Routine method for the analysis of microplastics in natural and drinking water by pyrolysis coupled to gas chromatography-mass spectrometry.

The presence of microplastics (MPs) in water intended for human consumption represents a growing concern due to their ubiquity in the aquatic environments and the potential adverse effects on human health. In this context, validated and standardized analytical methods are required to minimize uncertainties associated with the determination of MPs in water, especially during the drinking water treatment process. In this study, a simple water sampling and extraction procedure and analysis using pyrolysis with gas chromatography coupled to mass spectrometry (Py-GC-MS) was developed to determine 7 types of polymers in water. Quality parameters associated with the method were evaluated, including limits of detection (MDL) and quantitation (MQL), linearity, precision, accuracy, and extended uncertainty. The developed methodology was validated by participating in the EUROQCHARM interlaboratory exercise, and the Z-scores were within the acceptable range for 4 of the 5 polymers tested. Finally, MPs were determined in river water, reclaimed water, and drinking water from the urban area of Barcelona and total concentrations ranged from 11.3 µg/L to 77.1 µg/L. The proposed methodology allows for simple (direct filtration of 100-500 mL of water with a 13 mm glass fiber filter), quantitative (µg/L), and rapid (with a total analysis time of 20 min per sample, including both pyrolysis and GC-MS) analysis of MPs in water intended for drinking.

Indirect potable water reuse to face drought events in Barcelona city. Setting a monitoring procedure to protect aquatic ecosystems and to ensure a safe drinking water supply.

The climate change and increasing anthropogenic pressures are expected to limit the availability of water resources. Hence, active measures must be planned in vulnerable regions to ensure a sustainable water supply and minimize environmental impacts. A pilot test was carried out in the Llobregat River (NE Spain) aiming to provide a useful procedure to cope with severe droughts through indirect water reuse. Reclaimed water was used to restore the minimum flow of the lower Llobregat River, ensuring a suitable water supply downstream for Barcelona. A monitoring was performed to assess chemical and microbiological threats throughout the water treatment train, the river and the final drinking water, including 376 micropollutants and common microbiological indicators. The effects of water disinfection were studied by chlorinating reclaimed water prior to its discharge into the river. Data showed that 10 micropollutants (bromodichloromethane, dibromochloromethane, chloroform, EDDP, diclofenac, iopamidol, ioprimid, lamotrigine, ofloxacin and valsartan) posed a potential risk to aquatic life, whereas one solvent (1,4-dioxane) could affect human health. The chlorination of reclaimed water mitigated the occurrence of pharmaceuticals but, conversely, the concentration of halogenated disinfection by-products increased. From a microbiological perspective, the microbial load decreased along wastewater treatments and, later, along drinking water treatment, ultimately reaching undetectable values in final potable water. Non-chlorinated reclaimed water showed a lower log reduction of E. coli and coliphages than chlorinated water. However, the effect of disinfection vanished once reclaimed water was discharged into the river, as the basal concentration of microorganisms in the Llobregat River was comparable to that of non-chlorinated reclaimed water. Overall, our study indicates that indirect water reuse can be a valid alternative source of drinking water in densely populated areas such as Barcelona (Catalonia - NE Spain). A suitable monitoring procedure is presented to assess the related risks to human health and the aquatic ecosystem.

Monitoring the complex occurrence of pesticides in the Llobregat basin, natural and drinking waters in Barcelona metropolitan area (Catalonia, NE Spain) by a validated multi-residue online analytical method.

The European Directive 98/83/CE legislates the presence of pesticides in drinking water, but apart from a few compounds, nothing is said about which pesticides should be monitored. Nevertheless, water companies need to go beyond the accomplishment of the legislation and find out pesticide contamination in all sources of water in order to manage the hazard assessment, and to guarantee safe drinking water to all the population. The aim of this work was to develop an analytical multi-residue method for circa 100 compounds. The method analyses previously monitored compounds in Barcelona city and its metropolitan area, as well as many emerging pesticides and some transformation products. An on-line sample extraction (0.75 mL) coupled to fast UHPLC-MS/MS method was developed. Good linearity (r2 > 0.995, with less residuals than 15%), accuracies and precisions under 25%, and acceptable expanded uncertainties were obtained for most of the monitored compounds, according to ISO/IEC 17025, obtaining limits of quantification between 5 and 25 ng/L for all compounds. A monitoring campaign on natural and treated waters in the Barcelona metropolitan area was carried out during 2016-2017. Results showed that pesticide contamination at the low stretch of Llobregat River and in its aquifer is severe. The maximum concentrations were in the range of few µg/L for carbendazim, DEET, diuron and propiconazole, and in the range 0.1-0.5 µg/L for bentazone, imidacloprid, isoproturon, simazine, metazachlor, methomyl, terbutryn and tebuconazole. However, the efficiency of advanced treatments in the DWTPs involved in drinking water production in the Barcelona metropolitan area allows the complete removal of pesticides and a safe water production for consumers. The method shows a good analytical performance for most compounds with a fast sample preparation and analysis. In addition, it has updated the knowledge about the occurrence of pesticides in the Barcelona city area.

