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1.
J Clin Oncol ; 25(18): 2580-5, 2007 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-17577037

RESUMEN

PURPOSE: This multicentric, randomized, two-stage phase II trial evaluated three simplified weekly infusional regimens of fluorouracil (FU) or FU plus folinic acid (FA) and cisplatin (Cis) with the aim to select a regimen for future phase III trials. PATIENTS AND METHODS: A total of 145 patients with advanced gastric cancer where randomly assigned to weekly FU 3,000 mg/m2/24 hours (HD-FU), FU 2,600 mg/m2/24 hours plus dl-FA 500 mg/m2 or l-FA 250 mg/m2 (HD-FU/FA), or FU 2000 mg/m2/24 hours plus FA plus biweekly Cis 50 mg/m2, each administered for 6 weeks with a 1-week rest. The primary end point was the response rate. RESULTS: Confirmed responses were observed in 6.1% (two of 33) of the eligible patients treated with HD-FU, in 25% (12 of 48, including one complete remission [CR]) with HD-FU/FA, and in 45.7% (21 of 46, including four CRs) with HD-FU/FA/Cis. The HD-FU arm was closed after stage 1 because the required minimum number of responses was not met. The median progression-free survival of all patients in the HD-FU, HD-FU/FA, and HD-FU/FA/Cis arm was 1.9, 4.0, and 6.1 months, respectively. The median overall survival was 7.1, 8.9, and 9.7 months, and the survival rate at 1 year was 24.3%, 30.3%, and 45.3%, respectively. Grade 4 toxicities were rare. The most relevant grade 3/4 toxicities were neutropenia in 1.9%, 5.4%, and 19.6%, and diarrhea in 2.7%, 1.9%, and 3.9% of the cycles in the HD-FU, HD-FU/FA, and HD-/FU/Cis arms, respectively. CONCLUSION: Weekly infusional FU/FA plus biweekly Cis is effective and safe in patients with gastric cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Anciano , Cisplatino/administración & dosificación , Europa (Continente) , Femenino , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tasa de Supervivencia , Resultado del Tratamiento
2.
Eur J Cancer ; 40(14): 2077-81, 2004 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15341982

RESUMEN

The aim of the study was to assess the response rate and toxicity of high-dose 24 h infusion of 5-fluorouracil (5FU) in metastatic adenocarcinoma of the pancreas. Patients with measurable disease, performance status 0-2, and no prior chemotherapy were registered to receive cycles of leucovorin (LV) 500 mg/m2 (or l-LV 250 mg/m2 over 1 h followed by 5FU 2.6 g/m2 over 24 h, weekly for 6 weeks, followed by a 2-week rest. The main endpoints were the response rate and toxicity. From 37 patients, 36 were the analysed for toxicity, and 33 were eligible and analysed for response. The median age was 59 years (range 28-74 years), and the median performance status was 1. Partial response was observed in three patients (9%) (95% Confidential Interval (CI): [2-24]%). Main grade 3/4 National Cancer Institute (NCI) common toxicity criteria toxicities (patients) were diarrhoea (n = 3), vomiting (n = 2) and hand-foot syndrome (n = 5). Median time to progression was 7 weeks (95% CI: [6.4-11.7] weeks) and median survival 19 weeks (95% CI: [12-35] weeks). In conclusion, high-dose 5FU and folinic acid is well tolerated, but has only modest activity in pancreatic cancer.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Fluorouracilo/administración & dosificación , Leucovorina/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Analgésicos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad
3.
Anticancer Drugs ; 8(5): 454-8, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9215607

RESUMEN

In this phase IB study, 24 patients with advanced colorectal cancer were treated with escalating doses of weekly chronomodulated 48 h infusions of 5-fluorouracil (5-FU) biochemically modulated by methotrexate 40 mg/m2 and (6S)-leucovorin 8 x 45 mg orally. Two daily peak delivery periods (PDP), during which 65% of the daily dose was administered, were investigated: from 18.00 to 0.30 h and from 0.00 to 06.30 h. The maximal tolerated dose of 5-FU was 2800 mg/m2/48 h, with a PDP from 18.00 to 0.30 h.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antídotos/administración & dosificación , Antídotos/uso terapéutico , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Adenocarcinoma/patología , Adulto , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Ensayos Clínicos Fase I como Asunto , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/efectos adversos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Factores de Tiempo
4.
Neth J Med ; 46(3): 131-5, 1995 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-7537353

