Impact of a supportive care service for cancer outpatients: management and reduction of hospitalizations. Preliminary results of an integrated model of care.

PURPOSE: Supportive care in oncology is a primary need for every oncology department nowadays. In 2012, in our institution, a dedicated supportive care service (SCS) was created in order to deal with any need our on-treatment patients might have (e.g. tumour-related or treatment-related symptoms). We hypothesized that this service had a positive impact on the number of unplanned hospitalizations; to confirm our hypothesis, we decided to review admission data in 2011 and 2012. METHODS: Using our internal software, we compared admission data in 2011 (that is, the year before the dedicated service was created) and 2012 (when such service began, that is April of that year). We also made an evaluation of the costs of these hospitalizations. RESULTS: Despite an increase of the number of patients treated in our day hospital (+6.5 %), the number of unplanned hospital admissions decreased by 3.2 % (from 17.3 to 14.1 %). The number of patients accessing to emergency room went from 66 to 61 % (a reduction of 5 %). The costs of these hospitalizations were reduced by 2.2 %. CONCLUSIONS: The introduction of the dedicated SCS in our oncology department caused a net reduction by 3.2 % of the number of unplanned hospitalizations of on-treatment cancer patients.

Induction of oxidative stress in Prototheca zopfii by indole-3-acetic acid/HRP or 2,4-pentanedione/HRP systems and their oxidation products.

We investigated the toxic effects on Prototheca zopfii of indole-3-acetic acid (IAA) and 2,4-pentanedione (PD) combined with horseradish peroxidase (HRP) alongside the oxidation products of 3-methyl-2-oxindole (MOI) and indole-3-carbinol (I3C) from the IAA/HRP system and methylglyoxal (MGO) from the PD/HRP system. The microorganism was incubated in the absence (control) or presence of IAA, PD, IAA/HRP, PD/HRP, MOI, I3C and MGO and determined: (1) cytotoxicity by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) assay; (2) growth inhibitory concentration by resazurin assay and (3) antioxidant enzymes activities of: catalase (CAT), glutathione reductase (GR) and superoxide dismutase (SOD). P. zopfii was more susceptible to IAA at 40 mM than PD at the same concentration, which seems to indicate that IAA was more effective at initiating cell death. These data corroborate results from the resazurin assay. Concentrations of 40 mM of IAA, IAA/HRP and PD/HRP, 20 mM of PD/HRP, 10 mM of MOI, 2 mM of I3C and 8 mM of MGO inhibited the growth of P. zopfii. With sub-inhibitory concentrations of IAA and IAA/HRP at 30 mM, MOI at 8 mM and I3C at 1 mM, the activities of CAT and GR increased, whereas no statistical difference was observed for CAT activity with IAA/HRP. Thus, PD at 30 mM and MGO at 6 mM increased the activities of CAT and GR, whereas PD/HRP system at 15 mM decreased CAT activity and PD/HRP and MGO showed no statistical difference for SOD activity. In conclusion, IAA/HRP or PD/HRP systems and their oxidation products exert cytotoxic effects on P. zopffi; however, I3C and MGO appear to exert greater microbicidal effect on P. zopfii.

A multicenter phase II study of the combination of oxaliplatin, irinotecan and capecitabine in the first-line treatment of metastatic colorectal cancer.

The triple drug combination consisting of irinotecan, oxaliplatin and 5-fluorouracil (FOLFOXIRI) has demonstrated higher activity and efficacy compared to the doublet FOLFIRI. 5-Fluorouracil could be substituted in FOLFOXIRI regimen by capecitabine, an oral fluoropyrimidine with similar efficacy. Recently, a dose-finding trial has demonstrated the feasibility of the combination of irinotecan, oxaliplatin and capecitabine (XELOXIRI) and established their recommended doses. The aim of this study was to evaluate the activity of XELOXIRI. A total of 36 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg m(-2) and oxaliplatin 85 mg m(-2) on day 1 plus capecitabine 2000 mg m(-2) per day orally in two doses from day 1 to day 7, every 2 weeks. Grade 3-4 toxicities were infrequent, expect for neutropenia and diarrhoea, which were each observed in 30% of patients. Two complete and twenty-two partial responses were obtained, corresponding to an overall response rate of 67% (95% CI 51.4-82%). After a median follow-up of 17.7 months, the median progression-free and overall survival were 10.1 and 17.9 months, respectively. The substitution of 5-fluorouracil with capecitabine, in combination with irinotecan and oxaliplatin, is feasible and does not impair the activity of the regimen. However, the XELOXIRI combination is associated with a high incidence of diarrhoea and, therefore, should be considered as a not preferable alternative to FOLFOXIRI.