Dioxanes and dioxolanes in source waters: Occurrence, odor thresholds and behavior through upgraded conventional and advanced processes in a drinking water treatment plant.

Over the last years, the human probable carcinogen 1,4-dioxane and alkyl-1,3-dioxanes and dioxolanes have been detected and identified as the cause of several pollution episodes in the Llobregat River (Catalonia, NE Spain) and its aquifer. It is an issue of major concern to study these compounds which are released to the environment by resin manufacturing plants' spills and wastewater discharges spread along rivers and reach drinking water treatment plants (DWTPs) in order to protect the environment and public health. In this study four seasonal sampling campaigns were carried out over a year to determine the removal efficiency of the dioxanes and dioxolanes at each step of a DWTP including ozonation, granular activated carbon filters, ultrafiltration and reverse osmosis step's treatments. Additionally, a weekly sampling monitoring of 1,4-dioxane and alkyl-1,3-dioxanes and dioxolanes in raw water, groundwater and finished water was performed at a DWTP over more than two years. Aqueous odor concentration thresholds (OTCs) were established by the three-alternative forced choice method (3-AFC). Following a previous published methodology, samples were analyzed and results showed that the advanced treatment (Ultrafiltration followed by reverse osmosis) line removes more efficiently 1,4-dioxane, alkyl dioxanes and dioxolanes (80 ±â€¯6% for 1,4-dioxane, 97 ±â€¯7% for 5,5-DMD and 100 ±â€¯0% for 2,5,5-TMD) than the upgraded conventional treatment line (ozonation followed by granular activated carbon filters) (-12 ±â€¯50%, 25 ±â€¯62% and 50 ±â€¯51% respectively), where some desorption processes were eventually observed. From the monitoring study, results suggest that the presence of 1,4-dioxane is not only due to spills, but also from other sources of contamination. Whereas dioxolanes almost completely disappeared in time, 1,4-dioxane's concentrations remained low and fluctuant. A background concentration of 1,4-dioxane in surface waters (∼1 µg/L) has been determined with a relevant concentration up to 11.6 µg/L of 1,4-dioxane in groundwater. The perception values for some of the studied compounds were extremely low (few ng/L only), which confirms the relevancy of this group of compounds as malodorous agents in waters.

Techno-economic evaluation and comparison of PAC-MBR and ozonation-UV revamping for organic micro-pollutants removal from urban reclaimed wastewater.

The presence of sewage-borne Organic Micro-Pollutants (OMP) in Wastewater Treatment Plants (WWTP) effluents represents an increasing concern when water is reclaimed for irrigation or even indirect potable reuse. During eighteen months, an innovative hybrid water reclamation scheme based on a Membrane Biological Reactor (MBR) enhanced with Powder Activated Carbon (PAC) was operated at pilot-scale (70 m3/d) in order to compare it with state-of-the art Wastewater Reclamation System (WWRS) also revamped with a final step of ozonation-UV. Removal of persistent OMP, water quality and treatment costs were evaluated and compared for the different treatment schemes. OMP removal efficiency results for the different schemes concluded that established technologies, such as physico-chemical and filtration systems as well as MBR, do not remove significantly (>15%) the most recalcitrant compounds. The upgrading of these two systems through the addition of ozonation-UV step and PAC dosing allowed improving average recalcitrant OMP removal to 85 ±â€¯2 and 75 ±â€¯5%, respectively. In term of costs, PAC-MBR represents an increase of 37% of costs regarding conventional systems but presents improvements of 50% reduction in space and water quality. On the other hand, ozonation requires up to a 15% increase of foot-print; nevertheless, represents lower costs and lower carbon footprint. Ozonation-UV seems to be the best option for upgrading existing facilities, while PAC-MBR should be considered when space represents a critical limitation and produced water is reused for high water quality purposes.

