities in both groups were tolerable.

Wang Z, Liang L, Yu Y, et al.
Primary Tumour Resection Could Improve the Survival of Unresectable Metastatic Colorectal Cancer Patients Receiving Bevacizumab-Containing Chemotherapy.
Cell Physiol Biochem. 2016; 39(3):1239-46 [PubMed] Related Publications
BACKGROUND: The effect of primary tumour resection (PTR) among metastatic colorectal cancer (mCRC) patients remains controversial. Combination chemotherapy with bevacizumab could improve the clinical outcomes of these patients, which might change the importance of PTR in the multi-disciplinary treatment pattern.
METHODS: We performed a non-randomized prospective controlled study of mCRC pts whose performance status (PS) scored ≤2 and who received bevacizumab combination chemotherapy (FOLFOX/XELOX/FOLFIRI) as a first-line therapy. These patients were classified into the PTR group and the IPT (intact primary tumour) group according to whether they underwent PTR before receiving the systemic therapy. The progression free survival (PFS) time and overall survival (OS) time, which were recorded from the start of the primary diagnosis until disease progression and death or last follow-up, were analysed. We also compared severe clinical events (such as emergency surgery, radiation therapy, and stent plantation) between the two groups.
RESULTS: One hundred and nighty-one mCRC pts (108 male patients and 93 female patients) were entered in this prospective observational study. The median age was 57.5 years old. The clinical characteristics (age, gender, performance status, primary tumour site, RAS status, and the number of metastatic organs) did not significantly differ between the two groups. The median PFS and OS times of the PTR group were superior than those of the IPT group (10.0 vs 7.8 months, p < 0.01 and 22.5 vs 17.8 months, p < 0.01, respectively). The incidences of adverse events associated with systemic therapy were similar between the two groups. Specifically, sixteen patients (21.9%, 16/73) with IPT developed significant primary tumour-related complications, such as bleeding, obstruction or even perforation. Among these patients, five underwent emergency surgery, three patients received a stent, and eight patients underwent radiation therapy.
CONCLUSIONS: The mCRC patients who received PTR and bevacizumab combination chemotherapy had better clinical outcomes than patients who did not receive PTR. PTR also decreased the incidence of severe clinical events and improved quality of life.

Meulendijks D, Cats A, Beijnen JH, Schellens JH
Improving safety of fluoropyrimidine chemotherapy by individualizing treatment based on dihydropyrimidine dehydrogenase activity - Ready for clinical practice?
Cancer Treat Rev. 2016; 50:23-34 [PubMed] Related Publications
Fluoropyrimidines remain the cornerstone of treatment for different types of cancer, and are used by an estimated two million patients annually. The toxicity associated with fluoropyrimidine therapy is substantial, however, and affects around 30% of the patients, with 0.5-1% suffering fatal toxicity. Activity of the main 5-fluorouracil (5-FU) metabolic enzyme, dihydropyrimidine dehydrogenase (DPD), is the key determinant of 5-FU pharmacology, and accounts for around 80% of 5-FU catabolism. There is a consistent relationship between DPD activity and 5-FU exposure on the one hand, and risk of severe and potentially lethal fluoropyrimidine-associated toxicity on the other hand. Therefore, there is a sound rationale for individualizing treatment with fluoropyrimidines based on DPD status in order to improve patient safety. The field of individualized treatment with fluoropyrimidines is now rapidly developing. The main strategies that are available, are based on genotyping of the gene encoding DPD (DPYD) and measuring of pretreatment DPD phenotype. Clinical validity of additional approaches, including genotyping of MIR27A has also recently been demonstrated. Here, we critically review the evidence on clinical validity and utility of strategies available to clinicians to identify patients at risk of developing severe and potentially fatal toxicity as a result of DPD deficiency. We evaluate the advantages and limitations of these methods when used in clinical practice, and discuss for which strategies clinical implementation is currently justified based on the available evidence and, in addition, which additional data will be required before implementing other, as yet less developed strategies.