Steatosis and hepatic markers before and shortly after bariatric surgery.

BACKGROUND: We present new findings on liver steatosis detected in a group of 20 morbidly obese patients who were reassessed shortly after bariatric surgery (BS) by assaying hepatic markers in their serum. METHODS: We assayed aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, gamma-glutamyl transferase (gamma-GT), cholinesterase, cholesterol, total protein, and albumin, and measured the weight and the body mass index (BMI) of patients, before and one and three months after surgery. RESULTS: There were significant reductions in BMI following surgery and also falls in transaminases and gamma-GT activities three months after BS. No changes occurred in other parameters between periods, except that cholesterol was above reference values before BS and fell to normal levels three months after BS. CONCLUSIONS: We suggest that before undergoing surgery, the patients suffered from slight steatosis, while after BS the reduction in AST and gamma-GT indicated that this condition was corrected within three months. Moreover, these enzymes may be useful markers for excess fat in the liver.

Antioxidant activity of Agaricus blazei.

The ethanolic extract of Agaricus blazei and ethyl acetate and hydroalcoholic fractions were evaluated for their antioxidant activity.

Oral zidovudine, continuous-infusion fluorouracil, and oral leucovorin calcium: a phase I study.

A phase I clinical, pharmacologic, and biochemical evaluation of escalating oral zidovudine (AZT) given over 2 days with a fixed dose of continuous-infusion fluorouracil (800 mg/m2 per day X 3 days) and oral leucovorin calcium was performed. Eighteen patients were treated with doses of AZT ranging from 1.0 to 9.0 g/m2 per day. Nausea and vomiting were dose limiting, with a maximally tolerated dose of 7.5 g/m2 per day. Rash and mucositis occurred but were not dose limiting. A dose-related increase in peak plasma levels of AZT was observed, and the alpha half-life of AZT in plasma (75 min) was unaffected by these high doses. At doses above 4.0 g/m2 per day, trough levels significantly increased, perhaps reflecting prolonged absorption from the gut. No responses were observed; however, a significant increase in DNA single-strand breaks was observed in peripheral blood cells after a threshold dose of 4.0 g/m2 per day, confirming a biological effect of AZT in this regimen. Further trials with an intravenous formulation capable of maintaining plasma levels and circumventing dose-limiting toxicity are warranted.

Antioxidant activity of Maytenus ilicifolia root bark.

Maytenus ilicifolia is an important plant with potential on cancer treatment and has been largely used in Brazil and other countries. We have evaluated the crude ethanolic extract of M. ilicifolia as a potential antioxidant source using an assay based on the bleaching of the radical monocation 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(*+)) and by HOCl scavenger capacity. Trolox and uric acid were used as positive controls. The results indicated M. ilicifolia root bark as a great source of antioxidants based on its potential as scavenger of radicals.

5-Fluorouracil enhances azidothymidine cytotoxicity: in vitro, in vivo, and biochemical studies.

Preliminary in vitro studies suggest that the combination of 5-fluorouracil (FUra) and 3'-azido-3'-deoxythymidine (AZT) is more cytotoxic than either agent alone. Therefore, a biochemical and therapeutic evaluation of this combination was initiated. Quantitation of the cytotoxicity of FUra plus AZT against the growth of HCT-8 cells in vitro revealed that 1 microM FUra (approximately 10% inhibitory concentration) increased the cytotoxicity of AZT and decreased its 50% inhibitory concentration by 60%. Similarly, incubating HCT-8 cells in 5 microM AZT (approximately 10% inhibitory concentration) decreased the 50% inhibitory concentration of FUra by over 50%. Biochemical analysis indicated that AZT did not affect FUra-induced inhibition of thymidylate synthase or [3H]-FUra incorporation into nucleic acids. In contrast, incubation in 5 microM FUra increased the incorporation of [3H]-AZT (5 microM) into the nucleic acid fraction of these cells by 52% (P less than 0.05). Therapeutic evaluation of this combination in athymic (nude) mice bearing HCT-8 xenographs revealed that, while weekly FUra (85 mg/kg) or AZT (600 mg/kg) exerts minimal antineoplastic activity (after 4 courses, treatment/control = 0.81 and 0.70, respectively), their combination, at the same doses, inhibited tumor growth by nearly 70% (P less than 0.01 versus FUra alone). FUra-related host toxicity was not increased by the addition of AZT. Higher doses of FUra alone were not more effective than FUra plus AZT. In vivo, AZT did not affect the incorporation of [3H]-FUra into the nucleic acid fraction of various murine tissues, including HCT-8 xenografts. FUra, however, increased [3H]-AZT incorporation into nucleic acids in a tissue-specific manner. In the presence of FUra, the incorporation of [3H]-AZT in spleen, liver, and gut increased 40, 21, and 4%, respectively, while in HCT-8 xenografts [3H]-AZT incorporation increased more than 2-fold. Analysis of the activities of selected enzymes involved in pyrimidine metabolism suggests that this tissue-specific effect may be related to the pyrimidine salvage capacity of these tissues. These findings are described in light of their potential impact on human colon cancer chemotherapy.