Fluorescence spectroscopy and parallel factor analysis as a dissolved organic monitoring tool to assess treatment performance in drinking water trains.

Fluorescence excitation emission matrix (FEEM) spectroscopy was used to evaluate its applicability as a tool to track dissolved organic matter (DOM) in a drinking water treatment plant (DWTP) that incorporates a conventional line (consisting in ozonation and GAC filtration) and a membrane-based line (consisting in ultrafiltration, reverse osmosis and mineralization) working in parallel. Seven sampling points within the different process stages were characterized monthly during 2014. A global Parallel Factor Analysis (PARAFAC) was used to pull out underlying organic fractions from the fluorescence spectra. Accordingly a five components model was selected to describe the system and the pros and cons of the model were discussed by analysis of the residuals. Among the five fluorescent components, those associated to humic-like matter (C1, C3 and C4) showed a similar season variability in the river water feeding the DWTP (which resembled that of UV254 and TOC), whereas the two components associated to protein-like matter (C2 and C5) exhibited a different behavior. The maximum fluorescence intensity values (Fmax) were used to quantify DOM removals across the plant. Compared to the conventional line, water from the UF/RO membrane-based line showed between 6 and 14 times lower fluorescence intensity signal for the humic-like components and between 1 and 3 for the protein-like components as compared to the conventional line. The differences in DOM composition due to seasonal variations and along the treatment trains point out the suitability of using fluorescence measurements over other parameters such as UV254 as a monitoring tool to help optimize operation conditions of each treatment stage and improve produced water quality in a DWTP.

Do cytostatic drugs reach drinking water? The case of mycophenolic acid.

Mycophenolic acid (MPA) has been identified as a new river contaminant according to its wide use and high predicted concentration. The aim of this study was to monitor the impact of MPA in a drinking water treatment plant (DWTP) that collects water downstream Llobregat River (NE Spain) in a highly densified urban area. During a one week survey MPA was recurrently detected in the DWTP intake (17-56.2 ng L(-1)). The presence of this compound in river water was associated to its widespread consumption (>2 tons in 2012 in Catalonia), high excretion rates and low degradability. The fate of MPA in waters at each treatment step of the DWTP was analyzed and complete removal was observed after pretreatment with chlorine dioxide. So far, MPA has not been described as water contaminant and its presence associated with its consumption in anticancer treatments is of relevance to highlight the importance of monitoring this compound.

Odor Events in Surface and Treated Water: The Case of 1,3-Dioxane Related Compounds.

A study has been carried out to identify the origin of the odorous compounds at trace levels detected in surface waters and in Barcelona's tap water (NE Spain) which caused consumer complaints. The malodorous compounds were 2,5,5-trimethyl-1,3-dioxane (TMD) and 2-ethyl-5,5-dimethyl-1,3-dioxane (2EDD) which impart a distinctive sickening or olive-oil odor to drinking water at low ng/L levels. Flavor profile analysis (FPA) or threshold odor number (TON) were used for organoleptic purposes. Levels up to 749 ng/L for TMD and 658 ng/L for 2EDD were measured at the entrance of the drinking water treatment plant. Three wastewater treatment plants (WWTPs) using industrial byproducts coming from resin manufacturing plants to promote codigestion were found to be the origin of the event. Corrective measures were applied, including the prohibition to use these byproducts for codigestion in the WWTPs involved. A similar event was already recorded in the same area 20 years ago.

Analysis of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) and its brominated analogues in chlorine-treated water by gas chromatography coupled to triple quadrupole tandem mass spectrometry (GC-QqQ-MS/MS).

A simple, selective and sensitive method for the analysis of the strong mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) and its brominated analogues (BMXs) in chlorine-treated water has been developed. The method is based on gas chromatography coupled to triple quadrupole tandem mass spectrometry (GC-QqQ-MS/MS), previous liquid-liquid extraction (LLE) of a smaller sample volume compared to other methods and on-line derivatization with a silylation reactive. GC-QqQ-MS/MS has been raised as an alternative easier to perform than gas chromatography coupled to high resolution mass spectrometry (GC-HRMS) for the analysis of MX and BMXs, and it allows to achieve low LODs (0.3 ng/L for MX and 0.4-0.9 ng/L for BMXs). This technique had not been previously described for the analysis of MX and BMXs. Quality parameters were calculated and real samples related to 3 drinking water treatment plants (DWTPs), tap water and both untreated and chlorinated groundwater were analyzed. Concentrations of 0.3-6.6 ng/L for MX and 1.0-7.3 ng/L for BMXs were detected. Results were discussed according to five of the main factors affecting MX and BMXs formation in chlorine-treated water (organic precursors, influence of bromide ions, evolution of MX and BMXs in the drinking water distribution system, groundwater chlorination and infiltration of water coming from chlorination processes in groundwater).