RESUMEN

BACKGROUND: The results of palliative chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in patients with advanced breast cancer who received adjuvant therapy with the same regimen were investigated. RESULTS: Of 47 patients, 14 (30%) achieved an objective remission (median duration 9.5, range 5-21 months) and 8 (17%) stabilisation of disease (median duration 6, range 3-17 months). Objective remissions were observed in premenopausal as well as in postmenopausal women, in patients with all categories of dominant localisation of disease and regardless of the oestradiol receptor status of the primary tumour or eventual previous endocrine therapy. One of 4 and 13 of 43 patients who started palliative chemotherapy within or later than 12 months after the last adjuvant course obtained an objective remission. The median survival time from start of therapy of all treated patients was 12 (range 1-40) months. Patients with an objective remission or stable disease and patients with progressive disease had a median survival time of 20 (range 6-40) and 6 (range 1-35) months respectively (p < 0.0001). CONCLUSIONS: Palliative treatment with CMF should not be rejected for patients who have relapsed after adjuvant chemotherapy with the same modality.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Cuidados Paliativos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Terapia Recuperativa , Tasa de Supervivencia
5.
Cancer Res ; 54(16): 4321-6, 1994 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-8044779

RESUMEN

High-resolution 19F nuclear magnetic resonance spectroscopy at 7 T was used to study the effect of modulators on the metabolism of 5-fluorouracil (5-FUra, 115 mg/kg i.p.) in C38 murine colon tumors grown in C57BL/6 mice. Distinct 5-FUra metabolite patterns were found in perchloric acid extracts of these tumors after treatment. The 19F nuclear magnetic resonance spectra exhibited resonances representing 5-FUra, the catabolites alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta-alanine, as well as four distinct fluoronucleotide anabolites. Using this model system the effect of several modulators on 5-FUra tumor metabolite patterns was investigated: methotrexate (300 mg/kg); alpha-interferon (10(5) IU/animal); N-(phosphonacetyl)-L-aspartate (100 and 250 mg/kg); and leucovorin (300 and 750 mg/kg). A significant increase in the anabolite:catabolite ratio was observed for the groups treated with 5-FUra in combination with the modulators methotrexate (n = 8), alpha-interferon (n = 7), and high-dose leucovorin (n = 14), but not for low-dose leucovorin (n = 7). Cotreatment with high-dose N-(phosphonacetyl)-L-aspartate (n = 8) resulted in a significant decrease in the anabolite: catabolite ratio compared to treatment with 5-FUra alone (n = 16). Possible correlations of metabolite profiles with therapy response are discussed.


Asunto(s)
Ácido Aspártico/análogos & derivados , Neoplasias del Colon/metabolismo , Fluorouracilo/metabolismo , Interferón-alfa/farmacología , Leucovorina/farmacología , Metotrexato/farmacología , Ácido Fosfonoacético/análogos & derivados , Animales , Ácido Aspártico/administración & dosificación , Ácido Aspártico/farmacología , Femenino , Flúor , Interferón-alfa/administración & dosificación , Leucovorina/administración & dosificación , Espectroscopía de Resonancia Magnética , Metotrexato/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Ácido Fosfonoacético/administración & dosificación , Ácido Fosfonoacético/farmacología , Ratas , Células Tumorales Cultivadas
6.
Ann Oncol ; 4(5): 426-8, 1993 May.
Artículo en Inglés | MEDLINE | ID: mdl-8353077

RESUMEN

BACKGROUND: FAMTX (5-fluorouracil, adriamycin, methotrexate) is one of the most effective drug combinations in gastric cancer. Therefore, modifications of FAMTX appear of interest and the FEMTX-P regiment was conceived. PATIENTS AND METHODS: Fifty patients with unresectable locally advanced and/or metastatic gastric carcinoma were treated with methotrexate 1500 mg/m2 i.v. and 5-fluorouracil 1500 mg/m2 i.v. on day 1; leucovorin rescue 15 mg/m2 orally every 6 hours for 8 doses on days 2 and 3; epirubicin 60 mg/m2 i.v. and cisplatin 50 mg/m2 i.v. on day 15, q 4 weeks. RESULTS: Of forty-seven patients evaluable for response, five (11%) achieved complete responses and seventeen (36%) partial responses (total response rate 47%). The median duration of response was 8+ months (range: 5-25+ months). Four of 14 patients with locally advanced disease were successfully downstaged and subsequently resected. The median duration of survival of all patients was 10 months (range: 1-25+ months). Leukopenia grade 4 occurred in 18% of patients and thrombocytopenia grade 4 and mucositis grade 4 in 4% and 2%, respectively. Treatment postponement for hematologic toxicity was necessary in 54% of patients. CONCLUSIONS: The FEMTX-P regimen is an active regimen in advanced gastric carcinoma, with acceptable toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucopenia/inducido químicamente , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Trombocitopenia/inducido químicamente
7.
Bull Cancer ; 80(3): 255-60, 1993 Mar.
Artículo en Francés | MEDLINE | ID: mdl-8173178