[Cytomegalovirus-induced protein-losing gastropathy: a case report]. / Un raro caso di gastroenteropatia ipertrofica protido-disperdente da CMV.

Protein-losing gastropathy is an uncommon disease of uncertain etiology, known also as Menetrier's disease. In medical literature only 50 pediatric cases have been described. These childhood forms, in contrast to classic adult Menetrier's disease, have a typical benign and transient course, and require only supportive therapy. The role of Cytomegalovirus (CMV) in the pathogenesis has been demonstrated by gastric biopsy in one third of the cases. Also other infectious, allergic and immunological factors have been hypothesized. We describe a case of hypertrophic gastropathy with important protein-loss, admitted to our Pediatric Department for evaluation because of vomit, weight loss, abdominal pain and hypoalbuminemia. Gastric mucosal biopsy revealed a morphological evidence of CMV infection.

BRCA1 germline mutational spectrum in Italian families from Tuscany: a high frequency of novel mutations.

BRCA1 germline mutations confer susceptibility to familial breast and ovarian cancer. Mutational hot spots have never been detected in BRCA1 cDNA. Some mutations have been reported several times whereas some others appear to be population-related. In this study a group of 36 Italian families were analysed for BRCA1 germline mutations. All of them were screened by allele-specific oligonucleotide hybridization (ASO) for three recurrent mutations (185delAG, 5382insC, nt332-T>G). Twenty families, selected because of their high risk of carrying BRCA1 mutations, were subjected to analysis of the entire coding sequence of the gene. A total of eight mutations were found. ASO screening demonstrated only one known mutation in one patient, whereas cycle sequencing revealed five new mutations. Three of these new mutations were frameshifts: one occurred in exon 11 (1499insA), one in exon 16 (4873delCA) and one in the splice site of exon 3 (252delAAgt). Two were missense mutations (Cys64Arg; Asn158Tyr). The same frameshift mutation, 1499insA, was detected in three unrelated families. Haplotype analysis supported the hypothesis that two of these families may have had common ancestors, whereas in the third family the analysis was uninformative. BRCA1 germline mutations were found in one out of two families with ovarian cancer, in five out of eight families with breast-ovarian cancer, and in two out of 11 families with breast cancer. All three families with 1499insA mutations included at least one case of ovarian cancer. The majority of the ovarian cancers (4/5) associated with detectable BRCA1 germline mutations were of serous histotype.

Intracellular generation of electronically excited states. Polymorphonuclear leukocytes challenged with a precursor of triplet acetone.

When the enol of isobutanal is added to polymorphonuclear cells, it undergoes an intracellular, myeloperoxidase-catalyzed aerobic oxidation with the formation of triplet acetone. The latter induces considerable damage if the enol concentration exceeds 2 mM. Cells which do not have myeloperoxidase are not damaged.

Intravenous azidothymidine with fluorouracil and leucovorin: a phase I-II study in previously untreated metastatic colorectal cancer patients.