Survey of the occurrence of pharmaceuticals in Spanish finished drinking waters.

Fifty samples of finished drinking waters (FDWs) from Spain covering 12 million inhabitants were tested for 53 pharmaceuticals pertaining to 12 different Anatomical Therapeutic Chemical (ATC) classification system codes. The studied compounds are a combination of most commonly consumed pharmaceuticals with other barely reported in the literature. Five compounds, azithromycin, clarithromycin, erythromycin, sulfamethoxazole, and ibuprofen were tentatively identified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in some samples (2 to 15 %), but only ibuprofen and azithromycin could be confirmed when analyzed by liquid chromatography-high-resolution mass spectrometry (LC-HRMS) with a quadrupole-Orbitrap instrument. Concentration levels of ibuprofen in the positive samples ranged from 12 to 17 ng/L (n = 6) while for azithromycin values from 5 to 9.5 ng/L (n = 3) were found. Ibuprofen fragmentation behaviour in different mass spectrometry instrument configurations (triple quadrupole, quadrupole-ion trap, and quadrupole-Orbitrap) was evaluated.

Evaluation of the presence of drugs of abuse in tap waters.

A total of seventy samples of drinking water were tested for non-controlled and illicit drugs. Of these, 43 were from Spanish cities, 15 from seven other European countries, three from Japan and nine from seven different Latin American countries. The most frequently detected compounds were caffeine, nicotine, cotinine, cocaine and its metabolite benzoylecgonine, methadone and its metabolite EDDP. The mean concentrations of non-controlled drugs were: for caffeine 50 and 19 ng L(-1), in Spanish and worldwide drinking water respectively and for nicotine 13 and 19 ng L(-1). Illicit drugs were sparsely present and usually at ultratrace level (<1 ng L(-1)). For example, cocaine has mean values of 0.4 (Spain) and 0.3 ng L(-1) (worldwide), whereas for benzoylecgonine, these mean values were 0.4 and 1.8 ng L(-1), respectively. Higher concentrations of benzoylecgonine were found in Latin American samples (up to 15 ng L(-1)). No opiates were identified in any sample but the presence of methadone and EDDP was frequently detected. Total mean values for EDDP were 0.4 ng L(-1) (Spain) and 0.3 ng L(-1) (worldwide). Very few samples tested positive for amphetamines, in line with the reactivity of chlorine with these compounds. No cannabinoids, LSD, ketamine, fentanyl and PCP were detected.

Behavior of pharmaceuticals and drugs of abuse in a drinking water treatment plant (DWTP) using combined conventional and ultrafiltration and reverse osmosis (UF/RO) treatments.

The behavior along the potabilization process of 29 pharmaceuticals and 12 drugs of abuse identified from a total of 81 compounds at the intake of a drinking water treatment plant (DWTP) has been studied. The DWTP has a common treatment consisting of dioxychlorination, coagulation/flocculation and sand filtration and then water is splitted in two parallel treatment lines: conventional (ozonation and carbon filtration) and advanced (ultrafiltration and reverse osmosis) to be further blended, chlorinated and distributed. Full removals were reached for most of the compounds. Iopromide (up to 17.2 ng/L), nicotine (13.7 ng/L), benzoylecgonine (1.9 ng/L), cotinine (3.6 ng/L), acetaminophen (15.6 ng/L), erythromycin (2.0 ng/L) and caffeine (6.0 ng/L) with elimination efficiencies ≥ 94%, were the sole compounds found in the treated water. The advanced treatment process showed a slightly better efficiency than the conventional treatment to eliminate pharmaceuticals and drugs of abuse.

Monitoring of opiates, cannabinoids and their metabolites in wastewater, surface water and finished water in Catalonia, Spain.