Zhang Y, Zhu X, Huang T, et al.
β-Carotene synergistically enhances the anti-tumor effect of 5-fluorouracil on esophageal squamous cell carcinoma in vivo and in vitro.
Toxicol Lett. 2016; 261:49-58 [PubMed] Related Publications
Recently, we reported that β-carotene exhibited anticancer activity against human esophageal squamous cell carcinoma cells in vitro. In the present study, we examined a novel therapeutic strategy by combining β-carotene with 5-fluorouracil (5-FU) in human esophageal cancer in vitro and in vivo, and elucidated the underlying mechanisms. We found that the combination of 5-FU and β-carotene displayed greater growth inhibitory effects than did either compound alone in esophageal squamous cell carcinoma (ESCC) cells. In addition, the combination of 5-FU and β-carotene displayed greater tumor growth inhibition in an Eca109 xenograft mouse model than did a single agent with low systemic toxicity. β-Carotene enhanced 5-FU-induced apoptosis. TUNEL staining revealed that the rate of TUNEL-positive cells was markedly increased in tumor tissues after treatment with 5-FU and β-carotene. Western blotting and immunohistochemistry revealed the down-regulation of Bcl-2 and PCNA and the up-regulation of Bax and caspase-3 in tumor tissues. Further studies demonstrated that the combined administration of 5-FU and β-carotene significantly down-regulated the protein levels of Cav-1, p-AKT, p-NF-κB, p-mTOR and p-p70S6K in Eca109 cells more effectively than did 5-FU alone. These data suggested that the combined therapy of 5-FU and β-carotene exerted synergistic antitumor effects in vivo and in vitro and could constitute a novel therapeutic treatment for ESCC.

Lam SW, Guchelaar HJ, Boven E
The role of pharmacogenetics in capecitabine efficacy and toxicity.
Cancer Treat Rev. 2016; 50:9-22 [PubMed] Related Publications
Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) and approved for treatment of various malignancies. Hereditary genetic variants may affect a drug's pharmacokinetics or pharmacodynamics and account for differences in treatment response and adverse events among patients. In this review we present the current knowledge on genetic variants, commonly single-nucleotide polymorphisms (SNPs), tested in cohorts of cancer patients and possibly useful for prediction of capecitabine efficacy or toxicity. Capecitabine is activated to 5-FU by CES, CDA and TYMP, of which SNPs in CDA and CES2 were found to be associated with efficacy and toxicity. In addition, variants in genes of the 5-FU metabolic pathway, including TYMS, MTHFR and DPYD also influenced capecitabine efficacy and toxicity. In particular, well-known SNPs in TYMS and DPYD as well as putative DPYD SNPs had an association with clinical outcome as well as adverse events. Inconsistent findings may be attributable to factors related to ethnic differences, sample size, study design, study endpoints, dosing schedule and the use of multiple agents. Of the SNPs described in this review, dose reduction of fluoropyrimidines based on the presence of DPYD variants (*)2A (rs3918290), (*)13 (rs55886062), -2846A>T (rs67376798) and -1236G>A/HapB3 (rs56038477) has already been recommended. Other variants merit further validation to establish their definite role in explanation of interindividual differences in the outcome of capecitabine-based therapy.

Vishnoi K, Mahata S, Tyagi A, et al.
Human papillomavirus oncoproteins differentially modulate epithelial-mesenchymal transition in 5-FU-resistant cervical cancer cells.
Tumour Biol. 2016; 37(10):13137-13154 [PubMed] Related Publications
Etiological role of viral proteins E6 and E7 of high-risk HPV in cervical carcinogenesis is well established. However, their contribution in chemoresistance and epithelial-mesenchymal transition (EMT) that leads to advanced metastatic lesions and chemoresistance is poorly defined. In the present study, contribution of viral oncoproteins in acquisition of EMT character during onset of chemoresistance was assessed. A chemoresistant cell line (SiHaCR) was developed from an established HPV16-positive cervical cancer cell line, SiHa, by escalating selection pressure of 5-fluorouracil (5-FU). Expression of Survivin, ABCG2, Snail, Slug, Twist, and Vimentin was examined in SiHa and SiHaCR cells by reverse transcriptase-PCR (RT-PCR) and immunoblotting assays. Mesenchymal phenotype in SiHaCR cells was confirmed by assessment of migration and invasion potentials. SiHaCR cells displayed elevated level of functional and molecular markers associated with chemoresistance (Survivin, ABCG2) and EMT (Snail, Slug, Twist, Vimentin) and reduced E-cadherin. SiHaCR also showed increased levels of HPV16 E6 and E7 transcripts. Specific silencing of HPV16 E6, but not E7 using corresponding siRNA, demonstrated a differential involvement of HPV oncogenes in manifestation of EMT. HPV16 E6 silencing resulted in reduction of Slug and Twist expression. However, the expression of Snail and Vimentin was only marginally affected. In contrast, there was an increase in the expression of E-cadherin. A reduced migration and invasion capabilities were observed only in E6-silenced SiHaCR cells, which further confirmed functional contribution of HPV16 E6 in manifestation of EMT. Taken together, our study demonstrated an active involvement of HPV16 E6 in regulation of EMT, which promotes chemoresistance in cervical cancer.