RESUMEN

In this phase II study, fifty patients with unresectable locally advanced and/or metastatic gastric carcinoma were treated with methotrexate 1.5 g/m2 iv and 5-fluorouracil 1.5 g/m2 iv on day 1; leucovorin rescue 15 mg/m2 orally every 6 h for 8 doses on day 2 and 3; epirubicin 60 mg/m2 iv and cisplatin 50 mg/m2 iv on day 15, q 4 weeks. The median age of the patients was 59 years and their median performance status 1. In forty-eight patients evaluable for response, five (10.4%) of the patients achieved a complete response and seventeen (35.6%) obtained a partial response (total response rate 46%; 95% confidence interval: 32%-60%). The median duration of response was 8+ months (range: 5-25 months). The median duration of survival of all patients was 10 months (range: 1-25+ months). Toxicities > grade 2 included vomiting grade 3 (31%), leucopenia grade 4 (18%) and thrombocytopenia grade 4 (4%). Treatment postponement or dose reduction for hematologic toxicity was necessary in 54% of patients. Median survival was 10 months. In conclusion, the FEMTX-P regimen is an active treatment in advanced gastric carcinoma with acceptable toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Resultado del Tratamiento
8.
Semin Oncol ; 19(2 Suppl 3): 208-10, 1992 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-1557649

RESUMEN

Several reports on fluorouracil (5-FU) and alfa interferon (IFN-alpha) combination therapy in patients with advanced colorectal cancer have been published. In our study high-dose continuous infusion 5-FU (60 mg/kg per 48 hours), oral folinic acid (FA) (8 x 90 mg during 5-FU), and IFN-alpha three times weekly were combined. Because the addition of IFN-alpha has not been tested before, and serious toxicity of 5-FU plus IFN-alpha therapy has been reported, the IFN-alpha dose was escalated from 3 to 10 million units (MU)/dose in the first 11 patients. Grade 3 toxicity was noted in four patients, and consisted mainly of oral mucositis. No grade 4 toxicity occurred. Three partial responses were noted. Preliminary results of a phase II study, in which all patients received IFN-alpha at 10 MU/dose, show grade 3 and 4 toxicities in 24% and 4% of patients, respectively. This compares favorably with other trials in which 5-FU and IFN-alpha was used without FA.


Asunto(s)
Neoplasias Colorrectales/terapia , Administración Oral , Adulto , Anciano , Neoplasias Colorrectales/patología , Esquema de Medicación , Evaluación de Medicamentos , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Infusiones Intravenosas , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Persona de Mediana Edad , Metástasis de la Neoplasia
11.
Cancer Chemother Pharmacol ; 29(4): 326-8, 1992.
Artículo en Inglés | MEDLINE | ID: mdl-1537082

RESUMEN

A high rate of response to 5-fluorouracil (5FU) and alpha-interferon (alpha IFN) combination therapy has been reported in metastatic colorectal cancer patients. Therefore, designed a trial of high-dose continuous-infusion 5FU, oral leucovorin (LV), and alpha IFN in this group of patients. Because this combination has not previously been tested and severe toxicity has been reported for 5FU and alpha IFN combination therapy, we conducted a phase I trial in which 11 patients presenting with previously untreated metastatic colorectal cancer were treated with escalating doses of alpha IFN together with fixed doses of 5FU and LV. WHO grade III toxicity consisting mainly of oral mucositis was noted in four patients. No grade IV toxicity occurred. Although alpha IFN may enhance the toxicity of 5FU, the toxicity of this regimen remained manageable. Three partial responses were noted.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Interferón-alfa/administración & dosificación , Leucovorina/administración & dosificación , Adulto , Anciano , Evaluación de Medicamentos , Quimioterapia Combinada , Fluorouracilo/efectos adversos , Humanos , Infusiones Intravenosas , Interferón-alfa/efectos adversos , Leucovorina/efectos adversos , Persona de Mediana Edad , Metástasis de la Neoplasia , Inducción de Remisión , Factores de Tiempo
12.
J Clin Oncol ; 9(5): 827-31, 1991 May.
Artículo en Inglés | MEDLINE | ID: mdl-2016625