The occurrence of several opiates and cannabinoids in wastewaters and surface waters has been investigated. Most of the compounds (8 out of 11) were identified in both influent and effluents of fifteen wastewater treatment plants (WWTPs). Codeine, morphine, EDDP and methadone were detected in almost all samples with median values of 69ng/L; 63ng/L; 28ng/L and 18ng/L, respectively, whereas the main cannabinoid metabolite THC-COOH presented a median value of 57ng/L in influents. A rough estimate of heroin and cannabis consumption was performed from the analysis of target urinary metabolites in wastewater influents. Data obtained from influents of rural and urban WWTPs gave 0.07% of heroin consumption (0.67% for the largest urban WWTP) and 4% consumption of cannabinoids, respectively for the population aged between 15 and 64 years old. The presence of opiates and cannabinoids in surface waters used for drinking water production showed the presence of the same compounds identified in wastewater effluents at concentrations up to 76ng/L for codeine; 31ng/L for EDDP; 12ng/L for morphine and 9ng/L for methadone at the intake of the DWTP. A complete removal of all studied drugs present in surface water was achieved during the potabilization process except for methadone and EDDP (91% and 87% removal, respectively).

A review of taste and odour events in Barcelona's drinking water area (1990-2004).

The main, relevant, solved problems associated with taste and odour incidents in Barcelona's drinking water area in the last 14 years are reviewed. Events produced by creosote, dioxanes and dioxolanes, dicylopentadiene, and diacetyl, among the anthropogenic compounds; geosmin, MIB and iodinated trihalomethanes and chlorobromoanisoles as examples of compounds of natural origin are exemplified. The determination of the odour threshold concentrations of selected odorous compounds is also shown as a tool to gain a better knowledge of future taste and odour events.

Mutational spectrum of classical galactosaemia in Spain and Portugal.

Classical galactosaemia is an autosomal recessive inherited metabolic disorder due to deficient galactose-1-phosphate uridyltransferase (GALT). Over 180 different base changes and disease-causing mutations have been reported in the GALT gene. Mutation p.Q188R was found to be the most common molecular defect among caucasian classical galactosaemia patients. We have characterized the spectrum of GALT mutations in a group of 51 Spanish families and 32 Portuguese families with this disease. p.Q188R is also the most prevalent mutation in the Spanish and Portuguese population, accounting for 50% and 57.8% of galactosaemic alleles, respectively. An additional 15 mutations were also identified in Spanish patients, four of which were novel: p.D28H, p.S181A, c.658dupG and c.377+53_1059+87del. In the Portuguese population, 11 different mutations were found, three of which were novel: p.R33H, p.P185S, and p.S192G. The differences observed between the genotypes identified in Portuguese and Spanish galactosaemic populations are notable. Only mutations p.Q188R, p.R148Q and c.820+13g>a were identified in both populations. In spite of the geographical proximity of Spain and Portugal, it seems that they have received genetic influences from different populations. The repeated migrations that occurred in the Iberian Peninsula throughout centuries may explain such variability.

Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer.

PURPOSE: The efficacy of adjuvant chemotherapy in gastric cancer is controversial. We conducted a phase III, randomized, multicentric clinical trial with the goal of assessing the efficacy of the combination of mitomycin plus tegafur in prolonging the disease-free survival and overall survival of patients with resected stage III gastric cancer. PATIENTS AND METHODS: Patients with resected stage III gastric adenocarcinoma were randomly assigned, using sealed envelopes, to receive either chemotherapy or no further treatment. Chemotherapy was started within 28 days after surgery according to the following schedule: mitomycin 20 mg/m(2) intravenously (bolus) at day 1 of chemotherapy; 30 days later, oral tegafur at 400 mg bid daily for 3 months. Disease-free survival and overall survival were estimated using the Kaplan-Meier analysis and the Cox proportional hazards model. RESULTS: Between January 1988 and September 1994, 148 patients from 10 hospitals in Catalonia, Spain, were included in the study. The median follow-up period was 37 months. The tolerability of the treatment was excellent. The overall survival and disease-free survival were higher in the group of patients treated with chemotherapy (P =.04 for survival and P =.01 for disease-free survival in the log-rank test). The overall 5-year survival rate and the 5-year disease-free survival rate were, respectively, 56% and 51% in the treatment group and 36% and 31% in the control group. CONCLUSION: Our positive results are consistent with the results of recent studies; which conclude that there is a potential benefit from adjuvant chemotherapy in resected gastric cancer.

Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene.