Liu X, Xie T, Mao X, et al.
MicroRNA-149 Increases the Sensitivity of Colorectal Cancer Cells to 5-Fluorouracil by Targeting Forkhead Box Transcription Factor FOXM1.
Cell Physiol Biochem. 2016; 39(2):617-29 [PubMed] Related Publications
BACKGROUND/AIMS: Previously, we have shown that microRNA (miR)-149 suppresses the migration and invasion of colorectal cancer (CRC) cells by targeting forkhead box transcription factor (FOXM1). However, the roles of miR-149 in the chemoresistance of CRC cells to 5-Fluorouracil (5-FU) is unclear. The aim of this study is to investigate whether miR-149 targets FOXM1 to regulate the 5-FU resistance of CRC.
METHODS: The qRT-PCR assay was performed to detect the expression of miR-149 in 5-FU-resistant CRC cells (HCT-8/5-FU and LoVo/5-FU) and their parental CRC cells (HCT-8 and LoVo). Also, the effects of miR-149 expression on the sensitivity of CRC cells to 5-FU were determined by gain- and loss-of-function assays. Finally, whether miR-149 regulates the 5-FU resistance of CRC cells by targeting the mammalian Forkhead Box M1 (FOXM1) was investigated.
RESULTS: The expression of miR-149 was significantly downregulated in 5-FU-resistant CRC cells in comparison with their parental CRC cells. Re-expression of miR-149 could enhance the 5-FU sensitivity of 5-FU-resistant CRC cells by increasing 5-FU-inducing apoptosis, while downregulation of miR-149 could decrease the 5-FU sensitivity of parental CRC cells by decreasing 5-FU-inducing apoptosis. In addition, the luciferase assay indicated that miR-149 could bind to the 3'-UTR sequence of FOXM1 mRNA. The silencing of FOXM1 could mimic the effect of miR-149 upregulation on the 5-FU resistance of 5-FU-resistant CRC cells. Furthermore, the expression of miR-149 in the 5-FU-responding CRC tissues was significantly higher than that in the non-responding tissues and inversely correlated with FOXM1 mRNA level.
CONCLUSIONS: MiR-149 reverses the resistance of CRC cells to 5-FU by directly targeting FOXM1. Thus, targeting miR-149/FOXM1 signaling will be a potential strategy in the treatment of 5-FU-chemoresistant CRC.

Yoshida Y, Naito M, Yamada T, et al.
Adoptive Chemoimmunotherapy Using Activated αβ T Cells for Stage IV Colorectal Cancer.
Anticancer Res. 2016; 36(7):3741-6 [PubMed] Related Publications
BACKGROUND/AIM: Adoptive immunotherapy of cancer is evolving with the development of novel technologies that generate proliferation of large numbers of αβ and γδ T cells. We evaluated the safety and efficacy of the combination of adoptive immunotherapy using αβ T cells with chemotherapy for stage IV colorectal cancer (CRC).
PATIENTS AND METHODS: Fifteen patients with advanced or recurrent CRC received XELOX + bevacizumab + ex vivo expanded αβ T lymphocytes as a first-line chemoimmunotherapy.
RESULTS: Median age of the 15 patients (4 men, 11 women) was 65 years (range=49-80). Median progression-free survival was 21.3 months. Response rate was 80% (complete response (CR)=26.7%, partial response (PR)=53.3%, stable disease (SD)=20% and progressive disease (PD)=0%). Most adverse events were mild to moderate regarding their intensity and immunotherapy-associated toxicity was minimal.
CONCLUSION: Combination of adoptive αβ T cell immunotherapy with chemotherapy for stage IV CRC is feasible and safe.