PURPOSE: To determine the plasma pharmacokinetics and the maximum-tolerated dose (MTD) of intravenous (IV) azidothymidine (AZT) administered 90 to 120 minutes after fluorouracil (5-FU) and leucovorin and to preliminarily evaluate the antitumor activity of this combination in metastatic colorectal cancer. PATIENTS AND METHODS: 5-FU 500 mg/m2 IV bolus was administered once a week in the middle of a 2-hour infusion of leucovorin; AZT was given as a 90 to 120-minute IV infusion 60 minutes after 5-FU. Initial AZT dose was 0.5 g/m2, and it was escalated in successive cohorts of three patients by 0.5 to 2 g/m2. RESULTS: Thirty-five chemotherapy-naive metastatic colorectal cancer patients were entered onto the study, and AZT doses ranged from 0.5 to 10 g/m2. The peak AZT plasma concentration increased from 21.9 to 995.6 micromol/L. The area under the concentration/time curve (AUC) also showed a progressive, but not linear increase from 40.34 to 3,108 h x micromol/L. The most relevant toxicity was diarrhea, which was severe in six patients (17%). Toxicities were not AZT-dose-related, except fpr hypotension, which occurred in patients treated at AZT doses > or = 7 g/m2 and became dose-limiting for AZT 10 g/m2. Among 34 assessable patients, 15 objective responses were observed (44%; 95% confidence interval 27 to 62), lasting a median of 44 weeks; five (15%) were complete. CONCLUSION: AZT doses > or = 6 g/m2 administered IV over 90 to 120 minutes produce maximum plasma concentration and AUC similar to those previously reached in murine tumor models. Dose-limiting toxicity is hypotension, which occurs at AZT 10 g/m2. The recommended AZT dose for further studies is 8 g/m2. The combination of 5-FU plus leucovorin plus AZT is feasible with acceptable toxicities, and has promising activity in metastatic colorectal cancer.

High-dose versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin in suboptimal ovarian cancer: a randomized study of the Gruppo Oncologico Nord-Ovest.

PURPOSE: The aim of the study was to compare high-versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin as primary chemotherapy for suboptimal stage III and IV ovarian cancer. PATIENTS AND METHODS: One hundred forty-five patients were randomized to receive six courses of cisplatin 50 or 100 mg/m2 plus epidoxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2. The two treatment arms were well balanced; all patients had greater than 2 cm and 37.2% had greater than 5 cm of residual disease; 29.6% had stage IV disease. RESULTS: Patients in the high-dose arm received a double dose-intensity and double total dose of cisplatin. The high-dose regimen induced significantly more episodes of leukopenia (47.8% v 32.8%, P = .05), thrombocytopenia (21.7% v 3.2%, P = .003), anemia (37.6% v 12.5%, P = .002), nephrotoxicity (six v one patient), and neurotoxicity (30.4% v 6.3%, P = .002). There were no significant differences in efficacy in terms of clinical response rate (high-dose 57.5% v low-dose 61.1%), pathologic complete response (CR) (9.6% v 18.1%), median survival times (29 v 24 months), and median progression-free survival (18 v 13 months). CONCLUSION: This study shows that doubling the dose-intensity and total dose of cisplatin in combination with epidoxorubicin and cyclophosphamide has significant toxic effects and does not improve clinical outcome in patients with suboptimal ovarian cancer.

Indole ring oxidation by activated leukocytes prevents the production of hypochlorous acid.

Hypochlorous acid (HOCl) released by activated leukocytes has been implicated in the tissue damage that characterizes chronic inflammatory diseases. In this investigation, 14 indole derivatives, including metabolites such as melatonin, tryptophan and indole-3-acetic acid, were screened for their ability to inhibit the generation of this endogenous oxidant by stimulated leukocytes. The release of HOCl was measured by the production of taurine-chloramine when the leukocytes (2 x 10(6) cells/mL) were incubated at 37 degrees C in 10 mM phosphate-buffered saline, pH 7.4, for 30 min with 5 mM taurine and stimulated with 100 nM phorbol-12-myristate acetate. Irrespective of the group substituted in the indole ring, all the compounds tested including indole, 2-methylindole, 3-methylindole, 2,3-dimethylindole, 2,5-dimethylindole, 2-phenylindole, 5-methoxyindole, 6-methoxyindole, 5-methoxy-2-methylindole, melatonin, tryptophan, indole-3-acetic acid, 5-methoxy-2-methyl-3-indole-acetic acid, and indomethacin (10 microM) inhibited the chlorinating activity of myeloperoxidase (MPO) in the 23-72% range. The compounds 3-methylindole and indole-3-acetic acid were chosen as representative of indole derivatives in a dose-response study using purified MPO. The IC50 obtained were 0.10 +/- 0.03 and 5.0 +/- 1.0 microM (N = 13), respectively. These compounds did not affect the peroxidation activity of MPO or the production of superoxide anion by stimulated leukocytes. By following the spectral change of MPO during the enzyme turnover, the inhibition of HOCl production can be explained on the basis of the accumulation of the redox form compound-II (MPO-II), which is an inactive chlorinating species. These results show that indole derivatives are effective and selective inhibitors of MPO-chlorinating activity.