RESUMEN

In a prospective phase III multicenter trial, 213 patients with advanced measurable or nonmeasurable gastric cancer were randomized to receive methotrexate (MTX), fluorouracil (5-FU), and Adriamycin (doxorubicin; Farmitalia Carlo Erba, Milan, Italy) (FAMTX) or 5-FU, Adriamycin, and mitomycin (FAM). The results show a significantly superior response rate (41% v 9% [P less than .0001]), and survival (median, 42 weeks v 29 weeks [P = .004]) for FAMTX. There was a cumulative thrombocytopenia in FAM and not in FAMTX. The FAMTX protocol should be the reference treatment in future clinical trials that seek to improve the therapeutic outcome in advanced gastric cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Doxorrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Inducción de Remisión , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de Supervivencia
13.
Anticancer Res ; 9(6): 1835-40, 1989.
Artículo en Inglés | MEDLINE | ID: mdl-2483308

RESUMEN

Inhibitors of protein synthesis may modify cell response to cytotoxic drugs. The influence of protein synthesis inhibition using sparsomycin (Sm) on the cytotoxicity of seven classical cytotoxic drugs, 5-FU, ARA-C, MTX, doxorubicin, melphalan, bleomycin and vincristine, was studied. Preincubations, simultaneous incubations and postincubations with Sm were investigated in vitro on CHO cells. Preincubation with Sm antagonized the activity of the S phase specific drugs 5-FU, ARA-C, MTX as well as vincristine, while postincubation with Sm enhanced their effect. A similar pattern was observed with doxorubicin. Preincubation with Sm had a potentiated non-S phase specific like bleomycin and cisplatin, but not melphalan. Postincubation with Sm had a potentiating effect on bleomycin but had no effect on melphalan. These results indicate a strong, schedule dependent effect of Sm on various drugs and suggest some potentially useful combinations to be tested in vivo.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína , Esparsomicina/farmacología , Adyuvantes Farmacéuticos/farmacología , Animales , Bleomicina/farmacología , Línea Celular , Cisplatino/farmacología , Citarabina/farmacología , Doxorrubicina/farmacología , Fluorouracilo/farmacología , Melfalán/farmacología , Metotrexato/farmacología , Vincristina/farmacología
14.
Anticancer Res ; 8(6): 1381-5, 1988.
Artículo en Inglés | MEDLINE | ID: mdl-3218972

RESUMEN

Sparsomycin (Sm) is a well known inhibitor of protein synthesis with anticancer potential. In order to minimize toxicity of this drug and increase its activity, several analogues were synthesized. Deshydroxy-Sm (dSm) appeared to be a good candidate for further investigations because of its lower toxicity and significantly higher antitumor activity in several ascitic tumors in mice. Pharmacokinetic evaluation in beagle dogs was performed using either single iv bolus or continuous infusion administrations. The drug was eliminated with a terminal t1/2 beta of 0.8 +/- 0.08 hours (48 +/- 5 minutes). The mean volume of distribution was 0.4 +/- 0.06 l.kg-1. The mean total body clearance was 6.4 +/- 0.8 ml.min-1.kg-1. The drug is eliminated mainly by the kidneys (54%). Active tubular secretion and active tubular reabsorption of the drug were observed. The pharmacokinetics was linear until the lethal dose. The results of this study provided additional data useful in selection of potentially useful analogues for further preclinical studies.


Asunto(s)
Antibióticos Antineoplásicos/farmacocinética , Esparsomicina/farmacocinética , Animales , Perros , Evaluación Preclínica de Medicamentos , Femenino , Riñón/metabolismo , Masculino , Esparsomicina/análogos & derivados , Esparsomicina/sangre , Esparsomicina/orina
15.
Acta Otolaryngol ; 103(5-6): 529-36, 1987.
Artículo en Inglés | MEDLINE | ID: mdl-2441566

RESUMEN

This study deals with in vitro chemosensitivity testing of squamous cell carcinoma of the head and neck by measuring the drug-induced inhibition of [3H]thymidine incorporation. Cell suspensions and tumour slices obtained from four human tumour xenografts were used. These were grown in nude mice and tested in this animal for their sensitivity to bleomycin and cis-platinum. No reliable data could be obtained with the use of cell suspensions because of the rapid decrease in cell viability during incubation. The incubation of 400-microns-thick tumour slices using hyperbaric O2 revealed a stable control level of [3H]thymidine incorporation which persisted for more than 24 h. Cytotoxic drugs only demonstrated a significant and reproducible decrease in the incorporation of [3H]thymidine in those tumours which were found to be sensitive to these drugs in nude mice. This technique seems to be very promising but needs further evaluation of its application on tumour specimens obtained directly from patients.


Asunto(s)
Bleomicina/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Cisplatino/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Animales , Carcinoma de Células Escamosas/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Técnicas In Vitro , Ratones , Ratones Desnudos , Timidina/metabolismo
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