Classical galactosemia is caused by a deficiency in activity of the enzyme galactose-1-phosphate uridyl transferase (GALT), which, in turn, is caused by mutations at the GALT gene. The disorder exhibits considerable allelic heterogeneity and, at the end of 1998, more than 150 different base changes were recorded in 24 different populations and ethnic groups in 15 countries worldwide. The mutations most frequently cited are Q188R, K285N, S135L, and N314D. Q188R is the most common mutation in European populations or in those predominantly of European descent. Overall, it accounts for 60-70% of mutant chromosomes, but there are significant differences in its relative frequency in individual populations. Individuals homoallelic for Q188R tend to have a severe phenotype and this is in keeping with the virtually complete loss of enzyme activity observed in in vitro expression systems. Globally, K285N is rarer, but in many European populations it can be found on 25-40% of mutant chromosomes. It is invariably associated with a severe phenotype. S135L is found almost exclusively in African Americans. In vitro expression results are discrepant, but some individuals carrying S135L appear to exhibit GALT activity in some tissues. Duarte 1 (or Los Angeles) and Duarte 2 (or Duarte) variants carry the same amino acid substitution, N314D, even though D1 is associated with increased erythrocyte GALT activity and D2 with reduced activity. N314D is in linkage disequilibrium with other base changes that differ on the D1 and D2 alleles. N314D does not impair GALT activity in in vitro expression systems. However, there are differences in the abundance of GALT protein in lymphoblastoid cells lines from D2 and D1 individuals. It is unclear whether the specific molecular changes that distinguish the D1 and D2 alleles account for the different activities. The considerable genetic heterogeneity documented to date undoubtedly contributes to the phenotypic heterogeneity that is observed in galactosemia. The additional effects of nonallelic variation and other constitutional factors on phenotypic variability remain to be elucidated.

Anticachectic efficacy of megestrol acetate at different doses and versus placebo in patients with neoplastic cachexia.

Anorexia and cachexia are present in the majority of patients with advanced-stage cancer. Several agents have been tested for their ability to reverse weight loss in these patients. Megestrol acetate has been demonstrated to improve appetite and weight, independent of tumor response, when used in the treatment of metastatic breast cancer. Several trials have studied the ability of megestrol acetate to stimulate weight gain in patients with non-hormone-sensitive tumors. One hundred fifty patients with a weight lost of more than 5% in the 3 previous months were randomized between double-blind megestrol acetate 160 mg daily (LMA), megestrol acetate 480 mg daily (HMA), or placebo (P). Weight, mid-arm circumference, triceps skinfold thickness (TST), performance status (Karnofsky index), and a quality-of-life status by seven linear analogic self-assessment scales were assessed before the start of treatment and at 4, 8, and 12 weeks thereafter. One hundred seven patients were assessable at 4 weeks, 79 at 8 weeks, and 64 at 12 weeks. Sixty-eight percent of patients treated with HMA increased their weights during their permanence on study, versus 37% and 38% of patients treated with P or LMA (p < 0.03). The mean weight gain after 12 weeks of treatment with HMA was 5.41 kg. A significant increase on TST was observed in the HMA group versus the LMA and P groups. There was no gain in performance status or quality of life in any group of treatment. The toxicity registered was mild. There were no thromboembolic events. This trial supports the efficacy of megestrol acetate at 480 mg/day in the treatment of cancer-related cachexia and anorexia, with mild toxicity. However, performance status and quality of life were not influenced by this treatment.

Protracted treatment with tegafur and low dose oral leucovorin in patients with advanced colorectal carcinoma.

BACKGROUND: Protracted oral administration of tegafur (TG) and leucovorin (LV) attempts to simulate the continuous infusion of 5-fluorouracil, with a higher intracellular folate pool. In a prior dose-finding study with a fixed TG dose of 0.75 g/m2/day for a period of 21 days and continuous oral LV, the recommended dose of LV was 45 mg/day in 28-day cycles. METHODS: Thirty-nine patients with histologic confirmation of adenocarcinoma of the colon or rectum, either advanced or metastatic disease, and who were not candidates for radical treatment were included in a Phase II study using this schedule. RESULTS: One hundred sixty-three cycles of chemotherapy were delivered (median, 4 cycles per patient). Toxicity was observed in the form of diarrhea, which was severe in 12 patients (30.7%). Grade 3 (according to the World Health Organization criteria) oral mucositis was recorded in 7 patients (18%). Asthenia was severe in 10% of the patients. Recuperation from toxicity was rapid and managed primarily on an outpatient basis. Two complete (5.1%) and 13 partial (33.3%) responses were observed, with a global response index of 38.5% (95% confidence interval, 23.2-53.6%). The median overall survival was 11.3 months. CONCLUSIONS: The results of this study show that an all-oral regimen of tegafur and leucovorin can obtain biochemical modulation, with a significant response rate, in patients with advanced colorectal carcinoma. Randomized trials are needed to assess the possible advantage of this regimen over intravenous schedules.