Effect of therapeutic plasma concentrations of non-steroidal anti-inflammatory drugs on the production of reactive oxygen species by activated rat neutrophils.

The release of reactive oxygen specie (ROS) by activated neutrophil is involved in both the antimicrobial and deleterious effects in chronic inflammation. The objective of the present investigation was to determine the effect of therapeutic plasma concentrations of non-steroidal anti-inflammatory drugs (NSAIDs) on the production of ROS by stimulated rat neutrophils. Diclofenac (3.6 microM), indomethacin (12 microM), naproxen (160 microM), piroxicam (13 microM), and tenoxicam (30 microM) were incubated at 37 masculineC in PBS (10 mM), pH 7.4, for 30 min with rat neutrophils (1 x 10(6) cells/ml) stimulated by phorbol-12-myristate-13-acetate (100 nM). The ROS production was measured by luminol and lucigenin-dependent chemiluminescence. Except for naproxen, NSAIDs reduced ROS production: 58 +/- 2% diclofenac, 90 +/- 2% indomethacin, 33 +/- 3% piroxicam, and 45 +/- 6% tenoxicam (N = 6). For the lucigenin assay, naproxen, piroxicam and tenoxicam were ineffective. For indomethacin the inhibition was 52 +/- 5% and diclofenac showed amplification in the light emission of 181 +/- 60% (N = 6). Using the myeloperoxidase (MPO)/H2O2/luminol system, the effects of NSAIDs on MPO activity were also screened. We found that NSAIDs inhibited both the peroxidation and chlorinating activity of MPO as follows: diclofenac (36 +/- 10, 45 +/- 3%), indomethacin (97 +/- 2, 100 +/- 1%), naproxen (56 +/- 8, 76 +/- 3%), piroxicam (77 +/- 5, 99 +/- 1%), and tenoxicam (90 +/- 2, 100 +/- 1%), respectively (N = 3). These results show that therapeutic levels of NSAIDs are able to suppress the oxygen-dependent antimicrobial or oxidative functions of neutrophils by inhibiting the generation of hypochlorous acid.

Fruit of the jambolan tree (Eugenia jambolana Lam.) and experimental diabetes.

The fruit of Indian Eugenia jambolana have been shown to have therapeutic properties, but because the therapeutic potential of a plant is related to the geographic region in which the plant was grown and to the part of the plant used, we investigated Brazilian Eugenia jambolana fruit using the same preparation and experimental methods as have been used in India. The well-established metabolic cage model was used to evaluate the physiological and metabolic parameters associated with streptozotocin-induced diabetes in rats (n=10) which had been administered, by gavage, 50 mg per day of lyophilised Eugenia jambolana fruit-pulp extract for 41 days. We found that, compared to untreated controls, rats treated with the lyophilised fruit-pulp showed no observable difference in body weight, food or water intake, urine volume, glycaemia, urinary urea and glucose, hepatic glycogen, or on serum levels of total cholesterol, HDL cholesterol or triglycerides. No change was observed in the masses of epididymal or retroperitoneal adipose tissue or of soleus or extensor digitorum longus muscles. This lack of any apparent effect on the diabetes may be attributable to the regional ecosystem where the fruit was collected and/or to the severity of the induced diabetes.

Ventilatory targets after cardiac arrest.

The mortality of postcardiac arrest patients has gradually reduced in years but it still is as high as 50%, despite advancements in the diagnostic and therapeutic approaches, i.e. revascularization and therapeutic moderate hypothermia. However, recent evidence suggests that other therapeutic interventions aimed to minimize progressive deterioration of the brain and other organs function might be helpful to reduce in-hospital mortality and improve neurologic outcome as well as quality of life after cardiac arrest. In this article, we discuss the role of ventilator management on the prognosis after cardiac arrest. We performed a meta-analysis showing that in adult patients not only hypoxia but also hyperoxia was associated with higher in-hospital mortality, while hypercapnia and hypocapnia worse neurologic outcome. In pediatric patients, hypoxia and hyperoxia were not associated with higher in-hospital mortality, while hypocapnia and hypercabia with higher in-hospital mortality worse neurologic outcome. We propose a general bundle for ventilator treatment after cardiac arrest, including: 1) therapeutic hypothermia for 12-24 hours; 2) mean arterial pressure ≥65-75 mmHg; 3) PaO2 between 60-200 mmHg and PCO2 between 30 and 50 mmHg; 4) protective MV with tidal volume of 6-8 mL/kg and positive end expiratory pressure of between 5-10 cmH2O; 5) monitoring of respiratory mechanics, extravascular lung water, hemodynamics, non-invasive transcranial Doppler and intracranial pressure monitoring; and 6) others supportive care, i.e. blood sugar and seizures control.