Zeng Q, Wang Z, Liu C, et al.
Knockdown of NFBD1/MDC1 enhances chemosensitivity to cisplatin or 5-fluorouracil in nasopharyngeal carcinoma CNE1 cells.
Mol Cell Biochem. 2016; 418(1-2):137-46 [PubMed] Related Publications
Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer that is prevalent among people of southern Chinese ancestry in southern China and Southeast Asia. Radiotherapy and cisplatin (CDDP)-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to CDDP and radiotherapy. NFBD1 functions in cell cycle checkpoint activation and DNA repair following DNA damage. In this study, we identified the NFBD1 as a tractable molecular target to chemosensitize NPC cells. NFBD1 expression in NPC CNE1 cell lines was depleted using lentivirus-mediated short hairpin RNA, and the elevated sensitivity of these NFBD1-inhibited NPC cells to therapeutic reagent CDDP and 5-fluorouracil (5-FU) was evaluated using MTS assays. Flow cytometry analysis also showed that NFBD1 knockdown led to an obvious induction of apoptosis in CDDP- or 5-FU-treated CNE1 cells. Furthermore, we implicated the involvement of NFBD1 in Rad51 and DNA-PKcs foci formation following CDDP or 5-FU chemotherapy. In conclusion, NFBD1 knockdown improves the chemosensitivity of NPC cells by inhibiting cell growth and promoting apoptosis through the impairment of DNA damage repair, suggesting NFBD1 as a novel therapeutic target for NPC.

Wang Y, Wang ZQ, Jiang YX, et al.
A triplet chemotherapy regimen of cisplatin, fluorouracil and paclitaxel for locoregionally recurrent nasopharyngeal carcinoma cases contraindicated for re-irradiation/surgery.
Expert Opin Pharmacother. 2016; 17(12):1585-90 [PubMed] Related Publications
OBJECTIVE: Salvage treatment for locoregionally recurrent nasopharyngeal carcinoma remains a significant challenge. The present study was conducted to evaluate the efficacy, toxicity and prognostic factors of a triplet chemotherapy regimen involving cisplatin, fluorouracil and paclitaxel (TPF) for locoregionally recurrent nasopharyngeal carcinoma (NPC) cases contraindicated for re-irradiation/surgery.
METHODS: Patients with locoregionally recurrent NPC unsuitable for re-irradiation/surgery were treated with TPF therapy. The chemotherapy drugs were administered as follows: 135 mg/m(2) paclitaxel on day 1, 25 mg/m(2)/day cisplatin on days 1-3, followed by continuously infused intravenous fluorouracil for 120 h at a variable dosage from 600 to 800 mg/m(2)/day, depending on prior radiation.
RESULTS: Twenty-seven patients were enrolled. The overall response was 66.7%. The median progression-free survival (PFS) and overall survival (OS) were 8.5 and 27.2 months, respectively. Toxicity was mild to moderate. Neutropenia and leukopenia were the primary grade 3-4 chemotherapy toxicities. 6 patients who regained the potential for re-radiotherapy or surgery showed significantly better outcomes than those treated with chemotherapy alone (median PFS: 20.8 vs. 7.1 months, P = 0.005; median OS: 54.2 vs. 20.6 months, P = 0.021).
CONCLUSION: TPF triplet chemotherapy showed a high response rate for locoregionally recurrent NPC with an acceptable toxicity profile.

Chen XD, He FQ, Chen M, et al.
Can S-1 replace fluorouracil for advanced gastric cancer? A PRISMA-compliant systematic review and meta-analysis.
Medicine (Baltimore). 2016; 95(24):e3916 [PubMed] Free Access to Full Article Related Publications
It remains to be seen whether S-1 can be a replacement for infusional fluorouracil (5-FU) for advanced gastric cancer (AGC). The aim of this study was to compare the efficacy and safety of S-1 with 5-FU in AGC.PubMed and Cochrane Library were searched. Randomized controlled trials and meta-analyses comparing S-1 with 5-FU for AGC were eligible. Meta-analysis was performed using RevMan 5.2.Seven trials involving 2443 patients were included. Compared with 5-FU, S-1 showed no significant prolongation of overall survival (OS) (hazard ratio [HR] = 0.91, 95% confidence interval [CI] [0.83-1.01], P = 0.07) and progression-free survival (HR = 0.89, 95% CI [0.70-1.13], P = 0.35), but longer time to treatment failure (HR = 0.74, 95% CI [0.56-0.97], P = 0.03). The objective response rates were comparable (risk ratio [RR] = 1.36, 95% CI [0.95, 1.96], P = 0.10). Regarding treatment-related deaths and hematological toxicities, there was significant heterogeneity between Asian and non-Asian trials, and subgroup analysis was applied. In Asian patients, there was a significant increase in hematological toxicities such as leukopenia (grade 1-4: RR = 1.22, 95% CI [1.08, 1.37], P = 0.001; grade 3-4: RR = 2.21, 95% CI [1.52, 3.21], P < 0.0001), neutropenia (grade 1-4: RR = 1.29, 95% CI [1.11, 1.48], P = 0.0005; grade 3-4: RR = 1.87, 95% CI [1.11, 3.17], P = 0.02), and thrombocytopenia (grade 1-4: RR = 1.71, 95% CI [1.22, 2.41], P = 0.002) in S-1-containing regimens compared with 5-FU-containing regimens, but without significant difference in treatment-related mortality rate (risk difference [RD] = 0.00, 95% CI [-0.01, 0.01], P = 0.68). In non-Asian patients, S-1-containing regimens were, however, associated with significantly fewer treatment-related deaths (RD = -0.02, 95% CI [-0.05, -0.00], P = 0.04), as well as less all grade 1-4 and grade 3-4 hematological toxicities except anemia. There was no significant heterogeneity in nonhematologic toxicities between Asian and non-Asian trials. Lower incidence of grade 1-4 nausea, diarrhea, mucositis, grade 3-4 mucositis, increased creatinine, and decreased calculated creatinine clearance was observed in S-1-containing regimens.S-1 could not improve OS, but increase some hematological toxicities in Asian patients. Therefore, special attention on hematological toxicities should be paid to Asian patients because S-1 is administered on an outpatient basis.