Epidoxorubicin and lonidamine in refractory or recurrent epithelial ovarian cancer.

Lonidamine (150 mg x 3 day orally, days 1-5) plus high dose epidoxorubicin (120 mg/m2 intravenously, day 3) was tested in 26 patients with refractory or recurrent epithelial ovarian cancer, to assess the anti-tumour activity and the toxicity of this combination of drugs. All patients were evaluable for toxicity and 24 for tumour response. Two complete responses (8.3%) and six partial responses (25.0%) were recorded for a total response rate of 33.3%. 6 of 8 responding patients were pretreated with anthracyclines. Stable disease was obtained in 7 patients (29.2%). Toxicity was acceptable; only 1 (3.8%) patient stopped chemotherapy because of a left ventricular ejection rate reduction > 20%. The most relevant side-effect was leucopenia (grade 3-4, 34.6%). In conclusion, the association of lonidamine and high-dose epidoxorubicin has promising activity as second-line treatment in patients with refractory or recurrent epithelial ovarian cancer.

Etoposide v etoposide and cisplatin in the treatment of advanced non-small cell lung cancer: a FONICAP randomized study.

A multicenter Italian Cooperative Study Group (FONICAP) conducted a prospective, randomized trial comparing cisplatin and etoposide (VP-16) with single-agent etoposide. The national study accrued 216 patients with measurable or evaluable non-small cell lung cancer (NSCLC) with either unresectable stage III, or distant metastasis (stage IV). One hundred patients were evaluable for response in the single-agent arm, and 93 in the two-drug combination arm. The overall response rates for the etoposide group and cisplatin/etoposide (VP-16) group were 7% and 26%, respectively (P less than 0.005). Five patients (5.6%) in the combination arm and 1 (1%) in the single agent arm had a complete response. The overall median survival was 236 days for the two-drug arm and 178 days on the single-drug arm (P = 0.2). Treatment-related toxicity (nausea and vomiting, leukopenia, anemia, hearing-loss, peripheral neuropathy, serum creatinine elevation) was significantly more pronounced in the combined arm. The addition of cisplatin to etoposide gave a small non-statistically significant improvement in terms of performance status and thoracic symptoms.

Protracted continuous infusion of 5-fluorouracil and low-dose leucovorin in patients with metastatic colorectal cancer resistant to 5-fluorouracil bolus-based chemotherapy: a phase II study.

Continuous-infusion (c.i.) 5-fluorouracil (5-FU) can overcome resistance to bolus 5-FU, and leucovorin (LV) enhances the cytotoxic effects of 5-FU, mainly when the duration of exposure to the latter is prolonged. The main objective of this study was therefore to determine the activity of a prolonged infusion schedule of 5-FU + LV in patients with metastatic colorectal cancer resistant to a 5-FU bolus-based chemotherapy. Only patients with metastatic measurable disease in progression during or within 2 months of the end of a 5-FU bolus +/- LV-based chemotherapy were eligible for the study. 5-FU and l-LV were given as a 14-day c.i. every 28 days, the 5-FU dose being 200 mg/m2 per day and the l-LV dose being 5 mg/m2 per day. A total of 59 patients entered the study, of which 48 were resistant to 5-FU + LV and 11, to 5-FU + levamisole. Treatment was well tolerated, and WHO grade 3-4 toxicities were uncommon (11% of patients developed stomatitis and 7%, diarrhea). According to an intent-to-treat analysis, 10 of 59 patients obtained an objective response (1 complete response, 9 partial responses), for an objective response rate of 16% (95% confidence interval 8-25%). The median progression-free survival and overall survival were 4 and 9 months, respectively. The protracted 5-FU + LV c.i. schedule used in the present study is a well-tolerated and moderately active regimen in metastatic colorectal cancer patients resistant to 5-FU bolus +/- LV. Only randomized studies can determine whether this palliative treatment has advantages in comparison with other second-line therapies such as 5-FU c.i. without LV, irinotecan, or oxaliplatin.