Tsuchiya T, Honda H, Oikawa M, et al.
Oral administration of the amino acids cystine and theanine attenuates the adverse events of S-1 adjuvant chemotherapy in gastrointestinal cancer patients.
Int J Clin Oncol. 2016; 21(6):1085-1090 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Nutritional therapy is used to reduce the adverse events (AEs) of anticancer drugs. Here, we determined whether the amino acids cystine and theanine, which provide substrates for glutathione, attenuated the AEs of S-1 adjuvant chemotherapy.
METHODS: Patients scheduled to receive S-1 adjuvant chemotherapy were randomized to the C/T or the control groups. The C/T group received 700 mg cystine and 280 mg theanine orally 1 week before the administration of S-1, which then continued for 5 weeks. Each group received S-1 for 4 weeks. Blood sampling was performed and AEs were evaluated (CTCAE ver. 4.0) before and after the administration of S-1. S-1 was discontinued when AEs ≥ grade 2 occurred.
RESULTS: The incidences of AEs of any grade and those over grade 2 were lower in the C/T group than in the controls. The incidence of diarrhea (G ≥ 2) was significantly less (p < 0.05) in the C/T group (3.1 %) than in the controls (25.8 %). The duration and completion rate of the S-1 adjuvant chemotherapy were significantly longer (p < 0.01) and higher (p < 0.01), respectively, in the C/T group (complete ratio: 75.0 %, duration: 24.8 ± 5.8 days) than in the controls (complete ratio: 35.5 %, duration: 20.0 ± 7.7 days).
CONCLUSIONS: The oral administration of cystine and theanine attenuated the AEs of S-1 adjuvant chemotherapy and increased the S-1 completion rate, suggesting that cystine and theanine is a useful supportive care for chemotherapy.

Kobayashi S, Ueno M, Hara H, et al.
Unexpected Side Effects of a High S-1 Dose: Subanalysis of a Phase III Trial Comparing Gemcitabine, S-1 and Combinatorial Treatments for Advanced Pancreatic Cancer.
Oncology. 2016; 91(3):117-26 [PubMed] Related Publications
OBJECTIVE: In this subanalysis of a phase III trial using three categorized doses of S-1, the influence of the actual doses on safety and efficacy was evaluated.
METHODS: We compared the efficacy and safety of the S-1 or gemcitabine plus S-1 combination (GS) arm between the top 10% group and the bottom 10% group according to the initial doses of S-1: ≥77.6 versus ≤65.9 mg/m2/day (n = 28 vs. 28) in the S-1 arm, and ≥65.1 versus ≤53.8 mg/m2/day (n = 27 vs. 28) in the GS arm.
RESULTS: Overall and progression-free survival were not significantly different between these two groups: hazard ratios of 0.818 and 0.761 with p values of 0.498 and 0.330 in the S-1 arm, and hazard ratios of 0.836 and 0.759 with p values of 0.557 and 0.323 in the GS arm, respectively. Incidences of grade 3-4 hematological toxicities were significantly higher in the top 10% group than in the bottom 10% group: 42.9 versus 14.3 and 85.2 versus 57.1%, with p values of 0.037 and 0.037 in the S-1 and the GS combination arm, respectively.
CONCLUSIONS: Higher actual doses of S-1 were associated with a higher incidence of hematological toxicity even in the same dose setting.

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